AMINO AMSA International Competition 2021: World Hemophilia Day Competition

AMINO AMSA-Indonesia Competition Archive

AMSA International Competition 2021

All the works publicized here are the works of AMSA-Indonesia’s member who participated in AMSA International Competition

AMINO | AMSA INTERNATIONAL COMPETITION

FOREWORD

Steven Millenio Widjaja

Secretary of Academic AMSA-Indonesia 2020/2021

The AMSA-Indonesia Competition Archive or AMINO for short is a program by AMSA-Indonesia to facilitate all members to get inspiration on how to make a scientific masterpiece. AMINO acts as an archive where all the works submitted by participants in competitions in AMSA, including Pre-Conference Competition East Asian Medical Students’ Competition (PCC EAMSC), Indonesia Medical Students’ Training and Competition (IMSTC), Pre-Conference Competition Asian Medical Students’ Competition (PCC AMSC) and from AMSA International Competitions, are published.

In this series of AMINO, all the scientific masterpieces of AMSA-Indonesia in AMSA International Competition have been compiled, which consists of the following categories: Scientific Paper, Scientific Poster, Public Poster, and Online Social Campaign. We hope that through this volume of AMINO, we are able to further motivate and inspire our members to construct more scientific masterpieces.

On behalf of AMSA-Indonesia, I would like to extend my deepest gratitude to personal to all the participants of the AMSA International Competition, the Academic Team of AMSA-Indonesia, the Executive Board of AMSA-Indonesia 2020/2021, and other parties that have contributed to the creation of AMINO. Without each and every single contribution, AMINO would not have been possible.

May the release of AMINO increase the academic enthusiasm and ignite the potentials of AMSA-Indonesia members.

“Igniting Potentials, Unleashing Possibilities” Viva AMSA!

AMINO | AMSA International Competition

TABLE OF CONTENTS World Hemophilia Day Competition Scientific Paper • First Winner Recombinant Versus Plasma-derived Factor VIII Concentrates on Inhibitor Development in Previously Untreated Patients with Hemophilia A: A 2021 Update of Systematic Review and Meta-Analysis • Second Winner Exploring the Efficacy and Safety of Factor VIII–Mimetic Function of Humanized Bispecific Antibody (Emicizumab/ACE910) in Classic Hemophilia Patients with or without Inhibitors: A Systematic Review and Meta-Analysis • Third Winner Efficacy and Safety of Emicizumab for Treatment in Mild Hemophilia A Patient: A Systematic Review • Entries ■ Efficacy, Safety, and Immunogenicity of Rurioctocog Alfa Pegol (BAX 855) for Prophylactic Treatment in Previously Treated Patients with Severe Haemophilia A: A Systematic Review and Meta-Analysis of Clinical Trials ■ Exploring Therapeutic Effect of Yoga in Reducing Risks of Bleeding in Early Pregnancy for Women Suffering from Haemophilia A : A Literature Review ■ Valoctocogene Roxaparvovec (AAV5-hFVIII-SQ) as a Potential Cure for Patients with Hemophilia Type A: A Systematic Review ■ Defining the Propriety on Prophylaxis and On-Demand Treatment in People with Hemophilia A: A Systematic Review ■ Concizumab As A Novel Treatment for Hemophilia A and B Patients With or Without Inhibitors: A Systematic Review ■ Administration of F VIII therapy in Intracranial Bleeding in Hemophilia ■ Essential Role of Physical Activity with Protective Gear in Management of Children with Haemophilia ■ Hemophilia Treatment, Laboratory Test, and Government Health Insurance Compared with Indonesia’s Condition ■ Study About Hemophilia and How To Treat It

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21

55

64

84 89 113 132 145 155 169 180

AMINO | AMSA International Competition Scientific Poster • First Winner Oral Bioencapsulated Coagulation Factor IX Fused with Cholera Toxin β-Subunit Protein as a Promising Immune Tolerance Induction Therapy for Hemophilia B: A Systematic Review • Second Winner Effectiveness of Low-dose FVIII Prophylaxis as An Alternative Management in Resource-limited Settings for Haemophilia A in Pediatric Population: A Systematic Review and Meta-Analysis • Third Winner Factors Affecting Hemophilia in Pediatric Patients

194

195

196

AMINO | AMSA International Competition Public Poster • First Winner “TREAT THEM SPECIAL”: A practical guide for parents to educate their children with

197

hemophilia • Second Winner Safer Hemophilia With #HFA (Hemophilia For All)

200

• Third Winner Haemophilia: Reject the MYTHS, Remember the FACTS!

202

• Entries ■ Stop The BLEED with Rest and ICE ■ Revealing the “TRUTH” Behind Haemophilia ■ World Haemophilia Day: Play Your Part in Fighting Haemophilia Stigma ■ World Hemophilia Day Once Twice Thrice Premarital Check Up to Avoid The Hereditary Hemophilia ■ Battle the FLOOD, Settle Our BLOOD ■ Does My Baby Has Haemophilia ■ THE GIVEN THRONE: Act Like a Royal to be Treated Like a Royal ■ Don’t Disrespect, Simply Accept ■ Model Methods in Justifying Misconceptions of Haemophilia ■ Hemophilia Makes Bandage

204 206 209 212 214 217 219 222 224 226

SCIENTIFI

IC PAPER

AMINO | AMSA International Competition 2021

Kelvin Kohar AMSA-Universitas Indonesia 1st Winner of Scientific Paper Category “Recombinant versus Plasma-derived Factor VIII Concentrates on Inhibitor Development in Previously Untreated Patients with Hemophilia A: A 2021 Update of Systematic Review and Meta-Analysis”

First of all, I would like to thank AMSA International for holding this WHD competition, AMSA-Indonesia and AMSA-UI for giving me (and team) this chance to join the competition, also my great teammates (Stephanie and Kak Lowilius).

Personally, I participated in this competition to seek more experiences, especially in writing a good paper. Besides, WHD was an international competition and we had to compete with other teams from various countries. There are no “tips or tricks” that will be really helpful in the competition because you always have to start by persuading yourself to write and join the competition. Before that, you can start from finding a good team.

Honestly, I don’t have many past experiences in writing, but I do believe that writing is a thing that could be improved. Also, you are working with team, so don’t afraid to consult any problems with your teammates or even with expert people.

AMINO | AMSA International Competition 2021

Naily Fairuz Salma El Milla AMSA-Universitas Diponegoro 3rd Winner of Scientific Paper Category “Efficacy and Safety of Emicizumab for Treatment in Mild Hemophilia A Patient: A Systematic Review”

My team members and I didn’t have the experience in scientific writing before. However, we were interested in the opportunity to learn more about it. Fortunately, joining AMSA gave us the guidance and references in writing through programs such as LAT, AMINO, and A-Book. With those opportunities provided by AMSA, we challenged ourselves to participate in academic competition, and World Hemophilia Day Competition held by AMSA-International came at the right time for us.

At first, we were clueless on how to write a good scientific paper. We also struggled to find the right topic and sort through the references.

During those times, teamwork and communication played a crucial part, especially when we also juggled with our academic responsibilities.

For me, personally, WHDC wasn’t the first competition that I joined in AMSA. Before, I participated in White Paper category of PCC EAMSC and got 2nd place, thanks to my team’s effort. However, this was my first try at scientific paper. During the process, our team learnt so much regarding scientific writing. It was a great opportunity that we took, and it was a great honor to be able to finish with 2nd place despite of our shortcomings.

Recombinant versus Plasma-derived Factor VIII Concentrates on Inhibitor Development in Previously Untreated Patients with Hemophilia A: A 2021 Update of Systematic Review and Meta-Analysis Kelvin Kohar1, Stephanie Amabella Prayogo1, Lowilius Wiyono1 ABSTRACT Introduction: Hemophilia A, the most common hereditary disorder, is caused by clotting factor deficiency. Challenges present in the current treatment of Hemophilia A (factor VIII replacement therapy), since inhibitor development has caused ineffective treatment, morbidity, and mortality. However, there are no studies comparing both Factor VIII treatments in terms of inhibitor development rate. Therefore, we conducted this systematic review to search for the best treatment with lower risk of inhibitor development.

Material & Methods: Systematic review was conducted using PRISMA guidelines on several databases. Data extraction on study characteristics and outcomes were conducted. Reviewers also conducted risk of bias assessment on all studies. All eligible studies for quantitative analysis were then processed using RevMan 5.4.1 and the data is extrapolated into cumulative outcome and expressed in forest and funnel plots.

Result and Discussion: Nine studies were included in the meta-analysis, with a total of 2531 hemophilia A patients that were followed up from birth until death. A higher incidence of inhibitor development was found in recombinant FVIII (OR=1.57[0.95-2.59]; HR=1.89[1.153.12]). The same trend was also found for high-responding inhibitors (OR=1.38[0.70-2.70]; HR=1.42[0.84-2.39]).

Conclusion: Recombinant FVIII associated with higher risk of overall and high responding inhibitor development compared to plasma-derived FVIII. Keywords: hemophilia A, recombinant, plasma-derived factor VIII, recombinant factor FVIII, inhibitor development

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1.

INTRODUCTION

Hemophilia is a genetic condition causing prolonged bleeding and may be difficult to control due to inadequate clotting factor, Factor VIII or Factor IX which are needed for blood clot regulation. Internal bleeding remains as the main problems in patients. Bleeding or hemorrhage can occur in joints, such as elbows, ankles, and knees. This may be the result of an injury, but it may also start voluntarily in acute hemophilia.1 Hemophilia, as a rare inherited bleeding disorder, can be found in one out of 3333 people. Diagnosis and treatment methods vary greatly around the world, and mainly reflect the socio-economic status of a country. In low-income countries, most patients are underdiagnosed, resulting in patient dying prematurely due to lack of treatment.2 Hemophilia is mainly classified into three groups, namely hemophilia A, hemophilia B, and hemophilia C. Hemophilia A, B, and C results from deficiency or dysfunction of factor VIII, factor IX, and factor XI, respectively. Hemophilia A cases are the most common one comprising 80-85% of total cases. On the other hand, hemophilia C is rarely found. As it is a X-linked recessive genetic disease, it commonly affects male.3 Rarely, this disease can also be acquired. Acquired hemophilia is caused by the autoantibodies that develop against a coagulation factor.4 Current hemophilia A best treatment available is to replace the missing clotting factor, of which is Factor VIII by intravenous transfusion. This is usually done by injecting a therapeutic product, called clotting factor VIII concentrates, either plasma-derived or recombinant factor VIII.5 Clotting factor replacement therapy usage has progressed in developing countries; this includes a modern healthcare system and funding for the supply of clotting factors, which can be expected to have new normal value of life.6 However, the replacement therapy is capable to induce inhibitor development. Inhibitors develop in 30% patients with Hemophilia A on replacement therapy.7 Besides the clotting factor replacement therapy, some factors such as gene mutations, age, and family history are as well included as the risk factor for inhibitor development. Inhibitor development occurs when antibodies against “foreign” Factor VIII are produced, thus resulting in low efficacy of such treatment. People with anti-FVIII antibodies can be eradicated with immune tolerance induction (ITI) with 60-80% effectiveness.

Nonetheless, ITI is costly, demanding, requires regular infusion of FVIII for months to years, and sometimes even unsuccessful. Moreover, inhibitor recurrence is also reported in quite a fair portion of cases.8

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For many years, immune tolerance to factors has been a major concern, since the development of inhibitors will lower the quality of life and significantly increase the morbidity of patients.9 The type of replacement therapy, as one of the risk factors of inhibitor development (plasmaderived vs recombinant), received by patients can be improved to minimize the risk. Choosing the right type of replacement therapy (plasma-derived vs. recombinant) can be a way to reduce the probability of inhibitor development.

Even though systematic reviews have already been conducted in 2010 and 2012, the significance of the results were not shown. It also only included one arm studies, which results in ambiguous data and remains inconclusive. As more studies have been conducted during the period time of 2012-2021, thus, updated systematic review and meta-analysis are needed to give an answer to the question whether plasma-derived or recombinant Factor VIII results in increased inhibitor development and their comparison in clinical studies.10,11 2.

MATERIALS & METHODS

The systematic review was conducted using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines12 to objectively do a search and screening process on relevant studies on the topic.

2.1 Search Strategy Literature search was conducted in a blinded fashion by two independent investigators (SAP, KK). Any discrepancies were subjected to discussion among the authors (SAP, KK, LW).

Literature search was conducted through several scientific databases, consisting of PubMed, Scopus, and ScienceDirect, using the predetermined keywords and medical subject headings (MeSH) on hemophilia A, plasma-derived Factor VIII, recombinant Factor VIII, and inhibitors.

The keywords used in each database were enlisted on Table 1. Subsequently, the retrieved search results were deduplicated and screened using the pre-determined eligibility criterias.

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Table 1. Keywords or queries used in each database for the literature search process.

Database

Queries

Hits

PubMed

((plasma derived AND recombinant) AND ("Factor VIII"[Mesh])) AND (inhibitor) AND ("Hemophilia A"[Mesh])

280

Scopus

TITLE-ABS-KEY ((plasma derived AND “recombinant”) AND (“Factor VIII”) AND (inhibitor) AND (“Hemophilia A”))

283

ScienceDirect (plasma derived AND “recombinant”) AND (“Factor VIII”) AND (inhibitor) AND (“Hemophilia A”)

32

2.2 Study Eligibility Criteria Screening processes were then used to filter all articles found in three different databases. The initial hit of the searching process was 595 articles. All articles were then filtered using predetermined inclusion and exclusion criteria, based on the PICO (Patient, Intervention, Comparison, Intervention) criteria as mentioned in Table 2. The included studies consisted of prospective and retrospective cohort studies, randomized controlled trial, and case control which evaluated the comparison of plasma-derived FVIII and recombinant FVIII on their inhibitor incidence rate. Studies were considered to be excluded if any of the following criteria were fulfilled: (1) Review articles, case series or case reports, and letter to editors; (2) Animal studies (Non-human clinical studies); (3) inaccessible or irretrievable full-text articles; (4) nonEnglish articles; (5) published more than 10 years ago. Limitation on publication date is also conducted to include updated studies not included in the previous cumulative analysis on similar topics.

Table 2. PICO criteria used, consists of four parameters: patient, intervention, comparison, and objective criteria.

Parameter of PICO Inclusion Criteria Patient

Hemophilia A patients

Intervention

Recombinant Factor VIII

Comparison

Plasma-derived or human Factor VIII

Outcome

Incidence rate of inhibitor development

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2.3 Study Selection Search and screening process of all studies were conducted using Google Spreadsheet (Google LLC, Mountain View, CA, USA). The articles were then deduplicated to remove duplicates.

All articles were then independently reviewed by each investigator based on the PRISMA guideline scheme. Screening process was started with title and abstract screening of the selected articles to exclude studies according to the exclusion criteria. The investigators then mention the underlying reason of exclusion in the spreadsheet. Studies were included to the next step if there is uncertainty which is disputed by each investigator. Afterwards, all investigators independently read the full text of all selected studies to exclude studies which met any of the exclusion criterias. All selected studies were then validated by all reviewers to finalize the eligible studies for qualitative and quantitative analysis.

2.4 Data Extraction and Quality Assessment Data extraction was conducted using predetermined form with Google Spreadsheet (Google LLC, Mountain View, CA, USA). All investigators extracted the data from each eligible article independently. The following data was extracted from each study: study authors, publication years, study design, study location (geographical), sample size, patient characteristics, median patients’ age, and primary endpoint of the study. Investigators also recorded outcomes, in particular inhibitor incidence rate, high responding inhibitor incidence, low responding inhibitor incidence, and reported OR/HR value of each study.

The eligible studies were then assessed to methodological quality assessment in order to minimize systematic biases and inferential errors from the extracted data. All reviewers independently assessed risk of bias of the included cohort and case control studies using Newcastle-Ottawa Quality Assessment Scale (NOS).13 The NOS risk of bias tool evaluates non-randomized studies on systematic reviews on three quality parameters: study selection, comparability of the population and a determination of whether the exposure or outcome includes risk of bias.14 NOS evaluated each study quality and yielded a maximum score of nine points. Studies with NOS score greater than or equal to seven are considered high quality.

Studies scored five and six represent fair or moderate quality, whereas studies having NOS score less than five points indicate a high risk of bias.14 Meanwhile, RCT study is assessed using the Risk of Bias (RoB 2) tool by Cochrane. The tool assesses RCT on bias arising from randomization processes, deviations from intended interventions, missing outcome data, measurement of outcome, and selection of reported results.15

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2.5 Pooled Analysis Cumulative incidence of inhibitors was evaluated on each study and then categorized within groups. These were identified by the use of recombinant and plasma-derived FVIII. No further categorization on each FVIII product was conducted to assess all types of FVIII products.

Cumulative incidence were then categorized into high responding inhibitors (HR) and low responding inhibitors (LR). Summary data and related 95% confidence interval (CI) were then calculated by conventional meta-analysis pooling on logits [ln(odds)] from each individual study. Quantitative analysis was done using random effects-inverse variance, whereas logits were converted to rates, and data was reported as in odds ratio (OR). Studies which mention hazard ratio value were also analyzed into cumulative analysis to report cumulative hazard ratio (HR) value. Analysis on high responding inhibitor rates were also conducted. All results were then visualized into forest plot and funnel plot. The indexes of heterogeneity (X 2 or Q according to Cochran, I2 and tau2) were also calculated to analyze data distribution on each study.16 3.

RESULTS

3.1 Study Selection, Study Characteristics, and Quality Assessment The authors yielded a total of 595 records upon initial search. After removing 337 duplicates, the authors performed titles and/or abstracts screening and found 14 articles that would be assessed afterwards in full-text level. We further excluded 5 studies (of which 3 have ineligible data and 2 have inaccessible full-text). Completely, 9 articles were included in this systematic review.

All included studies (7 cohort, 1 case-control, and 1 randomized trial) were qualitatively and quantitatively synthesized. The studies were performed in hemophilia centers in various countries; 4 were conducted in multiple countries, 3 in Europe, and 2 in Asia. The articles included were published between 2011 and 2021; Meanwhile, the provided data were collected between 1980 and 2015 with follow-up duration varied across studies. Among the total 2.531 included participants, most of them were children (<18 years old) followed during the recruitment period since birth, the first therapy received, until death. Besides, the authors also included all Hemophilia A types based on the Factor VIII (FVIII blood-clotting protein), including severe and non-severe. Severe Hemophilia A was defined as FVIII concentration less than 1% of normal level. Instead, patients with FVIII concentration more than 1% of normal level were classified as non-severe Hemophilia A.

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The participants were next divided into two groups, either receiving recombinant Factor VIII (rFVIII) or plasma-derived Factor VIII (pdFVIII) products. rFVIII could be further divided into first, second, third, and fourth generations. However, only 3 studies reported clearly the exact given rFVIII products.

Each study was also assessed for its quality by using quality assessment tools as depicted in Appendix 1-3. In general, all studies categorized as good quality and low risk of bias.

Figure 1. PRISMA flowchart.12

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Table 3. Baseline characteristics of included studies.

No

Author; Year

Recruitment Period

Study Characteristics Country

1.

Blatny, et al; 2021

2005–2015

2.

Valzen, et al; 2020

1980-2011

3.

Calvez, et al; 2018 Pevyandi, et al; 2017

1994-2016 2010-2014

14 countries (SIPPET)

Batorova, et al; 2016 Blatny, et al; 2015 Gouw, et al; 2013

1997-2008

Slovakia

2003-2013

Czech

2000-2010

8.

Xuan, et al; 2013

2002-2012

29 Hemophilia center China

9.

Strauss, et al; 2011

1984-2008

Israel

4.

5.

6.

7.

Central and Eastern Europe (7 countries) 33 European centres and 1 Australian centre France

Study Design Cohort prospective

Patients Characteristics Children with severe Hemophilia A

Sample size (n)

Age

Groups I

Groups II

144

10 (7-14)

121 patients in rFVIII

23 patients (16%) in pdFVIII

Case-control

Nonsevere Hemophilia A

298

23 (5-44)

52 in FG; 45 in SG; 7 in TG

179 in pdFVIII

Cohort prospective Randomized trial

Children with Hemophilia A Children <6 years with severe Hemophilia Hemophilia A

395

NA

131 in pdFVIII

251

3.19 (1.039.91)

127 in SG; 137 in TG 126 in rFVIII

59

12.5 (4.5-12.5)

9 in rFVIII

50 in pdFVIII

Hemophilia A

96

45 in rFVIII

41 in pdFVIII

Severe hemophilia A

574

3 in rFVIII vs.

5 in pdFVIII 6.4 (4.0-8.9)

157 in TG; 260 in SG; 59 in FG

88 in pdFVIII

Hemophilia A and Hemophilia Ba Hemophilia A

235

NA

132 in rFVIII

203 in pdFVIII

479

30 (18-75) months in rFVIII vs. 60 (36-none) months in pdFVIII

43 in rFVIII

249 in pdFVIII

Cohort prospective Cohort prospective Cohort prospective Cohort retrospective Cohort prospective

a

125 in pdFVIII

Only Hemophilia A included Abbreviation: rFVIII = Recombinant Factor VIII; pdFVIII = Plasma-derived Factor VIII; R = Recombinant; PD = Plasma-derived; NA = Not available.

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Table 4. Outcomes of included studies.

No 1.

2.

3.

4.

5.

Author; Year

Group

Blatny, et al; 2021 Valzen, et al; 2020 Calvez, et al; 2018 Pevyandi, et al; 2017

rFVIII (121) vs. pdFVIII (23) rFVIII (119) vs. pdFVIII (179) rFVIII (264) vs. pdFVIII (131) rFVIII (264) vs. pdFVIII (131)

Overall 20/121 in R vs.

5/23 in PD 36/119 in R vs.

39/179 in PD 96/264 in R vs.

25/131 in PD 47/126 in R vs.

29/125 in PD

Inhibitor development Overall HR HR inhibitors LR inhibitors (95% CI; p-value) 13/121 in R vs.

NA 1.56 (0.24-10.06; 3/23 in PD p=0.64) NA NA NA

0.85 (0.24-2.99; p=0.80) NA

56/264 in R vs.

14/131 in PD 30/126 in R vs.

20/125 in PD

1.64 (0.82-3.25; p=0.16) 4.19 (1.18-14.8; p=0.03)

Batorova, et al; 2016 Blatny, et al; 2015 Gouw, et al; 2013 Xuan, et al; 2013 Strauss, et al; 2011

40/264 in R vs. 11 in PD 17/126 in R vs. 9/125 in PD 2/9 in R vs.

3/50 in PD 2/45 in R vs.

0/41 in PD NA

1.41 (0.83-2.38; p=0.21) 3.14 (1.01-9.74; p=0.05)

High

rFVIII (9) vs.

6/9 in R vs.

4/9 in R vs.

7.15 (1.65-31.36; NA pdFVIII (50) 7/50 in PD 4/50 in PD p=0.01) 6. rFVIII (45) vs.

22/45 in R vs.

3/45 in R vs.

1.07 (0.83-10.19; NA pdFVIII (41) 20/41 in PD 6/41 in PD p=0.95) 7. rFVIII (476) vs. 145/476 in R vs. 92/476 in R vs.

1.04 (0.65-1.66; 1.05 (0.63-1.74; pdFVIII (88) 29/88 in PD 21/88 in PD p=0.87) p=0.85) 8. rFVIII (203) vs. 14/203 in R vs.

9/203 in R vs.

NA NA NA pdFVIII (132) 19/132 in PD 15/132 in PD 9. rFVIII (43) vs.

14/43 in R vs.

14/43 in R vs.

9/43 in R vs.

3.43 (95% CI: 1.36- NA pdFVIII (249) 22/249 in PD 22/249 in PD 0/249 in PD 8.60; p=0.01) Abbreviation: rFVIII = Recombinant Factor VIII; pdFVIII = Plasma-derived Factor VIII; R = Recombinant; PD = Plasma-derived; HR = High Responding; LR = Low Responding NA = Not available.

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3.2 Study Outcomes The summary of all 9 studies outcomes was shown in Table 3. The major outcome presented on this table was inhibitor development. Firstly, for the overall inhibitor, the ratio of inhibitor development in both groups was obtained. Afterwards, more specific data about inhibitor development response, e.g. high responding or low responding inhibitors, were collected if available. These data were used to calculate odds ratio in overall and high responding inhibitors. Subsequently, the authors also included overall hazard ratio in rFVIII compared to pdFVIII data along with 95% CI and p-values provided by the studies.

3.2.1 Association of Factor VIII Types (Recombinant and Plasma-derived) with Overall Inhibitors Development – OR and HR Figure 2 shows two forest plots depicting the association between factor VIII types and overall inhibitor development based on pooled OR and HR. All studies were included to obtain overall inhibitor development, with a pooled OR of 1.57 towards rFVIII [95% CI: 0.95 to 2.59]. There is a significant heterogeneity as shown by an I2 value of 79% (Figure 2A). Furthermore, the pooled HR from 7 studies that provided necessary data also shows the same direction supporting higher inhibitor development even significantly in recombinant group compared to pdFVIII (pooled HR: 1.89 [95% CI: 1.15 to 3.12]). Otherwise, this I2 test shows a smaller value compared to the previous and implies moderate heterogeneity (I2=47%) (Figure 2B).

3.2.2 Association of Factor VIII Types (Recombinant and Plasma-derived) with High Responding Inhibitors Development – OR and HR The forest plots illustrating the association between factor VIII types and high responding inhibitor development shown in Figure 3. A total of 8 studies reported the related data were included, shows a pooled OR of 1.38 insignificantly towards recombinant one [95% CI: 0.70 to 2.70]. The heterogeneity test is significant with I2 value of 80% (Figure 3A). Besides, the second forest plot consists of 4 studies reported HR again support the previous result with pooled value of 1.42 [95% CI: 0.84 to 2.39]. Differently, the I2 test reports a homogeneity result with value of 38% (Figure 3B).

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Figure 2. Forest Plot: Association of Factor VIII Types (Recombinant and Plasmaderived) with Overall Inhibitors Development – OR (A); HR (B).

A

B

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Figure 3. Forest Plot: Association of Factor VIII Types (Recombinant and Plasmaderived) with High Responding Inhibitors Development – OR (A); HR (B).

A

B

4.

DISCUSSION

4.1 Hemophilia and Available Treatments Hemophilia A (HA) is the most common hereditary (X-linked) disorder occurs in one per 5000 males worldwide.17 Patients usually presents with bleeding, but laboratory examination reveals isolated Factor VIII (FVIII) deficiency.18 FVIII is a nonenzymatic cofactor that needed to activate FIXa and FX respectively. This factor will trigger the conversion of prothrombin to thrombin and will directly convert fibrinogen to fibrin, as the major blood clots component.19 The primary management of HA is FVIII concentrated infusions. Both plasma-derived FVIII (pdFVIII) and recombinant FVIII (rFVIII) concentrates are available treatment options. rFVIII can be further divided into first, second, third, and fourth generation.20 The exposure to each type could be a risk factor for inhibitor formation due to the body immunological response.21 4.2 rFVIII vs. pdFVIII: HR and OR Our pooled OR results showed the value of 1.57 towards rFVIII [95% CI: 0.95 to 2.59]. This is quite contrary with previous systematic review by Fachini, et al.22, which reported slightly higher cumulative rates of inhibitor in rFVIII (CR = 0.29 [95%CI: 0.26-0.32]) compared to

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pdFVIII (CR = 0.23 [95%CI: 0.15-0.33]). Their study analyzed 1.421 patients in 28 prospective cohort studies, which most of it were one arm studies or without comparison. Besides, they also found the similar HR result between both products (adjusted HR = 0.96; [95%CI : 0.621.49]). However, our study recorded the same direction but with significant value (pooled HR: 1.89 [95% CI: 1.15 to 3.12]). The study did not find any significant difference among three generations types available in recombinant groups.

Inhibitors development are further classified as high or low responding inhibitors based on patients’ anti-FVIII reaction after exposure to treatment.23,24 According to International Society on Thrombosis and Hemostasis Scientific and Standardization committee, the cut-off point is 5 Bayesian Unit (BU)/mL after repeat challenges with FVIII. Patient with inhibitor value above the cut-off point is considered a high-responding inhibitor and vice versa. High-responding inhibitors associated with higher cost, hospitalization, morbidity, mortality, and greater chance of treatment failure.25 Additionally, our study reviewed the HR and OR in high-responding inhibitors. Our result supported the findings from Iorio, et al10 which found greater incidence rate for rFVIII (17.4% [14.2-21.2]) compared to pdFVIII (9.3% [6.2-13.7]). This study consisted of 2.049 patients conducted to evaluate the incidence rates of inhibitor development in previously untreated Hemophilia A patients. Alongside, the HR from our study emphasized this result.

4.3 Mechanism of Inhibitor Development in Both Treatments Inhibitors are neutralizing antibodies that bind the non-functional epitopes of FVIII, which leads to inactivation of the product. Multifactorial risk factors, including genetic and environmental, are shown to affect the development. Nonsense mutations or large deletions in the F8 gene are strongly related to the condition.26 The development of inhibitors from the environment, one of which is the drug used, requires a usual complex immune mechanism.

During the factor injection, antigen presenting cells will capture and present the antigenderived peptides to the CD4+ T cell via HLA class II molecules. This T cell becomes activated and able to stimulate B cells to become plasma cells and produce antibodies. As the usual immune response mechanism, this process will require the second trigger to produce more. The main neutralizing antibodies are IgG1 and IgG4 subtypes.27 The result was proven with study by Whelan, et al28 which found a significant difference in value of both IgG subclasses (IgG1 and IgG4) in inhibitor patients. IgG4 was even completely not found in health subjects. Besides, our finding is correlated with an experimental study in

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mice conducted by Delignat, et al29 which found IgG4 titres were higher in mice treated with rFVIII compared to pdFVIII with values of 2.4 to 3.2-fold.

4.4 Implications in Clinical Practice This updated systematic review emphasizes the benefit of pdFVIII uses compared to rFVIII for a better prospect. In daily life, a doctor will face both treatment options. We recommend evaluating a patient’s risk factor in developing inhibitors first before choosing the appropriate treatment. Hence, patients with a high risk factor should not take the rFVIII product. Both the risk and benefit of each drug should be considered equally.

4.5 Limitations We acknowledge that this study has several limitations. First of all, all included studies have variation in the duration of recruitment period ranging from the oldest 1984 to the latest 2016.

Therefore, the results may be affected by the advanced development of drugs. Besides, most studies also did not provide drugs’ subclasses used in the treatment. In addition, not all studies reported the complete data that was needed in this review.

Although there are limitations, this study has some key strengths as well. Firstly, we found that the majority of included studies have a good score in bias assessment. Besides, most of the studies are cohorts, case-controls, and randomized clinical trials that are very capable in evaluating long term inhibitor effect in patients. Another strength is the variation of the countries participating in the studies, which is able to be implied globally.

5.

Conclusion

To summarize, this comprehensive meta-analysis demonstrates that Recombinant Factor VIII is more likely to cause inhibitors development, either overall or high responding, compared to the plasma-derived Factor VIII. 5.1 Future Recommendations Latest studies are always needed based on the advancement development of the drug. Studies could also touch upon the issues of the effect of inhibitors developed by each drug since patients’ effects are the main concern of all problems. We also recommend to analyze directly the association of drugs’ subclasses and the inhibitors development. Future research approaching the safest treatment without inducing the inhibitor is necessary

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REFERENCES 1.

Bhardwaj 2018 : Sona PS, Lingam CM. Hemophilia-an overview. International Journal of pharmaceutical sciences review and research. 2010;5(1):18-25.

2.

Stonebraker JS, Bolton-Maggs PHB, Brooker M, Evatt B, Lorio A, Makris M. The world federation of hemophilia annual global survey 1999-2018. Haemophilia. 2020 Jun 4 [cited on 2020 Mar 17];26(4);591-600.

3.

Mehta P, Reddivari AKR. Hemophilia. [Updated 2021 Jan 16]. In: StatPearls [Internet].

Treasure

Island

(FL):

StatPearls

Publishing;

2021

Jan-.

Available

from:

https://www.ncbi.nlm.nih.gov/books/NBK551607/ 4.

Haider MZ, Anwer F. Acquired Hemophilia. [Updated 2020 Aug 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560494/

5.

Centers for Disease Control and Prevention. Hemophilia [Internet]. USA: U.S. Department of

Health

&

Human

Services;

2020

Jul

17.

Available

from:

https://www.cdc.gov/ncbddd/hemophilia/treatment.html 6.

Barnes C. Recent Advances in Haemophilia Management.Current Pediatrics Reports.

2015 Jun 1;3(2):154-9.

7.

Gomez K, Klamroth R, Mahlangu J, Mancuso ME, Mingot ME, Ozelo MC. Key issues in inhibitor management in patients with haemophilia. Blood Transfus. 2014 Jan;12 Suppl 1(Suppl 1):s319-29. doi: 10.2450/2013.0246-12. Epub 2013 Dec 3.

8.

Jardim LL, Chaves DG, Rezende SM. Development of inhibitors in hemophilia A” an illustrated review. Research and Practice in Thrombosis and Haemostasis. 2020 May 26;4(5):752-60.

9.

Tieu P, Chan A, Matino D. Molecular Mechanisms of Inhibitor Development in Hemophilia. Mediterr J Hematol Infect Dis. 2020 Jan 1;12(1):e2020001.

10. Iorio A, Halimeh S, Holzhauer S, Goldenberg N, Marchesini E, Marcucci M, Young G, Bidlingmaier C, Brandao LR, Ettingshausen CE, Gringeri A, Kenet G, Knöfler R, Kreuz W, Kurnik K, Manner D, Santagostino E, Mannucci PM, Nowak-Göttl U. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost. 2010 Jun;8(6):1256-65.

11. Franchini M, Tagliaferri A, Mengoli C, Cruciani M. Cumulative inhibitor incidence in previously untreated patients with severe hemophilia A treated with plasma-derived versus

15

recombinant factor VIII concentrates: a critical systematic review. Crit Rev Oncol Hematol. 2012 Jan;81(1):82-93.

12. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement.

PLoS Med 6(7): e1000097 13. Wells GA, Connell DO, Peterson J, Welc V, Losos M, Tugwell P, Shea B. NewcastleOttawa quality assessment scale. Ottawa Hospital Research Institute(OHRI. 2014;3:2–4.

14. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA. Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration. 2014.

Available from: https://doi.org/doi:10.1002/978111953660 15. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898.

16. Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

17. Salen P, Babiker HM. Hemophilia A [Internet]. Treasure Island (FL): StatPearls Publishing;

2021

Jan

[Cited

2021

Mar

18].

Available

from:

https://www.ncbi.nlm.nih.gov/books/NBK470265/ 18. Tiede A, Collins P, Knoebl P, Teitel J, Kessler C, Shima M, Minno GD, et al. International recommendations on the diagnosis and treatment of acquired hemophilia A. Haematologica. 2020 Jul;105(7):1791-801.

19. Orlova Na, Kovnir SV, Vorobiev II, Gabibov AG, Vorobiev AI. Blood clotting factor VIII: From evolution to therapy. Acta Naturae. 2013 Apr-Jun;5(2):19-39.

20. Lieuw K. Many factor VIII products available in the treatment of hemophilia A: An embarrassment of riches? J Blood Med. 2017;8:67-73.

21. Witmer C, Young G. Factor VIII inhibitors in hemophilia A: rationale and latest evidence.

Ther Adv Hematol. 2013 Feb;4(1):59-72.

22. Franchini M, Coppola A, Rocino A, Santagostino E, Tagliaferri A, Zanon E, Morfini M, et al. Systematic review of the role of FVIII concentrates in inhibitor development in previously untreated patients with severe hemophilia A: A 2013 update. Semin Thromb Hemost. 2013;39:752-66.

23. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: A systematic review.

Haemophilia. 2003;9:418-35.

24. White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor

16

IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 2001 Mar;85(3):560.

25. Tu TC, Cheng SN, Chen JD, Cham TM, Chung MI. Economic burden of high-responding inhibitors in patients with Hemophilia A in Taiwan. Yonsei Med J. 2013 Mar 1;54(2):38565.

26. Astermark J. FVIII inhibitors: pathogenesis and avoidance. Blood. 2015 Mar 26;125(13):2045-51.

27. Pevyandi F, Miri S, Garagiola I. Immune responses to plasma-derived versus recombinant FVIII products. Front Immunol. 2020;11:591878.

28. Whelan SFJ, Hofbauer CJ, Horling FM, Allacher P, Wolfsegger MJ, Oldenburg J, Male C, et al. Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients. Blood. 2013 Feb 7;121(6):1039-48.

29. Delignat S, Dasgupta S, Andre S, Navarrete AM, Kaveri SV, Bayry J, Andre MH. Comparison of the immunogenicity of different therapeutic preparations of human factor VIII in the murine model of hemophilia A. Haemotologica. 2007 Oct;92(10):1423-6.

17

APPENDIX Appendix 1. Newcastle-Ottawa Quality Assessment Scale (Cohort Studies).

Studies

Selection

Comparability

Outcome

Total

Blatny et al.

****

-*

***

8 - Good

Valzen et al.

***-

-*

***

7 - Good

Calvez et al.

****

**

***

9 - Good

Batorova et al.

****

-*

***

8 - Good

Blatny et al.

****

**

***

9 - Good

Gouw et al.

****

-*

***

8 - Good

Xuan et al.

-***

*-

***

7 - Good

Strauss et al.

****

--

***

7 - Good

Appendix 2. Newcastle-Ottawa Quality Assessment Scale (Case-Control Study).

Studies Valzen et al.

Selection

Comparability

Outcome

***-

-*

***

Total 7 - Good

Selective reporting

Other bias

-

Incomplete outcome data

?

Blinding of outcome assessment

+

Blinding of participants and personnel

Allocation concealment

Pevyandi et al.

Random sequence generation

Appendix 3. Cochrane Risk of Bias for Randomized Clinical Trial Study.

-

+

+

+

+ (low risk of bias); - (high risk of bias); ? (unclear risk of bias)

18

Appendix 4. Funnel Plot: Association of Factor VIII Types (Recombinant and Plasma-

derived) with Overall Inhibitors Development - (A) OR; (B) HR. A

B

19

Appendix 5. Funnel Plot: Association of Factor VIII Types (Recombinant and Plasma-

derived) with High Responding Inhibitors Development - (A) OR; (B) HR. A

B

20

Exploring the Efficacy and Safety of Factor VIII–Mimetic Function of Humanized Bispecific Antibody (Emicizumab/ACE910) in Classic Hemophilia Patients with or without Inhibitors: A Systematic Review and Meta-Analysis

Introduction: Development of inhibitors causes suboptimal hemophilia A management in 2030% of patients with severe form despite the availability of factor VIII replacement. Factor VIIImimicking emicizumab (ACE910) has currently become the most promising novel therapeutic option to date. Nevertheless, many questions still left unanswered regarding its efficacy and safety aspects in patients with or without inhibitors. This meta-analysis aims to explore the state-of-theart research on the aforementioned areas.

Methods: We systematically searched through PubMed, Ovid EMBASE, EBSCOhost, Scopus and Wiley up to February 2021. Critical appraisal of included studies was performed using the ROBINS-I and ROBINS-E tools. The pooled estimate of number of patients that suffer from bleeding compared with total samples was analysed using random effect models in RevMan 5.4.

Result and Discussion: 17 peer-reviewed studies were included with a total of 855 patients. The treatment duration ranges from 24-57 weeks. We demonstrated that emicizumab administration in classic hemophilia with or without inhibitors does not differ significantly (Risk Difference: 0.007; 95%CI: -0.06-0.20).

Conclusion: Emicizumab utilization resembles similar efficacy in both inhibitors and noninhibitors patients with relatively safe adverse events ranging from mild to moderate ones.

Nevertheless, patient-tailored therapy remains the main pillar of management.

Keywords: hemophilia A, classic hemophilia, emicizumab, ACE910, inhibitors

21

1. Introduction Hemophilia A, also known as the factor VIII deficiency, has become the most common severe hereditary bleeding disorder in the world. Patients that suffer from this condition will have prolonged bleeding with or without trauma, in which the degree of severity greatly depends on the factor activity.1 The principal management for the patients is to avoid and treat bleeding as soon as possible. In addition, patients still require comprehensive management from an advanced center that is capable of providing interprofessional services for the patients and their families.2 Based on a meta-analysis by Iorio et al., 1,125,000 men have the inherited hemorrhagic disorder, these are approximately three times larger compared to the initial global estimated number of 400,000 people suffering from hemophilia. Studies also uncovered that the life expectancy of people with hemophilia become significantly less compared to the normal population, especially those coming from low-income countries who experience difficulties in accessing adequate treatment.3 The current challenge in the field of hemophilia lies in the fact that factor VIII replacement therapy as the existing management was considered to be suboptimal due to the development of inhibitors or neutralizing bodies in 20-30% of patients with hemophilia A replacement.4 This triggers the development of novel approaches, one of which is by utilizing a bispecific antibody that has the ability to bridge substrate factor X, and enzyme factor IXA, known as emicizumab.5 Various clinical trials and ongoing research work towards elucidating the efficacy, safety, and effects of emicizumab on patients.6-8 One of the most intriguing questions currently faced is whether it would be beneficial to administer emicizumab for patients who have already developed inhibitors or patients who lack inhibitors.

Many researchers are still questioning how the condition of inhibitors could influence and demonstrate distinct efficacy and adverse effects when administered with emicizumab. Answering this issue becomes crucial since it would greatly affect the overall approach and strategy in managing hemophilia A patients with or without inhibitors.9,10

22

Thus, in order to formulate the best strategy to attain the most optimal management for patients, this systematic review and meta-analysis is created with the objective to unveil the different effects of emicizumab on patients with hemophilia A with or without inhibitors.

2. MATERIALS & METHODS 2.1 Search Strategy For this review, the authors conducted a systematic literature search according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA).11 Relevant publications were retrieved by applying the following keywords: “hemophilia” AND “emicizumab” AND “inhibitors”. Mesh Terms and the synonyms of the keywords were used whenever applicable. In addition, we searched through the reference lists of the retrieved papers to find further relevant literature. The aforementioned strategy was applied in 5 online databases namely: Ovid EMBASE, Pubmed, Scopus, EBSCOhost, and Wiley Online Library to find relevant peer-reviewed papers that were published up to 28 February 2021. A detailed list of the keywords used in the literature search is shown in Appendix Table 1.

2.2 Inclusion and Exclusion Criteria Eligible studies were selected based on several inclusion and exclusion criteria. The inclusion criteria that were applied are: (1) clinical trials and observational studies, (2) studies reporting desired outcomes such as bleeding events, Annualized Bleeding Rate (ABR) and adverse events (AE), (3) studies investigating the use of emicizumab and, (4) studies published in English and Bahasa Indonesia.

Additionally, we excluded studies that have the following criteria: (1) irrelevant study designs such editorial letters, commentaries and conference abstracts, (2) studies investigating treatment that does not include emicizumab, (3) unextractable or unobtainable data notwithstanding having contacted the corresponding author and, (4) studies written in languages other than English and Bahasa Indonesia

23

2.3 Data Extraction, Study Outcomes, and Risk of Bias Assessment 2.3.1 Data Extraction The data extraction was performed by two independent reviewers with any discrepancies adjudicated by reaching a consensus with a third investigator. The details of information that were extracted from the included studies were as follows: (1) authors and year of publication; (2) study characteristics, including the study design, recruitment period, country of origin, types of patients with hemophilia A (with inhibitors or without inhibitors), duration of treatment, classification of the patients or dosing regimens, median duration of exposure; (3) subject characteristics, including the sample size, mean or median age, gender proportion, hemophilia severity at baseline, and comorbidities.

2.3.2 Study Outcomes The outcomes of interest observed in this review include annualized bleeding rate (ABR) of all bleeding events; ABR of treated bleeding events; proportion of zero bleeding events and all bleeding events; ABR of treated spontaneous bleeding; the numbers of treated bleeding, viz. joint bleeding, muscle bleeding, soft tissue bleeding, bruises/hematoma, breakthrough bleeding, miscellaneous types of bleeding; proportion of resolved target joints; numbers of mild-to-moderate adverse events (AE) and severe adverse events (SAE) along with the detailed lists.

2.3.3 Risk of Bias Assessment The assessment of methodological quality in terms of risk of bias was conducted using the Risk of Bias in Non-Randomized Studies - of Interventions (ROBINS-I)12, which was subsequently judged to be showing low, moderate, or high risk of bias. The ROBINS-I tool consists of 7 main domains separated to 2 pre-intervention domains and 5 at-intervention domains, each addressing specific parameters or domains to identify potential bias in the studies, namely confounding factors, participants selection, classification of interventions, deviations from the intended interventions, missing data, outcome measurement, and selection of the reported result with each domain judged as low, moderate, serious, critical, and no information.12 Each domain consists of signaling questions with 6 plausible responses, namely yes (Y); probably yes (PY); no (N); probably no

24

(PN); no information (NI); or not applicable (NA).12 This was applied in accordance to the protocol for clinical trials. As for observational studies, the Risk of Bias in Observational Studies - of Exposures (ROBINS-E) tool13 was used with similar domains to ROBINS-I with slightly different signaling questions for certain domains, viz. classification of exposures, deviations from intended exposures, and measurement of the outcome.13 The assessment was performed by three independent investigators, with conflicts being resolved through consensus of all authors.

2.4 Data Synthesis and Statistical Analysis In calculating and presenting the data, Review Manager version 5.41 software by Cochrane was used to perform quantitative analysis. The type of data used is dichotomous data which consist of the number of patients which suffer from bleeding compared with the total sample. Two groups were compared in the quantitative analysis, namely Patients with Hemophilia A (PwHA) with inhibitors and PwHA without inhibitors. Furthermore, the data were extracted based on eligible studies and pooled utilizing the fixed effects model (Wooldridge JM et al).14 The heterogeneity of data was also presented with I2, Cochrane Chi-square and Tau square method. Substantial heterogeneity can be concluded if the I2 score is greater than 50%. Therefore, considering the heterogeneity of the data, the models that were chosen were fixed effect models instead of random effect models, through the inverse variance method. Z score value was also calculated to measure the overall effect, while p value was used to analyze the statistical significance in which p-value was set at less than 0.05. Lastly, the publication bias can be measured through generating a funnel plot and visual inspection of the symmetry of the plot. However, due to the scarcities of the studies, it is not applicable to perform the funnel plot in this case.

3. RESULTS 3.1 Study Selection, Study Characteristics, and Quality Assessment The initial search yielded 1543 records from five different databases. After removing 54 duplicates, we performed the preliminary filtering by screening through the titles and abstracts which narrowed down our findings to 55 articles. These papers were then assessed on a full-text level to select a total of 17 studies that were included in this review, 4 of which eventually became the basis of the quantitative section. Several reasons for excluding the journals include

25

inappropriate study designs, different outcomes, unextractable data and irretrievable full text. A detailed illustration of the systematic search is shown in Figure 1.

The 17 included studies comprise different study designs; mostly clinical trials along with 3 observational studies and 1 non-interventional study. We include the latest papers in our analysis which bring up relatively updated information. This could possibly be explained due to the novelty aspect of emicizumab. Emicizumab has been tested around the world; 7 studies were performed at multi centers globally, 6 were done exclusively in Japan, 2 in the United States and 2 more in Israel. The treatment duration differs among studies, with the majority implementing 24 weeks, up to 57 weeks. Furthermore, the median duration of exposure to emicizumab varies, ranging from 4 weeks up to as long as 61.1 weeks. In total, 885 patients with hemophilia A (PwHA) were identified, including those who had or lacked the factor VIII inhibitors. Moreover, 40 individuals were recruited as participants of the phase 1 trial. Almost all of the patients were male, with only less than 1% was female (n=5), due to the X-linked inheritance pattern of classic hemophilia. We demonstrated extensive range of the mean age of the participants as both adults and children are included. Regarding the severity of hemophilia A, most of the patients had severe hemophilia at baseline. Some prominent comorbidities are also reported here, including HIV infection, Hepatitis B and chronic Hepatitis C. The baseline characteristics of the included studies are depicted in Table 1.

The detailed results of the risk of bias assessment consisting of every signaling question is exhibited in Appendix Table 2A & 2B. In general, the majority of the included studies have moderate risk of bias with only three studies considered as high risk, which the authors took into account when interpreting the results. The domains of bias with more proportions of unclear and high risk of bias include the confounding, outcomes measurement, and selective reporting, whereas the other domains for all the included studies suggest low risk of bias.

26

Figure 1. PRISMA Flowchart11

27

Figure 2A. ROBINS-I & ROBINS-E

Figure 2B. ROBINS-I & ROBINS-E

28

Table 1. Baseline Characteristics of Included Studies

29

KruseJarres R et al; 2019

30

31

32

Abbreviations: ABR: Annualised Bleeding Rate; BPA: Bypassing Agent; N/A: Not Available; PwHA: Patients with Hemophlia A; TMA: Thrombotic Microangiopathy

33

3.2 Study Outcomes Summary of study outcomes are presented within Table 2 which illustrates the total of 17 studies that have been chosen after passing through a rigorous selection process based on the eligibility criteria, exclusion and inclusion criteria as previously described. The major outcomes which became the main discussion on this paper were Annualized Bleeding Rates (ABR), along with various adverse events that followed the administration of emicizumab in both patients that suffered from hemophilia A with or without inhibitors. Firstly, for the ABR, the data that were retrieved are in the form of ABR of treated bleeds and ABR of all bleeds with their 95% Confidence Interval (CI) calculation. Secondly, with regards to adverse events, they are further divided into mild-to-moderate adverse events and severe adverse events, which were listed in the table.

Across 17 studies that have been garnered from literature searching, various dosing regimens can be observed in which different patients with different levels of inhibitors or without inhibitors are given emicizumab. Both ABR of all bleeds and ABR of treated bleeds demonstrate a similar trend where lower ABR values tend to be observed from cohorts of PwHA without inhibitors that were given with a higher dose of emicizumab compared to the PwHA with inhibitors. Furthermore, giving emicizumab as prophylaxis rather than episodic shows more benefit in decreasing ABR values in these patients. These similar results can also be observed in another variable; percentage of bleeding events. Various studies have demonstrated a tendency in which the percentage of bleeding events is higher in PwHA with inhibitors compared to PwHA without inhibitors when both are given emicizumab. Moreover, our data suggest that patients with inhibitors show lesser percentage of zero bleeding events.

Other variables such as spontaneous bleeding, joint bleeding, treated muscle bleeding, treated soft tissue bleeding, treated bruised/hematoma bleeding, and breakthrough bleed are very limited as only several studies are able to keep in record in such details. Thus, it becomes difficult to draw a conclusion on the trend of the data. Last but not least, regarding the adverse events, most of the recorded adverse events (AEs) are classified into mild-to-moderate AEs in which these events do not directly threaten patients’ life, including injection site erythema, arthralgia, and headache. On the other hand, severe AEs are much rarer, with examples such as hemarthrosis and thrombosis.

34

3.3 Quantitative Analysis of Number of Bleeding Events

Figure 3. Forest plot of number of bleeding events in PwHA with and without inhibitors From 17 included studies, only 4 studies that provide adequate data to be quantitatively analyzed and the final result can be seen on the figure above in the form of forest plot. The forest plot illustrates the number of all bleeding events as ‘Events’ against the total number of patients in the corresponding cohort as ‘Total’. The calculated risk difference is shown to be 0.07 (95% CI: -0.06 to 0.20) which favors slightly for the patients without inhibitors. However, it is not statistically significant and thus it can be concluded that giving patients with emicizumab with inhibitors or without inhibitors does not significantly differ in terms of number of bleeding events. The test for overall effect/z score showed the score of 1.00 in which it is not statistically significant (p=0.32).

The heterogeneity itself was found to be low, as seen by an I2 of 0% (p=0.98)

35

Table 2. Study Outcomes

36

37

KruseJarres R et al; 2019

PwHA without inhibitors

38

39

40

41

Abbreviations: ABR: Annualised Bleeding Rate; BPA: Bypassing Agent; N/A: Not Available; PwHA: Patients with Hemophilia A; TMA: Thrombotic Microangiopathy

42

4. DISCUSSION 4.1 The Existing Challenges in Treating Patients of Hemophilia A and Potential Utilization of Emicizumab in Improving the Status Quo The current standard of care for hemophilia A patients is factor replacement therapy using intravenous infusions of recombinant FVIII as both prophylactic and on-demand treatment.

Despite its widespread use, it has several limitations and complications as the risk of bleeding and joint damage remains high. Not only is this procedure invasive, but due to its short half-life of about 12 hours, it requires 2-3 weekly infusions to reach sufficient prophylaxis which is both costly and inconvenient, further adding onto the high burden of disease. Additionally, approximately 2030% of the patients receiving FVIII develop inhibitors against the factor itself which serves as a main challenge to the management, as this is the main complication of FVIII treatment.

Development of inhibitors lead to lower efficacy of therapy as they neutralise FVIII and leads to more difficult bleeding control, eventually resulting in further complications. The most effective way to eradicate the inhibitors is through immune tolerance induction (ITI) therapy by the use of bypassing agents (BPA) which include activated prothrombin complex concentrate (aPCC) and recombinant activated factor VIIa (rFVIIa). Nevertheless, the efficacy of ITI is still suboptimal as it is associated with hospitalisations, uncontrolled bleeding, poor response and early mortality.

Thus, a new safer approach with longer half-life and less immunogenicity is required to tackle these problems.5,9,19 A newly developed bispecific humanized monoclonal antibody used for the treatment of classic hemophilia, emicizumab or ACE910, exerts its pharmacological effect by linking FIXa and FX; thus restoring the function of missing activated FVIII which independently mimics FVIIIa in promoting effective hemostasis in the patients.15,23 Subcutaneous injection of emicizumab is used for prophylactic purposes in some countries, which serves as one of the advantages of emicizumab.15-18 Furthermore, the clinical trials15-30 included in our study together corroborate the pharmacokinetics efficacy of the agent’s longer half-life and therefore indicate higher bioavailability. This results in a reduced requirement of injection frequencies, which in turn improves the standard of care and cost-effectiveness from the angle of clinicians. From the patients’ perspective, less number of injections would provide more opportunities for activities

43

and less worries. Emicizumab could also reduce the mental burden of fear of spontaneous bleedings during daily activities which potentially may improve the quality of life in hemophilia patients.

Nevertheless, this could also imply that the subsequent increase in physical activities is accompanied by a higher risk of injury, especially in children who are more likely to be highly active and participate in high-risk, strong-impact sports.23 Thus, this may make them more prone to have a higher ABR even after being given the treatment. Another plausible explanation for the higher observed ABR among the pediatric patients lies upon the fact that the data collection methods to record joint bleeds in certain trials could be different between adult versus pediatric patients.18 Data of children's joint bleeds were recorded regardless of the number of symptoms they experience, while adults' joint bleeds require stricter and more precise criteria to be documented which may lead to the observed lower ABR in adults.18 4.2 Annualized Bleeding Rates (ABR) and Other Types of Bleeding Rates in Hemophilia A Generally, ABR of all bleeding events were shown to be similar between PwHA with and without inhibitors, with the exception of Misgav et al15, where the ABR was reported to be lower in the group of patients with inhibitors.15-30 This general trend was further highlighted in the forest plot analysis, in which there is no significant difference in the number of bleeding events when comparing patients with and without inhibitors upon emicizumab therapy. Several studies such as Krusse-Jarres et al, Mahlangu et al, and Oldenburg et al demonstrated that the efficacy of emicizumab is higher when used as a prophylactic rather than as an episodic treatment.18,21,26 This suggests that emicizumab is more suitable to be prescribed to prevent future bleeding episodes while direct bleeding management remains as the current standard. This trend is also similar in ABR of treated bleeding events.15-30 Other types of bleeding rates that are widely discussed in a plethora of papers include the numbers of treated joint bleeding.15-30 Target joints are defined as three or more bleeding events that happened over a 24-week period in major joints.22-25 In cases of pediatric hemophilia A patients, preventing bleeding in target joints result in lifelong benefit. It is important to terminate the joint

44

bleeding since failure to stop the bleeding would cause permanent damage. Another point to consider is the state of being overweight since it would impose additional pressure on the joints, making them even more vulnerable to bleed.22-25 4.3 Various Adverse Events that occurred in usage of emicizumab Overall, the safety profile of emicizumab is favorable as most adverse events that the patients experience are mild to moderate and does not cause the discontinuation of the treatment. The most common adverse event was a local injection site reaction. However, there are some patients who experience severe adverse events which are predominantly coagulation abnormalities such as thromboembolism and thrombotic microangiopathy. Mortality was also not found. Furthermore, there was no development of antibodies against emicizumab during the treatment.15-31 This is demonstrated to be consistent with immunogenicity findings where in silico analyses shows that the immunogenicity of emicizumab is lower or similar to other humanized antibodies that have received FDA approval. Thus, unlike rFVIII, there is a low risk of efficacy reduction due to development of inhibitors for emicizumab.32,33 Previous studies showed that emicizumab is less likely to affect the functions of clotting factor agents since its use with factor VIII or other bypassing agent (management for bleeding) was shown to be successful.30 However, more recent evidence has demonstrated the possibility of drugdrug interactions. Hence, it is noteworthy that not all adverse events are attributable merely to emicizumab. Physicians need to bear in mind that caution must be practiced when interpreting the data of adverse events. Studies have reported that there is no dose-dependent relationship between the AEs and emicizumab; however, there is still the possibility for adverse events to occur.9,19 These adverse events are of important considerations since they influence the quality of life of hemophilia patients.

4.4. Implications in Clinical Practice and Management Incorporating the novelty of our findings and other recent evidence, prophylaxis with emicizumab has been proven to have higher efficacy in PwHA as compared to on-demand or other prophylaxis (BPA and rFVIII). The reduction in bleeding frequency is associated with improvement in long-

45

term clinical outcomes and overall quality of life. However, regarding the dosing, there are different types of regimen available i.e., QW, Q2W, and Q4W. Determining the optimal dosing regimen needs to be tailored to each individual’s condition, and is influenced by numerous factors, such as age, activity, adherence, vial size, preferences, et cetera.32,33 There are also other issues to keep in mind when implementing emicizumab in clinical practice; for instance, the impact on laboratory monitoring. Despite no requirement of laboratory monitoring, emicizumab affects clot-based assays such as activated partial thromboplastin time (APTT), FVIII activity and inhibitor. However, chromogenic assays and global coagulation assays can be used to reliably measure these parameters.32,34 4.5. Study Limitations and Strengths We acknowledge that there are some limitations to this study. Firstly, there is currently no consensus on the definition of the outcome measure which may differ from one study to another.

Secondly, there is variation in the methodology of the clinical trials which is a factor to take into consideration when comparing and interpreting the results. Another limitation is the open-label nature of most clinical trials included.

Despite the aforementioned limitations, this study has several strengths as well. First of all, most of the studies have an overall moderate risk of bias with only a few having high risk. In addition, many trials were performed in multi centers around the world, reflecting its global applicability and lesser restrictions.

46

5. CONCLUSION In conclusion, this comprehensive review demonstrates that prophylaxis for patients with Hemophilia A using subcutaneous injection of emicizumab is effective and safe, regardless of the presence of FVIII inhibitors. In addition, dosing regimen should be personalized in accordance with the individual conditions.

5.1 Future Recommendations We recommend that future studies should recruit a larger sample size to avoid selection bias and to produce more accurate data. Additionally, more research is needed to investigate the long-term administration of emicizumab with regards to its efficacy and safety. Not only that, but future research could also examine the specific ability of emicizumab in treating particular types of bleeding whether it is best to be used for preventing bleeding from joints, soft-tissue, bruises, or others. Lastly, future efforts that aim to provide clear definitions for the outcome measures would contribute a substantial amount in terms of concept understanding.

47

REFERENCES 1. Soucie JM. Global hemophilia care: Data for action. Ann Intern Med. 2019 Oct 15; 171(8):585-6.

2. Zimmerman B, Valentino LA. Hemophilia: in review. Pediatr Rev. 2013 Jul;34(7):289-94.

3. Iorio A, Stonebraker JS, Chambost H, Makris M, Coffin D, Herr C, et al. Establishing the Prevalence and Prevalence at Birth of Hemophilia in Males: A Meta-analytic Approach Using National Registries. Ann Intern Med. 2019 Oct 15;171(8):540–6.

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https://www.ncbi.nlm.nih.gov/books/NBK551607/ 5. Peters R, Harris T. Advances and innovations in haemophilia treatment. Nat Rev Drug Discov. 2018;17: 493–508.

6. Kitazawa T, Shima M. Emicizumab, a humanized bispecific antibody to coagulation factors IXa and X with a factor VIIIa-cofactor activity. Int J Hematol. 2020;111: 20–30 7. Mahlangu JN. Bispecific Antibody Emicizumab for Haemophilia A: A Breakthrough for Patients with Inhibitors. BioDrugs. 2018:32;561–70.

8. Ferrière S, Lenting PJ. Antibodies in the Treatment of Haemophilia A-A Biochemical Perspective. Hamostaseologie. 2019 Feb;39(1):36-41.

9. Gelbenegger G, Schoergenhofer C, Knoebl P, Jilma B. Bridging the Missing Link with Emicizumab: A Bispecific Antibody for Treatment of Hemophilia A. Thromb Haemost.

2020 Oct;120(10):1357-70.

10. Oldenburg J, Young G, Santagostino E, Escuriola Ettingshausen C. The importance of inhibitor eradication in clinically complicated hemophilia A patients. Expert Rev Hematol.

2018 Nov;11(11):857-62.

11. Moher D. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. Ann Intern Med. 2009 Aug 18;151(4):264.

12. Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al.

ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.

BMJ. 2016 Oct 12;i4919.

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13. Bero L, Chartres N, Diong J, Fabbri A, Ghersi D, Lam J, et al. The risk of bias in observational studies of exposures (ROBINS-E) tool: concerns arising from application to observational studies of exposures. Syst Rev. 2018 Dec;7(1):242.

14. Bell A, Fairbrother M, Jones K. Fixed and random effects models: making an informed choice. Qual Quant. 2019 Mar;53(2):1051–74.

15. Misgav M, Brutman-Barazani T, Budnik I, Avishai E, Schapiro J, Bashari D, et al.

Emicizumab prophylaxis in haemophilia patients older than 50 years with cardiovascular risk factors: Real-world data. Haemophilia. 2021 Feb 17.

16. Barg AA, Livnat T, Budnik I, Avishai E, Brutman-Barazani T, Tamarin I, et al.

Emicizumab treatment and monitoring in a paediatric cohort: real-world data. Br J Haematol. 2020 Oct;191(2):282–90.

17. McCary I et al; 2020: McCary I, Guelcher C, Kuhn J, Butler R, Massey G, Guerrera MF et al. Real-world use of emicizumab in patients with haemophilia A: Bleeding outcomes and surgical procedures. Haemophilia. 2020 Jul;26(4):631-636.

18. Oldenburg J, Shima M, Kruse‐Jarres R, Santagostino E, Mahlangu J, Lehle M, et al.

Outcomes in children with hemophilia A with inhibitors: Results from a noninterventional study. Pediatr Blood Cancer [Internet]. 2020 Oct [cited 2021 Mar 19];67(10). Available from: https://onlinelibrary.wiley.com/doi/10.1002/pbc.28474 19. Shima M, Nagao A, Taki M, Matsushita T, Oshida K, Amano K, et al. Long‐term safety and efficacy of emicizumab for up to 5.8 years and patients’ perceptions of symptoms and daily life: A phase 1/2 study in patients with severe haemophilia A. Haemophilia. 2021 Jan;27(1):81–9.

20. Ebbert PT, Xavier F, Seaman CD, Ragni MV. Emicizumab prophylaxis in patients with haemophilia A with and without inhibitors. Haemophilia. 2020 Jan;26(1):41-46.

21. Kruse-Jarres R, Oldenburg J, Santagostino E, Shima M, Kempton CL, Kessler CM, et al.

Bleeding and safety outcomes in persons with haemophilia A without inhibitors: Results from a prospective non-interventional study in a real-world setting. Haemophilia. 2019 Mar;25(2):213–20.

22. Pipe SW, Shima M, Lehle M, Shapiro A, Chebon S, Fukutake K, et al. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with

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haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study.

Lancet Haematol. 2019 Jun;6(6):e295–305.

23. Shima M, Nogami K, Nagami S, Yoshida S, Yoneyama K, Ishiguro A, et al. A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors. Haemophilia. 2019 Nov;25(6):979–87.

24. Yada K, Nogami K, Ogiwara K, Shida Y, Furukawa S, Yaoi H, et al. Global coagulation function assessed by rotational thromboelastometry predicts coagulation-steady state in individual hemophilia A patients receiving emicizumab prophylaxis. Int J Hematol. 2019 Oct;110(4):419–30.

25. Young G, Liesner R, Chang T, Sidonio R, Oldenburg J, Jiménez-Yuste V, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019 Dec 12;134(24):2127–38.

26. Mahlangu J, Oldenburg J, Paz-Priel I, Negrier C, Niggli M, Mancuso ME, et al.

Emicizumab prophylaxis in patients who have hemophilia A without Inhibitors. N Engl J Med. 2018 Aug 30;379(9):811-822.

27. Mahlangu JN. Bispecific Antibody Emicizumab for Haemophilia A: A Breakthrough for Patients with Inhibitors. BioDrugs. 2018 Dec;32(6):561–70.

28. Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017 Aug 31; 377:809-818 29. Shima M, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K, et al. Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors. Blood Adv. 2017 Oct 10;1(22):1891–9.

30. Shima M, Hanabusa H, Taki M, T, Sato T, Matsushita T, Futukate K, et al. Factor VIIIMimetic function of humanized bispecific antibody in Hemophilia A. N Engl J Med. 2016 May;374(21):2044-2053.

31. Uchida N, Sambe T, Yoneyama K, Fukazawa N, Kawanishi T, Kobayashi S, et al. A firstin-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood. 2016 Mar 31;127(13):1633–41.

32. Le Quellec S. Clinical evidence and safety profile of emicizumab for the management of children with Hemophilia A. Drug Des Devel Ther. 2020;14:469-481.

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33. Franchini M, Marano G, Pati I, Candura F, Profili S, Veropalumbo E, et al. Emicizumab for the treatment of haemophilia A: a narrative review. Blood Transfus. 2019;17(3):223228.

34. Bowyer A, Kitchen S, Maclean R. Effects of emicizumab on APTT, one-stage and chromogenic assays of factor VIII in artificially spiked plasma and in samples from haemophilia A patients with inhibitors. Haemophilia. 2020 May;26(3):536-542.

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APPENDIX 1. Appendix Table 1 No.

Database

Keywords

1

Ovid EMBASE (555)

2.

Pubmed (99)

(((((a, hemophilia[MeSH Terms]) OR (classic hemophilia[MeSH Terms])) OR (haemophilia[MeSH Terms])) OR (as, hemophilia[MeSH Terms])) AND ((emicizumab) OR (hemlibra))) AND (inhibitors)

3.

Scopus (265)

"classic hemophilia" OR "hemophilia a" OR "classic haemophilia" OR "haemophilia a" AND "emicizumab" OR "hemlibra" OR “ACE910” OR “RO5534262” OR “RG6013” AND "inhibitors"

4.

EBSCOhost (597)

hemophilia OR hemophilia a OR haemophilia OR haemophilia a OR classic hemophilia AND emicizumab OR hemlibra OR ACE910 OR RO5534262 OR RG6013 AND inhibitors

5.

Wiley Online Library (27)

"hemophilia A OR haemophilia A OR classic hemophilia" anywhere and "emicizumab OR hemlibra OR ACE910 OR RO5534262 OR RG6013" anywhere and "inhibitors" anywhere

1. exp hemophilia/ 2. exp haemophilia/ 3. exp classic hemophilia/ 4. exp factor VIII deficiency/ 5. hemophilia.mp,ti,ab,kw.

6. haemophilia.mp,ti,ab,kw.

7. hemophilia A.mp,ti,ab,kw.

8. classic hemophilia.mp,ti,ab,kw.

9. Factor VIII deficiency.mp,ti,ab,kw 10. exp emicizumab/ 11. hemlibra.mp,ti,ab,kw.

12. emicizumab.mp,ti,ab,kw.

13. ACE910.mp,ti,ab,kw.

14. RO5534262.mp,ti,ab,kw.

15. RG6013.mp,ti,ab,kw.

16. inhibitors.mp,ti,ab,kw.

17. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 18. 10 or 11 or 12 or 13 or 14 or 15 19. 16 and 17 and 18

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2. Appendix Table 2A– ROBINS-I

53

3. Appendix Table 2B– ROBINS-E

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Efficacy and Safety of Emicizumab for Treatment in Mild Hemophilia A Patient: A Systematic Review Naily Fairuz Salma El Milla, Fatima Az Zahra, Yuniarhiza Srikandi Fiandini

ABSTRACT Introduction Hemophilia is a blood clotting disorder due to a hereditary lack of blood coagulation factor. According to the Annual Global Survey 2019 of the World Federation of Hemophilia, the most cases of hemophilia is hemophilia A with different severity levels such as mild, moderate, and severe. Current treatment of hemophilia appears to have some issues such as mental and physical burden for the multiple intravenous infusions, requires dose adjustment and the development of FVIII inhibitors. Emicizumab prophylaxis is an emerging new treatment which has primary safety and efficacy. This study aims to evaluate the efficacy and safety of Emicizumab treatment for patients with mild hemophilia A. Methods A systematic review was conducted in accordance to PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) statement, using databases such as PubMed, ScienceDirect, and Scopus using the keywords “Emicizumab AND Mild Hemophilia”, ”Emicizumab AND Safety”, ”Emicizumab AND Efficacy”, and ”Mild Hemophilia AND Prophylaxis”.

Results The search yielded 11 studies, with a total of 1168 patients. Among 184 patients who had Emicizumab as a prophylaxis reduces bleeding rate in 93% patients and causes 0 bleeding in 67% patients. A single subcutaneous injection of Emicizumab in 40 healthy patients demonstrated no clinically significant changes of blood pressure, pulse rate, and body temperature. Moreover, Emicizumab recipient has no hypercoagulation risk even at the upper FVIII levels seen in mild hemophilia A, mild or no adverse effect, no thrombosis, and more cost-effective than rFVIIa. Conclusion Emicizumab as a routine prophylaxis in hemophilia treatment yielded promising primary efficacy and safety with mild or no adverse effect, thus demonstrated statistically significant and clinically meaningful reductions of bleeding rate. Further, this study hopes to help in regards to formulate strategies and comprehensive guidelines of mild hemophilia treatment.

Key words: Emicizumab, efficacy, safety, mild hemophilia A, systematic review INTRODUCTION According to the Annual Global Survey 2019 of the World Federation of Hemophilia, the worldwide identified patients of hemophilia is 195.263 patients, with most cases being represented

by Hemophilia A (157.517 patients). Hemophilia can be mild, moderate, or severe depending on how much of the clotting factor is in a person’s blood. International Society of Thrombosis and Haemostasis (ISTH) defines mild hemophilia A as the less severe type of hemophilia A with FVIII:C >5 IU d/L and <40 d/L.(1) As for the prevalence of all three severity categories, 39,52% Hemophilia A patients in high-income countries have mild disease, 14,64% have moderate disease,

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45,52% have severe disease and 0,31% unknown. 22,32% Hemophilia A patients in upper middleincome countries have mild disease, 22,66% have moderate disease, 43,76% have severe disease and 11,25 % unknown. 10,84% Hemophilia A patients in lower middle-income countries have mild disease, 21,60% have moderate disease, 45,29% have severe disease and 22,28% unknown.(2) Hemophilia is a blood clotting disorder due to a hereditary lack of blood coagulation factor. It is inherited in sex-linked recessive in the X chromosome (Xh), characterized by spontaneous bleeding in patients with no previous family or personal history of bleeding. Hemophilia inheritance is caused by a defect in one of the genes that is responsible in the production of blood coagulation factor VIII or IX. F VIII gene and F IX gene is located in the X chromosome and it is recessive.

According to that, this disease is carried by a woman (XXh) and manifest clinically in man (XhY).

It manifests clinically in a woman if there are 2 abnormal X chromosomes (XhXh).(3) The primary aim of care is to prevent and treat bleeding with the deficient clotting factor. The current treatment of hemophilia is based upon replacing the missing factor and can be done either as needed when bleeding episodes occur (episodic or on-demand therapy) or in a preventative manner (prophylaxis). Referral to a hemophilia treatment center (HTC) to facilitate treatment, intravenous infusion of factor VIII concentrate is most effective when infused within one hour of the onset of bleeding. Prophylaxis is the treatment by intravenous injection of factor concentrate in order to prevent anticipated bleeding. Prophylactic infusions of factor VIII concentrate three times a week or every other day to maintain factor VIII clotting activity higher than 1% nearly eliminates spontaneous bleeding and prevents chronic joint disease. Prior to the advent of factor therapy and prophylaxis, the lack of effective treatment for hemophilia resulted in a shortened lifespan and severe morbidity. (3)(4) The infusion of Factor VIII as therapy develops several issues to the hemophilia patients. One is mental and physical burden for the multiple intravenous infusions, and the other one is and requires dose or dosing frequency adjustment to maintain FVIII:C > 1%. Other than that, hemophilia A patients treated with factor VIII are found to develop FVIII inhibitors. Frequent intravenous administration of these agents is required because of their unstable hemostatic efficacy caused by short half-lives. In order to solve issues found in FVIII infusion, new treatments with more convenient, effective and safe. Emicizumab, is a recombinant, humanized, bispecific monoclonal antibody (mAb) that binds to FIX/FIXa and FX/FXa and mimics FVIIIa cofactor activity in the

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tenase complex. Emicizumab prophylaxis is a promising treatment to develop in mild hemophilia cases judging by the good result of research with severe hemophilia patients.(5) METHODS This systematic review was conducted in accordance to PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) statement. The literature search was conducted using databases such as PubMed, ScienceDirect, and Scopus using the keywords “Emicizumab AND Mild Hemophilia”, ”Emicizumab AND Safety”, ”Emicizumab AND Efficacy”, and ”Mild Hemophilia AND Prophylaxis”. The search were limited to studies with English or Bahasa Indonesia, as these were the language compatible with the authors. Studies were screened according to inclusion criteria as follows: (1) studies of emicizumab treatment on hemophilia, (2) not older than 2011, and (3) written in English or Bahasa Indonesia. Afterwards, exclusion criteria were also set, including (1) irretrievable full-text article, and (2) irrelevant article. Details of study search strategy are shown in Figure 1.

Figure 1. Diagram flow of literature search strategy

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RESULTS The process of literature searching and selection is illustrated in Figure 1. From the databases such as PubMed, ScienceDirect, and Scopus, 3559 studies were yielded. After duplicates were removed, titles and abstracts were screened, and full-text articles were then assessed. 149 studies were excluded due to irrelevant study variables, language restrictions, irretrievable full-text, and irrelevant outcomes. This resulted in a final of 11 studies to be included in qualitative synthesis, consisting of 4 clinical trials, 2 cohort studies, 1 meta analysis, 1 review, 2 RCTs (Randomized Controlled Trial), and 1 case report. Study characteristics are shown in Table 1.

Table 1. Study Characteristics

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DISCUSSION a. Analysis of the study Based on the studies included above, we analyze the safety and efficacy of emicizumab on patients with mild hemophilia which has a higher titre of FVII than severe hemophilia.

Safety of emicizumab on mild hemophilia patient Emicizumab has been approved by the US Food and Drug Association as a routine prophylaxis to prevent or reduce bleeding episodes in patients with blood clotting disorders such as hemophilia. Emicizumab itself has gone through a few clinical trials, namely HAVEN 1-4.

Throughout the 4 clinical trials, there were adverse effects observed on the patients with emicizumab treatment. The most frequent AE was injection site reaction (ISR), which happened on 23% of patients across the 4 trials.(6) This frequency is comparable to that seen in other medications which are given through subcutaneous injection. However, a study by Uchida, 2016 found that Emicizumab injected to healthy patients did not cause hypersensitivity reactions. On the HAVEN 1 trial, microangiopathies and thrombosis events, which were the most severe and unexpected adverse events were found in 3 patients who also received aPCC treatment for acute kidney injury.(7) This however did not happen to other 381 patients who experienced mild adverse effects.

Based on a study by Nakajima, 2020, the coagulation activity during the registered dosing of emicizumab is currently not a problem. Derived to the adjusted clot, Emicizumab does not seem to potentially cause hypercoagulation even when combined with FVII treatment. In mild or moderate hemophilia patients, Emicizumab does enhance coagulation function, and does not cause clot forming above the normal range. This proves that Emicizumab is safe in terms of patients with mild hemophilia, who have higher titre of FVIII.(8)

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Uchida 2016, the first-in-human phase 1 study, showed no clinically significant changes of blood pressure, pulse rate, and body temperature on 40 healthy subjects that were randomized to receive a single subcutaneous injection of Emicizumab.(5) A case was reported on a patient with mild hemophilia A and FVIII inhibitors. The patient received six months of Emicizumab as a prophylaxis treatment. The patient did a self-injection of 3 mg/kg Emicizumab one weekly for 4 weeks, and maintained the treatment. The patient did not show any puncture site adverse effect or thrombosis event.(9) Efficacy of emicizumab on mild hemophilia patient 400 participants were included in the efficacy analysis of the HAVEN 1-4 studies by Callaghan 2020. The study demonstrated statistically significant and clinically meaningful reductions in Annual Bleeding Rates during the Emicizumab prophylaxis and continued to decrease with maintained Emicizumab treatment after 24 weeks of prophylaxis. During weeks 121-144, the vast majority (99.4%) of participants had ≤ 3 treated target joint bleeds and 82.4% of participants reported zero treated bleeds.(10) Moreover, a study conducted by Mahlanggu in 2019 found that the infrequent emicizumab injection will have a direct impact on reducing treatment and disease burden of patients. Other than that, the effect of Emicizumab is also still clinically meaningful and real. Preliminary data from HAVEN 4 show consistently high efficacy and acceptable Emicizumab given at a dose of 6 mg/kg once a month.(6) Another study done on 184 adult and pediatric patients with hemophilia A showed that Emicizumab successfully reduced the number of bleeding rates on 93,5% patients while the number of patients with 0 bleeding was 67%. The study concluded that Emicizumab could improve the patients’ quality of life by reducing the number of hemorrhagic events.(11) A study by Yaoi, 2021 assessed the effect of Emicizumab on type 2N Von Willebrand disease patients, a disease phenotypically similar to mild hemophilia through perfusion chamber experiment with 100 µg/ml Emicizumab as the intervention. The study found that Emicizumab effectively enhanced high shear-induced thrombus formation in all 3 cases. Emicizumab is also found to be more convenient and stable in the circulation than FVIII products, which had been the gold standard for hemophilia patients.(12) b. Study strength and limitations The strength of this study lies in the comprehensive assessment of the safety and efficacy of Emicizumab on mild hemophilia A patient on a relatively large number of samples and a wide

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range of areas. However, since the studies for Emicizumab are currently still on-going, the Randomized Controlled Trials (RCT) study on mild hemophilia patients is still lacking. This could be the limitation of this paper, as this paper relies not only on studies conducted by RCT design but also case reports and reviews, which might not be as reliable. The inaccessible full-text articles and incompatible language also serve as limitations for this study. c. Future applications The result of this systematic review could be applied to formulate strategies in regards to Emicizumab use in mild hemophilia patients, thus improving the effectiveness and efficiency of mild hemophilia treatment. Based on the aforementioned result, we suggest further studies done with larger sample size of patients with mild hemophilia A to reduce bias of studies with small sample size. We also recommend more studies to be done regarding mild hemophilia, as there have been a considerable number of mild hemophilia cases but less studies regarding the therapy for mild hemophilia. And since Emicizumab as a bispecific monoclonal antibody has shown significant effect on hemophilia patient compared to coagulation factors products, it is also recommended that more studies regarding monoclonal antibody therapy should be done to improve the efficacy and safety of hemophilia treatment.

CONCLUSION Based on the results and discussion above, it could be concluded that Emicizumab is effective in reducing the bleeding rate in mild hemophilia patients. Emicizumab also improves blood clotting function and thrombus formation. While the coagulation-enhancing trait of Emicizumab could help significantly in severe hemophilia cases, questions arose as to whether Emicizumab is safe for mild hemophilia patients, who have a higher titre of FVIII. From the studies observed, there seem to be almost no report of hypercoagulation on mild hemophilia patients from Emicizumab treatment. Other than that, the adverse effects of Emicizumab treatment are mostly mild and could happen in other subcutan-admission drugs. Healthy patients who received Emicizumab in the clinical trials also showed no significant changes in vital sign or adverse effects.

This further proves the safety of Emicizumab treatment on mild hemophilia patients. However, studies with larger sample size are required in order to reduce the bias of studies conducted on small sample size. This study hopes to help in regards to formulate strategies and comprehensive guidelines to improve the efficacy and safety of mild hemophilia treatment.

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REFERENCES 1.

Makris M, Oldenburg J, Mauser-Bunschoten EP, Peerlinck K, Castaman G, Fijnvandraat K. The definition, diagnosis and management of mild hemophilia A: communication from the SSC of the ISTH. J Thromb Haemost [Internet]. 2018;16(12):2530–3. Available from: https://pubmed.ncbi.nlm.nih.gov/30430726/

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Annual Global Survey - World Federation of Hemophilia [Internet]. Available from: https://www.wfh.org/en/our-work-research-data/annual-global-survey

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Jameson JL. Harrison’s Principles of Internal Medicine. 20th ed. McGraw Hill Education.; 2018.

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Balkaransingh P, Young G. Novel therapies and current clinical progress in hemophilia A. Ther Adv Hematol [Internet]. 2018;9(2):49–61. Available from: http://journals.sagepub.com/doi/10.1177/2040620717746312

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Uchida N, Sambe T, Yoneyama K, Fukazawa N, Kawanishi T, Kobayashi S, et al. A firstin-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood. 2016;127(13):1633–41.

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Mahlangu J. Emicizumab for the prevention of bleeds in hemophilia A. Expert Opin Biol Ther. 2019;19(8):753–61.

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Langer AL, Etra A, Aledort L. Evaluating the safety of emicizumab in patients with hemophilia A. Expert Opin Drug Saf. 2018;17(12):1233–7.

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Nakajima Y, Nogami K, Yada K, Furukawa S, Noguchi-Sasaki M, Hirata M, et al.

Emicizumab Improves Ex Vivo Clotting Function in Patients with Mild/Moderate Hemophilia A. Thromb Haemost. 2020;120(6):968–76.

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Camelo RM, Casaretto ES, Figueiredo SS, Dantas-Silva N, Álvares-Teodoro J. SIX MONTHS OF EMICIZUMAB PROPHYLAXIS IN A WOMAN WITH MILD HEMOPHILIA A AND INHIBITOR: EFFECTIVENESS, ECONOMIC OUTCOME, AND SAFETY. Hematol Transfus Cell Ther. 2020;42:76–7.

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Callaghan MU, Negrier CG, Paz-Priel I, Chang TY-C, Chebon S, Lehle M, et al. Longterm outcomes with emicizumab prophylaxis for hemophilia A with/without FVIII inhibitors from the HAVEN 1-4 studies. Blood. 2020;

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Pereira CMSB, Belo G V, de Almeida CR, de Sousa BM, de Andrade MIMDCDES, dos Santos CT, et al. PO292 Emicizumab: The Efficacy of Monoclonal Antibodies In

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Haemophylia A Prophylaxis. Glob Heart. 2018;13(4):442–3.

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Yaoi H, Shida Y, Kitazawa T, Shima M, Nogami K. Activated factor VIII-mimicking effect by emicizumab on thrombus formation in type 2N von Willebrand disease under high shear flow conditions. Thromb Res. 2021;198:7–16.

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Efficacy, Safety, and Immunogenicity of Rurioctocog Alfa Pegol (BAX 855) for Prophylactic Treatment in Previously Treated Patients with Severe Haemophilia A: A Systematic Review and Meta-Analysis of Clinical Trials Bendix Samarta Witarto, Visuddho, Andro Pramana Witarto ABSTRACT Introduction: This study aims to evaluate the efficacy, safety, and immunogenicity in a newlydeveloped prophylactic agent, rurioctocog alfa pegol, for previously treated patients with severe haemophilia A. Method: This systematic review and meta-analysis were conducted based on PRISMA statement involving five databases: PubMed, Scopus, Cochrane Library, Wiley Online Library, and CINAHL Plus (through EBSCOhost). Study qualities were assessed using the MINORS and Modified Jadad scales.

Result: Four studies involving 517 previously treated severe haemophilia A patients were included in this study. The pooled mean total ABR and haemostatic efficacy are 2.59 (95% CI = 2.04–3.14) and 92% (95% CI = 85%–97%), respectively. Only 30 (2.3%) non-serious and one (1.4%) serious adverse events were considered related to treatment. No development of FVIII inhibitory antibodies among all patients was observed at the end of the studies. None of the developed binding antibodies to FVIII, PEG-FVIII, or PEG was correlated to treatment efficacy and safety.

Discussion: The pooled mean total ABR of rurioctocog alfa pegol is lower compared to several conventional recombinant FVIIIs which indicates its advantage.

Conclusion: Rurioctocog alfa pegol appears to be safe, effective, and have low immunogenicity for prophylactic treatment in previously treated patients with severe haemophilia A.

Keywords: efficacy, safety, immunogenicity, prophylaxis, rurioctocog alfa pegol, BAX 855, haemophilia A

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INTRODUCTION Haemophilia A is a rare, X-linked recessive, congenital bleeding disorders caused by mutations or defects in the factor VIII (FVIII)-producing genes.1 Those mutations manifest as a congenitally absence or decrease of the FVIII, an important pro-coagulant cofactor in the bleeding haemostasis.2 Haemophilia A occurs more commonly than haemophilia B, in 1 out of 5,000 male live births in the world and also accounts for 80% of overall haemophilia cases.2,3 Haemophilia A may be further classified into severe, moderate, and mild, based on the FVIII levels.1 The severe form of haemophilia A is defined as having FVIII levels <1% of normal.3 Patients with severe haemophilia often present with internal bleeding, especially in the joints and soft tissues. Joint and soft tissue bleeding, along with painful feeling, may restrict patients from their daily activities due to the restriction on their range of motions.3,4 If this bleeding continues without any interventions, haemophilic patients can progress further to haemophilic arthropathy.3 The current management of haemophilia A relies on two options: (1) episodic or ondemand FVIII replacement if the patients present with any bleedings to prevent further bleeding or (2) prophylactic FVIII treatment to maintain the FVIII levels and prevent any future bleedings.5 However, option (1) was no longer recommended as a primary long-term management due to no alteration found in its natural disease course.6 To date, standard of care for haemophilia A, especially the severe form, is still relying on a regular prophylactic FVIII replacement therapy which administered intravenously. More than 30% of patients with haemophilia A may develop ‘inhibitors’ or referred to as neutralizing anti-drug antibodies to the standard prophylactic treatment which has a high immunogenicity in inducing its formation.3 Thus, use of extended half-life and safer prophylactic agents may be beneficial in reducing the daily treatment burden and in the same time, those agents may maintain better clinical presentations and improve the treatment efficacy.7 One of the previously mentioned agents is rurioctocog alfa pegol or also known as BAX 855, a 3rd generation recombinant FVIII (rFVIII) with a modification in its polyethylene glycol (PEG) component.8 This modification was intended to prolong the half-life of rFVIII by 1.4–1.5 fold to the original rFVIII, thereby reducing the administration frequency and maintaining a better bleeding haemostasis of the haemophilic patients.8,9 Yet, to the best of our knowledge, there is no pooled studies assessing the efficacy, safety, and immunogenicity of rurioctocog alfa pegol. Therefore, this study aims to evaluate these three important characteristics in a newly-developed prophylactic agent, rurioctocog alfa pegol, for previously treated patients with severe haemophilia A. 2 65

METHODS Data Search Strategy This systematic review and meta-analysis were conducted based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.10 Computerized and systematic data searching of relevant studies was conducted in PubMed, Scopus, Cochrane Library, Wiley Online Library, and CINAHL Plus (through EBSCOhost) from inception to 16 February 2021. Keywords were constructed based on Medical Subject Headings (MeSH) terms and other additional terms listed as follows: (("Rurioctocog Alfa Pegol") OR ("Bax 855") OR ("TAK‐660") OR ("SHP660") OR ("Adynovate") OR (“Adynovi”)) AND (("hemophilia A") OR ("haemophilia A") OR ("factor VIII deficiency") OR ("factor 8 deficiency") OR ("classic hemophilia") OR (“classic haemophilia”)). The search was limited to human participants and no language restriction were applied.

Eligibility Criteria The inclusion criteria of this study were as follows: (1) study design of clinical trial; (2) study population consists of previously treated severe haemophilia A patients with or without healthy subjects as control; (3) rurioctocog alfa pegol as a prophylactic treatment intervention; and (4) the reported outcomes were any of the annualized bleeding rate (ABR), number of patients with zero bleeding, haemostatic efficacy, adverse events (AEs), number of deaths, development of factor VIII (FVIII) inhibitors, and/or events of binding antibodies to FVIII, pegylated (PEG)-FVIII, or PEG. Whilst, the exclusion criteria were as follows: (1) irrelevant titles and abstracts; (2) irretrievable full-text articles; (3) incompatible language (language other than English and Indonesian); and (4) inappropriate study method.

Data Extraction and Quality Assessment Three investigators (BS, V, AP) screened the literatures independently. Any disagreements were resolved in a consensus involving all authors. The following relevant data were extracted from the included studies: (1) author and year of publication; (2) study location; (3) clinical trial number; (4) study design; (5) total patients included for prophylactic treatment, gender, and age; (6) definition of target joint (TJ); (7) regimen type; (8) patient characteristics (with or without target joints); (9) total patients in per-protocol analysis set (PPAS) or analyzed for ABR based on regimen type and target joints; (10) outcomes related to efficacy (total ABR, spontaneous ABR, injury ABR, joint ABR, number of patients with zero bleeding during treatment, and/or haemostatic efficacy); (11) outcomes related to safety (number of patients 3 66

with AEs, total AEs, AEs considered related to treatment, and/or number of deaths); and/or (12) outcomes related to immunogenicity (development of FVIII inhibitors and/or events of binding antibodies to FVIII, PEG-FVIII, or PEG). The quality assessment of the included studies was performed using the Methodological Index for Non-Randomized Studies (MINORS) scale11 for non-randomized clinical trials and Modified Jadad scale12 for randomized clinical trials. Studies with a MINORS score of ≥ 12 or a Jadad score of ≥ 4 were considered as high-quality studies. Otherwise, studies were considered as low-quality studies.

The quality assessment was conducted by three reviewers (BS, V, AP) collaboratively through a group discussion, and final decision was taken based on the agreement of all reviewers.

Statistical Analysis Statistical analyses were performed using the latest version of OpenMeta[Analyst] from the Brown University Evidence-Based Practice Center13 and MetaXL 5.3 (EpiGear International, Sunrise Beach, Australia). Single-arm meta-analysis of mean and standard deviation values was performed for four different efficacy outcomes: (1) total ABR; (2) spontaneous ABR; (3) injury ABR; and (4) joint ABR. Whilst, meta-analysis of proportions was performed for two different efficacy outcomes: (1) zero bleeding prevalence and (2) haemostatic efficacy with the rating of excellent or good. Subgroup analysis based on target joints (TJs) for total ABR was also performed. For the purpose of single-arm meta-analyses, 95% confidence intervals were transformed into standard deviation values based on a method suggested by the Cochrane Handbook in Chapter 6.14 The t-value to calculate standard deviations for studies with samples less than 100 were determined using Microsoft Excel (Microsoft, Redmond, WA, USA).

Heterogeneity between studies was assessed with a chi-square test (Cochran’s Q statistic) and quantified with the Higgins’ I2 statistic. P-value < 0.1 from the chi-square test indicated a statistical heterogeneity, whereas level of heterogeneity was determined using I2 values. I2 < 25% was considered as low heterogeneity, 25%– 75% as moderate heterogeneity, and I2 > 75% as high heterogeneity. If the I2 value was greater than 50%, a random-effect model was used for the meta-analysis. Otherwise, a fixed-effect model was applied. Publication bias assessment using funnel plot was not performed due to the small number of the included studies (less than 10).

4 67

RESULT Overview of Literature Search The initial search of this study yielded a total of 232 studies obtained from PubMed, Scopus, Cochrane Library, Wiley Online Library, and CINAHL Plus database in EBSCOhost.

Of those, 174 studies were screened by titles and abstracts after duplicates removal. 23 were fully reviewed based on the eligibility criteria and 19 of these were excluded due to: studies with a subgroup analysis of other included studies (n = 2); not reporting outcome of interest (n = 7); or conference abstracts or posters that had been published in an included full-text article (n = 10). Finally, four clinical trials5,7,9,15 were included in this systematic review and metaanalysis. The overall study selection process is illustrated in Figure 1.

Figure 1. PRISMA flow diagram of the study selection process.

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Characteristics of the Included Studies Table 1 provides a summary of the studies included in the systematic review. The four uncontrolled clinical trials5,7,9,15 included a total of 517 previously treated severe haemophilia A patients for prophylactic treatment, with the overall mean ± SD age of 23.9 ± 14.8. Only two studies by Mullins et al.9 and Chowdary et al.7 included a female patient. The trials were published between 2015 and 2020, and were all multicentered with the range number of 11 to 23 countries. 37,9,15 out of 4 studies were a phase 3 clinical trial. One study by Konkle et al.5 was a phase 2/3 trial. All of the studies were non-randomized trial with the exception of Klamroth et al.15 Definition of target joint was the same across all studies except for Klamroth et al.15 There were two different prophylactic regiment type used between the studies (twice weekly and pharmacokinetic (PK)-guided). Details of the quality assessment using MINORS and Modified Jadad scale are provided in Table 2. All non-randomized studies5,7,9 (were considered high in quality, whereas the randomized study by Klamroth et al.15 was considered low in quality.

6 69

Table 1. Characteristics of the Included Studies.

Author, Year

Study Location

Age*

Definition of Target Joint

66 (1)

6.0 ± 2.7

A joint (ankles, knees, hips or elbows) with ≥ 3 spontaneous bleeding episodes in any consecutive 6-month period

Phase 3b, openChowdary NCT01945593 label, nonMulticenter et al., (CONTINUATION randomized, (23 countries) 20207 study) uncontrolled clinical trial

216 (1)

22.8 ± 15.7

A joint with ≥ 3 spontaneous bleeding episodes in any consecutive 6-month period

Phase 2/3, openlabel, nonrandomized, uncontrolled clinical trial

120 (0)

28.7 ± 9.0

A joint with ≥ 3 spontaneous bleeding episodes in any consecutive 6-month period

57 (0)

31.0 ± 13.6

58 (0)

31.6 ± 12.9

Mullins et Multicenter al., 20179 (11 countries)

Clinical Trial Number

Study Design

NCT02210091

Phase 3, openlabel, nonrandomized, uncontrolled clinical trial

Total Patients Included for Prophylactic Treatment (F)

NCT01736475 Konkle et Multicenter (PROLONG-ATE al., 20155 (20 countries) study)

Phase 3, openKlamroth Multicenter NCT02585960 label, randomized, et al., (22 countries) (PROPEL study) uncontrolled 202015 clinical trial

A joint with ≥ 4 spontaneous bleeding episodes in any consecutive 6-month period

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Continuation of Table 1.

Author, Year

Total Patients in Regimen Patient PPAS or Analyzed Type Characteristics for ABR based on Regimen Type & TJ

Twice Mullins et weekly al., 20179 prophylaxis Twice weekly Chowdary prophylaxis et al., 20207 PK–guided prophylaxis

Konkle et al., 20155

Twice weekly prophylaxis

PK–guided prophylaxis Klamroth (1–3%) et al., 202015 PK–guided prophylaxis (8–12%)

With TJs

14

Total ABR Mean or Mean (95% CI)

Spontaneous ABR

SD

3.54 4.11 (1.89–6.64)

Mean or Mean (95% CI)

SD

Injury ABR Mean or Mean (95% CI)

52

2.92 3.99 (2.02–4.24)

With and without TJs

186

2.23 1.20 3.06 2.33 (1.85–2.69) (0.92–1.56)

With TJs

32

2.64 1.87 (1.70–4.08) 3

4.9

SD

1.23 2.26 (0.96–1.58) N/A

25

Mean or Mean (95% CI)

1.20 2.09 1.10 2.22 2.93 2.58 (0.92–1.56) (1.49–2.93) (0.64–1.91)

Without TJs

With and without TJs

SD

Joint ABR

N/A

0.96 0.92 (0.54–1.71) 2.2

1.40 0.99 (0.91–2.17)

3.7 N/A

2.2

3.2

1.2

2.4

N/A

Without TJs

69

3.7

4.4

1.9

2.9

With and without TJs

52

2.8

3

1.7

2.5

1.1

1.9

1.8

2.2

With and without TJs

43

1.2

2.4

0.6

1.5

0.7

1.7

0.8

2.3

8 71

Continuation of Table 1.

Haemostatic Efficacy Author, Year

Mullins et al., 20179

Chowdary et al., 20207

Konkle et al., 20155

Klamroth et al., 202015

Patients with Zero Bleeding during Treatment

Rating

Number of Non-SAEs SAEs Number of Total Patients with Total Number of Considered Total Considered Deaths Events number Any AEs NonPatients Related to SAEs Related to of bleeds (Non-SAEs SAEs with SAEs Treatment Treatment and SAEs)

25

Excellent Good Fair None Not reported

34 29 4 0 3

51

Excellent Good Fair None Not reported

438 368 48 4 52

40

Excellent / Good Fair / None / Not reported

498

70

N/A

43

152

0

3

4

0

0

910

174

786

20

33

52

0

1 (considered unrelated to treatment)

518

73

166

7

5

5

0

0

34

97

2

3

4

0

0

36

98

1

4

5

1

0

20

24 36

Adverse Events

N/A

N/A

9 72

Continuation of Table 1.

Author, Year

Mullins et al., 20179

Development of FVIII Inhibitory Antibodies

No subjects developed inhibitory antibodies

Development of Binding Antibodies to FVIII / PEG-FVIII / PEG during Study - 16 developed binding antibodies to FVIII, PEG-FVIII, or PEG prior to exposure, but turned negative while on treatment - 5 developed antibodies to PEG-VIII during treatment (2 were transient; 2 were only at study completion; and 1 was with decreasing titre) - No development of persistent binding antibodies that affected efficacy or safety

Chowdary No subjects developed et al., inhibitory antibodies 20207

- 5 developed binding antibodies to FVIII - 8 developed binding antibodies to PEG-FVIII - Only one persisted to the study end without any notable safety or efficacy findings

Konkle et al., 20155

No subjects developed inhibitory antibodies

- 7 developed transient binding antibodies to PEG-FVIII or FVIII - No subjects developed persistent binding antibodies to FVIII, PEG-FVIII, or PEG - Binding antibodies that were detected could not be correlated to impaired treatment efficacy or related AEs

No subjects developed inhibitory antibodies

- 3 had single positive binding antibodies to PEG-FVIII and PEG at baseline only - Binding antibodies that were detected could not be correlated to impaired treatment efficacy or related AEs

1 subject (resolved at the study end)

- 8 developed transient binding antibodies to PEG-FVIII or FVIII. - Binding antibodies that were detected could not be correlated to impaired treatment efficacy or related AEs

Klamroth et al., 202015

*Data are presented in mean ± SD. ABR, annualized bleeding rate; CI, confidence interval; F, female; FVIII, factor VIII; N/A, not available or not applicable; Non-SAEs, non-serious adverse events; PEG, pegylated; PK, pharmacokinetic; PPAS, per-protocol analysis set; SAEs, serious adverse events; SD, standard deviation; TJ(s), target joint(s).

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Table 2. MINORS Scale and Modified Jadad Scale Quality Assessment MINORS Scale Items

Modified Jadad Scale

Mullins et Chowdary et Konkle et al., 20179 al., 20207 al., 20155

A clearly stated aim

2

2

2

Inclusion of consecutive patients

2

2

2

Prospective collection of data

2

2

2

Endpoints appropriate to the aim of the study

2

2

2

Unbiased assessment of the study endpoint

0

0

0

Follow-up period appropriate to the aim of the study

2

2

2

Loss to follow up less than 5%

2

2

2

Prospective calculation of the study size

1

1

Klamroth et al., 202015

Items

Randomization

1

Concealment

0

Blinding

0

Withdrawal or drop-out

1

1

Results

Results

Total Score

13

13

13

Total Score

2

Study Quality

High

High

High

Study Quality

Low

MINORS, Methodological Index for Non-Randomized Studies.

Efficacy Outcomes Total ABR A total of 473 haemophilia A patients from the four studies5,7,9,15 were included in this subgroup single-arm meta-analysis (Figure 2) to calculate pooled estimate of mean total ABR after rurioctocog alfa pegol treatment. A random-effect model was used for the analysis since heterogeneity among studies was greater than 50% (I2 = 67%). The overall pooled mean total ABR is 2.59 (95% CI = 2.04–3.14).

Two studies5,9 reporting mean total ABR individually for patients with target joints (TJs) and without target joints were included in Subgroup 1 and Subgroup 2, respectively. The 11 74

pooled mean total ABR in patients with TJs is 3.21 (95% CI = 1.87–4.54). Whilst, the pooled mean total ABR in patients without TJs is 3.33 (95% CI = 2.56–4.09). Subgroup 3 included other two studies7,15 with combined mean total ABR for patients with and without TJs. The pooled value is 2.21 (95% CI = 1.57–2.84).

Total ABR (95% C.I.)

Studies Mullins et al., 2017 (TJs) Konkle et al., 2015 (TJs) Subgroup 1 (I2 = 0%, P = 0.70)

3.54 (1.39, 5.69) 3.00 (1.30, 4.70) 3.21 (1.87, 4.54)

Mullins et al., 2017 (no TJs) Konkle et al., 2015 (no TJs) Subgroup 2 (I2 = 3.56%, P = 0.31)

2.92 (1.84, 4.00) 3.70 (2.66, 4.74) 3.33 (2.56, 4.09)

Chowdary et al., 2020 (twice weekly) Chowdary et al., 2020 (PK−guided) Klamroth et al., 2020 (PK−guided 1−3%) Klamroth et al., 2020 (PK−guided 8−12%) Subgroup 3 (I2 = 72.59%, P = 0.01)

2.23 (1.79, 2.67) 2.64 (1.91, 3.37) 2.80 (1.98, 3.62) 1.20 (0.48, 1.92) 2.21 (1.57, 2.84)

Overall (I2 = 66.86%, P = 0.00)

2.59 (2.04, 3.14) 1

2

3 Total ABR

4

5

Figure 2. Forest Plot of Subgroup Single-Arm Meta-Analysis for Total ABR

Spontaneous ABR The four studies5,7,9,15 with a total of 473 haemophilia A patients were included in this meta-analysis (Figure 3A). Heterogeneity between studies was greater than 50% (I2 = 64%); therefore, a random-effect model was used for the analysis. Result of the pooled mean spontaneous ABR is 1.24 (95% CI = 0.91–1.58).

Injury ABR A total of 161 haemophilia A patients from two studies9,15 that reported mean injury ABR were included in this meta-analysis (Figure 3B). A random-effect model was used for the analysis since heterogeneity was greater than 50% (I2 = 80%). The pooled analysis data of mean injury ABR is 1.26 (95% CI = 0.53–1.99).

Joint ABR A total of 473 haemophilia A patients from the four studies5,7,9,15 were evaluated in this subgroup analysis of injury ABR (Figure 3C). The heterogeneity across studies was low (I2 = 0%); therefore, a fixed-effect model was used for the analysis. The pooled mean injury ABR is 1.31 (95% CI = 1.12–1.50).

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A Spontaneous ABR (95% C.I.)

Studies Mullins et al., 2017 Chowdary et al., 2020 (twice weekly) Chowdary et al., 2020 (PK−guided) Konkle et al., 2015 (TJs) Konkle et al., 2015 (no TJs) Klamroth et al., 2020 (PK−guided 1−3%) Klamroth et al., 2020 (PK−guided 8−12%)

1.16 (0.62, 1.70) 1.20 (0.87, 1.53) 0.96 (0.60, 1.32) 2.20 (0.92, 3.48) 1.90 (1.22, 2.58) 1.70 (1.02, 2.38) 0.60 (0.15, 1.05)

Overall (I2 = 63.93%, P = 0.01)

1.24 (0.91, 1.58) 0.5

1

1.5 2 Spontaneous ABR

2.5

2 2.5 Injury ABR

3

3

B Studies

Injury ABR (95% C.I.)

Mullins et al., 2017 Klamroth et al., 2020 (PK−guided 1−3%) Klamroth et al., 2020 (PK−guided 8−12%)

2.09 (1.38, 2.80) 1.10 (0.58, 1.62) 0.70 (0.19, 1.21)

Overall (I2 = 79.68%, P < 0.01)

1.26 (0.53, 1.99) 0.5

1

1.5

3.5

4

C Studies

Joint ABR (95% C.I.)

Mullins et al., 2017 Chowdary et al., 2020 (twice weekly) Chowdary et al., 2020 (PK−guided) Konkle et al., 2015 (TJs) Konkle et al., 2015 (no TJs) Klamroth et al., 2020 (PK−guided 1−3%) Klamroth et al., 2020 (PK−guided 8−12%)

1.10 (0.48, 1.72) 1.23 (0.91, 1.55) 1.40 (1.01, 1.79) 2.20 (1.09, 3.31) 1.20 (0.63, 1.77) 1.80 (1.20, 2.40) 0.80 (0.11, 1.49)

Overall (I2 = 0%, P = 0.22)

1.31 (1.12, 1.50) 0.5

1

1.5 2 Joint ABR

2.5

3

Figure 3. Forest Plots of Single-Arm Meta-Analysis. (A) Mean Spontaneous ABR, (B) Mean Injury ABR, (C) Mean Joint ABR.

Zero Bleeding Prevalence All four studies5,7,9,15 were included in this meta-analysis of zero bleeding prevalence (Figure 4A). A random-effect model was used due to the heterogeneity of the data (I2 = 88%).

The pooled prevalence result is 40% (95% CI = 27%–54%).

Haemostatic Efficacy Three studies5,7,9 that reported haemostatic efficacy with the rating of excellent or good were included in this meta-analysis (Figure 4B). A random-effect model was used due to the heterogeneity across studies (I2 = 93%). The pooled haemostatic efficacy is 92% (95% CI = 85%–97%).

13 76

A

Studies Mullins et al., 2017 Chowdary et al., 2020 Studies Konkle et al., 2015 Mullins al., 2017 Klamroth et al.,et2020 (PK-guided 1-3%) Chowdary et al., 2020 Klamroth et al., 2020 (PK-guided 8-12%)

Zero Bleeding (95% CI) Weight (%) 0.38 (0.26, 0.50) 19.5 0.24 (0.18, 0.30) 21.9 Zero Bleeding (95% Weight 0.40CI) (0,30, 0.49) (%) 20.6 0.38 (0.26, 0.50) 19.5 0.42 (0.30, 0.55) 19.0 0.24 (0.18, 0.30) 21.9 0.62 (0,49, 0.74) 19.1 0.40 (0,30, 0.49) 20.6

Konkle et al., 2015 Klamroth et al., 2020 (PK-guided 1-3%) Overall 2 Klamroth et al., 2020 (PK-guided 8-12%) Q = 33.20, P = 0.00, I = 88%

0.42 (0.30, 0.55) 19.0 0.40 (0.27, 0.54) 0.62 (0,49, 0.74) 19.1 0.2

Overall Q = 33.20, P = 0.00, I = 88%

0.4

0.6 0.40 (0.27, 0.54)

100.0

100.0

2

0.2

B

0.4 0.6 Zero Bleeding

Studies Mullins et al., 2017

Haemostatic Efficacy (95% CI) Weight (%) Zero Bleeding

0.90 (0.82, 0.96)

27.0

Chowdary et al., 2020

0.89 (0.86, 0.91)

36.9

Konkle et al., 2015

0.96 (0.94, 0.98)

36.1

Overall

0.92 (0.85, 0.97)

100.0

Q = 28.35, P = 0.00, I2 = 93% 0.8 0.9 1 Haemostatic Efficacy

Figure 4. Forest Plots of Meta-Analysis of Proportions. (A) Zero Bleeding Prevalence, (B) Haemostatic Efficacy (Excellent or Good).

Safety Outcomes A total of 1,299 non-serious adverse events (non-SAEs) occurred during the four studies.5,7,9,15 However, only 30 (2.3%) of them were considered related to rurioctocog alfa pegol treatment. Whilst, a total of 70 serious adverse events (SAEs) were observed in the four studies and only one (1.4%) of them – as reported by Klamroth et al.15 – were considered related to treatment. Among all studies, only one death case was reported by Chowdary et al.7 and was not considered to be related to rurioctocog alfa pegol treatment.

Immunogenicity Outcomes Three studies5,7,9 reported no development of FVIII inhibitory antibodies among all patients. Klamroth et al.15 reported one patient with development of FVIII inhibitory antibodies and was resolved at the end of the study. Development of binding antibodies to either FVIII, PEG-FVIII, or PEG among patients were detected in 52 patients from the four studies.

14 77

However, none of them was correlated to impaired rurioctocog alfa pegol treatment efficacy and AEs.

DISCUSSION This study was the first far-reaching, single-arm meta-analysis which evaluate the efficacy, safety, and immunogenicity of the newly developed recombinant FVIII (rFVIII) product with prolonged half-life, rurioctocog alfa pegol, as a prophylactic treatment for previously treated patients with severe haemophilia A. Rurioctocog alfa pegol or BAX 855 is a pegylated full-length rFVIII product designed to reduce the frequency of prophylactic infusions while maintaining haemostatic effficacy in patients with haemophilia.16,17 This study revealed long-term safety and efficacy which were consistent with the study of rurioctocog alfa pegol for perioperative haemostasis in haemophilia A patients18,19, also with the previous parent studies.20–22 The overall pooled mean total ABR of rurioctocog alfa pegol is lower compared to the several conventional rFVIIIs (Advate®, Xyntha®, Novoeight®, REFACTO®) with their total ABR ranged from 3.3 to 6.5.23 This indicated that rurioctocog alfa pegol has advantages over conventional recombinant antihemophilic FVIII. The findings of ABR were also similar for spontaneous and injury related bleeding. Any reduction in joint bleeds is considered as an improvement in quality of life for haemophilia patients.24 Decreased bleeding in joints thereby shows better joint health, activity, and satisfaction for the patients.25 The mean ABR for patients with target joints was similar to those without target joints which showed that rurioctocog alfa pegol had equal efficacy for both group of patients. Moreover, all of the studies reported that rurioctocog alfa pegol had good and excellent haemostatic efficacy. This data was comparable with results reported for other rFVIII preparations.26–29 The efficacy of rurioctocog alfa pegol was also supported by the finding on the pooled zero bleeding prevalence.

This study also demonstrated the safety of rurioctocog alfa pegol in patients by assessing the non-SAEs and SAEs. A study by Brand et al.18 using rurioctocog alfa pegol for perioperative haemostasis in patients with haemophilia A also revealed the tolerable and safety with minor findings in both non-SAEs and SAEs. Most of the adverse reactions in our findings were mild and this was also consistent with the US Food & Drug Administration approval of rurioctocog alfa pegol use for children and adults with haemophilia A.30 Additionally, rFVIII usage decreased the risk of blood borne infections and restored longer life expectancies.31 This

15 78

extended half-life recombinant also improves adherence to prophylactic regimen which reduces the burden of treatment.32,33 The development of FVIII inhibitors is a significant issue in patients treated with blood coagulation factor products. The development of neutralizing alloantibodies against FVIII can reduce the treatment benefits.34,35 Current available studies reveal some predictor of inhibitor development, but the predictive power remains low.36,37 Some studies also reported either transient or persistent inhibitor development in patients treated with plasma-derived FVIII.38,39 However, our findings showed no development of persistent FVIII inhibitory antibodies. There were some development of binding antibodies observed. However, this development did not interfere with rurioctocog alfa pegol treatment safety and efficacy until the end of the study.

Nevertheless, high heterogeneity existed in these included studies. We used the random-effect models to minimize the bias. Substantial efforts were made to explore the possible source for heterogeneity, revealing that different dose regimens and prior prophylactic drug for treatment could responsible for the high heterogenity. For zero bleeding prevalence (Figure 4A), a difference was observed among studies that used different dose regimens.

Different dose regimens were considered because pharmacokinetic profile, target of FVIII level, and age group varied among the patients.6 Several other limitations exist in this meta-analysis. First, our present study only included single-arm clinical trials. The highest possible quality cannot be ensured because the lack of control arms. However, since haemophilia is a rare genetic disease, comparison with a control arm receiving prophylaxis with other conventional FVIII products was not recommended, as stated by the regulatory guidance.40 Second, diverse prior prophylactic strategy in patients before switching to rurioctocog alfa pegol may affect the treatment outcomes. Finally, only few published studies can be evaluated in this meta-analysis since rurioctocog alfa pegol is a newly-developed drug. However, these limitations were partly diminished by the multicentered settings of the included studies.

CONCLUSION Our study suggests that rurioctocog alfa pegol appears to be safe, effective, and have low immunogenicity for treating severe haemophilia A in previously treated patients. The results support the use of rurioctocog alfa pegol as a new extended half-life recombinant FVIII for prophylactic treatment. Larger studies are warranted to further confirm our findings.

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Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: Results from the phase 3 PROPEL study. Blood. 2020; 16. Mahlangu J, Young G, Hermans C, Blanchette V, Berntorp E, Santagostino E. Defining extended half-life rFVIII—A critical review of the evidence. Haemophilia.

2018;24(3):348–58.

17. Tiede A. Half-life extended factor VIII for the treatment of hemophilia A. J Thromb Haemost. 2015;13(S1):S176–9.

18. Brand B, Gruppo R, Wynn TT, Griskevicius L, Lopez Fernandez MF, Chapman M, et al.

Efficacy and safety of pegylated full-length recombinant factor VIII with extended halflife for

perioperative haemostasis

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Haemophilia.

2016;22(4):e251–8.

19. Gruppo R, López-Fernández MF, Wynn TT, Engl W, Sharkhawy M, Tangada S. Perioperative haemostasis with full-length, PEGylated, recombinant factor VIII with extended half-life (rurioctocog alfa pegol) in patients with haemophilia A: Final results of a multicentre, single-arm phase III trial. Haemophilia. 2019;25(5):773–81.

20. Auerswald G, Thompson AA, Recht M, Brown D, Liesner R, Guzmán-Becerra N, et al.

Experience of advate rahf-pfm in previously untreated patients and minimally treated patients with haemophilia a. Thromb Haemost. 2012;107(6):1072–82.

21. Khair K, Mazzucconi MG, Parra R, Santagostino E, Tsakiris DA, Hermans C, et al. Pattern of bleeding in a large prospective cohort of haemophilia A patients: A three-year followup of the AHEAD (Advate in HaEmophilia A outcome Database) study. Haemophilia.

2018;24(1):85–96.

22. Shapiro AD, Schoenig-Diesing C, Silvati-Fidell L, Wong WY, Romanov V. Integrated analysis of safety data from 12 clinical interventional studies of plasma- and albumin-free 18 81

recombinant factor VIII (rAHF-PFM) in haemophilia A. Haemophilia. 2015;21(6):791–8.

23. Iorio A, Krishnan S, Myrén KJ, Lethagen S, McCormick N, Yermakov S, et al. Indirect comparisons of efficacy and weekly factor consumption during continuous prophylaxis with recombinant factor VIII Fc fusion protein and conventional recombinant factor VIII products. Haemophilia. 2017;23(3):408–16.

24. Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, et al.

Guidelines for the management of hemophilia. Haemophilia. 2013;19(1):1–47.

25. Manco-Johnson MJ, Lundin B, Funk S, Peterfy C, Raunig D, Werk M, et al. Effect of late prophylaxis in hemophilia on joint status: a randomized trial. J Thromb Haemost.

2017;15(11):2115–24.

26. Kulkarni R, Karim FA, Glamocanin S, Janic D, Vdovin V, Ozelo M, et al. Results from a large multinational clinical trial (guardianTM3) using prophylactic treatment with turoctocog alfa in paediatric patients with severe haemophilia A: Safety, efficacy and pharmacokinetics. Haemophilia. 2013;19(5):698–705.

27. Young G, Mahlangu J, Kulkarni R, Nolan B, Liesner R, Pasi J, et al. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. J Thromb Haemost. 2015;13(6):967–77.

28. Mahlangu J, Powell JS, Ragni M V., Chowdary P, Josephson NC, Pabinger I, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood.

2014;123(3):317–25.

29. Lentz SR, Misgav M, Ozelo M, Šalek SZ, Veljkovic D, Recht M, et al. Results from a large multinational clinical trial (guardianTM1) using prophylactic treatment with turoctocog alfa in adolescent and adult patients with severe haemophilia A: Safety and efficacy. Haemophilia. 2013;19(5):691–7.

30. U.S. Food and Drug Administration (FDA). Adynovate [Bula]. 2016;1–27.

31. Castro HE, Briceño MF, Casas CP, Rueda JD. The history and evolution of the clinical effectiveness of haemophilia type A treatment: A systematic review. Indian J Hematol Blood Transfus. 2014;30(1):1–11.

32. Pipe SW. New therapies for hemophilia. Hematol (United States). 2016;2016(1):650–6.

33. Schrijvers LH, Uitslager N, Schuurmans MJ, Fischer K. Barriers and motivators of adherence to prophylactic treatment in haemophilia: A systematic review. Haemophilia.

2013;19(3):355–61.

34. Santagostino E, Young G, Carcao M, Mannucci PM, Halimeh S, Austin S. A contemporary look at FVIII inhibitor development: still a great influence on the evolution of hemophilia 19 82

therapies. Expert Rev Hematol. 2018;11(2):87–97.

35. Garagiola I, Palla R, Peyvandi F. Risk factors for inhibitor development in severe hemophilia a. Thromb Res. 2018;168(March):20–7.

36. Spena S, Garagiola I, Cannavò A, Mortarino M, Mannucci PM, Rosendaal FR, et al.

Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement. J Thromb Haemost. 2018;16(4):778–90.

37. Xi M, Makris M, Marcucci M, Santagostino E, Mannucci PM, Iorio A. Inhibitor development in previously treated hemophilia A patients: A systematic review, metaanalysis, and meta-regression. J Thromb Haemost. 2013;11(9):1655–62.

38. Elalfy MS, Elbarbary NS, Eldebeiky MS, El Danasoury AS. Risk of bleeding and inhibitor development after circumcision of previously untreated or minimally treated severe hemophilia A children. Pediatr Hematol Oncol. 2012;29(5):485–93.

39. Cannavò A, Valsecchi C, Garagiola I, Palla R, Mannucci PM, Rosendaal FR, et al.

Nonneutralizing antibodies against factor VIII and risk of inhibitor development in severe hemophilia A. Blood. 2017;129(10):1245–50.

40. European Medicines Agency. Guideline on the clinical investigation of recombinant and human plasma-derived factor VIII products Guideline on the clinical investigation of recombinant and human plasma-derived factor VIII products Table of contents. 2012;44 (July

2011).

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Exploring Therapeutic Effect of Yoga in Reducing Risks of Bleeding in Early Pregnancy for Women Suffering from Haemophilia A : A Literature Review

ABSTRACT Introduction : Haemophilia A is the most common type of haemophilia. As an X-linked chromosome disorder, symptomatic haemophilia rarely happens in women. However, women suffering from haemophilia will be in considerably high risk when it comes to pregnancy.

Early pregnancy is a fragile moment for pregnant women, especially for haemophilia patients. In this literature review, we will seek the effectiveness of yoga to help reduce risks of bleeding in early pregnancy for women suffering from haemophilia A. Methods : We searched the following electronic database for our literature review : Pubmed.

Results : A study shows that exercise in pregnancy has multiple benefits for the mother, especially for the mother’s physical ability and mental health. There are no proven risks to the fetus if practiced safely. Therefore, it is recommended to do a gentle exercise regularly during pregnancy, such as doing yoga. Yoga is an exercise which involves a combination of muscular gentle-stretching, regularity of breath, strength building, and self-focus.

Discussion : It is recommended to do a gentle exercise regularly during pregnancy, such as doing yoga. Prenatal yoga usually focuses on gentle stretching, focused breathing, and mental centering.

INTRODUCTION Haemophilia is an inherited bleeding disorder in which the blood can’t clot properly.

Haemophilia is caused by a mutation of a gene responsible for making particular clotting factor proteins needed to form a blood clot. These genes are located on the X chromosome.

Haemophilia is sorted into 3 types, such as Haemophilia A, Haemophilia B, and Haemophilia C.

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Haemophilia A is the most common type of haemophilia. According to the report on Annual Global Survey (2019), there are 195.263 out of 358.749 people identified with bleeding disorders from registered countries, had been suffering from haemophilia. And over 149.764 people identified with haemophilia A. As an X-linked chromosome disorder, a symptomatic haemophilia rarely happens in women. However, women suffering from haemophilia will be in considerably high risk when it comes to pregnancy.

Early Pregnancy is a fragile moment for pregnant women, especially for haemophilia patients. Bleeding most likely happened during this phase.

This literature review aims to review all the literature to assess the effectiveness of yoga to help reduce risks of bleeding in early pregnancy for women suffering from haemophilia A.

METHODS This review is written as a literature review. It is reviewed comprehensively with an electronic database : PubMed. The keyword of collecting these datas are “yoga for pregnancy”, “exercise for pregnant women with high risk”, “pregnancy and haemophilia”, “management for haemophilia pregnancy”, “prenatal yoga”, and “yoga and bleeding disorder”

RESULT Haemophilia is an inherited rare disorder. Haemophilia is categorized as the most common bleeding disorder after Von Willebrand disease. Haemophilia A is the most common type of haemophilia. As an X-linked chromosome disease, a symptomatic haemophilia rarely happens in women. However, women suffering from haemophilia will be in considerably high risk when it comes to pregnancy.

There are procedures which necessarily be taken when a couple decides to have a child. This procedure includes prenatal tests, which is taken to analyze the condition and help

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the doctor determine the right treatment during pregnancy, management for delivery, and after the baby is born. These tests are used both for the mother and the baby.

Aside from a perfect pregnancy plan, the soon to-be mother has to maintain a good health condition. It is needed to go through a thoughtful diet and a balanced physical and mental health.

A study shows that exercise in pregnancy has multiple benefits for the mother, especially for the mother’s physical ability and mental health. There are no proven risks to the fetus if practiced safely. Therefore, it is recommended to do a gentle exercise regularly during pregnancy, such as doing yoga.

Yoga is a form of mind-body fitness which involves a combination of physical muscular activity implemented as gentle movement, mental, and spiritual of individuals, which is managed by controlled breathing and self-focus. A study shows that yoga practice can improve muscular strength and body flexibility, enhance respiratory and cardiovascular function, relieve stress, anxiety, depression, and chronic pain, and improve sleeping quality, which help improve self-awareness and energy to live life fully with genuine enjoyment.

DISCUSSION Yoga is an activity involving a combination of muscular gentle-movement, regularity of breath, strength building, and self-focus.Thus resulting in series of body postures, giving tranquility on mind, sense of energy flow, well-being, optimism, and fitness on the body which are the main goals of yoga itself.

In yoga for pregnancy or prenatal yoga, the activity typically focuses more on : 1. Gentle stretching. The mother will be encouraged to gently move some parts of the body like neck, arms, and legs until they make the appropriate prenatalyoga posture. For example, during the first trimester, it is best and safe to do basic standing or standing balancing poses such as the warrior poses, side angle pose, and crescent lunge.

2. Focused breathing. Focus on the nose to breathe in-out deeply and slowly, this will help the breath shortness during pregnancy.

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3. Mental centering. At the end of the yoga, the mother will be encouraged to listen to their breath, relax their muscles, and bring about the sense of inner calm.

Continuous yoga work-out during early pregnancy will give more advantages such as sleep improvement, reduce stress, and may also mean a less-pain during labor.

When it comes to women with haemophilia A, hereditary coagulopathies in women during pregnancy can result in severe consequences in antepartum, intrapartum, and postpartum period, if treated inappropriately. Normally, during pregnant, the body experiences hemostatic changes, including progressive increase in several fibrinogen FVII, FVIII, FX, FXII, von Willebrand activity and von Willebrand antigen. However, pregnant woman with hemophilia A, the level does not increase until the second trimester. Thus increasing the bleeding risk during early pregnancy.

Besides modern medical treatment or medication, yoga can be a good alternative to exercise as it is less-risk for people with haemophilia. Yoga encourage ones, in this case the pregnant mother with haemophilia, to released tension physically and mentally with some gentle movements. This will calm their body as the energy flows throughout the body, allowing the body to shift from the sympathetic system to a parasympathetic system which then helps relieve the excess nerve stimulation or pain. Most of all, it helps to reduce the tendency of early pregnancy bleeding risk as it lowers the heart rate also decreases the blood pressure.

CONCLUSION By providing a tranquil ambience inside the body, mentally and physically, yoga helps pregnant mothers with hemophilia, lowers the heart rate, and also decreases the blood pressure. Thus, reduce the bleeding risk in early pregnancy and certainly, this form of exercise is less-risk.

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REFERENCES :

1.

Woodyard C. Exploring the therapeutic effects of yoga and its ability to increase quality of life. Int J Yoga. 2011;4(2):49–54.

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Sharma V, Khalid A, Cohen AJ. Management of pregnancy in a patient with severe hemophilia type a. AJP Rep. 2013;3(1):29–32.

3.

The Royal Australian College of General Practitioners. RACGP - exercise in pregnancy. [cited 2021 Mar 19]; Available from: https://www.racgp.org.au/afp/2014/august/exercise-in-pregnancy/

4 Prenatal yoga: What you need to know [Internet]. Mayoclinic.org. 2021 [cited 2021 Mar . 19]. Available from: https://www.mayoclinic.org/healthy-lifestyle/pregnancy-week-byweek/in-depth/prenatal-yoga/art-20047193 5.

Hermans C, Kulkarni R. Women with bleeding disorders. Haemophilia. 2018;24 Suppl 6:29–36.

6.

World Federation of Haemophilia. Report on the Annual Global Survey 2019. 2019.

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NHS Foundation Trust. Information about Pregnancy for Haemophilia Carriers. Oxford, England: Oxford University Hospitals; 2019.

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Valoctocogene Roxaparvovec (AAV5-hFVIII-SQ) as a Potential Cure for Patients with Hemophilia Type A: A Systematic Review Donnatella Valentina, Leony Santoso Winaryo, Stella Frederica Djamhari Abstract Introduction: Current remedies for Hemophilia A (HA) are proven ineffective as breakthrough bleeds and haemophilic arthropathy continue to occur. Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an AAV5-mediated gene therapy that offers magnificent results in increasing FVIII levels for patients of HA. From being classified as having severe hemophilia, one recipient successfully classified as non-hemophilic after infusion of AAV5-hFVIII-SQ. Materials and Methods: This systematic review was conducted with Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement guidelines. The literature search was done using four databases: PubMed, ProQuest, ScienceDirect, and EBSCO. Results and Discussion: The main findings from included studies are : (a) Single intravenous administration of AAV5-hFVIII-SQ shows most promise in the high-dose cohort with an increase in factor VIII activity levels from <1 IU/dL up to >50 IU/dL, 86% of participants were free of bleeding events, and decreased factor VIII infusions from 177 to 5 infusions per year was observed. The other three cohorts show much less favorable outcome in all aspects; (b) Adverse events' severity varies from mild to serious with increasing alanine aminotransferase levels being the most common adverse event.

Conclusion: AAV5-FVIII-SQ may pose as the first ever cure for HA patients.

Keywords: AAV5-hFVIII-SQ; Adeno Associated Virus Type 5; Hemophilia A; Systematic Review; Valoctocogene roxaparvovec

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I.

Introduction Hemophilia is a rare, hereditary X-linked bleeding disorder due to deficiencies in

coagulation factor VIII (FVIII) or IX, in hemophilia A and B respectively. Mutations of the specified clotting factor genes correspond to the reduction of its amount in the body.1 Based on the latest annual report by the World Federation of Hemophilia, in 2019, 195,263 people out of over 5.5 billion people surveyed are diagnosed with hemophilia; 157,000 being hemophilia A (HA), 32,000 hemophilia B, while the rest are unclassified.2 Despite only making up 0,0035% of the entire population surveyed, hemophilia patients are at risk for prolonged and excessive bleeding that may cause death, therefore effective management and treatment strategies are critical.

Until today, treatment of HA includes FVIII replacement therapy or novel therapies administered either on-demand or prophylactically.3 Even with the existence of these remedies, patients of HA are endlessly faced with developing bleeds and progressive hemophilia arthropathy, furthermore, the relatively short half-life of available FVIII makes frequent infusions necessary, causing adherence to therapy and preservation of proper hemostasis a burden which detrimentally affects patients’ quality of life.

Other than ongoing remedies for HA, adeno-associated viruses (AAVs) may provide a potential cure for patients of HA. Single-stranded DNA viruses, AAVs, belong to Parvoviridae and dependovirus with various serotypes.4 Adeno-associated virus type 5 (AAV5) is an AAV serotype that works primarily in the liver, central nervous system, and lungs. In this case, AAV5 can also be utilized to transfer complementary DNA encoding functional FVIII proteins for patients of HA.5 They possess multiple beneficial characteristics that makes it an excellent vector for gene transfer including an easily manipulated genome, ability to be purified at extremely high titers, easily stored, and considered relatively safer compared to corresponding viral-based vectors as they are non-pathogenic and possess a considerably low innate immunogenicity.6 Recently discovered valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an AAV5-based gene therapy that encodes a codon-optimized, B-domain deleted human FVIII protein (hFVIII-SQ) with a hybrid liver-specific transcription promoter, administered as a single

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intravenous infusion (IV) for patients of HA that shows phenomenal results.3 Seeing that one participant was successfully cured after 3 years of follow-up, this AAV5-mediated gene therapy may act as a curative regimen for persons with HA in the near future.5 AAV5-hFVIII-SQ in the study was manufactured with the use of a baculovirus – Spodoptera frugiperda (Sf9) – insect-cell production system.7 One limitation of AAV5-based gene therapy is due to common exposure of AAVs in the environment, former studies have shown that up to 90% of the human population have been exposed to AAVs, resulting to the development of neutralizing antibodies (NAbs) which reduces the transduction efficiency of AAV-based gene therapies. Fortunately, the prevalence of AAV5 antibodies are found to be lower compared to other serotypes, with 3.2% up to 40% compared to 60%.6 The aim of this systematic review is to review the efficacy and long-term safety of valoctocogene roxaparvovec to treat patients of HA.

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II.

Materials and Methods This systematic review was conducted using Preferred Reporting Items for Systematic

Reviews and Meta-analysis (PRISMA) statement guidelines to identify the efficacy of valoctocogene roxaparvovec gene therapy in HA treatment. Population, Intervention, Comparison, and Outcomes (PICO) questions were also used to develop the inclusion criteria of this systematic review. The answer of those questions in order: Patients confirmed suffering of HA; Intervention with AAV5-hFVIII-SQ; Comparison with prophylactic intravenous infusion of clotting FVIII; Outcomes measured are FVIII levels, annual bleeding rate, and use of exogenous FVIII post-AAV5 gene therapy. The other inclusion criteria for this study is the study design which had to be a Non-Randomized Controlled Trial (NRCT) with participants confirmed as HA patients.

The literature search was done using four databases: PubMed, ProQuest, ScienceDirect, and EBSCO, with “Hemophilia A,” “AAV5-hFVIII-SQ,” “Adeno-Associated Virus Type 5,” “Valoctocogene Roxaparvovec” as the main keywords until March 12, 2020. No language restrictions were imposed. The complete keywords are listed in Table 1 in the appendix. The result of the search was then imported to Zotero and the duplicates were removed. All authors participated through each phase of the review independently by screening the titles and abstracts, assessing the full text for eligibility criteria, then including the relevant studies. Data collection was done by three independent reviewers (DV, LS, SF) and entered into a predesigned data extraction form.

The Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool is utilized in the quality assessment of the studies to assess the risk of bias in the two studies reviewed. Included study quality will be classified as low, moderate, or serious risk of bias.8 Disagreements found throughout the process of evaluation are solved by discussion among the review team.

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III.

Results Patients of HA face continual bleeding episodes due to a lack of coagulation FVIII.

Valoctocogene roxaparvovec has incredibly high potential to cure persons with HA based on the information provided on both studies by Rangarajan et al. and Pasi et al.5,7 These two studies are the only studies out of 157 others that matched the authors’ criteria for inclusion. Both study designs are Non-randomized Controlled Trials involving male adults with severe HA. By utilizing PICO questions for the inclusion criteria, appropriate data that matches the review’s outcomes are extracted from both studies. ROBINS-I tool is used to assess the quality of studies reviewed.

Search Results A literature search from four online databases provided 157 studies. There were 93 remaining studies obtained after duplicates were removed. After titles and abstracts of studies were screened, 66 studies were excluded, with 27 studies that met the inclusion criteria set by the authors. The result showed that two studies matched the criteria for inclusion. Search flowchart and selection method is summarized in Fig 1.

Study Characteristics All of the studies included were conducted using the NRCT study design. Inclusion and exclusion criteria of both studies showed resemblance. Study population involved a total of 24 male adults (aged 22-45 years) with severe HA (FVIII Activity <1 IU/dL) based in England.

Studies are published within three years difference, 2017 for the first study and 2020 for the second. Detailed characteristics of the included studies are summarized in Table 2.

Data Extraction Using PICO questions as guidance for our inclusion criteria, all available data from the two included studies that are aligned with the authors’ determined outcome are extracted for this review. These outcomes include recipients’ FVIII levels, annualized bleeding rate, and use of exogenous factor VIII post-gene transfer to test the efficacy of AAV5-hFVIII-SQ for patients of HA. An additional important information was that recipients of valoctocogene roxaparvovec

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infusions were required to discontinue exogenous FVIII consumption at the time of study enrollment, unless bleeding episodes were to occur after valoctocogene roxaparvovec infusion.

Quality Assessment Based on ROBINS-I tool, mixed levels of bias were found from different domains of selection and reporting bias, ranging from low to serious risk for both studies. Serious risk of bias was found only in one study as there was an increase in dosage administered to a single patient, which may question the reliability of the results. Both studies have a moderate risk in detection bias resulting from inadequate data. In general, both studies have a moderate risk of bias based on the author’s judgment. Risks of bias for both studies are assessed from the ROBINS-I tool is summarized in Fig 1.8 Clinical Efficacy of AAV5-hFVIII-SQ A 2017 study by Rangarajan et al. involved nine men that were followed through 1 year while a more recent study conducted in 2020 by Pasi et al. involved 15 men that were followed through up to 3 years, both with severe HA (FVIII level <1 IU per deciliter). Both studies divided recipients to cohorts based on dosage variations of AAV5-hFVIII-SQ infused and both studies had equal doses of AAV5-hFVIII-SQ in three cohorts: low-dose (6×1012 vector genomes (vg) per kilogram of body weight), intermediate-dose (2×1013 vg/kg), and high-dose (6×1013 vg/kg).5,7 One study included an additional dose of 4×1013 vg/kg as their fourth cohort which the authors label the upper-intermediate cohort.5 The low-dose, intermediate-dose, upper intermediate-dose, and high-dose cohorts from both studies combined include the following number of recipients in consecutive order: 2,2,7,13.5,7 All recipients who had been taking prophylactic FVIII infusions in both studies were required to terminate its use at the start of AAV5-hFVIII-SQ therapy, with the exception of whenever bleeding episodes were to take place, self-administered FVIII use is permitted. In addition, the time at which FVIII activity levels of recipients were recorded differs between the two studies; 54 weeks and 156 weeks post-valoctocogene roxaparvovec infusion.5,7

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Factor VIII activities of AAV5-hFVIII-SQ in the low-dose cohort of both studies demonstrate a consistent FVIII activity prior to and post-gene therapy, which is maintained below 1 IU/dL, as assessed using the chromogenic assay. Chromogenic assays are the more conservative assay that consistently showed FVIII levels of approximately 1.65× less than those observed on one-stage assays. Furthermore, an increased consumption of exogenous FVIII is observed in the first study from 95 infusions before gene transfer to 123 infusions after.7 Meanwhile, recipients infused with intermediate-dose of AAV5-hFVIII-SQ present a slight increase of FVIII expression from below 1 IU/dL to a range of 0.6—1.8 IU/dL, having the values independently converted from those recorded on one-stage assays: <1 IU/dl to 1-3 IU/dL to an approximate value obtained in chromogenic assays by dividing value of FVIII levels obtained from one-stage assays by 1.65.5,7 This was done to accurately compare results and maintain coherence. The other study shows a constant FVIII expression of less than 1 IU/dL recorded on chromogenic assays.5 One study also recorded a decreased FVIII consumption from 104 infusions to 14.7 Increased trend in annualized bleeding rate is observed which ranged from 3 to 11 bleeding events after infusion.7 Unfortunately, information on exogenous FVIII consumption and annual bleeding rates aren’t provided in the intermediate-dose cohort of one study, therefore no comparison can be made.

Both studies provide a comparable upward trend of FVIII expression after the infusion of AAV-hFVIII-SQ in the high-dose cohort. In one study, 20 weeks post-infusion, 6 of the 7 recipients had FVIII activity levels of more than 50 IU/dL measured in a one-stage assay (30 IU/dL on chromogenic assay).7 While the remaining recipient had FVIII levels ranging from 7—20 IU/dL once converted (original value from one-stage clot assays÷1.65). On the other hand, the mean FVIII activity levels assessed in chromogenic assay in six recipients of the other study followed up at the end of year 1,2, and 3 are 64 IU/dL, 36 IU/dL, and 33 IU/dL in a succeeding manner.5 At the end of the third year, 86% from a total of 15 participants were free from bleeding events and all participants resolved bleeding in target joints by the end of year 2 (major: ≥3 bleeding events within 6 months; resolved: ≤2 bleeding events within 12 months). prior to gene therapy, the mean annualized number of FVIII infusions of each participant were 136.7±22.4, which decreased by 96% to a mean of 5.5±9.4 infusions by the third year.5 The mean

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reduction in rate of annual FVIII use from the other study fell from 137 to 5 infusions per year after AAV5-hFXIII-SQ therapy.7 One participant successfully stopped consumption of FVIII after gene transfer and other four participants followed through two weeks after.7 Three years ensuing infusion of valoctocogene roxaparvovec, one participant classifies as non-hemophilic, eleven as having mild hemophilia, and one as having moderate hemophilia.5 A detailed classification of hemophilia based on its severity is summarized in Table 3. Both studies recognized a decreased trend in annualized rate of bleeding events. In one study, the annualized bleeding rate dropped from 16 events to 1 event per year (mean: 16 events to 2 events), correspondingly the other study recorded a decreased mean of 16.3±15.7 to 0.7±1.6 bleeding events per year.5,7 Favourable outcomes are also observed in recipients of the upper-intermediate cohort although inconsistent results were recorded between the end of year 1 and 2. Factor VIII activity levels of 18.8 IU/dL were recorded at the end of year 1 and 13.9 IU/dL at the end of year 2.

Original data was obtained from one-stage assays and independently converted to chromogenic assay values by authors. The annualized bleeding events decreased by 92% from a mean of 12.2±15.4 pre-gene therapy to a mean of 1.2±2.4 after. At the end of year 2, 67% of the participants were free from bleeding episodes. The mean annualized number of FVIII infusions per participant decreased by 95% from 146.5+41.6, to a mean of 6.8±15.6. Excluding participant 15, all participants in cohort 4 of one particular study achieved resolution for bleeding in joints by the end of the second year.5 Safety Regarding the Adverse Events In both studies conducted, adverse events (AEs) were observed in some participants, varying in severity from mild to serious. Classified as mild, elevations in alanine aminotransferase (ALT) levels were found in most participants. These elevations could reach up to 1.5 times higher than the normal range. ALT is commonly used as a biomarker of hepatic health. Hepatocytes are presumably the main host of AAV5-hFVIII-SQ derived FVIII protein expression due to the use of liver specific promoter as well as AAV5’s tropism in which is why an increase in ALT level may highly suggest liver injury.9 Eight participants (low-dose: 1

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participant; high-dose: 7 participants) had an increased value of ALT level with peak values ranging from 59 to 128 IU/L (normal range: 4—43 IU/dL).7 A total of 14 reported events from 11 participants was found with increased ALT levels with two of the events being unrelated to the treatment.5 Prior to any additional treatments, each participant’s ALT level subsequently decreased following an increase in FVIII activity level.

Prophylactic glucocorticoids were administered to overcome this event with varied doses depending on the elevation of ALT levels. All the participants in the high-dose cohort received glucocorticoids.5,7 In some participants, the rise in ALT levels is concurrent with lifestyle including hepatotoxic medication, alcohol consumption, or heavy exercises in which are unrelated to the treatment.7 Glucocorticoid were used on demand by 4 out of 6 participants in the upper-intermediate cohort while the remaining participants didn’t receive any. Varying doses of glucocorticoids are administered to participants with different elevated levels of ALT; for recipients with ALT levels elevated 1.5x baseline value, 60 mg were administered per day, for recipients with ALT levels elevated 1.5x the upper limit of normal range, 40 mg were administered per day. No apparent relationship between ALT levels and anti-capsid T cell response was found and no symptoms of liver dysfunction were recorded.

Apart from the common AEs, mild events such as arthralgia, back pain, increasing aspartate aminotransferase, fatigue, and progressive cough were also classified as the AEs. Moderate AEs such as arthralgia (1 case) and increased level of aspartate aminotransferase (1 case) were also reported, both of which are asymptomatic and resolved without any sequelae.7 There were in total four serious AEs that transpired in the two studies reviewed; three out of four serious AEs were associated with arthropathies that required hospitalizations and subsequent knee replacement surgeries (one participant experienced chronic arthropathy progression) and 2 patients from the other study had serious AEs associated with preexisting hemophilic arthropathies (not related to treatment).5,7 One participant of the study experienced grade 2 pyrexia with myalgia and headache within 24 hours of AAV5-hFVIII-SQ infusion and was directly hospitalized. This event was resolved in 48 hours after the participant received acetaminophen.5

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IV.

Discussion This systematic review concludes similar findings from two studies. Both studies present

comparable results in terms of outcome after AAV5-hFVIII-SQ infusion, which include FVIII activity levels, annualized bleeding episodes, and use of exogenous FVIII. Unencouraging results were recorded for recipients receiving low (6×1012 vg/kg) and intermediate (2×1013 vg/kg) doses of AAV5-hFVIII-SQ as there were minor to no increases of FVIII levels. Meanwhile, recipients infused with high dose (6×1013 vg/kg) presents the most favourable outcome after three years where men initially classified with severe HA subsided in severity to being classified mostly as having mild hemophilia, and one participant favourably classified as non-hemophilic or in other words cured from HA. Safety measures of a potential cure is of vital importance. Recently, the priority review for valoctocogene roxaparvovec was accepted by the U.S. Food and Drug Administration (FDA).10 This acceptance is the first accepted application for gene therapy for any kinds of hemophilia. Some AEs were recorded and categorized by severity as mild, moderate, and serious. Safety measures will also include the long-term clinical effectiveness, such as AEs. The most common AE found in nearly all participants from both studies is an elevated level of alanine aminotransferase, which was overcome by administration of prophylactic glucocorticoids. Other AE such as arthralgia, back pain, increase in aspartate aminotransferase, fatigue and many others also occurred in the studies.

Differences in Various Aspects of the Regimen Despite nearly identical outcomes reported from both studies, several discrepancies are observed. The major differing factor between the two studies are the time at which the outcomes are recorded; Rangarajan et al. reported results of at most one year post-valoctocogene roxaparvovec infusion while the study by Pasi et al. recorded results throughout the span of three years which may pose unreliability in data comparison presented.

Another distinguishable factor observed is the type of assay used in both studies to record FVIII levels of recipients. The study by Rangarajan et al. utilized the one-stage clot assay in comparison to the more conservative chromogenic assay used in the study by Pasi et al.

Although both studies repeatedly mention that the one-stage clot assay consistently show FVIII levels that are 1.65 as high as those recorded in the chromogenic assay, the outcomes measured

10 98

using different assays may result to inaccuracies in the comparison of data presented in this review, as the three authors had to independently calculate and convert data shown in one-stage clot assay to an approximate presumed value obtained in chromogenic assays.

One last difference observed is the additional dose cohort, labeled upper-intermediate cohort (4×1013 vg/kg) that is only presented in one out of the two studies reviewed. Therefore, comparison of results for that specific dose is unattainable.

Limitation of AAV5-based Gene Therapy Despite all the benefits AAV5-hFVIII-SQ has to offer, limitation recorded is the formation of neutralizing antibodies (NAbs) against AAV5 due to wild-type AAV2 exposure.

Non-antibody transduction inhibitors (TI) are also known to prohibit AAV5-hFVIII-SQ transduction efficiency.11,12,13 Recent study conducted by Falese et al. presents that among 100 participants, 18% of the participants shows positive for both NAbs and TI, 5% were positive for NAbs only, and 24% were positive for having TI only.14 This information is supported by previous studies which observed that NAbs against AAV2 cross-neutralize other serotypes of AAV which is detrimental to therapy because even a low level of NAbs are known to disturb transduction efficiency.1,15 The prevalence of NAbs increased steadily throughout one of the studies conducted from 8% (5 out of 62 participants ) to 25.8% (16 out of 62 participants). Other than anti-AAV5 antibodies, TI is also considered as another hindrance for AAV-hFVIII-SQ therapy. Factors that support inhibitor development include the type of vector used and route of delivery.13 Methods to counter the limitations are generating capsid mutants by DNA shuffling (specifically for NAbs), co-administration of immunosuppressive agents, pre-injection of empty capsids to consume the reactive antibodies, and optimizing the capsids to evade neutralizing antibodies. A way simpler method to counter both limitations might also be done by screening potential AA5-hFVIII-SQ recipients to detect the presence of NAbs or TI to determine who are eligible for therapy.11,12,16,17 Comparison of AAV5-hFVIII-SQ with Prophylactic IV Infusion of Clotting Factor VIII Current ongoing remedies for persons with HA are proven to be less effective as patients of HA are still faced with breakthrough bleeds and chronic haemophilic arthropathies.

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Prophylactic IV infusion of coagulation factor VIII have been the leading regimen to treat and manage bleeding episodes in patients of HA. Despite its favourable clinical outcomes such as decreasing bleeding episodes and preventing joint bleeds, major, inevitable problems are found that heavily interrupt patients’ compliance to therapy. The short half-life of conventional FVIII concentrates, complicated venous access, high cost, and requirement for frequent therapy sessions pose challenges towards patients’ adherence to therapy.18,19 The primary issue of this coagulation FVIII replacement therapy is the relatively low adherence of patients to therapy. A 2017 study by Thornburg, CD. and Duncan, NA. found that using the validated hemophilia-regimen treatment adherence scale – prophylaxis (VERITAS-Pro) measurement to assess hemophilia therapy adherence, a total of 23 adults scored 45.8 on a scale of 24 (most adherent) to 120 (least adherent) total adherence scoring system.19 Standard accessible FVIII products are known to have an average half-life of estimatedly 8-12 hours, hence making frequent administration of replacement FVIII necessary, even up to three times per week. Studies have shown that the requirement for frequent IV administration of coagulation concentrates correlates to poor adherence to therapy. This is an issue of major concern as patients who miss or skip an infusion are prone to more bleeding episodes.18 Our proposed regimen, AAV5-FVIII-SQ, provides magnificent results that ameliorate all major problems found on the application of prophylactic IV infusion of coagulation factor VIII. Unlike the ongoing clotting factor replacement therapy, AAV5-FVIII-SQ is one-time administered to a peripheral vein, therefore patients’ adherence to therapy is not a problem of concern. Despite only receiving a single infusion of AAV5-FVIII-SQ, recipients of the study experienced immense elevations in FVIII levels, a decrease in annualized bleeding rates, resolved haemophilic arthropathies, and a decreased to no use of exogenous FVIII post gene therapy. With that said, AAV5-FVIII-SQ undoubtedly offer extremely reassuring results while at the same time disregarding all concerns of the currently prominent regimen to treat patients of HA.5,7

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Strength and Limitation of Each Study The study by Rangarajan et al. provides more consistent information for each cohort.

Unfortunately, the period of time recorded is considerably short compared to the other study.

Outcomes are followed through every several weeks throughout the entire 52 weeks of observation. The one-stage clot assay is utilized in this study which may be a limitation of the study as they are known to be less conservative. The number of recipients enrolled in the study is another drawback of the study. Assessed study by Rangarajan et al. presented an overall high risk of bias deeming it less credible.

Meanwhile, the study by Pasi et al. provides more accurate results compared to the study

by Rangarajan et al. as a longer timespan is taken to observe participants’ outcomes post-AAV5-hFVIII-SQ infusion, which is three years compared to one year in the other study.

This study also utilized the more conservative, chromogenic assay to measure FVIII levels in recipients, and in some cases also provide the value for the one-stage clot assay, therefore both assays are used, which provides higher reliability for the study. One liability of the study though, is the fact that the time at which outcomes of recipients in cohort 4 are recorded differs from the time taken to record outcomes from recipients in all other three cohorts, namely two years for cohort 4 compared to three for other cohorts. Another liability is the inconsistency in outcomes measured, annualized bleeding rates and use of exogenous FVIII is measured in cohorts 3 and 4 but is not presented for cohorts 1 and 2.

For both studies, unequal distribution of recipients in cohorts may provoke inaccuracy in the results obtained. The study by Rangarajan et al. and the study by Pasi et al. both only involved one recipient for the low-dose and intermediate-dose cohort, which means the result for those cohorts are solely represented by one person suffering from HA, meanwhile the high-dose cohorts involve at least six recipients in both studies, hence more accurate results can be obtained, however, it is to be put into account that 6 participants might not represent the entire HA population considering the small amount of participants being clinically tested. The absence of analytic statistical analysis also appears to be the limitation for both studies as both studies only provide the descriptive statistical analysis. The absence of analytic statistical analysis may

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cause a non-quantitative decision but instead a more qualitative one which can question the credibility of the studies included.

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V.

Conclusion Based on the two studies reviewed, AAV5-hFVIII-SQ has proven to be highly effective

in increasing coagulation FVIII levels, decreasing annualized bleeding episodes, and lessening use of exogenous FVIII in persons suffering from HA. Based on the fact that one recipient was successfully categorized as non hemophilic, AAV5-FVIII-SQ may pose as the first ever cure for patients of HA. Issues of patient adherence to prophylactic factor VIII replacement therapy as the currently most used regimen to treat patients of HA is resolved in AAV5-FVIII-SQ infusion as it only requires single IV administration. An important factor to consider is that to ensure effectiveness of AAV5-hFVIII-SQ, an exact dosage of 6×1013 vg/kilogram is the author’s recommended use for patients of HA. Authors recommend doing further clinical trials and research encompassing more recipients from different geographic locations to provide more inclusivity for patients of HA, and to include more recipients from varying doses of AAV5-hVIII-SQ to ensure which dose is the most effective.

VI.

Conflict of Interest The authors declare that there are no unsolved nor contrasting interests in the study.

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VII.

References 1. Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, et al.

Guidelines for the management of hemophilia. Haemophilia. 2013 Jan;19(1):e1–47.

2. Annual Global Survey - World Federation of Hemophilia [Internet]. [cited 2021 Mar 11].

Available from: https://www.wfh.org/en/our-work-research-data/annual-global-survey 3. Long BR, Veron P, Kuranda K, Hardet R, Mitchell N, Hayes GM, et al. Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A. Molecular Therapy. 2021 Feb 3;29(2):597–610.

4. Stanford S, Pink R, Creagh D, Clark A, Lowe G, Curry N et al. Adenovirus-associated antibodies in UK cohort of hemophilia patients: A seroprevalence study of the presence of adenovirus-associated virus vector-serotypes AAV5 and AAV8 neutralizing activity and antibodies in patients with hemophilia A. Research and Practice in Thrombosis and Haemostasis. 2019;3(2):261-267.

5. Pasi K, Rangarajan S, Mitchell N, Lester W, Symington E, Madan B et al. Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. New England Journal of Medicine. 2020;382(1):29-40.

6. Tellez J, Vliet KV, Yu-Shan T, Finn JD, Tschernia N, Almeida-Porada G, et al.

Characterization of Naturally-Occurring Humoral Immunity to AAV in Sheep. PLoS One. 2013 Sep;8(9):e75142.

7. Rangarajan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, et al. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. N Engl J Med. 2017 Dec 28;377(26):2519–30.

8. ROBINS-I

tool

[Internet].

[cited

2021

Mar

26].

Available

from:

/methods-cochrane/robins-i-tool 9. Gwaltney-Brant S. Nutraceuticals in Hepatic Diseases. Nutraceuticals. 2016;:87-99.

10. BioMarin’s Biologics License Application for Valoctocogene Roxaparvovec Accepted for Priority Review by FDA with Review Action Date of August 21, 2020 [Internet]. [cited 2021 Mar 12]. Available from: https://www.prnewswire.com/news-releases/biomarins-biologics-license-application-forvaloctocogene-roxaparvovec-accepted-for-priority-review-by-fda-with-review-action-dat e-of-august-21-2020-301008771.html

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11. Long BR, Sandza K, Holcomb J, Crockett L, Hayes GM, Arens J, et al. The Impact of Pre-existing Immunity on the Non-clinical Pharmacodynamics of AAV5-Based Gene Therapy. Molecular Therapy Methods & Clinical Development. 2019 Jun 14;13:440–52.

12. Li C, Narkbunnam N, Samulski RJ, Asokan A, Hu G, Jacobson LJ, et al. Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia. Gene Ther. 2012 Mar;19(3):288–94.

13. Jobson J, Brown B. Micromanaging Tolerance in Hemophilia A Gene Therapy.

Molecular Therapy. 2017;25(8):1739-1740.

14. Falese L, Sandza K, Yates B, Triffault S, Gangar S, Long B et al. Strategy to detect pre-existing immunity to AAV gene therapy. Gene Therapy. 2017;24(12):768-778.

15. Sen D, Balakrishnan B, Gabriel N, Agrawal P, Roshini V, Samuel R et al. Improved adeno-associated virus (AAV) serotype 1 and 5 vectors for gene therapy. Scientific Reports. 2013;3(1).

16. Jose A, Mietzsch M, Smith J, Kurian J, Chipman P, McKenna R et al. High-Resolution Structural Characterization of a New Adeno-associated Virus Serotype 5 Antibody Epitope toward Engineering Antibody-Resistant Recombinant Gene Delivery Vectors.

Journal of Virology. 2018;93(1).

17. Stanford S, Pink R, Creagh D, Clark A, Lowe G, Curry N et al. Adenovirus-associated antibodies in UK cohort of hemophilia patients: A seroprevalence study of the presence of adenovirus-associated virus vector-serotypes AAV5 and AAV8 neutralizing activity and antibodies in patients with hemophilia A. Research and Practice in Thrombosis and Haemostasis. 2019;3(2):261-267.

18. Castaman G, Linari S. Prophylactic versus on-demand treatments for hemophilia: advantages and drawbacks. Expert Review of Hematology. 2018;11(7):567-576.

19. Thornburg C, Duncan N. Treatment adherence in hemophilia. Patient Preference and Adherence. 2017;Volume 11:1677-1686.

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VIII.

Appendices

Table 1. Search Keywords Databases

PubMed

Keywords

Articles

("Hemophilia A"[Mesh] OR Hemophilia As[Title/Abstract]

35

OR

Hemophilia,

Classic[Title/Abstract]

Hemophilia[Title/Abstract] Congenital[Title/Abstract] A[Title/Abstract]

OR OR

OR

As[Title/Abstract]

OR

Hemophilia

Congenital

Hemophilia

Congenital

OR

A.

Hemophilia

Hemophilia

As,

Congenital[Title/Abstract]

OR

Classic

Hemophilia[Title/Abstract]

OR

Classic

Hemophilias[Title/Abstract]

OR

Hemophilias,

Classic[Title/Abstract] OR Haemophilia[Title/Abstract] OR Autosomal Hemophilia A[Title/Abstract] OR As, Autosomal Hemophilia[Title/Abstract] As[Title/Abstract]

OR

Autosomal

OR

Autosomal[Title/Abstract]

Hemophilia

Hemophilia OR

Autosomal[Title/Abstract]

Hemophilia

As,

Factor

VIII

OR

Deficiency[Title/Abstract]

OR

Congenital[Title/Abstract]

OR

A,

Factor

8

Factor VIII

Deficiency, Deficiency,

Congenital[Title/Abstract]

OR

Deficiency,

Factor

VIII[Title/Abstract])

("Adeno-associated

virus-5"

[Supplementary

AND

Concept]

5[Title/Abstract] virus[Title/Abstract]

OR

OR

Adeno-associated

Bovine OR

adeno-associated Adeno-associated

virus-5[Title/Abstract] OR AAV5[Title/Abstract])

18 106

virus

ScienceDirect

Hemophilia OR Congenital Hemophilia OR Autosomal Hemophilia

OR

Deficiency

(Factor

VIII)

10

AND

Adeno-associated virus 5 OR Bovine adeno-associated virus OR Adeno-associated virus-5 OR AAV5

EBSCOhost

AB

( Hemophilia As OR Hemophilia, Classic OR

Hemophilia OR Hemophilia A. Congenital OR Congenital Hemophilia

A

OR

Congenital

Hemophilia

As

OR

Hemophilia As, Congenital OR Classic Hemophilia OR Classic

Hemophilias

OR

Hemophilias,

Classic

OR

Haemophilia OR Autosomal Hemophilia A OR As, Autosomal Hemophilia OR Autosomal Hemophilia As OR Hemophilia A, Autosomal OR Hemophilia As, Autosomal OR Factor VIII Deficiency OR Factor 8 Deficiency, Congenital OR Factor VIII Deficiency, Congenital OR Deficiency, Factor VIII ) AND AB ( Adeno-associated virus 5 OR Bovine adeno-associated virus OR Adeno-associated virus-5 OR AAV5 )

19 107

59

ProQuest

ab(Hemophilia As OR Hemophilia, Classic OR Hemophilia OR Hemophilia A. Congenital OR Congenital Hemophilia A OR

Congenital Hemophilia As OR Hemophilia As,

Congenital OR Classic Hemophilia OR Classic Hemophilias OR Hemophilias, Classic OR Haemophilia OR Autosomal Hemophilia A OR As, Autosomal Hemophilia OR Autosomal Hemophilia

As

OR

Hemophilia A,

Autosomal OR

Hemophilia As, Autosomal OR Factor VIII Deficiency OR Factor 8 Deficiency, Congenital OR Factor VIII Deficiency, Congenital

OR

Deficiency,

Factor

VIII)

AND

ab(Adeno-associated virus 5 OR Bovine adeno-associated virus OR Adeno-associated virus-5 OR AAV5)

20 108

53

Table 2. Characteristics of the Study

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Table 3. Relationship of Bleeding Severity to Clotting Factor Level (One stage assay) Clotting factor level

Severity Severe

Bleeding episodes

<1 IU/dL (<0.01 IU/ml) or <1% of

Spontaneous bleeding into joints or

normal

muscles, predominantly in the absence of identifiable hemostatic challenge

Moderate

1-5 IU/dL (0.01-0.05 IU/ml) or

Occasional spontaneous bleeding;

1-5% of normal

prolonged bleeding with minor trauma or surgery

Mild

5-40 IU/dL (0.05-0.4 IU/ml) or

Severe bleeding with major trauma or

5-<40% of normal

surgery. Spontaneous bleeding is rare

Source: World Federation of Hemophilia: Guidelines for the Management of Hemophilia 2nd Edition

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Fig 1. PRISMA flow diagram of the identification and selection of studies included in the analysis

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Fig 2. Risk of Bias Summary

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Defining the Propriety on Prophylaxis and On-Demand Treatment in People with Hemophilia A: A Systematic Review Erlangga Saputra Arifin, Charens, Precia Widyatomo Abstract Introduction​: The World Federation of Hemophilia (WFH) has recorded a total of 157,517 Hemophilia A patients in 2019. In severe cases, complications can lead to death; thus appropriate treatment is needed to minimize such incidents.

Objectives​: To analyze the efficacy based on the annualized bleeding rate (ABR) and safety between prophylaxis and on-demand therapy for Hemophilia A. Methods​: Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement guidelines were used. The literature search was done using four databases: ​PubMed, ProQuest, ScienceDirect, and EBSCO​. Data collection was done and entered into a predesigned data extraction form. Cochrane risk of bias tool 2.0 was utilized in the quality assessment of the studies.

Results and Discussion​: Search strategies identified 317 studies. Seven relevant full-text articles met our inclusion criteria. Overall studies had an unclear risk of bias. Following are the main findings from available data: (a) Prophylaxis given for an overall of 12 months resulted in a lower ABR compared to on-demand treatment with generalized p-values lower than 0.05 (b) No treatment-related adverse events are reported and none developed FVIII inhibitors.

Conclusion​: Prophylactic treatment is superior in terms of efficacy compared to on-demand and both modalities are safe.

Keywords​:​ ​Hemophilia A; Prophylaxis; On-demand; Inhibitor; Factor VIII; Systematic Review.

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I.

Introduction Hemophilia A is a hereditary condition characterized by the lack of coagulation factor

VIII. This deficiency causes bleeding manifestations due to the disruption of clotting property.​1 Latest survey done by the World Federation of Hemophilia (WFH), which is in the year 2019, recorded a total of 157,517 people suffering from this condition.​2 Hemophilia A is classified as a chronic illness that results in a more diminished quality of life by causing complications depending on the bleeding site.​3 However, death can occur in some cases such as bleeding into the brain. Thus, proper intervention is needed to prevent this from happening.​4 There is no available cure for hemophilia A up to this day.​5 Symptomatic treatment by administering the missing coagulation factor is the primary goal in the therapy of this disease.​6 The most promising and extensively researched intervention is gene therapy. Using a viral vector to transfer genes that code for the missing coagulation factor is proven possible.​7 However, there is no FDA-approved gene therapy for hemophilia A.​8 Therefore, the main treatment principle is to prevent further complications and assure that the patients may live a normal life.

Life-long replacement therapy or prophylaxis is usually needed to maintain proper hemostasis.​9 Along with this, many downsides need to be accounted for. Risks of infection are one of them due to the frequent implantation of central venous access devices (CVAD).​10 The overall cost of treatment would also be high given it be long-term.​11 Lastly is the development of an inhibitor.​12,13 Approximately 1 in 5 people with hemophilia A will develop a certain type of antibody called the inhibitor, which interferes with the replacement therapy. As a result, this disease becomes more difficult to treat as further treatment is required. The development of inhibitors also further increases the cost of care, since the current primary treatment, bypassing agents (BPA) comes at a high cost. In addition, people with hemophilia who develop an inhibitor are twice likely to be hospitalized compared to those without inhibitors for bleeding complications - thus adding more weight to the cost of care.​14,15 Many researchers have considered the use of on-demand treatment since it will greatly reduce these downsides. For this reason, the objective of this systematic review is to analyze the efficacy and safety between prophylaxis and on-demand treatment.

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II.

Materials and Methods

Study Methodology This systematic review was conducted with Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement guidelines to identify the efficacy and safety between prophylaxis and on-demand coagulation factor VIII treatment of hemophilia A.​16 Search Strategy The literature search was done using four databases: PubMed, ProQuest, ScienceDirect, and EBSCO with “Hemophilia A,” “Prophylaxis,” “on-demand,” “Inhibitor,” and “factor VIII” as the main keywords until February 8, 2020. No language restrictions were imposed. The complete keywords are listed in Table 1 in the appendix.

Study Selection The result of the search was imported to EndNote X9, and the duplicates were removed.

All authors participated through each phase of the review independently by screening the titles and abstracts, assessing the full text for eligibility criteria, then including the relevant studies.

Data collection was done by three independent reviewers (EA, C, and PW) and entered into a predesigned data extraction form. Differences arising between the three reviewers regarding study eligibility were resolved by consensus. Meta-analysis was not planned for the continuation of this systematic review.

Eligibility Criteria Population, Intervention, Comparison, and Outcomes (PICO) questions were also used to formulate the inclusion criteria of this systematic review. The answer of those questions consecutively: Population confirmed as hemophilia A patient with no history of inhibitor elicited; Intervention with a factor VIII replacement therapy given on demand; Comparison with the same therapy given prophylactically; Outcomes measured are efficacy (annualized bleeding rate) and safety (induced inhibitor) of both modalities. ​The difference between the study population and factor VIII used will be analyzed qualitatively based on the outcomes. The other

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inclusion criteria for this study are the study design and full-text availability. The study design had to be a randomized controlled trial (RCT) and all included studies must have full text.

Risk of Bias in Individual Studies Cochrane risk of bias tool 2.0 was utilized in the quality assessment of the studies which covers the following seven domains of risk. Included study quality will be classified as low, unclear, or high risk of bias.​17 Disagreements arising in the process of the evaluation were all resolved by discussion among the review team.

III.

Result

Search Results A literature search from electronic databases yielded 317 studies. After removing the duplicates, 173 remaining studies. Screening through the titles and abstracts, the authors excluded studies which give rise to a total of 18 studies to be assessed for its full-text articles.

The result showed that seven studies matched the criteria for inclusion.​18-24 Search flowchart and selection method were summarized in Fig 1.

Study Characteristics All of the included studies were done using the RCT design. Inclusion and exclusion criteria across studies showed similarities. Most of the studies were a multicenter trial with populations included from various countries across the continents (Europe, South Africa, North America, South America, Asia).​19-24 There are some varieties found in the study populations and coagulation FVIII used. The treatment dosage and the outcome measured have only minor differences amongst studies with efficacy and safety analysis. Detailed characteristics of the included studies were summarized in Table 2.

Quality Assessment There were unclear risks for all studies from the domain of detection and reporting bias.

Low risk was given for the domain of performance and other bias in all studies. Concealment of

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randomization was only done in one study.​19 Also, two studies did not mention randomization​21,24 and only three studies applied proper randomization methods in the trial.​18,19,23 Attrition bias assessment showed two studies having unclear risk.​21,24 Overall studies had an unclear risk of bias based on the author's judgement. The risk of bias based on authors’ judgments was summarized in Fig 2.

Effectivity in Lowering Annualized Bleeding Rate Studies done by Yang et al., Kavakli et al., and Fujii et al. are all reported from a trial called Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease (LEOPOLD II). This trial was held multinational in 11 countries to compare replacement therapy given prophylaxis and on-demand. Yang et al. and Fujii et al. studies reported from specific populations, which are from Chinese and Japanese subgroups, respectively. Interventions were divided into high-dose prophylaxis, low-dose prophylaxis, and on-demand groups. Yang et al. summarized the results into Chinese and non-Chinese patients. The median annualized bleeding rate (ABR) for Chinese patients is significantly higher in the on-demand compared to the combined prophylaxis group, which measured in the first six months (65.9 vs 2.0, P=0.002) and the last six (61.3 vs 2.0, P=0.002). Similar results were found in the non-Chinese patients, which is also measured in the first six months (51.6 vs 3.8, P<0.0001) and the last six (58.5 vs 1.0, P<0.0001). Kavakli et al. showed similar significant results measuring mean ABR after 12 months with samples not limited to a specific subgroup (57.7±24.6 vs 4.9±6.8, P<0.0001). Fujii et al. also recorded similar results after 12 months of follow up in Japanese (48.2±22.7 vs 5.3±8.7) and non-Japanese (44.8±22.5 vs 3.3±5.8) patients.

Another study done by Tiede et al. used Human-cl rhFVIII, which is a new generation rFVIII expressed in a human cell line. This study was analyzed from two different but similarly designed studies, as a result, the patient population used is different but still shows similar characteristics. The first is a group of 32 patients who are treated prophylactically with 30-40 IU FVIII kg​-1 body weight every other day for ≥50 exposure days and ≥6 months. While the other 22 patients who receive on-demand treatment are treated as needed. The median annualized bleeding rate (ABR) is as expected, whereby the value during prophylaxis is 2.30 in comparison to the onset of on-demand treatment of 57.54, equating to a 96% lower ABR during prophylaxis.

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Meanwhile, a study done by Chozie et.al. does not use a recombinant factor, but a low-dose of plasma-derived concentrate. It was an open, randomized controlled trial with two parallel groups: 25 patients in the prophylaxis group which received FVIII 10 IU/kg two times per week and 25 in the on-demand group, which is safe to assume to have received treatment according to needs only. Subjects from both groups were aged between 4-18 years old, and all were monitored for 12 months. One of the primary outcomes for this study is the total bleeding episode. There are a total of 8 bleeds in the prophylaxis group (Q1: 5.5, Q3: 13.5) and 25 bleeds (Q1: 17, Q3: 39.5) in the on-demand group. In addition, the data provided are statistically significant with a p-value <0.0001.

A study done by Mahlangu et al. recruited males with severe hemophilia A (FVIII activity <1%), previously treated with FVIII (>150 exposure days [EDs] prior to enrollment), and aged between 12 and 65 years. Participants were assigned to either prophylaxis or on-demand treatment using the rVIII-SingleChain. From the 173 patients that completed the study, 146 received prophylaxis and 27 received on-demand treatment. At the screening, hemophilic arthropathy was reported by 15 patients (56%) assigned to on-demand treatment and by 71 patients (49%) assigned to prophylactic therapy. The observed mean ± SD ABR was 3.11 ± 5.05 across all prophylaxis and 31.14 (35.56) for on-demand treatment.

Turoctocog alfa, a third-generation rFVIII molecule, was used in a study by Lentz et al. where they recruited previously treated patients (PTPs) with severe hemophilia A with no history of FVIII inhibitors. A total of 207 patients were treated prophylactically (27 on the less-frequent regimen) and 19 were treated on-demand. In those on prophylaxis, 1782 bleeds were reported in 170/207 patients. The overall median ABR for the prophylaxis group was 1.37 bleeds/y (0.00 – 17.82). For the on-demand treatment, the overall median ABR was 30.44 bleeds/y.

Safety Regarding FVIII Inhibitor Similar results were found in all studies regarding the induction of an inhibitor antibody.

To begin with, all study populations baseline characteristics in these seven studies showed no presence of an inhibitor antibody. There were no reported cases of FVIII inhibitors being induced for both the prophylaxis and on-demand study group at the end of the trial. This

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summarizes that there is no superiority found in these two modalities when it comes to the danger of induced inhibitor antibodies.

IV.

Discussion All seven studies resulted in rather similar outcomes. In terms of effectiveness, all

prophylaxis groups showed superiority with a much lower ABR compared to the on-demand groups. The median ABR can be as high as 65.9 in the on-demand group and as low as 1.0 in the prophylaxis group.​20 Similar results were also found regarding the safety of each modality. Both groups did not show any signs of an induced inhibitory antibody against FVIII. These same results need to be investigated regarding the varieties found across each study.

Differences in Various Aspects of the Treatment The difference in the coagulation FVIII used was found across several studies. This is crucial since it puts the homogeneity of the systematic review at risk. The first difference is between the use of a plasma-derived FVIII and a recombinant one. Recombinant FVIII is a coagulation factor that was made synthetically, thus has a lower risk of blood-borne infections.​25 However, both are similar in terms of effectivity (ABR) and safety (induced inhibitor).​26 For the recombinant factor alone, it is further divided into first and third generations.​27 Six studies used the recombinant FVIII and all of it was the third generation.​19-24 This generation, when compared to the first or a plasma-derived one, has much better pharmacokinetics (PK) in terms of longer half-life and reduced renal clearance. The superior PK leads to decreased amount of infusion needed for a period of time. However, this too does not influence the effectiveness and safety of the FVIII used.​27 Another difference that needs to be discussed is the range of age groups used in the studies. Most of the studies reviewed range between the age of 12-65 years. However, patients who enrolled in the study done by Tiede et al. were all adults by means of 18 years of age and above, despite 12 years of age being eligible to apply. Meanwhile, the study done by Chozie et

119

al. only included children 4-18 years of age.​18,22 Nevertheless, this difference can be ignored since it does not have an impact on the results of bleeding rate. One recent study done by Michael B. Nichol had investigated the impacts of changes in participants’ age on annualized bleeding rates. Three groups were classified in this particular study, including children (aged 2-11 years), adolescents (aged 12-20 years) and adults (aged ≥ 21 years). Results showed that the mean annualized bleeding rate was not statistically significant (P>0.05) between the baseline data of the participants from the two-year observational study (2005-2007) with those who continued for the long-term follow-up study in 2014. Moreover, the bleeding rates among age groups in the follow-up study also show an insignificant value (P=0.06).​28 As in the aspect of safety, recent data showed that the development of FVIII inhibitors is not associated with the age of the patient.​29 Although, the initial administration of treatment before the age of three months showed a significant impact on high-titer inhibitor development. Hence administration to children should be treated carefully.​30 Strengths and Limitations of The Studies Several of the included studies had also emphasized their strengths and limitations. One distinguishable strength is the supporting evidence on the benefits of low-dose tertiary prophylaxis given in Chozie et al’s study.​18 As opposed to standard high-dose prophylaxis, low-dose prophylaxis remains superior to on-demand treatment in reducing bleeding events and better joint function. With less dosage, it also remained cost-effective. Therefore, low-dose prophylaxis was highly recommended in countries with limited resources.​18,31 Meanwhile, the first inherent limitation is population-wise. Both studies were done by Fuji et al. and Chozie et al. only used a small population of subjects for the trial. However, the studies still provide beneficial information in terms of comparing prophylaxis and on-demand treatment.​18,19 Meanwhile Tiede et al.’s study used patient populations from two separate studies.

This claim can also be tolerated since both patient populations showed similar inclusion and exclusion criteria, as well as corresponding joint health scores.​22 Moreover, in the course of the study, Chozie et al. discovered that all subjects had joint abnormalities after they undergo Hemophilia Early Arthropathy Detection Ultrasound (HEAD-US).​18 Another downside is the use of open-label design by all seven reviewed studies whereby both participants and researchers

120

were aware of the treatment received by the former.​23,32 Nevertheless, these two additional limitations did not interfere with our conclusion as joint abnormalities could not increase the superiority of either prophylaxis or on-demand treatment; subjects are also unable to validate their judgment on a bleeding episode despite being aware of the treatment they receive since screening will have to be done subsequently.

V.

Conclusion This systematic review has an objective to compare two modalities of treatment in terms

of efficacy and safety. Results in efficacy from all seven studies favor prophylactic treatment.

However, both are proven safe, in that no inhibitors are induced. The use of low-dose prophylaxis is recommended for future studies since it has been proven as effective and may lead to better cost-effective treatment. To conclude, based on this review, the prophylactic treatment is superior in terms of lowering ABR and is safe in terms of not inducing the formation of an inhibitory antibody.

VI.

Conflict of Interest

The authors declare that there are no competing interests in this study.

121

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4. CDC. “What is Hemophilia | Hemophilia | NCBDDD | CDC.” Centers for Disease Control

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PMCID: PMC3629762. PMID: 23610614 13. Arshad S, Singh A, Awasthi NP, Kumari S, Husain N. Clinicopathological parameters influencing inhibitor development in patients with hemophilia A receiving on-demand therapy. SAGE. 2018. Ther Adv Hematol. doi: 10.1177/2040620718785363 14. Meeks SL, Batsuli G. Hemophilia and inhibitors: current treatment options and potential new

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16. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097 17. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. Published 2019 Aug 28. doi:10.1136/bmj.l4898 18. Chozie N, Primacakti F, Gatot D, Setiabudhy R, Tulaar A, Prasetyo M. Comparison of the efficacy and safety of 12-month low-dose factor VIII tertiary prophylaxis vs on-demand treatment in severe haemophilia A children. Haemophilia. 2019;00:1–7.

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19. Fujii T, Hanabusa H, Shima M, Morinaga T, Fukutake K. Analysis of the Japanese subgroup in LEOPOLD II: a phase 2/3 study of BAY 81-8973, a new recombinant factor VIII product. International Journal of Hematology. 2016;105(3):280-286.

20. Yang R, Sun J, Zhao Y, Wang X, Wu D, Tseneklidou-Stoeter D et al. Efficacy and safety of prophylaxis with BAY 81-8973 in Chinese patients with severe haemophilia A enrolled in the LEOPOLD II trial. Haemophilia. 2019;25(3):1–6.

21. Lentz S, Janic D, Kavakli K, Miljic P, Oldenburg J, C. Ozelo M et al. Long-term safety and efficacy of turoctocog alfa in prophylaxis and treatment of bleeding episodes in severe haemophilia A: Final results from the guardian 2 extension trial. Haemophilia.

2018;24(6):e391-e394.

22. Tiede A, Oldenburg J, Lissitchkov T, Knaub S, Bichler J, Manco-Johnson M. Prophylaxis vs. on-demand treatment with Nuwiq®(Human-cl rhFVIII) in adults with severe haemophilia A. Haemophilia. 2015;22(3):374-380.

23. Kavakli K, Yang R, Rusen L, Beckmann H, Tseneklidou-Stoeter D, Maas Enriquez M et al. Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: results from a randomized trial ( LEOPOLD II). Journal of Thrombosis and Haemostasis. 2015;13(3):360-369.

24. Mahlangu J, Kuliczkowski K, Karim F, Stasyshyn O, Kosinova M, Lepatan L et al.

Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A. Blood. 2016;128(5):630-637.

25. IHTC. Plasma-derived and Recombinant Products for Hemophilia [Internet]. Ihtc.org.

2021

[cited

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2021].

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https://www.ihtc.org/hemophilia-plasma-derived-vs-recombinant-products 26. Franchini M. Plasma-derived versus recombinant Factor VIII concentrates for the treatment of haemophilia A: recombinant is better. Blood Transfus. 2010;8(4):292–296.

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27. Schiavoni M, Napolitano M, Giuffrida G, Coluccia A, Siragusa S, Calafiore V et al.

Status of Recombinant Factor VIII Concentrate Treatment for Hemophilia A in Italy: Characteristics and Clinical Benefits. Frontiers in Medicine. 2019;6:261.

28. Michael B. Nichol, Randall Curtis, Yuchen Ding, Elmar R. Aliyev, Marion A. Koerper, Mimi Lou, Megan M. Ullman, Duc Quang Tran, Judith Baker, Brenda Riske, Joanne Wu; Impact of Prophylaxis Usage on Bleeding Rates Among Persons with Hemophilia A: Evidence from Longitudinal Analyses in the USA. Blood 2018; 132 (Supplement 1): 494. doi:​ https://doi.org/10.1182/blood-2018-99-119215 29. Witmer C, Young G. Factor VIII inhibitors in hemophilia A: rationale and latest evidence. Ther Adv Hematol. 2013;4(1):59-72. doi:10.1177/2040620712464509 30. Halimeh, Susan, et al. “Risk Factors for High-Titer Inhibitor Development in Children with Hemophilia A: Results of a Cohort Study.” BioMed Research International, 2 Oct. 2013, doi:​https://doi.org/10.1155/2013/901975​.

31. Gouider, E. Show me the evidence: Effectiveness of low-dose prophylaxis. Haemophilia.

2020; 26: 1– 2.​ https://doi.org/10.1111/hae.13892 32. Open-Label Trial | ClinicalInfo. https://clinicalinfo.hiv.gov/en/glossary/open-label-trial​.

Accessed 17 Mar. 2021.

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APPENDICES Table 1. Search Keywords Databases

PubMed

ProQuest

Keywords ((((((((((Hemophilia A[MeSH Terms]) OR ("Hemophilia A"[Title/Abstract])) OR ("Classic hemophilia"[Title/Abstract])) OR ("Factor VIII Deficiency"[Title/Abstract])) OR ("Congenital Hemophilia A"[Title/Abstract])) OR ("Autosomal Hemophilia A"[Title/Abstract])) OR ("Haemophilia A"[Title/Abstract])) AND ((((((Prophylaxis[Title/Abstract]) OR (prevention[Title/Abstract])) OR (preventions[Title/Abstract])) OR (preventing[Title/Abstract])) OR (prophylactic[Title/Abstract])) OR ("preventive treatment"[Title/Abstract]))) AND ((on-demand[Title/Abstract]) OR ("on demand"[Title/Abstract]))) AND ((Inhibitor[Title/Abstract]) OR (inhibitors[Title/Abstract]))) AND (((((factor VIII[MeSH Terms]) OR ("factor VIII"[Title/Abstract])) OR ("Factor 8"[Title/Abstract])) OR ("Coagulation Factor VIII"[Title/Abstract])) OR (FVIII[Title/Abstract])) ((ti("Hemophilia A" OR "Classic hemophilia" OR “Classic hemophilias” OR "Factor VIII Deficiency" OR "Congenital Hemophilia A" OR "Autosomal Hemophilia A" OR "Haemophilia A") OR ab("Hemophilia A" OR "Classic hemophilia" OR "Factor VIII Deficiency" OR "Congenital Hemophilia A" OR "Autosomal Hemophilia A" OR "Haemophilia A")) AND (ti(Prophylaxis OR prevention OR preventions OR preventing OR prophylactic OR “preventive treatment”) OR ab(Prophylaxis OR prevention OR preventions OR preventing OR prophylactic OR “preventive treatment”)) AND (ti(On-demand OR “on demand”) OR ab(On-demand OR “on demand”)) AND (ti(Inhibitor OR inhibitors) OR ab(Inhibitor OR inhibitors))) AND (ti("factor VIII" OR "Factor 8" OR "Coagulation Factor VIII" OR FVIII) OR ab("factor VIII" OR "Factor 8" OR "Coagulation Factor VIII" OR FVIII))

("Hemophilia A" OR "Classic hemophilia" OR "Factor VIII ScienceDirect Deficiency" OR "Haemophilia A") AND (Prophylaxis OR prevention) AND On-demand AND (Inhibitor OR inhibitors)

126

Articles

159

27

10

EBSCO

( (TI ( "Hemophilia A" OR "Classic hemophilia" OR “Classic hemophilias” OR "Factor VIII Deficiency" OR "Congenital Hemophilia A" OR "Autosomal Hemophilia A" OR "Haemophilia A" ) OR AB ( "Hemophilia A" OR "Classic hemophilia" OR "Factor VIII Deficiency" OR "Congenital Hemophilia A" OR "Autosomal Hemophilia A" OR "Haemophilia A" )) AND (TI ( Prophylaxis OR prevention OR preventions OR preventing OR prophylactic OR “preventive treatment” ) OR AB ( Prophylaxis OR prevention OR preventions OR preventing OR prophylactic OR “preventive treatment” )) AND ((TI ( On-demand OR “on demand” ) OR AB ( On-demand OR “on demand” )) AND (TI ( Inhibitor OR inhibitors ) OR AB ( Inhibitor OR inhibitors )) ) AND (TI ( "factor VIII" OR "Factor 8" OR "Coagulation Factor VIII" OR FVIII ) OR AB ( "factor VIII" OR "Factor 8" OR "Coagulation Factor VIII" OR FVIII ))

127

121

Fig 1. PRISMA flow diagram of the identification and selection of studies included in the analys

128

Multinational, randomized, open-label crossover, phase 2/3 study

Multinational, randomized, open-label crossover, phase 2/3 study

Multinational, randomized, open-label crossover, phase 2/3 stud

Open-label multicenter phase 2/3 study

Open, randomized controlled trial

Kavakli et at., 2015

Fujii et al., 2016

Tiede et al., 2015

Chozie et al., 2019

Study Design

Indonesia

Austria, Bulgaria, Germany, UK, and USA

11 countries across Europe, South Africa, North America, South America, Asia

11 countries across Europe, South Africa, North America, South America, Asia

11 countries across Europe, South Africa, North America, South America, Asia

Location

4-18 years old

N = 50

12-65 years

N = 54

12-65 years

N = 80

12-65 years

N = 80

12-65 years

N = 80

Samples

Plasma-derived FVIII

Human-cl rhFVIII (simoctocog alfa [Nuwiq])

BAY 81-8973 (octocog alfa [Kovaltry])

BAY 81-8973 (octocog alfa [Kovaltry])

BAY 81-8973 (octocog alfa [Kovaltry])

Clotting Factor Used

Table 2. Characteristics of the Included Studies

Yang et al., 2019

Author, Year

129 Prophylaxis infusion of FVIII 10 IU/kg 2x per week

Prophylaxis group received a dose of 30–40 IU/kg every other day

Prophylaxis group received either 20–30 IU/kg administered twice weekly (low dose) or 30–40 IU/kg administered 3 times weekly (high dose).

Prophylaxis group received either 20, 25 or 30 IU/kg administered twice/week or 30,35 or 40 IU/kg administered 3 times/week.

Prophylaxis group received either 20–30 IU/kg administered twice weekly (low dose) or 30–40 IU/kg administered 3 times weekly (high dose).

Prophylaxis

On-demand

Administered as needed

Administered as needed

Administered as needed

Administered as needed

Administered as needed

Interventions

Prophylaxis: 12.8 ± 0.9 months, on-demand: 12.3 ± 0.5

Prophylaxis (180 days), on-demand (335 days)

12 months

12 months

12 months

Duration of Follow-up

ABR and induced inhibitor

ABR and induced inhibitor

ABR and induced inhibitor

ABR and induced inhibitor

ABR and induced inhibitor

Outcomes Measured

On-demand (25, Q1: 17; Q3: 39.5)

Prophylaxis (8, Q1: 5.5; Q3: 13.5)

96% lower ABR during prophylaxis

Prophylaxis: 2.30 (CI: 1.54, 3.44) With p-value <0.0001.

On-demand treatment 57.74 (CI: 43.36, 76.91)

Non-Japanese patients - On-demand (44.8±22.5) vs prophylaxis (3.3±5.8)

Japanese patients - On-demand (48.2±22.7) vs prophylaxis (5.3±8.7)

Prophylaxis (4.9±6.8) with P<0.0001

On-demand (57.7±24.6)

Non-Chinese patients (P<0.0001) - First 6 months: on-demand (51.6) vs prophylaxis (3.8) - Last 6 months: on-demand (58.5) vs prophylaxis (1.0)

Chinese patients (P=0.002) - First 6 months: on-demand (65.9) vs prophylaxis (2.0) - Last 6 months: on-demand (61.3) vs prophylaxis (2.0)

Effectivity (ABR)

Adverse events

No FVIII inhibitors were reported

No FVIII inhibitors were reported

No FVIII inhibitors were reported

No FVIII inhibitors were reported

No FVIII inhibitors were reported

Result

Phase 3b, non-randomized, open-label, multicentre, multinational, single-arm extension trial

Lentz et al., 2018

52 sites in 19 countries

N/A

: Confidence Interval

CI

: International Unit

: Kilogram

: Not Available

: Number of Participants

: Year

IU

kg

N/A

N

y

FVIII : Factor 8

: Annualized Bleeding Rate

Across all ages

N = 213

12-65 years old

N = 173

ABR

Abbreviations:

Open-label, non-randomized, multicenter, phase 1/3 clinical study

Mahlangu et al., 2016

130

Turoctocog alfa (NovoEight)

rVIII-SingleChain (lonoctocog alfa [afstyla])

Prophylaxis group received either 20-50 IU/kg once every second day or 20-60 IU/kg 3 times weekly)

Prophylaxis group received either 20-40 IU/kg every second day or 20-50 IU/kg 2-3 times per week

Administered as needed

Administered as needed

N/A

N/A

months

ABR and induced inhibitor

ABR and induced inhibitor

On-demand: 30.44 bleeds/y

Prophylaxis: 1.37 bleeds/y

Prophylaxis (3.11 ±5.05)

On-demand (31.14 ± 35.56)

With P<0.001

No FVIII inhibitors were reported

No FVIII inhibitors were reported

Fig 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study

131

Concizumab As A Novel Treatment for Hemophilia A and B Patients With or Without Inhibitors: A Systematic Review

Abstract Introduction: Hemophilia is a blood-related disorder caused by mutations on the X chromosome commonly occurring in males. The gene mutation involved in hemophilia renders this disease incurable, and thus only supportive treatment is available. Current standard treatment has many flaws. Concizumab is a novel therapy for hemophilia A and B patients with or without inhibitors.

Methods: Studies were obtained from 5 databases (PubMed, EBSCO, Proquest, Google Scholar and Science Direct). The PRISMA flowchart was used as a guide to select studies related to this review. This review included only randomized-controlled trial studies that were published in the last 10 years, studies that targeted hemophilia A and B patients, and studies that evaluated the safety and efficacy of concizumab administration.

Results: Thus far, concizumab is safe and effective for hemophilia A and B patients with or without inhibitors.

Conclusions: Concizumab is a promising novel therapy for hemophilia A and B patients with or without inhibitors.

Keywords: hemophilia, concizumab

Introduction Hemophilia is an inherited bleeding disorder wherein blood doesn’t clot normally.

People with this disease have very little amounts of either factor VIII (hemophilia A) or factor IX (hemophilia B). Factors VIII and IX hold an important role in clotting. Clotting factor shortage results in a longer bleeding process than healthy people. 1,2 Complications associated with hemophilia include hemophilic arthropathy3 and may cause other health problems. As hemophilia is a genetic disorder inherited through the X chromosome,4 this blood disorder occurs mostly in males as they have XY chromosomes while females have XX chromosomes.

A female with one affected X chromosome becomes a carrier while a male with an affected X chromosome will have hemophilia.

According to the CDC, in the United States, 400 babies are born with hemophilia A each year. The gene mutation involved in hemophilia makes this disorder incurable. Hence, only supportive treatment can be done for patients with hemophilia. 5 Standard treatment is to replace the missing factor so that blood can clot properly by injection of clotting factor concentrate. There are multiple weaknesses to this therapy. The first is that IV administration may lead to lower patient compliance and complications such as infection. Secondly, continuous administration of exogenous FVIII or FIX clotting factors leads to the development of inhibitors, which render treatment ineffective. Therefore, there is

132

a need for non-replacement therapy. Recently, a novel therapy, emicizumab, has been approved by the FDA. Yet, emicizumab has only been approved for hemophilia A patients with or without inhibitors, and not for hemophilia B patients. 6 Concizumab is a novel therapy given subcutaneously for haemophilia A and hemophilia B patients irrespective of inhibitor status or severity of disease. It acts as a rebalancing agent that binds to the Kunitz-2 domain of tissue factor pathway inhibitor (TFPI), molecules that contribute to downregulation of coagulation, thereby preventing TFPI from binding to and blocking the factor Xa (FXa) active site. When the TFPI inhibitory activity is decreased, sufficient FXa is produced by the FVIIa-tissue factor complex to achieve hemostasis. 7

Methods In this systematic review, all studies were obtained from 5 databases, such as PubMed, EBSCO, Proquest, Google Scholar and Science Direct. The search was completed on March 13, 2021. The keywords that were used to obtain these studies were hemophilia, concizumab and their synonyms. In this systematic review, we included only randomized-controlled trial studies that were published in the last 10 years, studies that targeted patients with hemophilia A or patients with hemophilia B, and studies that evaluated the safety, pharmacodynamics, pharmacokinetics as well as efficacy of concizumab in reducing bleeding rate in patients with hemophilia. Our exclusion criteria were clinical trials with no control group.

To exclude duplicates, we used Zotero citation manager. Then, we applied the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flowchart as guidance in selecting studies related to this review. The tiles and abstracts of each study obtained through application of the keywords stated above were then screened independently by two or more writers. After, we read the full-text version of relevant studies. Those that matched our inclusion criteria were included in this systematic review. Therefore, a total of three randomized-controlled clinical trials were assessed in this study, and we graded risk of bias in accordance with Revised Cochrane Risk-Of-Bias Tool for Randomized Trials (RoB 2), the results of which are present in Table 1.

133

Table 1. Quality of Study Assessment Category

Chowdary, P. et al. (2015)

al. (2018)

al. (2019)

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Domain 1: Risk of bias arising from the randomization process Domain 2: Risk of bias due to deviation from intended interventions Domain 3: Risk of bias due to missing outcome data Domain 4: Risk of bias in measurement of the outcome Domain 5: Risk of bias in selection of the reported result OVERALL RISK OF BIAS

Eichler, H. et Shapiro, AD et

Low risk of bias Low risk of bias Low risk of bias

Results A total of three studies were included in this systematic review. Search flowchart and methods used in this systematic review are summarized in Figure 1. Characteristics of included studies are given in Table 2.

134

Table 2. Summary of Study Characteristics Author (Date of Location

Type of Study

Number

Publication)

Other interventions Results

Adverse Events

participants

Chowdary, P. et Explorer1: 9 Phase al. (2015)

of Dosage

countries

1, 52 participants

Healthy

+ With FVIII or FIX

multicenter RCT,

concizumab

(on

dose-escalation

(i.v.):

prophylactically)

trial

0.5, 5, 50, 250

functional levels after 5 days post

μg/ kg

decreased

Hemophilia +

demand

and

1. Free TFPI plasma Superficial concentration residual

& thrombophlebitis as

TFPI local skin tenderness

administration

2. Decreased mean concizumab,

concizumab

fibrinogen

disappeared

(i.v.):

concentration

spontaneously

250,

1000,

3000,

(still

within

normal range)

9000 μg/kg Healthy

3. Increased level of +

D-dimers

&

concizumab

prothrombin F1+2

(s.c.):

→

50, 250, 1000

coagulant activity

μg/kg

of concizumab

135

confirm

of

Hemophilia +

4. Prevent bleeding

concizumab

in hemophilia A

(s.c.):

and B

1000,

3000

5. No

μg/kg Eichler, H. et al. 18 sites in 13 Explorer 3: (2018)

countries

24 participants

bleeding

events occurred.

0.25mg/kg

FVIII

Multinational,

0.5mg/kg

for

multicenter,

0.8mg/kg

episodes

RCT,

double-

every

blind,

multiple-

dose,

dose-

fourth

day

concentrate bleeding

1. TFPI level decreased 56 with

increasing (2 moderate and 54

doses

mild)

2. Residual

TFPI Headache,

activity decreased 3. TG

escalation

and 13 AEs ‘probably’

prothrombin above

F1+2 related the concizumab

normal reference in administration.

0.8mg/kg patients.

5. Mean

fibrinogen

values decreased by 20%

136

site

erythema.

4. D-dimer

levels

nasopharyngitis,

potential injection

increased

trial

AEs

to

6. Bleeding with were

episodes

concizumab lesser

than

placebo Shapiro, AD. et explorer4: 12 Explorer 4: RCT Explorer4: al. (2019)

countries

(inhibitor trial)

participants

26 Explore4

and on-demand rVIIa

explorer5: 0.15

Injection 1. Effective

site

bruising, hematoma,

mg/kg

prevention

concizumab

bleeding episodes nasopharyngitis;

daily

(with

of or

haemorrhage;

2. Low number of infection of upper

dose escalation

treatment-

if

emergent adverse 1 serious

criteria

fulfilled)

events occurrence

respiratory tract.

and event

adverse

in

of concizumab arm (not

anti-drug

estimated

antibodies

have been caused by

3. rVIIa safe when concizumab.) exposed concizumab

137

the

to

to

Chowdary et al.8 recruited healthy participants and those with hemophilia to evaluate the safety as well as the pharmacokinetics (PK) and pharmacodynamics (PD) of escalating single-dose concizumab given intravenously or subcutaneously.

Healthy volunteers were dosed first, and once switching criteria were fulfilled, continued in hemophilia patients. Switching criteria was predefined as a consistent increase in D-dimers and/or prothrombin fragment 1 + 2 (F1 + 2) and/or a maximum intravenous (i.v.) dose of 250 μg/kg and a maximum subcutaneous (s.c). dose of 1000 μg/kg. First dose was administered at the minimum anticipated biological effect level of 0.5 μg/kg i.v., and once safety had been proven, healthy volunteers were given 50 μg/kg s.c.

The primary end-point of this study was safety. Adverse events (AEs) were evaluated up to 43 days after concizumab treatment. Local injection-site reactions, clinical laboratory assessments, vital signs, physical examination and electrocardiogram results were also recorded.

Platelet count, protein C and S, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen concentration and antithrombin activity were determined from plasma before dosing and at multiple time-points after dosing. No clinically relevant changes were found and there were no signs of disseminated intravascular coagulation (DIC). However, fibrinogen levels showed high variations, all still within the normal range, and without any clinically relevant changes. Evaluation of anti-concizumab antibodies, bound and free, was also performed.

There were no serious AEs during the trial and up to 43 days after, and no anticoncizumab antibodies were detected. Moderate AE in the concizumab arm manifested as a small superficial thrombophlebitis in a healthy volunteer. Mild AEs were trace protein in urine and abdominal pain in hemophilia volunteers that received 250 and 9000 μg/kg i.v. concizumab, respectively. No dose relationship was concluded to the number of AEs observed.

PK endpoints included total exposure (AUC0–∞), maximum plasma concentration (Cmax), clearance (CL), t1/2, mean absorption time, volume to distribution at steady state, bioavailability, and time to maximum concentration. Plasma concizumab concentrations were measured through free concizumab and concizumab in a 1:1 complex with TFPI. PD endpoints included free TFPI in plasma, residual TFPI functionality in plasma, and D-dimer and prothrombin F1 + 2 as markers of procoagulant effect.

Functionality of residual TFPI was determined by detection of FXa activity. Increased drug doses were associated with increased FXa generation and were inversely proportional to free TFPI concentration (i.e. TFPI concentration decreased when concizumab dose increased).

The markers of procoagulant effect, D-dimer and F1 + 2, showed a dose-dependent increase.

However, D-dimer results in hemophilia patients were lower than healthy volunteers at the

138

same dose level. At lower concentrations, concizumab was cleared quickly. However, higher concentrations of concizumab had a longer t1/2. AUC0–∞ and an increased Cmax.

Eichler et al.9 investigated five escalating dose cohorts, each consisting of eight participants and divided into two blocks, given either concizumab or placebo. Participants were allowed to treat bleeding with FVIII concentrate, but antifibrinolytics, anticoagulants, and FVIII bypassing agents weren’t allowed during the trial.

The trial’s primary objective parameters were to evaluate safety, antithrombin time, prothrombin time, activated partial thromboplastin time, D-dimers, prothrombin F1+2 levels, protein C, and protein S. Secondary objectives included the assessment of pharmacokinetics and pharmacodynamics of multiple doses of concizumab in haemophilia A patients.

The trial was conducted for 13 months with a total of 24 eligible patients that were randomized and distributed between three concizumab dose groups (0.25, 0.5, 0.8 mg/kg every four days). In each group, two participants received placebo and six others received concizumab. All AEs except one were classified as mild. Occurrence of myalgia in the 0.25 mg/kg concizumab cohort was classified as moderate. All patients with AEs had full recoveries.

There were no clinically significant changes in primary objectives related to concizumab treatment. However, the secondary objectives showed that concizumab exposure (AUC) and thrombin generation (TG) potential increased with increasing concizumab dose, meanwhile unbound TFPI and residual TFPI activity levels decreased with increasing concizumab dose.

D-dimer and prothrombin F1+2 levels were above the normal range in 0.8 mg/kg cohort patients, mean fibrinogen values decreased while mean levels of soluble fibrin were above the normal range in the 0.8 mg/kg cohort. These changes indicated activation of coagulation and fibrinolytic pathways. Besides that, bleeding episodes occurred less in the concizumab cohort.

In this trial, there were no thromboembolic events or abnormal bleeding patterns. No anti-drug antibodies were detected.

Shapiro et al.6 assessed the efficacy and safety of 24 weeks of subcutaneous concizumab treatment in hemophilia A and hemophilia B patients with inhibitors (HAwI/HBwI), seen from the number of bleeding episodes, number of treatment-emergent adverse events (TEAEs), and whether or not concizumab antidrug antibodies (ADAs) were found, measured from time of treatment onset. The study also evaluated the safety of rVIIa when given alongside concizumab.

Patients in the concizumab arm were given a loading dose of 0.5 mg/kg and daily subcutaneous injections of 0.15mg/kg. If the patient had 3 or more spontaneous bleeding episodes within the preceding 12 weeks, the patient was then escalated to the next dose level of 0.20 and 0.25 mg/kg. Patients in the control group were given rFVIIa. Breakthrough

139

bleeding episodes were treated with ≤90 μg/kg rFVIIa. This study involved only male patients older than 18 from multiple nationalities. Prior to the concizumab experiment, most participants received only on-demand treatment.

Efficacy of concizumab was judged from dose escalation and bleeding episodes. Fifteen from the seventeen participants randomized to the concizumab arm did not need dose escalation, whereas the remaining two had dose escalation to 0.20 mg/kg.

Participants in the concizumab arm had an estimated annualized bleeding rate (ABR) of 4.5 (95% CI, 3.2; 6.4); the rFVIIa on-demand arm had an estimated ABR of 20.4 (95% CI, 14.4; 29.1). None of the participants had severe bleeds. The ABR ratio between the two groups was less than one, hence, the study succeeded in demonstrating clinical proof of concept. The concizumab arm experienced a significant bleed reduction (P<.001) for all treated bleeds and for spontaneous and joint bleeds when compared to those in the rVIIa arm.

Safety and toleration of concizumab administration was seen from the number of adverse events (AE) and immunogenicity. No severe AEs were reported, there were no AErelated withdrawals, and no participant experienced thromboembolic events. Treatment of breakthrough bleeding episodes with rVIIa in the concizumab arm did not result in AEs. All in all, AE rates were low and unlikely to be related to concizumab treatment.

Three of the patients in the concizumab arm had positive ADA tests with medium titers.

However, when compared to patients without ADAs, there were no differences in bleeding pattern, PK/PD parameters, AEs, or laboratory coagulation-related parameters.

Discussion Chowdary et al. and Eichler et al. assessed the pharmacodynamics and pharmacokinetics of concizumab administration. In both studies, free TFPI decreased when dosing increased, showing that with increasing dose levels, more concizumab were bound to TFPI. TFPI itself is a binding site for FXa, enhanced by protein S. Preventing FXa from binding to TFPI avoids inhibition of the coagulation cascade and an increase in FXa generation.

D-dimer is a fibrin degradation product and F1+2 is released from prothrombin during thrombin formation, a key part in the coagulation cascade. Both studies also showed that increasing concizumab dose led to an increase in D-dimer and F1+2 levels while mean fibrinogen levels decreased. The aforementioned results indicate procoagulant activity by concizumab that helps in bleed prevention.

Summary of the pharmacokinetics and pharmacodynamics of concizumab are presented in Table 3.

140

Table 3. Pharmacokinetics and Pharmacodynamics of Concizumab with Increasing Dose Treatment Dosage

Parameter ↓ Free TFPI ↑D-dimer and F1+2 ↑

↑ AUC, t1/2, Cmax ↓ Residual TFPI Activity ↓ Mean fibrinogen values

All three studies assessed safety, judged from the number and severity of treatment related adverse events as well as formation of anti-drug antibody. There were no serious adverse events caused by concizumab administration. That concizumab is administered subcutaneously instead of intravenously is also estimated to increase patient compliance.

Chowdary et al. and Eichler et al. did not discover the presence of anti-drug antibodies.

However, Shapiro et al. recorded three patients with very low to medium titer anti-drug antibodies, but there were no associated clinical effects and no differences in results between those with ADA and those without. In addition, coadministration of rFVIIa-a bypassing agent for patients with inhibitors-and concizumab did not cause any adverse effects.

Throughout the three studies, multiple doses of concizumab were administered.

Chowdary et al. allowed participants to treat bleeds with standard FVIII or FIX concentrated either prophylactically or on-demand. Nonetheless, as the main aim of Chowdary et al. was to assess safety, pharmacodynamics, and pharmacokinetics, we did not see this as a weakness in the study.

At 0.8 mg/kg of concizumab every four days, Eichler et al. stated that the concizumab arm had lesser bleeding episodes when compared to those in the placebo arm. However, only one study by Shapiro et al. actively observed the efficacy of concizumab administration as a primary endpoint, measured through bleeding rates. Shapiro et al. gave a loading dose of 0.5 mg/kg and subcutaneous injections of 0.15 mg/kg daily. The results of this study showed that participants receiving concizumab had a significantly lower bleeding rate than those in the control group.

While Shapiro et al. recorded the safety of rFVIIa in conjunction with concizumab administration, the study did not assess the safety of activated plasma-derived prothrombin complex concentrated (pd-aPCC), another common bypassing agent for patients with inhibitors. Even so, this study included a heterogeneous group of participants in terms of nationality.

141

All the studies included in this systematic review are high-quality randomized controlled trials. The minimal number of high-quality RCTs may be an impediment in this systematic review. While sample sizes were small, the studies were conducted in multiple nations with various ethnic backgrounds, minimizing the possibility of concizumab treatment results differing due to genetic differences.

Conclusion Concizumab is a safe, well-tolerated, and promising treatment for hemophilia A and B patients with or without inhibitors. However, more studies with larger sample sizes are needed to further confirm the efficacy and safety of concizumab treatment. Further analysis on the effects of concizumab anti-drug antibody is also needed, as well as the outcome of concizumab when administered concomitantly with pd-aPCC.

142

REFERENCES 1. What is Hemophilia | CDC [Internet]. [cited 2021 Mar 16]. Available from: https://www.cdc.gov/ncbddd/hemophilia/facts.html 2. Haemophilia - The Haemophilia Society [Internet]. [cited 2021 Mar 16]. Available from: https://haemophilia.org.uk/bleeding-disorders/haemophilia/ 3. Possible Complications of Hemophilia | Indiana Hemophilia & Thrombosis Center [Internet]. [cited 2021 Mar 16]. Available from: https://www.ihtc.org/hemophiliacomplications 4. Hemophilia - Symptoms and causes - Mayo Clinic [Internet]. [cited 2021 Mar 16].

Available from: https://www.mayoclinic.org/diseases-conditions/hemophilia/symptomscauses/syc-20373327 5. CDC. Data & Statistics | Hemophilia | NCBDDD | CDC [Internet]. Centers for Disease Control

and

Prevention.

2020

[cited

2021

Mar

16].

Available

from:

https://www.cdc.gov/ncbddd/hemophilia/data.html 6. Shapiro AD, Angchaisuksiri P, Astermark J, Benson G, Castaman G, Chowdary P, et al.

Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Blood. 2019 Nov 28;134(22):1973–82.

7. Shapiro AD. Concizumab: a novel anti-TFPI therapeutic for hemophilia. Blood Advances.

2021 Jan 12;5(1):279–279.

8. Chowdary P, Lethagen S, Friedrich U, Brand B, Hay C, Karim FA, et al. Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. Journal of Thrombosis and Haemostasis. 2015;13(5):743–54.

9. Eichler H, Angchaisuksiri P, Kavakli K, Knoebl P, Windyga J, Jiménez‐Yuste V, et al. A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A. Journal of Thrombosis and Haemostasis. 2018;16(11):2184– 95.

143

Appendix

Figure 1. PRISMA flowchart

144

World Haeomophilia Day Competition Administration of F VIII therapy in Intracranial Bleeding in Hemophilia

Mentaria Naibaho[1] , Gloria V.C. Semula [2] , Santa Theresia Nauli. T.[3] 1Program Studi Kedokteran, Fakultas Kedokteran, Universitas Kristen Indonesia, Jakarta 2Program Studi Kedokteran, Fakultas Kedokteran, Universitas Kristen Indonesia, Jakarta 3Program Studi Kedokteran, Fakultas Kedokteran, Universitas Kristen Indonesia, Jakarta

Abstract Hemophilia is a bleeding disorder or recessive x-linked gene-disease caused by a gene mutation.

Hemophilia A and B are caused by a mutation in the factor VIII (F VIII) and factor IX (F IX) genes.2,4 There is also hemophilia C caused by a mutation in factor XI (F XI) gene and an autoimmune process.3 These factors take part in the intrinsic pathway of blood clotting, so that affected individuals have severe, moderate, and mild forms of the disease, which are determined by their respective plasma factor levels.4 The clinical manifestations that often occur in people with hemophilia A and B are bleeding that is more frequent and in a longer period than in normal people, both outside the body and inside the body.5 As a disease caused by a genetic disorder that is transmitted or inherited by the family, the biggest risk factor for a person to develop hemophilia is when his family has a history of hemophilia. If not treated immediately, hemophilia has the risk of causing complications such as anemia, hematuria, and even damage itself. If bleeding continues, hemophilia can lead to hypovolemic shock, which is organ failure due to excessive blood loss.5 Keywords : hemophilia, prevention, treatment, therapy F VIII Preliminary

clotting factors so that it only manifests in men, whereas in women it only becomes a

Hemophilia is a hereditary bleeding

carrier or a carrier of this disease. Factor VIII

disorder related to recessive X chromosome

(FVIII) in hemophilia A and factor IX (FIX)

(X-linked) which makes it difficult for blood

in hemophilia B are the most frequent blood

to clot due to a congenital deficiency of blood

clotting factors.

145

Epidemiology, the most common

the fact that the amount of factor VIII

recessive X-linked disease in the world and

produced is decreased, there are abnormal

the second most common factor deficiency

and non-functional proteins or even both.

bleeding disease after von Willebrand's

Activation of factor X in the mixed

disease is hemophilia A. less of hemophilia A

coagulation pathway can occur in the

is about 1 per 25,000 to 30,000 males. The

presence of factor VIIIa and factor IXa, so

percentage of cases of hemophilia A was

that both hemophilia A and B have very

quite high, namely 80% - 85% of cases, while

similar clinical features. In hemophilia

hemophilia B only had an incidence of 14%,

patients the amount of thrombin formed is

and the rest were cases of other blood clots.

greatly reduced, so that the blood clot formed becomes very weak, mobile, and is very

Pathophysiology, in general, in the human

body,

there

is

a

process

susceptible to fibrolysis.

of

homeostasis to stop daily bleeding and also

Clinic manifestations, the clinical

bleeding that is more severe. Bleeding is

symptom

usually caused by an injured blood vessel.

bleeding. Although hemophilia A and B have

Usually, to stop bleeding is done by three

very similar clinical features, more severe

main steps including (1) blood vessel spasm,

cases are found in patients with hemophilia A

(2) platelet plug clotting, and (3) blood

than in hemophilia B.

coagulation.

of

hemophilia

is

excessive

Based on blood clotting factors in

The transformation of blood from a

plasma, hemophilia can be classified into

liquid into a solid gel is known as blood

three, namely mild, moderate and severe

coagulation. Factors VIII, IX, XI and XII are

hemophilia.

purely part of the intrinsic pathway in the

hemophilia without adequate treatment may

blood coagulation process, while factors III

develop recurrent hemarthrosis resulting in

and VII are the extrinsic part of the blood

hemophilic arthropathy occurring in young

coagulation process.

adulthood. Approximately 75% of bleeding

Individuals

with

severe

in patients with severe hemophilia is

In patients with hemophilia A, factor

hemarthrosis. Hemarthrosis occurs when the

VIII which functions in the blood is in

capillaries below the synovium are damaged

decreased amounts. The decrease in the

by mechanical trauma caused by everyday

amount of factor VIII in the blood is due to

146

wear. The knees, elbows, feet, hands, and

Risk

and

complication

factors,

hips are the joints most commonly affected.

various types of bleeding, both spontaneous

Hemarthrosis usually occurs when a child

and due to trauma, are most common in

with hemophilia begins to walk.

individuals with severe hemophilia. Bleeding often

Hemophilia is categorized as mild if it

hemophilia

has a blood clotting level in plasma of 6% -

Method and Results

blood clotting factor levels in the plasma, the greater the risk of bleeding. Mild hemophilia

This research is a literature study by

has clinical features, namely (1) secondary

examining in-depth many journals related to

bleeding due to trauma or surgery, and (2)

hemophilia in children. Each data is obtained

occurs,

from libraries and sources that have been

moderate hemophilia has clinical features,

analyzed in depth. The subjects included in

namely (1) bleeding secondary to trauma or

the data were hemophiliacs aged 3 to 15

surgery, and (2) sometimes spontaneous

years.

hemarthrosis, whereas severe hemophilia has

Therapy

between

patients

with

hemophilia A and B will be different. For

clinical features, namely (1) spontaneous

hemophilia, A therapy is carried out by

bleeding from infancy, and (2) frequent

administering factor VIII (concentrate or

spontaneous hemarthrosis and other bleeding

cryoprecipitates), while for hemophilia B

requiring additional factors.

therapy is carried out by administering factor

Other bleeding symptoms that are

IX (concentrate or FFP) for 7 to 14 days.1

often found in hemophilia are hematoma, cyst),

Recurrent

disability.

plasma of less than 1%. This means, the less

(blood

hemarthrosis.

severe

eventually arthropathy will occur and cause

severe if it has a blood clotting level in

pseudotumor

with

occurs repeatedly will cause pain and

- 5%, while hemophilia is categorized as

rarely

is

patients

symptom of hemophilia. Joint bleeding that

if it has a blood clotting level in plasma of 1%

bleeding

in

bleeding, especially in joints, is the main

40%, hemophilia is categorized as moderate

spontaneous

occurs

The results listed are research data on

hematuria,

hemophilia

patients

with

intracranial

intracranial bleeding, mucous membrane

bleeding by the Department of Pediatric

bleeding, and bleeding in the mouth and the

Health, Faculty of Medicine, University of

result of surgery.

Indonesia, Cipto Mangunkusumo Hospital in

147

Jakarta. Can be seen in table 1 shows that 10 out of 11 patients their condition improved during therapy.1 Table 1. Patient characteristics, clinical manifestations, Duration of therapy, and outcome No. Initial Age

Levels of Clinical

Duration of Outcome

F

Therapy F

VIII

(%) 1.

TN

3

1,1

4 2.

RR

5

19

6

VIII (day) Irritability

9

Getting better

Irritability, retch

11

Epilepsy

Headache

8

Getting better

Retch

7

Getting better

3.

P

15

<1

Loss of consciousness

1

Dead

4.

PD

3

1,3

Paresis N VII, XII, hemiparesis

15^

Getting better

5.

RNY

5

2,40

Headache,

seizures,

retch, 10

Getting better

Headache, retch, seizures, loss of 14

Getting better

hemiparesis 6.

AAN

12

6

consciousness 7.

MD

12

3,8

Headache, retch

8

Getting better

8.

K

3

<1

Seizures, paresis N VII peripheral

15

Getting better

9.

DS

15

1,4

Headache, seizures

8^

Craniotomy day 2, getting better*

10.

MB

12

2,4

Headache,

retch,

loss

of 16

Getting better

16

Getting better

consciousness 11.

E

14

2,7

vulnus laceratum, headache

*No CT re-scan was performed

^Inhibitor F VIII : negative

According to the data listed, the number of

retch (6), seizures (4), loss of consciousness

clinical manifestations are headache (7),

(3), irritability (2), paresis motor (2), cranial

148

nerve paresis (2), and vulnus lacenatum in head (1).1 Discussion

All episodes of intracranial bleeding in our study were experienced by hemophilia

Intracranial bleeding that occurs in

A patients. Research in Brazil showed ICH in

hemophilia patients enrolled in our institution

33/362 hemophilia patients A and 2/39

is 7.1%. Antunes et al[12] reported 45

hemophilia patients B.[12] In this study, the

episodes of intracranial bleeding from 40[6]

ratio of hemophilia patients A and B was

hemophilia patients in Brazil in the period

362/39 (9.2: 1)[12] while in our institutions

1987-2001. French Intracranial Hemorrhage

120/18 (6.7: 1). A multicenter survey report

(ICH) Study Group[11] in 2005 reported

on

observations for 10 years, there were 123

ICH prevalence in hemophilia A with

are estimated to be about 400,000 hemophilia

hemophilia B (3.5% vs. 6.3%).8

patients, but only recorded 1280 patients

The median age of our patients

(data of the Indonesian Hemophilia Society,

experiencing intracranial bleeding 6 years (3

2010), making it difficult to know the bleeding

by

ICH 30) showed no significant difference in

with a population of about 220 million there

intracranial

conducted

Hemostasis (number of patients 744, episode

patients in France (multicenter). In Indonesia,

of

patients

GTH/German Society of Thrombosis &

episodes of intracranial bleeding from 106

incidence

pediatric

– 15 years). The average age of hemophilia

in

patients

hemophilia patients. We suspect that the high

in

Brazil

who

experienced

intracranial bleeding was 10.6 years and 60%

incidence of intracranial bleeding in our

occurred at the age of fewer than 10

institutions is related to the way of treatment

years.[12] French ICH Study Group[11] in

on demand (only in case of bleeding) that has

2005 reported 17.9% (22 out of 123 episodes)

been embraced so far in Indonesia and

occurred at the age of 1- <24 months, 21.1%

generally other developing countries. Reports

(26 out of 123 episodes) at age 2- < 15 years,

from developed countries showed no cases of

and the rest in other age groups. In our study,

intracranial bleeding in patients receiving

there were no episodes of intracranial

prophylactic treatment, suggesting the most

bleeding at the age of < 3 years. This

likely protective effect of prophylactic

difference may be due to the smaller number

treatment on intracranial bleeding.[9]

of our study subjects.

149

Most researchers report that there is a

and one moderate hemophilia A patient each

history of head trauma in 50%-80% of

experienced two episodes of intracranial

intracranial

hemophilia,

bleeding, all preceded by head trauma. Based

especially at a young age and in children.

on this, we think head trauma plays an

Mishra et al[14] reported a 66% history of

important

head trauma in 57 episodes of intracranial

intracranial bleeding in mild and moderate

bleeding in hereditary coagulation disorder

hemophilia.

hemorrhage

in

patients aged 1 month – 22 years in

the

occurrence

of

management of intracranial bleeding in

the results of the ICH survey on the pediatric

hemophilia is replacement therapy adequate

population had a 57% history of head trauma

dose (plasma level target 80-100%) and on

in 30 ICH episodes out of 744 hemophilia

time.

patients. In our study, eight out of 13 episodes

Inadequate

dose

or

delay

in

replacement therapy will increase mortality

of ICH were preceded by head trauma.

and morbidity. Education for patients and

Different results were reported from a 1992

families is very important so that there is no

survey in Argentina, of 156 episodes of

delay in coming to the hospital, especially if

intracranial bleeding in 106 hemophilia

the patient has head trauma. The availability

patients aged 14 ± 8 years, 85% of cases were

of clotting factors for replacement therapy

spontaneous bleeding without a previous

and multidisciplinary teamwork is essential

history of head trauma.[15]

for improving the externality of hemophilia

The French ICH Study Group[11] in

patients

2005 reported that one-third of cases of

In

our

who

experience

intracranial

bleeding.[18]

intracranial bleeding occur in mild or hemophilia.

in

The most important aspect in the

Bangalore, India. Klinge et al8 reported that

moderate

role

Clinical manifestations of intracranial

study,

hemorrhage in the most common hemophilia

intracranial bleeding in mild and moderate

in children over the age of 2 years are

hemophilia was more numerous than severe

headache

hemophilia, i.e. 9/13 or about 2/3 of the entire

(46.9%),

coma

(21%),

and

vomiting (12,3%).6 It is similar to our study,

episode. Eight of the nine episodes were

the most frequent clinical manifestations are

preceded by head trauma, while in one

headache,

episode there was no known previous head

vomiting,

and

loss

of

consciousness. Studies in Brazil show that

trauma. One patient with mild hemophilia A

150

44.4% of patients experiencing intracranial

lower than in the period 1960s and 1990s,

bleeding do not experience typical clinical

most likely related to the widespread use of

symptoms.[12]

study

freezing factor concentrates and improved

report of Hemophilia Treatment Center

health facilities.[9] De Tezanos Pinto et

Children's Hospital of that 5 out of 9

al[15] reported 29.2% deaths (data from 1960

incidences of intracranial bleeding come to

-1991), while Nuss et al[2] reported 18.2%

the hospital within 1–10 hours post-traumatic

(2001), Antunes et al[12] in 2003 reported

head without clinical symptoms ICH.[16] In

3/35 (8.6%) hemophilia patients die from

hemophilia patients with complaints of

intracranial bleeding. In our study, 1/13

headache, vomiting, or neurological deficits,

(7.6%) the patient dies within less than 24

even without a previous history of head

hours of treatment, most likely due to

trauma, should be considered the possibility

extensive bleeding due to previous head

of intracranial bleeding and performed a CT

trauma. Antunes et al[12] reported 3 out of 35

scan of the head.7

hemophilia A patients after intracranial

The

retrospective

The mortality rate from intracranial

bleeding experienced neurological sequels.

bleeding in hemophilia is currently relatively

In our study, one case (Case no. 1) had

lower than in the period 1960s and 1990s,

complications of secondary generalized

most likely related to the widespread use of

partial epilepsy, as evidenced by an EEG

freezing factor concentrates and improved

examination

health facilities.4 De Tezanos Pinto et al[15]

activity in the left middle temporal and left

reported 29.2% deaths (data from 1960 -

temporooxyitoparietal slowdown.

that

showed

epileptiform

1991), while Nuss et al [7] reported 18.2% (2001), Antunes et al[12] in 2003 reported

Conclusion

3/35 (8.6%) hemophilia patients die from intracranial bleeding. In our study, 1/13

Factor VIII (FVIII) in hemophilia A

(7.6%) the patient dies within less than 24

and factor IX (FIX) in hemophilia B are the

hours of treatment, most likely due to

most

extensive bleeding due to previous head

Hemophilia is categorized as mild if it has a

trauma.

blood clotting level in plasma of 6% - 40%,

frequent

blood

clotting

factors.

The mortality rate from intracranial

hemophilia is categorized as moderate if it

bleeding in hemophilia is currently relatively

has a blood clotting level in plasma of 1% -

151

5%, while hemophilia is categorized as

making it difficult to know the incidence of

severe if it has a blood clotting level in

intracranial bleeding in hemophilia patients.

plasma of less than 1%. Mild hemophilia has

Reports from developed countries showed no

clinical features, namely secondary bleeding

cases of intracranial bleeding in patients

due to trauma or surgery, and spontaneous

receiving prophylactic treatment, suggesting

bleeding rarely occurs, moderate hemophilia

the

has clinical features, namely

prophylactic

bleeding

most

likely

protective

treatment

on

intracranial

of

intracranial

bleeding.

sometimes

hemarthrosis,

bleeding in our study were experienced by

whereas severe hemophilia has clinical

hemophilia A patients. The average age of

features, namely spontaneous bleeding from

hemophilia

infancy,

spontaneous

experienced intracranial bleeding was 10.6

hemarthrosis and other bleeding requiring

years and 60% occurred at the age of fewer

additional factors.

than 10 years. French ICH Study Group in

and

frequent

episodes

of

secondary to trauma or surgery, and spontaneous

All

effect

patients

in

Brazil

who

In Indonesia, with a population of

2005 reported 17.9% (22 out of 123 episodes)

about 220 million there are estimated to be

occurred at the age of - Administration of F

about 400,000 hemophilia patients, but only

VIII therapy in Intracranial Bleeding in

recorded

Hemophilia

Indonesian

1280

patients

Hemophilia

(data Society,

of

the

2010),

Daftar Pustaka 1. Novie AC, Gatot D, Windiastuti E, Hnadryastuti

S.

handle/123456789/57327/Cover.pdf?

Perdarahan

sequence=8&isAllowed=y

intrakranial pada hemofilia. Sari

3. Susanto M, Kurniawan A. Hemofilia.

pediatri. 2011. Vol.13 [4].

2. Kosman kemampuan

AS.

MEDICINUS. 2016. Vol. 6 [1].

Perbandingan

fungsional

4. Franchini M, Manucci PM. Past,

anak

present and future of hemophilia: a

penderita hemofilia dengan anak

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Artificial

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pada

hemofilia.

Jurnal

Msy

RAMLI,

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154

Essential Role of Physical Activity with Protective Gear in Management of Children with Haemophilia

Abstract Introduction: Haemophilia is a bleeding disorder associated with haemorrhaging into joints and muscles. Children with haemophilia should not feel limited in their condition in participating in physical activity. Besides, physical activity often used to aid recovery after bleeds, it also can promote a better life quality Method: We searched PubMed, Science Direct, and Google Scholar. We use the following keyword in the search field (“protective gear, physical activity, haemophilia, children with haemophilia) in conjunction with a range of time from 1958 until 2020 Result: There were significant differences between children who do sports and those who don’t.

Children who do sports have a much way better mobility, endurance, and coordination than the children who don’t do sports Discussion: Physical activity should be encouraged, with attention paid to muscle strengthening, coordination, general fitness, physical functioning, healthy body weight, and self-esteem. It doesn’t just improve the ability and muscle tone, it also subsequently improving the coagulation factors in mild patients Keywords: physical activity, haemophilia, children with haemophilia, protective gear.

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Introduction Haemophilia, which means love (philia) of blood (hemo), is the most common severe hereditary hemorrhagic disorder.1 Haemophilia is an X-linked recessive inherited bleeding disorder caused by the absence, deficiency, or dysfunction of plasma coagulation factor VIII or IX, in which the genes responsible for the synthesis of factor VIII and factor IX are located on the X chromosome.2,3 Males with the defective X chromosome are affected; females are carriers and may also exhibit signs of coagulopathy. Each child of a carrier has a 50% chance of inheriting the defective gene.3 There were two types of haemophilia: haemophilia A, due to deficiency of coagulation factor VIII (FVIII), and haemophilia B, caused by the reduction of coagulation factor IX (FIX).4 Based on the residual activity of the defective factor, haemophilias were divided into three different degrees of severity: severe, moderate, and mild. In severe haemophilia, the plasma content of coagulation factor activity (FVIII: C for haemophilia A and FIX: C for haemophilia B) is less than 1% of normal, compared with 1 to 4% in moderate haemophilia and 5 to 40% in mild cases.5,6 Precise and consistent estimates from a meta-analysis of seven established national haemophilia registries found that the expected number of PWH worldwide to be 1 125 000, of whom 418 000 are living with severe haemophilia, based on a prevalence at birth (per 100 000 males) of 24.6 cases for haemophilia A and 5.0 cases for haemophilia B.7 Patients with haemophilia suffer from recurrent bleeding episodes, mostly occurring in the joints, resulting in permanent and crippling arthropathy. Furthermore, life-threatening internal bleeding, including central nervous system bleeding, can occur and tends to occur most commonly in young children.8 The goal of treatment of a child with haemophilia is to enable the patient and their families to manage the illness as independently as possible and therefore lead more normal healthy lives.9 Unfortunately, even with today’s best preventative therapies, the fact remains that children with haemophilia do experience joint bleeds and to a lesser extent, muscle bleeding.

Prophylaxis certainly helps decrease the frequency and severity of joint and muscle bleeds, as well as early joint damage. But it does not prevent all bleeds, nor can it give a child with haemophilia the normal factor levels like in children who do not have a bleeding disorder.10 Until the mid-1970s, patients with haemophilia (PWH) were advised to refrain from PA because of a perceived increased risk of bleeding.11,12,13 However, such recommendations may lead to

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physical dysfunction and obesity among PWH.14-16 Since then, PA, which is recognized as being essential for health maintenance11,12,17 is now recommended by the World Federation of Haemophilia.18 Many studies reported that PA can improve treatment efficacy and prevent bleeding in PWH.11,12,19 Therefore it is important to identify the effectiveness of physical activity in children with haemophilia. This study aimed to conduct a systematic review of the published literature to identify additional physical activity benefits for children with haemophilia along with the importance of protective gear during physical activity to prevent trauma or injury.

Method Literature searching was conducted with databases in PubMed, Science Direct, and Google Scholar. We use the following keyword in the search field (“protective gear, physical activity, haemophilia, children with haemophilia). The search results were downloaded to a personal database. The inclusion criteria used in this literature searching were the following: 1. The study was published between 1958-2020, 2. Was written in English, 3. Was fully accessible, and 4.

Was correlated to the aim of this paper. The articles which did not meet the criteria were excluded.

Result Until the mid-1970′s, it was usual practice to discourage sporting activity in those with haemophilia because of the bleeding risk.20 Today this attitude is more flexible, with many clinicians believing that sport is, in fact, beneficial for physical,21 social,22 and psychological well-being.23 According to literature research that we conducted, physical activity has a crucial role in management in patients with haemophilia including pediatric patients. Unfortunately, there is still a lack of evidence regarding this specific topic, resulting in limited result data that can be provided in this systematic review. First, a multi-center study into the ‘Evaluation of the Impact of Sport Activities on Health Related Quality of Life of Haemophilia Patients’ (EIS Study) that was designed Khair et al.,24 where 120 children invited to participate 84, with a mean age of

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11.52 years (SD = 3.4, range 5.83– 17.86), were enrolled into the study (70%). 92.3% had haemophilia A, half were severely affected, 22.6% had moderate and 27.4% had mild haemophilia. From total of eightyfour participants, seventy-seven boys (95.17%) thought that doing sport was good, with arguments that it: ‘is healthy and keeps you fit’ (n = 36), ‘is fun’ (n = 21), ‘makes you active’ (n = 6) and ‘is social’ (n = 2). Other arguments in favour of sport were that it ‘got you outside’, ‘gives you confidence’ and ‘is good when eating junk food’. Seventyone boys (93.4%) reported that they would like to continue sports when they are older.

In the generic KINDL questionnaire children reported a quite good overall HRQoL in the total score, being highest in the youngest age group (I: M = 77.61, SD = 14.2; II: M = 70.40, SD = 8.9; III: M = 70.38, SD = 12.3), while for the chronic-generic module best values were reported by the oldest age group (I: M = 82.67, SD = 17.6; II: M = 82.98, SD = 20.9; III: M = 86.88, SD = 11.8). Haemophilic children reported the highest impairments in the dimension ‘school’ (See Table 1).24

Table 1 HRQoL scores across age groups (KINDL, Haemo-QoL).24

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Fig. 1. Comparison of HRQoL (Haemo-QoL) across boys doing sport and those not doing sport.24

Sport did not prove to have an impact on the HRQoL of children in age group I. By contrast there was a significant difference in HRQoL between children in age groups II and III grouped together doing sport and those not doing sport. Boys who did not do sport were more impaired in the dimension ‘feeling’ (P < 0.014) and ‘family’ (P < 0.13) than those doing sport (see Fig. 1).

Children practicing sport 3 times per week (M = 22.34, SD = 15.5) reported a better ‘view of themselves’ (P < 0.017) than children doing sport twice a week or less (M = 33.83, SD = 18.5).24 Psychometric testing of the child-adapted version revealed excellent values in terms of reliability ranging from Cronbach’s a = 0.855 for ‘endurance’ to a = 0.936 for ‘the HEP-Test-Q total score’.24 There was significant difference between children doing and not doing sport in all domains of physical performance (see Table 2). This demonstrates that children who do not do sport perceive their physical performance worse than those who do. A difference was also seen for sedentary lifestyles of children who watched television or played video games for more than 1–2 h on a weekday, who reported more impairment in ‘endurance’ (P < 0.001), ‘body perception’ (P < 0.024) and ‘total physical performance (P < 0.004) than children who spent less time in front of the TV/computer (see Fig. 2). Boys doing sport 3 times per week (M = 93.43, SD = 7.9) had significantly better ‘co-ordination’ (P < 0.009) than children doing less frequent sport (M =

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85.55, SD = 15.0). Those boys who reported doing 5 h sport per week (M = 81.52, SD = 13.0) reported significantly better ‘endurance’ (P < 0.008) than children practicing less sport (M = 70.69, SD = 17.6).24

Table

2

performance children

Physical in

doing

67 sport

and those not doing sport (HEP-Test-Q).24

Fig. 2. Physical performance (HEP-Test-Q) based on hours of TV/computer games.24

Another randomized controlled trial of a musculoskeletal exercise intervention versus usual care for children with haemophilia was also conducted.25 Nine children participated in the feasibility study: seven were diagnosed with severe haemophilia A and two with severe haemophilia B. Five were randomly allocated to the exercise intervention and four to usual care. The mean age

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of the children was 9.77 years (SD 2.18). From this RCT study, they reported that muscle strength of ankle plantar flexors and knee extensors, distance walked in six-minutes and time taken to ascend and descend 12 steps improved in children receiving the intervention compared with those who did not (See Table 3).25

Table 3. ANCOVA for muscle

strength,

function and quality of life—change baseline, means

from adjusted

and

75%

confidence intervals.25

Another study conducted by Beheshtipoor N et al., investigated the effect of a 14-week yoga intervention on the life quality of the children and adolescents with haemophilia at children’s hospital in Shiraz, southern Iran.26 From the results of Friedman test through this study indicated a significant difference in QOL before the intervention and 8 and 14 weeks after that (X2=50.29, P<0.001). Also, the results showed a significant reduction in the mean number of bleeding events (x2=44.07, P<0.001), referrals to the haemophilia clinic (x2=18.28, P<0.001), and school absences (x2=40.13, P<0.001) throughout the assessment stages.26

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Discussion.

According to the “Global Recommendations on PA for Health” by the World Health Organization (WHO), physical inactivity is the fourth leading risk factor for mortality, accounting for 6% of deaths globally, following hypertension (13%), smoking (9%), and high blood glucose (6%).27 Health problems associated with physical inactivity are more severe for People With Haemophilia (PWH) than the general population. Furthermore, obesity is linked to an increased risk of cardiovascular disease and chronic arthropathy, which promotes intraarticular bleeding and the risk of fracture.28,29,30,31 In addition, musculoskeletal disorders caused by hemophilic arthropathy and aging are risk factors for falling injuries. Furthermore, parents with affected children may restrict activity due to parental concern, musculoskeletal pain or deconditioning. Although haemophilia itself does not negatively affect fitness or athletic performance, chronic hemophilic arthropathy may lead to impaired neuromuscular function, diminished muscle strength and endurance.30 Thus, promotion of Physical Activity (PA) is especially important for PWH to reduce the risk of falling injuries and lifestyle-related diseases. physical activity, individual sport, it is usually possible to control factors such as speed, length of time, intensity and movements as needed for the protection of muscles and joints. Children with haemophilia can increase their strength and improve their fitness levels through physical training. In childhood this physical training occurs mostly through physical activities and sports.10 Physical activity should be encouraged, with attention paid to muscle strengthening, coordination, general fitness, physical functioning, healthy body weight, and self-esteem. The choice of activities should reflect an individual’s preference/interest, ability, physical condition, and resources. If non-contact sports (such as swimming, cycling, and walking) should always be encouraged.32 Specifically, a child with haemophilia would benefit from exercise and sport, both because a good muscle tone can decrease the frequency of bleeds, joint problems, and loss of bone mineral density and because it can contribute to improving their quality of life.32-36 Furthermore, acute exercise sessions increment the levels of Factor VIII, subsequently improving coagulation in mild patients.38 Physical activity should be encouraged, with attention paid to muscle strengthening, coordination, general fitness, physical functioning, healthy body weight, and self-

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esteem. The choice of activities should reflect an individual’s preference/interest, ability, physical condition, and resources. If non-contact sports (such as swimming, cycling, and walking) should always be encouraged, high contact sport (soccer, rugby, boxing) or highvelocity activities (motocross) are best avoided unless the individual is on good prophylaxis to cover such activities.32 Patients with moderate or mild haemophilia may experience more bleeding with physical activity since they do not receive prophylaxis.37 Physical activity also helps school-age children develop socially and emotionally. In competitive sports, they learn teamwork and how to win and lose. Being recognized for their accomplishments also increases your child’s self-esteem—especially when the recognition comes from friends and classmates. Their emotional state can even affect bleeding; as children become more confident and independent, they often show marked clinical improvement, with fewer spontaneous bleeding episodes.38 Efforts should be made to maximize safety for patients with haemophilia participating in organized sport including the appropriate use of safety equipment, proper footwear, and the timing of prophylaxis (if applicable) to maximize the factor level at the time of sports participation. Toddlers should also be encouraged to try running, jumping, climbing, and riding wheeled toys that are low to the ground. Their playtime should be well supervised, and they should use appropriate safety equipment, like helmets, elbow pads, and knee pads. At home, it is important to inform parents to consider putting cushioned, protective corners on tables, carpeting on hard floors, and gates at the tops and bottoms of staircases. Toddlers also begin to play more with other children, so educate the parents to help their children to learn playing safely and cooperatively.39 Sports that involve high speed, heavy contact, and collisions, such as football and hockey, are not recommended. Communication with the Haemophilia treatment centers (HTCs) is very important before undertaking any sporting activities.40

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Conclusion Haemophilia is an X-linked recessive inherited bleeding disorder caused by the absence, deficiency, or dysfunction of plasma coagulation factor VIII or IX, in which the genes responsible for the synthesis of factor VIII and factor IX are located on the X chromosome.

There were two types of haemophilia: haemophilia A, due to deficiency of coagulation factor VIII (FVIII), and haemophilia B, caused by the reduction of coagulation factor IX (FIX).

PA, which is recognized as being essential for health maintenance is now recommended by the World Federation of Hemophilia. Many studies reported that PA can improve treatment efficacy and prevent bleeding in PWH. Physical Activity (PA) is especially important for PWH to reduce the risk of falling injuries and lifestyle-related diseases. Physical activity should be encouraged, with attention paid to muscle strengthening, coordination, general fitness, physical functioning, healthy body weight, and self-esteem. According to literature research that we conducted, physical activity has a crucial role in management in patients with haemophilia including pediatric patients.

HELPFUL WEB SITES • Canadian Hemophilia Society – www.hemophilia.ca • World Federation of Hemophilia – www.wfh.org • National Hemophilia Foundation – www.hemophilia.org • Association of Hemophilia Clinic Directors of Canada – www.ahcdc.ca • Hemophilia Emergency Care – www.hemophiliaemergencycare.com

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14. Falk B, Portal S, Tiktinsky R, Weinstein Y, Constantini N, Martinowitz U. Anaerobic power and muscle strength in young hemophilia patients. Med Sci Sports Exerc.

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15. Engelbert RHH, Plantinga M, Van der Net J, et al. Aerobic capacity in children with hemophilia. J Pediatr. 2008;152(6):833–838.

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18. Treatment Guidelines Working Group, on behalf of the World Federation of Hemophilia (WFH) [webpage on the Internet]. Guidelines for the Management of Haemophilia. 2nd ed. Blackwell Publishing Ltd; 2012. [Available July 6, 2012; about 7–8, 11, 59–61].

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Hemophilia Treatment, Laboratory Test, and Government Health Insurance Compared with Indonesia’s Condition Liana1, Aura Arsy Prinsesa2 1

Liana.102020020@civitas.ukrida.co.id

2

Aura.102020055@civitas.ukrida.co.id

Abstract Introduction: Hemophilia is a hereditary bleeding disorder that caused by deficiency or dysfunction of the coagulation proteins factor. Hemophilia can be classified into 3 types based on its coagulen proteins factor.

Methods: This literature review is doing by searching on journal databases. Besides that, searching is also done in related websites.

Result: Laboratory diagnoses of hemophilia contains of Platelet Count, Bleeding Times, Prothrombin Time, and Activated Partial Thromboplastin Time. There’s no special medication for hemophilia. Treatment for hemophilia patients is focusing on preventing and stopping bleeds. For the sake of Sustainable Development Goals, the government made Badan Penyelenggara Jaminan Sosial Kesehatan (BPJS-K) as a solution for people in getting better health treatment.

Discussion: Diagnosis in laboratory for hemophilia composed by basic continuation checking.

Besides that, Indonesia has been left behind for providing own licensed hemophilia medication.

Conclusion: Hemophilia screening test contains of basic and continuation screening test.

Treatment for people with hemophilia is different depending on their complications. It is very important for hemophilia patients to know about their own disease and recognize the symptoms in their bodies. There’re some problems in facing hemophilia in Indonesia. They are limation informations, limitation of health facilities, and high cost of hemophilia’s treatment.

Keywords : hemophilia condition in Indonesia, laboratory diagnosis hemophilia, treatment for hemophilia,

Introduction Hemophilia is a hereditary bleeding disorder that inherited by X- sex linked recessive. This disease is caused by deficiency or dysfunction of the coagulation proteins factor. Hemophilia can be classified into 3 types based on its coagulen proteins factor.1 Hemophilia A occurs if someone has disfunction of coagulen factor VIII (FVIII) and hemophilia B is caused by coagulen factor IX (FIX).1,2 Hemophilia A is type of hemophilia that more common than other type of hemophilia such as hemophilia B and hemophilia C. The disease happen because of deficient plasma concentration

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of coagulen factor VIII. Protein factor VIII is circulated in an inactive form bound to Von Willerband factor. The circulation also protect the protein from proteolytic degradation. Females that carrier of hemophilia A are usually asymptomatic but it doesn’t mean they have not bleeding symptom. Some of them often got easy bruises, menorrhagia, or excess bleeding after trauma. 1 Other types of hemophilia are Hemophilia B, Hemophilia C, and Hemophilia B-leyden.

Hemophilia B causes by dificiency of coagulent factor IX. Hemophilia C is caused by absence or dificiency of factor XI. And the last is Hemophilia B Leyden that said as unusual form of factor IX dificiency. Classic hemophilia B is a life long disorder whereas individuals with hemophilia B leyden usually outgrow the disorder at puberty or adulthood. 3 The incidence of hemophilia A is higher than hemophilia B. Based on international statistic, total incidence of hemophilia A is about 85% and hemophilia B is 15%. The probability of having hemophilia due to gene mutation is just 30%. In 2018, there are 2092 people recorded of having hemophilia in Indonesia. However, this number isn’t the exact number of total hemophilia patient because people spread in many islands so that it’s difficult to identify. 2 Looking that there is plenty of hemophilia cases in Indonesia, this journal has a purpose to give information about hemophilia. This journal also shows the condition of this disease and compare it with World Federation of Hemophilia guideline and other journals.

Methods This literature review is doing by searching on journal databases, like Pubmed, Researchgate, and google scholar. The keywords are hemophilia, screening test in hemophilia, and treatment of hemophilia. Besides that, searching is also done in related websites, such as Himpunan Masyarakat Hemofilia Indonesia, Sustainable Development Goals (SDGs), and National Hemophilia Foundation.

Articles were selected based on the following criteria. Inclusion criteria are articles that explain about definition and types of hemophilia, treatment of hemophilia, laboratory diagnosis of hemophilia, Indonesia’s condition related to hemophilia, and articles are in Indonesian and English language. Exclusion criteria are articles which explain about x-linked ressesive disorder, medicine for hemophilia, gene therapy for hemophilia disease, articles in other languages except Indonesian and English language, and articles that only abstract was available.

Result Clinical Laboratory Tests for Hemophilia When someone suspected got hemophilia, there will show some symptoms such as spontaneous bleeding to joints, muscles and soft tissues, hemarthrosis, and deep muscle hematomas. However, sometimes a bleeding disorder may have very similar symptoms one and another. The diagnosis needs to be more confirmed to ensure patient receives the appropriate treatment by doing

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laboratory test for making a correct diagnosis. This test is also to get know more about how bleeding potential caused. Other than that, the laboratory needs three essensial aspects, so they are allowed to do laboratory test. There are knowledge and expertise in coagulation laboratory testing, use of the correct equipment and reagents, and quality assurance (QA). Laboratory diagnoses of hemophilia contains of Platelet Count (PT), Bleeding Times (BT), Prothrombin Time, and Activated Partial Thromboplastin Time (APTT). 3 Platelet Count is important in clinical laboratory test for studying of bleeding tendency of patient with hemophilia. Hemophilia patients generally have normal range of platelet count.

Hemophilia patient that has a higher basal level of platelet activation is hemophilia A. Platelet count someone that diagnoses have a hemophilia will be normal because platelet count has no alteration in the production and consumption of platelet. 3 Bleeding time is the time interval between making a small standard cut and the moment the bleeding stops. Bleeding time measures platelet adhesion and activation , so it is said to be normal in hemophilia. it was found out that mean bleeding time of hemophilia patients were prolonged than the normal controls. This prolongation was not associated with the severity of the disease, use of NSAIDs or transfusions. Bleeding time testing lacks sensitivity and specificity, and it is also prone to performance-related errors. FVIII and IX are not required in the hemostatic plug formation.3,4 Prothrombin Time (PT) is to count the coagulation by assessing the coagulation proteins involved in the extrinsic pathway and common pathway.Test sample is anticoagulated with 3.2% sodium citrate. Anticoagulated patient plasma is incubated with tissue thromboplastin (recombinant human or isolated animal tissue factor) for several minutes. In the next step citrated plasma mixture is recalcified by the addition of excess CaCl2. Then the time required for clot formation is measured. PT is used to assesses the coagulation proteins of the extrinsic system and common pathway. So, if someone got hemophilia, they still has a normal PT. 3 Activated Partial Thromboplastin Time (APTT) called as “activated” PTT because the reagent used for APTT assay contains a negatively charged surface that accelerates the rate of the reaction.

The test sample is collected with 3.2 g% sodium citrate as anticoagulant. The ratio of anticoagulant to whole blood is 1 part anticoagulant to 9 parts whole blood. First step in APTT assay is anticoagulated patient plasma is incubated with a mixture of a negatively charged surface, phospholipid for several minutes. After incubation period the sample is recalcified by addition of excess of calcium chloride. Then the time required for clot formation is measured. 3 The APTT assay is used to assesses the coagulation proteins involved in the intrinsic system and common pathways.So, if someone got hemophilia their APTT prolonged because APTT assess the intrinsic and common pathways. For laboratory investigation of patients being assessed due to clinical suspicion of hemophilia, the WFH recommends that an APTT result within the reference range not be used to rule out the presence of mild hemophilia A or B. 3,4

Table 1 Screening for diagnosis

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______________________________________________________________________________ __ Possible diagnosis

PT

APTT*

BT

Platelet count

______________________________________________________________________________ __ Normal

Normal

Normal

Normal

Normal

Hemophilia A

Normal

Prolonged*

Normal

Normal

Normal or

Normal or

Normal or

prolonged*

prolonged

reduced

Normal

Normal or

Normal or

Prolonged

reduced

Or B ** VWD

Platelet defect

Normal

Normal

______________________________________________________________________________ *Results of APTT measurements are highly dependent on the laboratory method used for analysis. **The same pattern can occur in the presence of FXI, FXII, prekallikrein, or high molecular weight kininogen deficiencies.

Source from: https://onlinelibrary.wiley.com/doi/10.1111/hae.14046

Figure 1 APTT screening test

Source from: http://www.hkki.org/uploads/20170730083503.Rahajuningsih_The_roleof_Lab_in_Manag_Hem ophilia.pdf

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Factor VIII activity can be assessed using 3 methods, there are one stage clot based assay, twostaged clotting assay and chromogenic assay.One stage clot based assay is an one-stage assay based on APTT. One stage assay measures the ability of a patient plasma to decrease the APTT of a FVIII deficient plasma . The FVIII deficient plasma and patient sample are pre incubated with the APTT reagent and calcium chloride is added to it, as calcium promotes fibrin clot formation, which is the endpoint of the APTT. 3 FVIII concentration in the patient sample is the rate-limiting determinant of the clotting time in this APTT assay. This result is compared with the standard curve generated from samples with known FVIII activities, several types of FVIII assay including chromogenic and fluorogenic clotting assays are available. laboratory investigation of patients being assessed due to clinical suspicion of hemophilia A, the WFH recommends the use of both the one-stage FVIII assay and the chromogenic FVIII:C assay in the initial diagnostic workup and laboratory investigation of patients being assessed due to clinical suspicion of hemophilia B use of the one-stage FIX assay in the initial diagnostic workup. One-stage clotting assays based on APTT are the most commonly used techniques in most regions.3,4 The two‐stage coagulation assay, where FXa is produced in the first incubation stage with FVIII activity just a few of them and the amount of FXa is estimated in a second clotting stage, The two‐stage clotting assay, devised in 1955, is avaliable in a certain laboratory that already professional to hold this case.. FVIII is the rate‐limiting factor (normal/excess of everything except FVIII) and in the first stage, diluted sample plasma, which has been treated with Al(OH)3 to remove prothrombin, is mixed with a combined reagent (human serum, factor V, phospholipids and calcium). This leads to generation of FXa, and in the second stage, a subsample from the first stage is mixed with normal plasma, providing prothrombin and fibrinogen, and the clotting time is measured to deduce the amount of FVIII present. There is no need to use FVIII‐deficient plasma.5 Chromogenic assay or chromogenic substrate is done by two stages assay. In the first stage patient plasma which contains an unknown amount of functional FVIII is added to a reaction mixture. Reaction mixture consists of thrombin or prothrombin, FIXa, FX, calcium, and phospholipid. This reaction immediately produces FVIIIa, which on action with FIXa activate FX. When the reaction is stopped, FXa production is assumed to be proportional to the amount of functional FVIII present in the sample. In the second stage FXa is measured through cleavage of a FXa specific peptide nitroanilide substrate. P-nitroaniline is produced, which gives a color that can be measured photometrically by absorbance at 405 nm. The color produced is directly proportional to the amount of functional FVIII present in the sample based on a standard curve. 3

Chronic hemophilic arthropathy is one of examples of musculoskeletal complications that can occur in people with hemophilia. The goals of treatment with this case are generally similar with treatment of hemophilia in general. They are to reduce the incidence of hemarthroses (bleeding in joint cavity), improve joint function, relieve pain, and help patients to continue their normal

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activities of living. Patients also should be given appropriate analgesics with control. Those options of treatment depend on many factors: the stage of condition, patient’s symptoms, patient’s age, impacts on the patient’s lifestyle and functional abilities, and resources available. 4 Pain due to chronic hemophilic atrophaty is treated by analgesics, and functional training and adaptation. Pain medications that may be used by people with hemophilia for chronic hemophilic athropathy include paracetamol/acetaminophen, selective COX-2 inhibitors, tramadol, and opioid analgesics. Other NSAIDs (nonsteroidal anti-inflammatory drugs) should be avoided. Codeine should not be given to childer under 12 years old. 4 Similar to musculoskeletal complication, hemophilia patients with specific complications and cormobidities should also get access to the therapist or specialist related to their complication because those conditions may affect their health worsen. There are specific conditions that people with hemophilia may have, such as carries of hemophilia, medical issues with aging, and cormobidities age-related disorder.4 The most severe forms of hemophilia typically affect males, females usually have been designated as carriers. Carries often do not show symptoms of hemophilia because their X chromosome has two typicals, one of them has an abnormal FVIII or FIX and the other one contains a normal FVIII or FIX gene. In contrast, not all carriers do not have symptoms of hemophilia. Some carries of hemophilia experience bleeding problems, including joint hemorrhages. Furthermore, in some cases, they may experience heavy menstrual bleeding. They are called symptomatic carriers.4 Similar to people with hemophilia, carriers also need to get a consultation with specialist, especially symptomatic carriers. Carries possibly experience a significant impact on various aspects of their lives and need specific care to reproductive issues, including genetic counselling, genetic testing, prenatal diagnosis and planning, newborn testing, and psychosocial counselling. It is important for symptomatic carriers to have a gynecologist for their treatment. 4 People with hemophilia are very risk to get injuries and hemorage. They can get pain from all parts of the body, such as joint and muscle. Treatment is depend on the source of the pain. In general, there is no medication given for pain caused by venous access. Medical staff may applicate a local anasteric spray or cream at the site of venous access if required. In contrast, Coagulen factor to stop bleeding is given for joint or mucle bleeding. Additional medications are often needed for pain control. In this case, other adjunctive measure may also be required. For cases dental pain, patients should always be referred for a professional dental consultation. Proportionate pain management should be applied.4 (See Table 2) Table 2 Pain management strategies for people with hemophilia 1

Paracetamol/acetaminophen If not effective

2

COX- 2 inhibitor (e.g., celecoxib, meloxicam, nimesulide, and others) or

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paracetamol/acetaminophen plus codeine (3- 4 times/day) or paracetamol/acetaminophen plus tramadol (3- 4 times/day) 3 Morphine: Use a slow- release product with a rapid- release product as an escape analgesic. Increase use of the slow- release product if the rapid- release product is used more than 4 times/day.

Note : If for any reason medications have been stopped for a period of time, individuals who have been taking and tolerating high-dose narcotic drugs should restart the drug at a lower dose, or use a less powerful painkiller, under the supervision of a physician. COX- 2 inhibitors should be used with caution by people with hemophilia with hypertension and renal dysfunction.

Source from: https://onlinelibrary.wiley.com/doi/10.1111/hae.14046 Physical activity is an important action for people with hemophilia to promote normal neuromuscular development and physical fitness. People with hemophilia may have a higher risk of low bone mineral density rather than general population due to risk factors. Ways to promote bone health are preventing hemarthrosis, regular exercise, and adequate vitamin D and calcium intake. Hemophilia patients are advised to do non-contact sport, such as swimming, walking, golf, badminton, and archery, rather than high-contact sport, like soccer, boxing, and rugby. Those things is absolutely to prevent hemorrhage and trauma. The choice of activities should depend on their interest and physical condition. Consultation with physical therapist also an important thing to do in deciding sports or physical activities. 4 Self-management can be done by people with hemophilia’s self. They can apply it in daily life to keep their health under control. The key self-management skills are bleed recognition, selftreatment skill, self care, medicine management, pain management, risk management, and conceptualizing preventive therapy. Self-care skills refers to nutrition and physical fitness.

Medicine management consists of record-keeping, treatment routines, maintenance of adequate treatment supply, skills in storage, reconstitution, and administration of treatment products). it is important for people with hemophilia to have knowledge about treatment and realize changes in their bodies.4

Specific Hemorrhages If we got trauma in our body, the body will quickly recovered, but it will be different When someone got hemophilia, they become more susceptible having hemorrhage when they got trauma when their fall or accidentally hit sometthing. There are 3 stages of hemorrhage : mild bleeding episodes, moderate bleeding episodes, and severe bleeding episodes. In Indonesia, mild bleeding such as nasal and gums bleeding haven’t specific treatment and just being observated. Moderate bleeding such as hemartrosis, muscle and oral bleeding, and repetitive nasal bleeding is usually treated with checking bleed rating and giving coagulen factor. Severe bleeding such as intracerebral hemorrage, eye bleeding, and any bleeds that treaten life is treated by doing cephal CT-scan or MRI, giving coagulen factor, and is monitored by medical team in emergency room.6

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The primary clinical hallmarks of hemophilia are prolonged spontaneous or traumatic hemorrhages, most commonly within the musculoskeletal system and predominantly intraarticular bleeding into the large synovial joints, example : the ankles, knees, and elbows, and frequently into the shoulder, wrist, and hip joints. Hemophilia bleeding is also common in muscle and mucosal soft tissues, and less common in other soft tissues, the brain, and internal organs.

Without adequate treatment, such internal bleeds may lead to serious complications and even become life-threatening. In general, the main treatment for bleeding episodes in patients with severe hemophilia is prompt clotting factor replacement therapy and rehabilitation. However, different types of bleeds and bleeding at particular anatomical sites may require more specific management with additional measures. But, the management suggested don’t be doing alone. It is important to consult the appropriate specialists for the management of bleeds related to specific sites. he aim of management of specific hemorrhages is not only to treat the bleed, but also to prevent bleed recurrence, limit complications, and restore tissue andor organ function to a prebleed state.4 Main treatment for patient with severe hemophilia are rehabilitation and clotting factor therapy.

The rehabilitation can be doing by the appropriate specialist. While, clotting factor replacement therapy is a treatment of acute hemarthrosis that has a goal to stop the bleeding as soon as possible.

Treatment should ideally be given as soon as the patient suspects a bleed and before the onset of overt swelling, loss of joint function, and pain. Clotting factor concentrate (CFC) should be administered immediately at a dose sufficient to raise the patient’s factor level high enough to stop the bleeding. Response to treatment is demonstrated by a decrease in pain and swelling, and an increase in range of motion of the joint. bleeding continues over the next 6-12 hours, a revised plan of assessment including further diagnostic assessment ( factor assays) and intensification of factor replacement therapy should be adopted. 4

Indonesia’s Hemophilia Problems and Indonesia Government Insurance Program Sustainable Development Goals (SDGs) are a global action plan which agreed by governments, including Indonesia, to end the poverty, reduce social inequality, and saving environment. SDGs are made for the next 15 years and expected to be achieve by 2030. This plan filled by 17 goals and 169 targets. Those goals are no poverty, zero hunger, good health and well-being, quality education, gender equality, clean water and sanitation, affordable and clean energy, decent work and economic growth, industry, innovation and infrastructure, reduced inequality, sustainable cities and communities, responsible consumption and production, climate action, life below water, life on land, peace and justice strong institutions, and partnerships to achieve the goal. 7 For the sake of Sustainable Development Goals (SDGs) especially giving health care access for all population in Indonesia equally, the government made Badan Penyelenggara Jaminan Sosial Kesehatan (BPJS-K) as a solution for people in getting better health treatment. Jaminan Kesehatan Nasional (JKN) is a program from ministry of health to upgrade the quality of health service in Indonesia. This program is like an insurance that compulsory people to pay every month and can use it whenever we get a problem in health. Due to the increase of reimbursement for

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catastrophic diseases, diseases that has high cost and high risk, such as heart disease, hemophilia, stroke, hypertension, and diabetes, the government doesn’t included these disease into JKN. It means that patients with catastrophic disease can’t use JKN for their treatment. 8 There’re some problems in facing hemophilia in Indonesia. The informations of hemophilia are still limited. Many people don’t understand or even don’t know about this disease and its symptoms. Not all people in Indonesia can get information about hemophilia easily. For instance, there are some areas in Indonesia still not connected to internet connection and even some of them don’t have electricity while internet is needed in this modern era. Limitation of health facilities.

Not all laboratory examination can be done in all hospitals. PT/APTT (Parameter prothrombin time/Activated partial thromboplastin time) can’t be examined in first stage health care, like Puskesmas (Pusat Kesehatan Masyarakat). This diagnosis can be done only in hospital laboratory.

One stage clote factor assay, to diagnose the deficiency of FVIII and its inhibitors, can only be done in central hospital in some province. This diagnose can only be done in specific time.

Moreover, FVIII inhibitor is just be able to examine in RSCM (Rumah Sakit Cipto Mangunkusumo) Jakarta as the central hospital in DKI Jakarta. The price of treating hemophilia is very expensive because there’s no medication production in Indonesia. The medication also rare, especially medication for FIX.2 The government has made an application of hemophilia, namely Hemofilia Indonesia. This application can be installed in android smartphone. It helps government to make statistics about hemophilia patients in Indonesia. People can regist themselves if they have this disease. They also can read all about hemophilia. However, this application only provides general information of hemophilia and not in specific.9

Discussion First diagnosis for a patient that alleged has a hemophilia by checking in laboratorium with the basic checking. There are Bleeding Time (BT), Platelet Count, Prothrombin Time (PT), and Activated Partial Thromboplastin Time (APTT). For continuation checking to ensure the diagnoses by checking coagulant factor in the blood that avaliable 3 options : one stage clote assay, two staged clote assay, and chromosome assay. One stage clote assay function is to checking the ability of patient to lowered APTT. Two staged assay similar to Chromosome assay. It’s important to measure a mixture plasma that can produce fVIIIa. Unfortunetly in Indonesia, the diagnosis that frequently used just as stopping in one stage clote assay that kinda same like APTT and there is no case that used chromosome assay. It maybe happen because based on ECAT foundation survey, in 214 laboratory, 193 laboratory using one clote stage assay (90,2%) and just 13 laboratory that using chromosome assay (6,1%), the rest is using two stage clote assay that is rarely use in laboratory for diagnoses. This thing will make Indonesia less to settle an acurate diagnosis. 9 Regarding to simplicity in getting a medicine, Indonesia has been left behind. One of medication that hard to obtain is medicine for hemophilia B, already know the case is more rarely then hemophilia A.2 This condition may affect treatment less optimal. On the other hand, America

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has the licensed of hemophilia medication on its own. 10 So, it’s easier for them to get and use coagulen factor for treating hemophilia patients.

As stated before, FVIII inhibitor laboratory diagnosis can only be checked in RSCM , This thing shows that Indonesia‘s health facilities have not prevalent. In conclusion, it’s very hard to do the diagnosis by laboratory examination in Indonesia.

In Amerikc, they already have a health insurance that is provided by their government for helping people defray their treatment cost. This insurance called ACA (Affordable Care Act). ACA can also cover treatment cost for bleeding disorder. This insurance is one of many solutions for patients with bleeding disorder because other insurances usually don’t cover treatment related to this case. NHF supports ACA’s policies for solving problem related to financial difficulties, including maintaining the current out-of-pocket maximum, financial assistance for low-income individuals, and reinsurance.10 As explained before, Indonesia’s government also provides a health insurance called JKN (Jaminan Kesehatan Nasional). However, JKN is different with ACA. JKN doesn’t cover treatment cost for catastrophic disease such as mellitus diabetes,hemophilia, stroke, and hypertension. It means that people with hemophilia can’t use JKN for their treatment. This may become a problem in lower class population. Hemophilia is a disease with high-risk bleeding that needs high cost to pay the treatment. So, it’s very rare that insurance willing to cover bleeding disorder. Besides, an insurance that can cover bleeding disorder like ACA will be needed for hemophilia patients. In consequence, Indonesia is expected to pay attention with this case.

Indonesia needs an insurance that can cover bleeding disorder like hemophilia. 8

Conclusion Hemophilia screening test contains of basic and continuation screening test. Basic screening test consists of Platelet Count (PT), Bleeding Times (BT), Prothrombin Time, and Activated Partial Thromboplastin Time (APTT). Continuation screening test consists of one cloth stage assay and chromosome assay.

Treatment for people with hemophilia is different depending on their complications and where the complication is. For instance, in joint or muscle bleeding case, people with hemophilia are given coagulen factor to stop bleeds. There are 3 stages of hemorrhage : mild bleeding episodes, moderate bleeding episodes, and severe bleeding episodes. Hemophilic bleeding is also common in muscle and mucosal soft tissues. Clotting factor replacement therapy is a treatment of acute hemarthrosis that has a goal to stop the bleeding as soon as possible. People with hemophilia should get an access to do consultation with specialists, such as gynecologist, dentist and physical therapist.

It is very important for hemophilia patients to know about their own disease and recognize the symptoms in their bodies. People with hemophilia can control their health by doing selfmanagement, like bleed recognition, self-treatment skill, self care, medicine management, pain

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management, risk management, and conceptualizing preventive therapy. These action can be done in their daily activities.

There’re some problems in facing hemophilia in Indonesia. They are limation informations, limitation of health facilities, and high cost of hemophilia’s treatment. Actually, the government has made a health insurance but based on the newest insurance policy, this insurance not already coverage catastrophic disease due to high cost for the treatment.

References 1. Kizilocak H, Young G. Diagnosis and treatment of hemophilia. Clin Adv Hematol Oncol [Internet]. 2019 Jun [citied 2021 Feb 16];17(6):344-351. Available from: https://www.hematologyandoncology.net/files/2019/06/ho0619KizilocakYoung-1.pdf 2. Gatot D. Hemofilia : Situasi, tatalaksana & permasalahannya. [Powerpoint Presentation].

Himpunan Masyarakat Hemofilia Indonesia. 2020 Feb 8 [citied 2021 Feb 16]. Available from: https://hemofilia.or.id/wp-content/uploads/2020/02/01-jogya-Prof-Djaja.pdf 3. Priya V.S. A study on the coagulation profile and it’s clinicopathological correlation of the haemophilia patients at the day care centre of Tirunelveli Medical College. Urkund Analysis Result [Internet].2019 [citied 2021 March 7]. Available from: https://1library.net/document/ozlk6lq4-coagulation-profile-clinicopathologicalcorrelation-haemophilia-patients-tirunelveli-medical.html 4. Srivastava A, Santagostino, Dougall A, et all. WFH guideline for management of hemophilia 3rd edition [Internet]. 2020 Aug 3 [citied 2021 Feb 7]. Available from: https://onlinelibrary.wiley.com/doi/10.1111/hae.14046 5. Potgieter JJ, Damgaard M, Hillarp A. One-stage vs. chromogenic assays in haemophilia A. Eur J Haematol [Internet]. 2015 Feb [citied 2021 March 11];77:38-44. Available from: https://pubmed.ncbi.nlm.nih.gov/25560793/ 6. Yoshua V, Angliadi E. Rehabilitasi Medik Pada Hemofilia. Jurnal Biomedik: JBM [Internet].

2013 [2021 Feb 7];5(2).

Available from: https://ejournal.unsrat.ac.id/index.php/biomedik/article/viewFile/2587/2130 7. https://www.sdg2030indonesia.org/ [citied 2021 Feb 28].

8. Affandi MR. Kontrol kualitas system pelayanan diabetesmelitus berbasis pay-forperformance:menuju strategi komprehensif menghadapi penyakit katastropik di Indonesia [Internet]. 2018 [citied 2021 Feb 16]. Available from: http://pilmapres.ristekdikti.go.id/file/kti/SARJANA_IPA_MOHAMAD_REZA_AFFAN DI_18016408_KTI.pdf 9. https://hemofilia.or.id/ [citied 2021 Feb 21].

10. https://www.hemophilia.org/ [citied 2021 March 7].

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STUDY ABOUT HEMOPHILIA AND HOW TO TREAT IT

ABSTRACT Hemophilia is a blood clotting disorder, so that in people with hemophilia the blood will be difficult to clot. Hemophilia is passed from parents to children, although 30% of hemophilia sufferers do not have a family history but the possibility of a genetic mutation occurs.Hemophilia itself cannot be cured but can be managed properly so that patients can live normally. Therefore, in this study, health orientation was chosen to find out about the attitudes that the subjects chose towards hemophilia. This study focuses on the health orientation carried out by hemophiliacs in the treatment process as well as the background for the patient to determine the place of treatment in terms of social action theory from Max Weber. The paradigm used to understand the problems in this study is the social definition paradigm with a qualitative approach.

The subjects in this study were a number of seven people who underwent treatment at RSUD Dr. Soetomo Surabaya. The method of determining the subject used was purposive. The data collection method in this study was direct interviews using the interview guide research instrument. The results found in this study include: 1) the treatment system chosen by hemophilia sufferers, among others, is more oriented to the scientific and combination treatment system (scientific and popular) 2) action orientation in choosing a treatment system is motivated by treatment effectiveness, belief system, economy and social conditions.

Keywords: Hemophilia sufferers, treatment process, health orientation, treatment effectiveness, social conditions

Background Every human being in general wants a healthy life for himself and all members of his family. However, in reality, some of the diseases a person suffers are due to the descendants of their parents, so that from birth they have suffered from a disease.

Hereditary disease itself is a disease caused by genetic disorders passed from parents to children, one of the hereditary diseases caused by genetic disorders and passed from

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parents to children is hemophilia. Hemophilia is a blood clotting disorder, so if the patient experiences bleeding it will be difficult to stop it. As with other hereditary diseases, hemophilia is inherited from the X gene, which means that it is passed from mother (as a carrier) to her son from birth1 however 30% of people with hemophilia do not have a family history but the possibility of spontaneous genetic mutations in the patient, this hemophilia disease itself can be classified into 2 types, namely Hemophilia A and hemophilia B, where in patients with Hemophilia A known as classic hemophilia there is a lack of blood clotting factor FVIII, while in Hemophilia B it is known as Christmas Disease. occurs due to a deficiency of blood clotting factor F IX. Hemophilia A and B can be in classify into 3 categories, namely Hemophilia severe, moderate and light.

In the Hemophilia group This weight has blood clotting factor F VIII / F IX only 1% or less with the condition of having a factor below 1% This patient has symptoms such as frequent bruising, swelling, or joint pain due to minor trauma, and it can also occur for obvious reasons. , approximately 2-4 times / month and bleeding that is difficult to stop due to minor surgery. Patients with moderate hemophilia have 1-5% factors. Blood clotting with the condition of having factor F VIII / F IX 1-5% of these patients have symptoms of frequent bruising, swelling or joint pain due to trauma or minor impact, and can also occur for no apparent reason approximately 1 time a month and bleeding that is it is difficult to stop because of minor surgery and in patients with mild hemophilia they have 5-40% blood clotting factors, where in patients with this group bleeding occurs due to minor operations such as circumcision or tooth extraction.

Hemophilia was chosen in this study because so far hemophilia is considered an incurable disease4 but if it is properly handled and managed properly, the patient can live normally in addition to good and correct management, both the patient and the family, the importance of getting in-depth knowledge in order to be correct. really understand about Hemophilia, because sufferers don't it only requires routine treatment but also requires both material and moral support from the family and the surrounding environment so that they have the confidence and enthusiasm to stay healthy.

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But often public understanding and awareness about hemophilia is still very low and limited so that often there is a delay in diagnosis. This can be seen until 2015 in Indonesia, only about 1,025 patients were diagnosed out of the predicted number of sufferers of around 25,000 people in Indonesia. Delays that often occur in hemophilia sufferers often affect the health orientation chosen by the sufferer, in relation to the focus of the health behavior model according to E.A.Suchman6 that socio-cultural aspects influence a person's decision to access health services. The hypothesis is that there is a relationship between health orientation and social interactions and relationships or group structure. In his note, the most important thing in Suchman's model is that the social pattern of sick behavior is seen in the search for and doing health care.

In addition, Suchman argues that health behavior reflects the health orientation and affiliation of each social group, where the health orientation itself can be distinguished from a scientific orientation and a popular health orientation, it can be seen that scientific or popular health orientation can be measured by several things, namely the level of knowledge about illness, skepticism of medical treatment, individual dependence due to disease. In reality, in Indonesian society, there are many popular health orientations, including hemophilia sufferers, causing delay in diagnosis.

The two health orientation categories do not occur simultaneously just like that, in choosing a health orientation both scientifically and popularly occurs because someone's actions reflect that health orientation, the actions taken by a person are inseparable from the socio-cultural elements around them this is due to the condition of the community which is still in a transition period towards modern society. Even though Indonesian people are familiar with modernity, until now they have not been able to abandon traditional values.

So far, there is no cure for hemophilia disease, so as has been said before that hemophilia cannot be cured, it just can be managed properly. The most important thing that people with hemophilia should do is get enough rest and avoid physical activities that pose a big risk. However, if there is swelling or bleeding in a patient with hemophilia, the first thing to do is RICE (rest, ice, compression, elevation).

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The first treatment if it is not effective, people with hemophilia can do Hemophilia therapy, namely by replacing blood clotting factors that are lacking intravenously. This blood clotting factor can be obtained from several products such as 8 fresh blood, Cryoprecipitate, clotting factor concentrates (FVIII / FIX).

This study examines the health orientation developed by hemophiliacs in the treatment process, although hemophilia cannot be cured, it can only be managed properly so that patients can live a normal life. Therefore, the focus of the problems in this study are: 1. How is the Health Orientation developed by Hemophilia sufferers in the Process Treatment at RSUD Dr. Soetomo Surabaya?

2. What is the background of the patient with hemophilia in determining the choice of treatment?

This study aims to identify and provide an understanding of the health orientation developed by hemophiliacs and what lies behind hemophilia sufferers in the process and selection of treatment sites.

Theoritical Review Hemophilia is mostly suffered by men because of the influence of the X chromosome where the recessive gene associated in males consists of only one fruit. If the mother is a carrier of hemophilia, it can be ascertained that hemophilia is inherited directly in the son because there are two X chromosomes in girls. Based on data issued by the Data and Information Center of the Ministry of Health of the Republic of Indonesia, which is quoted from the specialist in Hematology-Oncology who is also the Chairperson of the Indonesian Hemophilia Society Association (HMHI) Prof. Dr. Djajadiman Gatot, in 2012 there were 20 thousand people in Indonesia who suffered from hemophilia, it can be ascertained that hemophilia sufferers exceeds that number.

Max Weber (1864-1920) was a classical sociologist who developed several macro theories in sociology. Max Weber is also one of the figures whose theory is paradigmatic of social definitions. Weber defines sociology as a science that seeks to provide understanding and interpretation of social action and social relations to the

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point of cause and effect. In this sense, there are two basic concepts, namely the concept of social action and the concept of interpretation and understanding, second This concept is interrelated where the concept of interpretation and understanding concerns the method for explaining the concept of social action. This concept is interrelated where the concept of interpretation and understanding concerns the method for explaining the concept of social action. For Weber, studying social action can be through interpretation and understanding. For him, if someone only examines behavior, Weber does not believe that the action has a subjective meaning and is directed at others. Weber himself also mentioned that sociology is a science that seeks to understand social action. Individuals take an action based on their respective experiences, as well as based on their experiences, perceptions, understanding, and interpretations of a particular stimulus object or situation. Individual action is a rational social action, which is an action that achieves goals or objectives with appropriate means. Weber introduces four types of action that are important for understanding Weber's theory of human social action. Weber's social actions are classified as 1. Rational instrumental (Zweck- rational) Instrument rational (Zweck rational) Instrumental rational action is a social action that bases itself on rational human considerations when responding to the external environment (as well as other people outside of itself in an effort to meet the needs of life). In other words, this instrumental rational action is a social action aimed at achieving the maximum possible goal by using the minimum possible funds and power, it is calculated and pursued rationally. In this context, for example, by the action of an individual who is experiencing illness, going to a doctor to get treatment which has the ultimate goal of getting cured.

2. Wert-rational

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The rational act of value is a rational social action. However, relying on certain absolute values. The values on which this relies can be ethical, aesthetic, religious or other values. So that in this value rational action man always relies his rational action on a belief in a certain value. In this context, for example, the action of an individual who is experiencing illness goes to alternative medicine which is believed by his environment or ancestors to be the best treatment.

3. Intellectual Affective action is an action that occurs or arises because of emotional motivational impulses. Affective actions are determined by the actor's emotional state. For example is the action of a relative or family to someone who is experiencing illness by taking him to a doctor to get healing, this action is carried out based on the impulse of love.

4. Traditional Traditional actions are social actions that are driven by past traditions and oriented to the past. Tradition in this sense is a habit of action that developed in the past and is based on normative laws that have been firmly established by society. For example, with someone who is sick trying to treat himself by taking traditional medicines which are believed to be hereditary can cure the disease.

Broadly speaking, Weber's theory is based on the concept of social action that he initiated himself11 in this case, Weber pays more attention to actions that are more complex and involve thought processes. These actions have meanings that are generated between events involving the process of response stimulus.

Actions can be said to occur when individuals attach subjective meanings on their actions. Sociological analysis, according to Weber, includes the interpretation of action in terms of its subjective meaning12 in his theory of Weber's social action focuses on individual, not collective action. But on the other hand, Weber did not deny the importance of collective action in the actions of an individual, however, Weber again emphasized that the sociology

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of action ultimately pays attention to individuals, not their collectivities.Thus, actions that arise from an individual are not instant and just happen , however, through a series of processes that involve external and internal aspects of the individual.

Method The data that has been collected by the author are raw data and need to be processed. The steps taken by the author in processing the data are: Data Reduction At this stage the authors carry out activities to check and rearrange the raw data that has been collected, such as the characteristics. This data can of course contain data that is not yet valid or there are some parts that we don't need or are wordy so that it can slow down the research process if it is inserted in the data we are going to study, therefore the activities at this stage are regarding the sorting of parts of the data that need to be given. code, pieces of data that must be discarded or patterns that must be summarized. This stage aims to make the raw data collected by the author simpler and in accordance with the author's needs, making it easier for him to draw conclusions later. So at this stage the writer can be said to simplify and correct the general data obtained.

2. Presentation of Data After the data reduction stage, at this stage the data that has been collected and simplified regarding the general properties and contents of eggshells, briquettes, and the way of making briquettes have been arranged as a collection of information so as to provide the possibility for the author to draw conclusions and take action. Presentation of data is done in a narrative or textual way, in which the author presents the data using sentences and explains all procedures and results after observing the data, which can be in the form of an image, table, graphic or event that the author sees directly. Presentation of data using this natarif method can make it easier to clarify qualitative data because presenting data using a narrative method has been compiled with the theme, data and opinion sections that must be part of the presentation of the data.

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Results and Discussion This study involved seven informants as the main data source, one female subject and six male subjects. Four out of seven sufferers of hemophilia have a job while two subjects are still pursuing higher education and one subject does not work and does not take any education. The health orientation developed by hemophiliacs is very diverse. In BNF subjects, who have a modern family background and have an open mind and do not have economic problems. The initial action he took was to conduct an examination at a hospital in the city of Surabaya because in the city of origin of BNF, the regional hospital did not have sufficient equipment to carry out this check. rational BNF perform blood factor injection at RSUD Dr. Soetomo because it is the best hospital in the city of Surabaya, he and his family went to the doctor with the hope that doctors who are more skilled in the health sector, BNF in taking medication from the start did not make changes, he continued to do medical treatment. In this case, it can be seen that the health orientation undertaken by the BNF is a scientific health orientation which, according to Suchman, is objective, professional and impersonal.

Not much different from the type of family from BNF, which is a modern and open-minded family, in the subjects HN, MSZ and HW, and RY. The initial action taken was to do an examination in the hospital. In HN subjects who grow and develop in modern families, are highly educated and are in the upper middle class, doing an examination at a hospital in the city of Surabaya is an initial action taken by his family, doing a complete blood count, not only on himself but on the older brother of HN. After being examined, both of them were suffering from hemophilia and had blood transfusions to replace the blood that came out due to bleeding, HN's initial action was an action that reflected a scientific health orientation. However, this initial action by HN was deemed ineffective so that HN does other treatment, namely consuming traditional medicines such as ant nests, herbs and etawa goat milk but again HN and their families feel that these traditional medicines are less effective so that HN

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returns to medical treatment but is no longer blood transfusion but weekly injection of factor VIII. In the MSZ subject, who came from a middle class family in the city of Pasuruan, had a bachelor's degree, and worked and lived in a family that mostly worked as a teacher, the MSZ family had quite an open mind with new things. When MSZ was 13 years old, he found that he was injured because he was exposed to gravel and the bleeding never stopped. The first action taken by the family was to take him to the hospital for examination and get the best treatment. However, medical treatment with blood transfusions is considered less effective Because it requires extra time so that he tries to do other non-medical treatments, alternative treatment through a shaman is also done with egg media, but there is no result MSZ tries traditional treatment, which is consuming etawa goat's milk, for him there is an effect on his body when consuming it. However, the etawa goat's milk was not effective so that MSZ also returned to medical treatment with blood factor injection. MSZ has a scientific and popular health orientation.

Likewise, what happened to HW subjects who grew and developed in families from the middle and educated circles. The initial action taken when HW is bleeding is to take him to the doctor. To obtain treatment and recovery, however, at that time, the development of Hemophilia treatment was not as effective as currently in its treatment, so HW try to take other actions that show that he has shifted his health orientation from scientific to popular, he takes treatment with alternative ways, namely massage therapy and undergoing rukiyah. However, using massage therapy actually exacerbates the situation because hemophilia sufferers are not allowed to use massage therapy while rukiyah does not provide any changes. Because of this, HW returned to undergo medical treatment with blood factor injections until now, which means that HW shows a scientific health orientation. Instrumental rational social action at the beginning of this treatment was not only carried out by subjects who came from the middle and upper middle class but on RY subjects who came from the lower middle class and believed enough in magic things the initial action was taken

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when they found out that RY was swollen in his body and not recovering is taking him to the hospital for Checking and getting the best treatment, the health orientation that was reflected at the start of RY's treatment was scientific health orientation but it was not enough, RY was not satisfied with the work of medical treatment, so he did a combination of medical treatment with traditional medicine. By consuming snail saliva, honey, turmeric, herbal medicine, ginger and also black cumin, this is done because it feels effective when doing a combination.

Other social actions taken by the subject are those that occur in BD and AG subjects, for BD subjects who come from Madurese ethnic and family environments who still uphold noble values. which is believed from generation to generation can cure the swelling which is made from betel leaf and kencur which are processed together in the traditional way and then drink and apply it to the leg that has swelling, this method of treatment lasts for about 13 years.

This initial treatment action carried out is a traditional social action which according to Weber's definition Traditional action is a social action that is driven by past traditions and oriented to the past. Tradition in this sense is a habit of action that developed in the past and is based on normative laws that have been firmly established by society. In other words, the action taken by BD is an action that has developed since the past and is trusted by the BD environment, in this phase if it is associated with the concept of a person's behavior when ill BD is included in the second treatment, namely selfmedicating this based on trust and experience ago, this experience was obtained from his ancestors. Even so, BD feels less the traditional herb was so effective that he added it to medical treatment when he was growing up because he remembered the many activities BD went through and he needed more effective treatment. So that BD performs medical treatment with blood factor injection.

BD's decision to undertake this treatment reflects a popular scientific and health orientation. Another case with AG subjects who come from the lower middle class, and live in a family that is thick with religious and spiritual values so that

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they still believe in magical things, the initial social action chosen when experiencing bleeding when it was to bring AG to treatment. alternatively, the family brings AG to people who are considered smart, traditional healers, kiai and the like who are believed to be able to heal and stop bleeding up to 17 times.

AG alternates with alternative medicine models. This kind of social action can be categorized as value-rational social action, which according to Weber in his theory of social action is a rational value action is a rational social action.

However, relying on certain absolute values. The values on which this relies can be ethical, aesthetic, religious or other values. So that in this value rational action man always relies his rational action on a belief in a certain value.

This initial action carried out by AG reflects a popular health orientation where in this case it is seen that according to Suchman the popular health orientation is characterized by a low level of knowledge about disease, a high level of skepticism towards medical treatment and a high level of dependence on a person due to disease. In popular health oriented people tend to be parochial group affiliation. Just as AG is oriented towards tradition and authority in the family, the AG family believes Regarding traditional medicine, and choosing treatment to a traditional healer to treat AG pain, however, the treatment to a dukun did not have the expected results, but what happened was that it made the situation worse because it was not handled properly. After AG felt there was no result, he finally switched treatment, namely medical treatment, by injecting blood factor.

Conclusion Hemophilia is a disorder of blood clotting, so that if the patient experiences bleeding it will be difficult to stop it. As with other hereditary diseases, hemophilia is passed down from parents to their children, even though 30% of hemophilia sufferers do not have a family history but the possibility of spontaneous genetic mutations in sufferers, blood clotting disorders that occur in hemophilia sufferers often result in death. at an early age or disabilities in the body persists due to joint or muscle bleeding, Hemophilia disease itself can be

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classified into 2 types, namely Hemophilia A and hemophilia B, where in patients with Hemophilia A known as classic hemophilia there is a deficiency of blood clotting factor F VIII, while in Hemophilia B known as Christmas Disease occurs due to lack of blood clotting factor F IX. , hemophilia is common in men while most women act as carriers. Hemophilia A and B can be classified into 3 categories, namely severe, moderate and mild hemophilia. A person suffering from hemophilia will experience a dilemma in himself, where the disease does not guarantee a cure for the sufferer but if it is not handled properly it will accelerate death.

Information about hemophilia is still minimal, if it is not properly explained, various kinds of perceptions of hemophilia will appear both scientifically and non-scientific this is related to the understanding possessed by patients and their families so that social factors have a lot of influence in determining social action taken. This study was carried out by taking seven hemophilia sufferers purposively.

Based on data analysis and theoretical analysis, several conclusions can be drawn about the health orientation of hemophilia sufferers in the treatment process. The conclusions that can be drawn include: 1. Health orientation developed by hemophilia sufferers in RSUD Dr. Soetomo is a Scientific and Combined health orientation (scientific and popular) 2. Hemophilia patients mostly do more than one health orientation before determining the current health orientation 3. Scientific Health Orientation is shown by patients who are looking for the effectiveness of treatment in a fast and definite time can have an immediate effect 4. The combination health orientation is shown by patients who have more knowledge about traditional medicines as an alternative treatment for their hemophilia disease. As well as the skepticism of sufferers towards modern medical health services, which is often considered to exaggerate the

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diagnosis when the patient is experiencing a decline in health conditions, besides that sufferers do a combination because they are afraid of the impact of modern medical treatments in the long term that can cause inhibitors.

5. The combination treatment orientation shows that there is a non-linear treatment system so that a combination appears which is a form of action taken that is inconsistent with the motive.

6. In the choice of scientific health orientation in patients, it is influenced by the sufferer's social network such as family, friends, relatives and so on

DAFTAR PUSTAKA Creswell,John W. 2012. Research Design: Pendekatan Kualitatif, Kuantitatif dan Mixed. Yogyakarta: Pustaka Pelajar Dipa Care.2011.Booklet Hemofilia. Jakarta. PT Dipa Pharmalab Intersains Illich, Ivan. 2017. Batas-batas Pengobatan :Perampasan Hak Untuk Sehat.

Jakarta:Yayasan Obor Indonesia Kiswari, Rukman. 2014. Hematologi dan Transfusi, Jakarta:Erlangga Muzaham, Fauzi. 2017. Memperkenalkan Sosiologi Kesehatan. Jakarta:Penerbit Universitas Indonesia Narwoko, J. DwidanBagong, Suyanto. 2011. Sosiologi: Teks Pengantar dan Terapan.

Jakarta: Kencana.

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Notoatmodjo, Soekidjo.2013.

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Perilaku

Kesehatan.

Jakarta:

Berparadigma

Ganda.

RinekaCipta Ritzer,

George.

2013.Sosiologi

Ilmu

Pengetahuan

Jakarta:Rajawalipers Ritzer, George dan Goodman, Douglas J. 2017. Teori Sosiologi Modern. Jakarta: Kencana Ritzer, George. 2012. Teori Sosiologi: Dari Sosiologi Klasik Sampai Perkembangan Terkahir Postmodern (Edisi Kedelapan). Yogyakarta: Pustaka Pelajar.

Siahaan, Hotman M. 2016.Pengantar ke Arah Sejarah dan Teori Sosiologi. Jakarta: Erlangga Suryaputra, Michelle. 2015.Relasi Kekuasaan dalam Interaksi Dokter dan Pasien pada Pemberian Layanan Kesehatan: Studi Kualitatif pada Dokter dan Pasien yang Melakukan Pengobatan di Rumah Sakit Umum Dr. Soetomo, Surabaya.

Skripsi. Surabaya: Universitas Airlangga Margaretha, Melisa. 2013. Pola Penggunaan Obat Pada Penderita Hemofilia Anak: Studi di Instalasi Rawat Jalan Hematologi dan Onkologi Departemen/SMF Ilmu Kesehatan Anak RSUD Dr. Soetomo. Skripsi. Surabaya: Universitas Airlangga Surabaya

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SCIENTIFI

IC POSTER

AMINO | AMSA International Competition 2021

Muhammad Mikail Athif Zhafir Asyura AMSA-Universitas Indonesia 2nd Winner of Scientific Poster Category

“Effectiveness of Low-dose FVIII Prophylaxis as An Alternative Management in Resource-limited Settings for Haemophilia A in Pediatric Population: A Systematic Review and Meta-Analysis”

Joining the World Haemophilia Day (WHD) could possibly be one of the most interesting experiences I had as an AMSA member. Being interested in scientific writing, I wanted to explore my capabilities at an international stage, especially after competing in multiple national competitions.

Although, because my team and I were on a very tight schedule before, we chose to make a scientific poster which was something new for us as well. During the synthesis of the poster, we realised how important it is to think concisely, especially with the limited amount of space given in one sheet of A2 paper. Furthermore, we also compared and referenced previous scientific posters to get pointers on expressing your ideas in a visually attractive method. Moreover, we decided to divide ourselves based on our interests and decided to not limit ourselves in writing as the excess information could possibly be useful for future papers and publications. In that regard, participating in the WHD competition provided us with valuable lessons to be implemented in our next endeavours in AMSA

AMINO | AMSA International Competition 2021

Dewa Vighneshwara AMSA-Universitas Kristen Indonesia 3rd Winner of Scientific Poster Category “Factors Affecting Hemophilia in Pediatric Patients”

So I join a WHD it presents many experience in a competition. A student competition is a great setting to learn. By participating in competitions where the topic is in your main field you learn a lot and can also discover that it happened to be exactly that field which you were great at.

Participating in the competition makes its own fun for me.

There are no specific tips and tricks. In my opinion, hearing the material from the webinar that discusses scientific posters is very helpful in doing the assignments in this competition. Then, asking for advice from experienced friends and seniors is helpful too. Support from parents always adds motivation. Praying will also make every effort launched and blessed.

There are challenges in making scientific posters because I have little experience with scientific posters. It's not easy to read a lot of journals in a short amount of time. Making scientific posters also trains you to divide your time with assignments in lectures.

Oral Bioencapsulated Coagulation Factor IX Fused with Cholera Toxin β-Subunit Protein as a Promising Immune Tolerance Induction Therapy for Hemophilia B: A Systematic Review ABSTRACT

Clonia Milla – Bellinda Z. Tazkira – Salma Firdaus

Introduction: Addressing complications of inhibitor production and hypersensitivity reactions in replacement therapy of hemophilia B, this systematic review aimed to investigate oral bioencapsulated cholera toxin β-subunit (CTB) fused with coagulation factor IX (FIX) as a promising immune tolerance induction (ITI) therapy. Method: Probing pre-clinical studies with keywords ("hemophilia B" OR "haemophilia B“) AND "CTB" AND "tolerance" was conducted from seven databases based on PRISMA Statement and assessed using SRYCLE’s Risk of Bias Tool. Result: A total of four studies (116 subjects in total) were included to evaluate the efficacy of oral bioencapsulated FIX fused with CTB in inducing tolerance to FIX. This systematic review presented significant decrease of total FIX inhibitor, IgE and IgG1 in those receiving intervention from included studies. Discussion: Result of this study showed that CTB-fused FIX capsule successfully suppressed FIX inhibitor production and ITI-related hypersensitivity reactions, making it a step closer to be trialed in humans.

Table 1. Responses in Preclinical Studies INTRODUCTION RESULTS *QA: Quality Assessment Hemophilia B is a genetic disorder Sample Outcome Resulting in an abnormal bleeding due to an absence or deficiency of Animal Q Author, Year coagulation factor IX (FIX). The primary treatment for hemophilia B A Control Intervention Model FIX Inhibitor IgG1 IgE (n) (n) currently is the frequent intravenous injection of recombinant or plasmaderived FIX. However, replacement therapy is severely complicated with Hemophilia B WT the formation of neutralizing antibodies (inhibitor), which may cause an pLS + CTB6 Su, untransformed C3H/HeJ FFIX lettuce mice (F9 20153 10 increase morbidity and mortality of the disease. Therefore, immune (18) (11) deletion) tolerance induction (ITI) to eliminate these inhibitors is required to restore effectiveness of factor replacement therapy.1 ITI protocols require frequent high-dose factor administration for prolonged periods— making Hemophilia B WT pLD-Ctv + 4 Wang, untransformed C3H/HeJ the cost become extremely high. Moreover, ITI protocols itself often CTB-FFIX tobacco mice (F9 20154 10 (8) 2 (8) deletion) cannot be completed due to anaphylactic reactions. To address these unmet medical needs, researchers have developed an alternative approach using transplastomic technology for a low-cost industrial production and pLD-Ctv+ Unfed CTB-FIX (11) potentially tolerogenic FIX fused with cholera toxin β-subunit (with or (17) Hemophilia B without a furin cleavage site; CTB-FFIX/CTB-FIX), expressed in 5 Verma, C3H/HeJ mice (F9 20105 10 WT pLD-Ctv+ chloroplasts bioencapsulated in plant cells ideal for oral delivery, which deletion) untransformed CTB-FFIX tobacco (15) could suppress inhibitory antibodies formation and prevent life(10) threatening anaphylactic reactions in animal model.3 This review aims to evaluate the efficacy of oral-delivered FIX fused with CTB in published control control control Hemophilia B pLS + CTBpreclinical studies. The primary outcome of our study will be addressed Herzog, 4 Unfed unbred dogs FFIX 6 (F9 missense (4) 2017 through the total number of FIX inhibitor, IgE and IgG1 in those (4) 10 mutation) intervention receiving intervention approach to induce tolerance in hemophilia B. intervention Intervention

METHODS

DISCUSSION

The summary of four included studies was demonstrated in Table 1 with 116 total sample size (control = 44 and intervention = 62). Three studies used mice and a study used dog as the animal model. Half of the studies used pLD-Ctv chloroplast to deliver FIX, and pLS was used for the remaining studies. In all of the studies, CTB-FFIX is administered towards the animal model; however, one of them also experimented using CTB-FIX.

A computer-based article searching was • Systematic review conducted in PubMed, Science Direct, process based on PRISMA Statement Scopus, Sage, ProQuest, Cochrane and EBSCOhost (CINAHL Plus). Boolean • Explore and extract all operator was used to narrow the search required data in various database result using the keywords such as ("hemophilia B" or "haemophilia B" AND • Screening studies based "CTB" AND "tolerance") and its on inclusion and exclusion criteria synonym. Each study are assessed for their quality using SRYCLE’s Risk of Bias Tool.

• Total of samples in four The inclusion and exclusion criteria are as eligible studies: 116 follows: Inclusion criteria: • Collect data and graphic 1. Animal model with hemophilia B from included studies 2. Oral bioencapsulated CTB-FIX or CTB-FFIX as intervention 3. Pre-clinical study Figure 1. Conceptual Framework Exclusion criteria: Records identified Additional records 1. Irrelevant study or outcome through database identified through searching other sources 2. Wrong PICOs component (n = 25) (n = 1) 3. Review report or editorial article 4. Not written in English or Bahasa Records after duplicates removed (n = 21) 5. Irretrievable full text Identification

FIX is one of the proteins needed to activate the coagulation cascade, especially that of the intrinsic pathway. 7 In these studies, the factor needed by those with hemophilia B is combined with CTB, a homopentameric non-toxic transmembrane protein produced by Exclusion criteria: Vibrio cholerae.8 CTB binds to GM1 ganglioside, and therefore introduces FIX to CD 1. Irrelevant study or outcome 103+ dendritic cells in mammalian's gut. When combined with replacement therapy, 2. Wrong PICOs tolerance is induced by component proliferation of CD4+ LAP+ and CD4+ CD25+ Tregs and production of IL-10 and or TGF-β to suppress FIX inhibitor production. 4 In all of the 3. Review report editorial article included studies, results showed significant decreases of total FIX inhibitor titer in those 4. Not written in English or Bahasa who had been administered with bioencapsulated CTB-FIX/CTB-FFIX. These studies 5. Irretrievable full textcapsule successfully suppressed the production of FIX show that the oral-administered inhibitor, unravelling one of the problems arose from the usual replacement therapy. It has also been mentioned that regular ITI protocols often cause anaphylactic reactions.

However, in the included studies, all of them demonstrated lower level of IgE and IgG1, the galvanizer of the following hypersensitivity reaction: type I and II. 9

Eligibility

Records excluded due to irrelevant title/abstract (n = 6)

Full-text articles assessed for eligibility (n = 15)

Full-text articles excluded, with reasons 1. Irretrievable full text (n = 3) 2. Irrelevant intervention (n = 1) 3. Review article (n = 7)

Included

Studies included in qualitative synthesis (n = 4)

Figure 2. PRISMA Diagram Flowchart

CONCLUSION

In conclusion, the oral delivery of bioencapsulated FIX fused with CTB successfully showed suppression towards FIX intolerance and related hypersensitivity reactions. Further research of oral-administered FIX fused with CTB in human clinical trial is strongly suggested.

REFERENCES

Screening

Records screened (n = 21)

The results of present study have provided a proof for this concept as a tolerance induction protocol for hemophilia B in the future. With further accruement, the idea of bioencapsulated CTB-fused FIX is at hand to be tested in humans.

1. Berntorp E, Shapiro AD. Modern haemophilia care. The Lancet. 2012;379(9824):1447-56.

2. DiMichele DM. Immune tolerance in haemophilia: the long journey to the fork in the road. British journal of haematology. 2012;159(2):123-34.

3. Su J, Zhu L, Sherman A, Wang X, Lin S, Kamesh A, Norikane JH, Streatfield SJ, Herzog RW, Daniell H. Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B. Biomaterials. 2015 Nov 1;70:84-93.

4. Wang X, Su J, Sherman A, Rogers GL, Liao G, Hoffman BE, Leong KW, Terhorst C, Daniell H, Herzog RW. Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+ CD4+ T cells. Blood. 2015;125(15):2418-27.

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5. Verma D, Moghimi B, LoDuca PA, Singh HD, Hoffman BE, Herzog RW, Daniell H. Oral delivery of bioencapsulated coagulation factor IX prevents inhibitor formation and fatal anaphylaxis in hemophilia B mice. Proceedings of the National Academy of Sciences. 2010;107(15):7101-6.

6. Herzog RW, Nichols TC, Su J, Zhang B, Sherman A, Merricks EP, Raymer R, Perrin GQ, Häger M, Wiinberg B, Daniell H. Oral tolerance induction in hemophilia B dogs fed with transplastomic lettuce.

Molecular Therapy. 2017 Feb 1;25(2):512-22.

7. Chaudhry R, Babiker HM. Physiology, coagulation pathways. StatPearls [Internet]. 2019 Apr 17.

8. Baldauf KJ, Royal JM, Hamorsky KT, Matoba N. Cholera toxin B: one subunit with many pharmaceutical applications. Toxins (Basel). 2015;7(3):974-996. Published 2015 Mar 20. doi:10.3390/toxins7030974 9. Tomasiak-Łozowska MM, Klimek M, Lis A, Moniuszko M, Bodzenta-Łukaszyk A. Markers of anaphylaxis–a systematic review. Advances in medical sciences. 2018 Sep 1;63(2):265-77.

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Factors Affecting Hemophilia in Pediatric Patients Dewa Vighneshwara - Putri Valentine Siringo Ringo - Tivany Bulan Cristy Manurung AMSA-Indonesia

INTRODUCTION

DISCUSSION

Hemophilia is bleeding that occurs caused by deficiency by plasma clotting factors (F) VIII, IX, and X. Hemophilia is classified into Hemophilia A (Deficiency of factor XIII), Hemophilia B (Deficiency o factor IX), and Hemophilia C (Deficiency of factor XI). This hemophilia is a disease that is inherited by the presence of X-linked recessive. This bleeding disorder is chronic. Hemophilia A is more common in boys with a prevalence of 1: 5.000 and hemophilia B is determined to be 1: 30.000 for every boy born. Hemophilia can affect anyone, regardless of ethnicity and race. Hemophilia is characterized by bleeding in the soft tissue and hemarthrosis.

In infants and toddlers, the ankle is the most common place followed by the knee. In older children, the knees and elbows are frequently involved. The most common joints involved in patients not wearing prophylaxis are the knees, followed by the elbows, ankles, shoulders, and wrists. In those on prophylaxis, the ankle is usually affected.

Occasionally, bleeding mucosa (epistaxis, gum, gastrointestinal, genitourinary) may be the cause of the feature. The central nervous system (CNS) bleeding can occur at any age, silently or after minor trauma.

MATERIAL AND METHOD

Hemophilia cases that often occur in children, especially infants and toddlers, are often located in the ankles and knees. In older children, they are located on the knees and elbows, in hemophiliacs who wear prophylaxis, usually on the ankles. Occasionally patients with hemophilia are located in the mucosa which sometimes can cause epistaxis to bleed in the central nervous system. in the case of hemophilia, the patient generally manifests at the age of 6-8 months.

The biggest factor in the occurrence of hemophilia is genetics, when parents have a history of hemophilia, the offspring will have a high risk of suffering from hemophilia disorders. Hemophilia cases are very rare in people without a lineage who have this hemophilia disorder, but some cases are caused other than heredity, namely a lack of blood clotting factors. hemophilia is due to a deficit or deficiency of blood clotting substances. This blood-clotting substance is a type of iron, besides that the lack of protein that plays a role in the blood clotting process can be a cause of hemophilia. In addition to iron, there are blood clotting proteins, which are responsible for helping accelerate and smooth blood clotting. These proteins are denoted by Roman numerals I to XIII (factor 1 to factor 13). These 13 factors are important in the running of the blood clotting process in a person. The lack of one factor alone can cause hemophilia and difficult blood clotting.

The HA and HB genes are located in the respective terminal section of the X chromosome arm in the Xq28 and Xq27 bands. Women inherit the disorder with a 50% chance while men will not bring this disorder to their sons but will carry it to their daughters. HA can occur due to genetic mutases, gene deletions, stopping codon abnormalities, frameshift mutations, and insertion mutations. The mutation resulted in the division and inactivation of the FVIII gene

RESULT Based on data obtained from the Pediatric Journal of Pediatric Research, out of a total of 93 pediatric hemophilia patients, the majority of 61% were from the 11 to 18 year age group, 2.1% were less than 1 year old, 17.2% were in the age group 1- 5 years, and 19.35% are in the 6-10 year age group. In general, men with hemophilia suffer more than women who generally come from low economic status.

CONCLUSION Children with hemophilia should be treated with the utmost discipline. This treatment must be assisted by a hematologist with experience in the environment of pediatric patients, surgeons in children, psychologists and social volunteers, pharmacists, orthopedics, physiotherapy, and requires nurses to help the patient's family. The relationship between children with hemophilia and their families must be harmonious. to increase trust and good communication.

The aim of all this is to avoid all complications of bleeding and joint damage in children with hemophilia so that as adults they can achieve better quality health.

Based on data obtained from the Pediatric Journal of Pediatric Research, type A hemophilia was found in the highest patients with a scale of 87% while hemophilia type b was only found in 13% of patient

References: 1. Islam S, Morshed A, Khan ZJ. Hemophilia In Children. Journal of Paediatric Surgeons of Bangladesh. 2015;6(22):63-54 2. Swary ADK, Hajat A, Andarsini MR. Profile of Pediatric Hemophilia A Patients: One Hospital Study. Biomolecular And Health Science Journal. 2019;2(1):12-9 3. Singh M, et all. Hemophilia in children: a clinic-epidemiological profile and review. International Journal of Pediatric Research. 2020;7(2):72-66 4. Kuhne AH, et all. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. 2009;94(4):575-566 196

PUB

BLIC POSTER

AMINO | AMSA International Competition 2021

Nathaniel Gilbert Dyson AMSA-Universitas Indonesia 1st Winner of Public Poster Category “TREAT THEM SPECIAL: A practical guide for parents to educate their children with hemophilia”

Hello! my name is Nathaniel Gilbert Dyson as the representative of our team in World Hemophilia Day Public Poster Competition. At first, we were interested in the competition as it would be a very valuable experience to participate in an international competition. We also think WHD provides a chance to explore an interesting topic rarely brought up in most competition. To be honest we feel like we don’t really have some tips and tricks to win this competition. I think the most important thing is to find a topic you're really interested and passionate about.

While making our poster, we learned a lot and came to care a lot about the topic, and I think that contributes to making a good and impactful work. Because of that, making the poster is also easier and fun. Having our ideas recognized in this prestigious international competition and having the chance to present in front judges is such a valuable learning experience for us. In conclusion, this competition is such an enjoyable and precious learning experience for us, and we are grateful for the chance AMSA have given for us to participate and win in this competition. So, don't hesitate to participate, and most of all, good luck and have fun!

AMINO | AMSA International Competition 2021

Indy Zahrotul Firdaus AMSA-Universitas Brawijaya 2nd Winner of Public Poster Category “Safer Hemophilia With #HFA (Hemophilia for All)”

We were studying hematology lecture when WHD announced, so we thought that it a perfect moment to share our knowledge in hemophilia in order to build people awareness and attention on people with hemophilia I personally think that there isn't a special trick, but the most important things are team working and learning. Teamwork means that we should help each other by doing our job properly and always learn by observing any poster, especially for the poster that wins 1st place in any competition.

In making WHD poster, we shared the job based on what we can do in it.

Me and my friend Rindang, we did the design after observing poster reference in our past competition, and Tiara, she did the greatest job in determining the content of the poster. Since there is a great pandemic of COVID-19, we thought that telemedicine is the most suitable to develop and apply in health topics. We hope that #HFA can be a great start and something that can be developed further especially in Indonesia.

AMINO | AMSA International Competition 2021

Karen Kurnia AMSA-Universitas Hasanuddin 3rd Winner of Public Poster Category “Haemophilia:

Reject

the

MYTHS,

Remember

the

FACTS!”

In my university, there’s no organization that allows us to compete with international medical students, other than AMSA. It is one of the biggest privilege, so when the chance is there, just do it! The more we participate in poster competitions, the more we know what a good poster is like. Plus, it’s free. See, there’s no reason not to join WHD! Since this is a team-based competition, then the first thing to do is to find a good team. Although maybe the task was different between members, but all of us had to discuss together to find a final idea. Always ask ourselves, what makes my artwork different from others? What makes my artwork worth to win this competition?

We had fun in making our poster and we gained new knowledge regarding the topic, haemophilia. So even without winning, we still got a lot of advantages. Thank you AMSA International!

“TREAT THEM SPECIAL” : A practical guide for parents to educate their children with hemophilia Hemophilia is an inherited bleeding disorder caused by inadequate clotting factor in the blood. Although considered rare, with only 400 babies being born annually, hemophilia remains one of the biggest issue in human health, especially in children.1 Study by Agasani et al has revealed that 52.9% of children with hemophilia have impaired quality of life.2,3 In line with that, another study shows that overprotective parenting style with many restrictions is one of the biggest contributing factor.4 This is very important as children can suffer from isolation and pessimism, thus hindering their growth and development.5 Therefore, we proudly present our public poster titled “TREAT THEM SPECIAL” which is a practical guide for parents to educate their children with hemophilia. We choose the mnemonic “SPECIAL” to indicate that children with hemophilia is extraordinary and deserve more attention and not to be isolated from the community. Moreover, the poster design dominantly uses red color to represent a bleeding disorder and other colors in soft hues to leave a feeling of optimism and playfulness. In conclusion, we hope that this poster can raise awareness in the community about the proper way to educate and treat children with hemophilia to improve their quality of life.

References 1. CDC. Hemophilia [Internet]. Centers for Disease Control and Prevention. 2021 [cited 18 March 2021]. Available from: https://www.cdc.gov/ncbddd/hemophilia/data.html 2. Agasani F, Soedjatmiko, Windiastuti E. Quality of life children with hemophilia in Dr. Cipto Mangunkusumo Hospital. Sari Pediatri. 2019;21(2) 3. Zhang H, Huang J, Kong X, Ma G, Fang Y. Health-related quality of life in children with hemophilia in China: a 4-year follow-up prospective cohort study. Health and Quality of Life Outcomes. 2019;17(1).

4. Abalı O , Zülfikar O , Demirkaya S . An examination of the symptoms of anxiety and parental attitude in children with hemophilia. Turkish Journal of Medical Sciences. 2014; 44(6): 1087-1090.

5. Wang M, Álvarez-Román MT, Chowdary P, Quon DV, Schafer K. Physical activity in individuals with hemophilia and experience with recombinant factor VIII Fc fusion protein

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and recombinant factor IX Fc fusion protein for the treatment of active patients: a literature review and case reports. Blood Coagul Fibrinolysis. 2016;27(7):737–44.

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Abstract Safer Hemophilia With #HFA (Hemophilia For All)

Hemophilia is a blood disorder that is inherited by x-linked chromosome abnormalities. This disorder results in a low blood clotting factors. Low level of blood clotting factors makes a person with Hemophilia (PwH) to have improper blood clotting in mild trauma and injury, even as small as getting a vaccine is hard for PwH. Hence, creating a safe environment and creative steps in approaching with medication and vaccination for people with hemophilia is important to integrated the services needed for people with Hemophilia, increase their health and lower acute and chronic complications, increase their quality of life (QoL), and to maintain people with hemophilia’s compliance for their medication and other health requirements to adapt well to the disorders.

This public poster aims to increase people’s attention to new approaches in Hemophilia treatment, especially in this pandemic, it is hard to meet with health providers even for nonhemophilic patients, that is why creating a more advance and integrated PwH app such as #HemophiliaForAll that helps people with hemophilia not to only track their medications, track their society, video chat and teleconsultations with doctors, but also have a current update on other things such as pandemics and covid-19 vaccines.

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Haemophilia: Reject the MYTHS, Remember the FACTS! Introduction : Haemophilia is a blood clotting disorder caused by the lack of factor VIII or factor XI in the blood1. Currently, there are around 200 thousand people with haemophilia worldwide and approximately 20.000 people with haemophilia to be born each year 2.

Haemophilia is usually a hereditary disease, but in some cases a person can develop haemophilia later in life. The cause of this disease is a mutation of genes that regulate the formation of clotting factor proteins. Furthermore, the lower amount of the factor, the more likely it is that bleeding can lead to serious health problems, even death1.

Method : This public poster was prepared using the literature study method by collecting and presenting information from valid sources such as CDC and WHF. Results : We managed to find five misinformations about haemophilia, such as minor cut could lead to death, people with haemophilia cannot do exercise or play sports, the causes of this disease, only males can affect by haemophilia, and the life expectancy of the patient 3.

Discussion : There are lots of misinformation about haemophilia spreading in society. This poster aims to provide knowledge by giving five facts behind the myths to correct the misinformation.

Bibliography : 1.

CDC. What is Haemophilia | CDC [Internet]. 2020 [cited 2021 Mar 19]. Available from: https://www.cdc.gov/ncbddd/haemophilia/facts.html

2.

WFH. WORLD FEDERATION OF HAEMOPHILIA REPORT ON THE [Internet].

2020 [cited 2021 Mar 19]. Available from: www.wfh.org

3.

WFH. Fast Facts | National Haemophilia Foundation [Internet]. Report on the Annual Global

Survey.

Quebec;

2020

[cited

2021

Mar

19].

Available

https://www.haemophilia.org/bleeding-disorders-a-z/overview/fast-facts

202

from:

203

Stop The BLEED with Rest and ICE Maria Alvenia Chaterina Revita, Ahmad Abizart, Ratu Basyasyah Cianora Introduction: Haemophilia is a bleeding disorder in which the blood does not clot properly caused by lack of clotting factors in blood. Until 2021, there are estimated 400.000 people living with haemophilia worldwide.

Method: This poster studies are based on several reports from CDC, national and international health services, associations related to haemophilia, and journal publications.

Results: The nature of inheritance of haemophilia making it hard to prevent. At the same time, we also face the problem of myths and misconceptions existing within the global community regarding haemophilia. These myths were later clarified in our poster in order to create a right perspective and maintain a better treatment for haemophilia patients so that they can live longer with high quality of life.

Discussion: We aim to increase community awareness by providing the information about how to live with haemophilia. A simple mnemonic “BLEED” was used to describe the signs and symptoms of haemophilia which are longer Bleeding from wounds, Large numbers of bruises, Elbows and other joints’ internal bleeding, Excessive bleeding of mouth and gums, and longer bleeding after Drawing blood. Another simple mnemonic “Rest and ICE” also used to explain the first aid for injury in haemophilia patients.

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Revealing the “TRUTH” Behind Haemophilia Andrea Melynda Panggalo; Ennian Yuniarti Br Bancin; Revina Raissa Gunawan

ABSTRACT Haemophilia is defined as a bleeding disorder characterized by clotting protein factor insufficiency or dysfunction that impair the body’s ability to clot blood (1,2). This impairment cause Haemophilic patient bleed for a long time after an injury, and has a higher risk to have deep internal bleeding (3). In 2018, the worldwide incidence of haemophilia is approximately 21 per 100.000 males(4).

According to Kementerian Republik Indonesia, there are still people in the society with minimal knowledge about this disease(5). In addressing this problem, our team suggest a public poster: “Revealing the TRUTH Behind Haemophilia”.

The data attached below are from several medical and official database, such as NCBI Pubmed, CDC, with the key words: “Haemophilia”, “Definition”.

The “TRUTH” we suggest is a mnemonic for: ● Treat appropriately to increase life expectancy ● Recovery can’t be obtained pharmacologically ● Unstoppable bleeding can happen both internally and externally ● Tracing of Hereditary illness before marriage is highly suggested ● Hemophilia mostly occur in male but can also occur in female Finally, the urge to increase the community’s knowledge regarding Haemophilia is a must, since we can prevent, and treat this disease accordingly to prevent the complication.

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BIBLIOGRAPHY 1. World Federation of Hemophilia. WFH has spearheaded a scientific study updating the prevalence of hemophilia to higher numbers than preciously estimated. [Internet].

2019 [cited 19 March 2021]. Available from: https://news.wfh.org/wfh-hasspearheaded-a-scientific-study-updating-the-prevalence-of-hemophilia-to-highernumbers-than-previously-estimated/ 2. RSUD dr. Mohammad Soewandhie. Pengertian Hemofilia: Apa itu Hemofilia?

[Internet].

2020

[cited

19

March

2021].

Available

from:

https://rs-

soewandhi.surabaya.go.id/pengertian-hemofilia-apa-itu-hemofilia/ 3. Zanon E., Pasca S. Intracranial haemorrhage in children and adilts with haemophilia A and B: a literature review of the las 20 years. [Internet]. 2018 [cited 19 March 2021]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774931/ 4. Centers for Disease Control and Prevention. Hemophilia. [Internet]. 2020 [cited 18 March 2021]. Available from https://www.cdc.gov/dotw/hemophilia/index.html 5. Pusat Data dan Statistik Kementrian Kesehatan Republik Indonesia. Hari Hemofilia Sedunia.

[Internet].

2015

[cited

19

March

2021].

Available

from:

https://pusdatin.kemkes.go.id/article/view/15042000001/hari-hemofilia-sedunia.html

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WORLD HAEMOPHILIA DAY

TRUTH REVEALING THE ________ BEHIND HAEMOPHILIA

In 2018

H A E M O P H I L I A is a bleeding disorder characterized by clotting protein factor insufficiency or dysfunction that impairs the body’s ability to clot blood.

The Worldwide incidence of haemophilia is

This impairment cause Haemophilic patient bleed for a long time after an injury, and has a higher risk to have deep internal bleeding

approximately

21/100.000 males

SIGN AND SYMPTOMS

Excessive Blood Nosebleed with Bleeding bleeding in urine no apparent gums from injuries cause

COMPLICATIONS

Several bruises on the body

Chronic joint Seizure disease and paralysis

WHAT IS THE TRUTH BEHIND HAEMOPHILIA?

T

R

U

UNSTOPPABLE RECOVERY CAN'T TREAT BLEEDING BE OBTAINED APPROPRIATELY PHARMACOLOGIC CAN HAPPEN TO INCREASE LIFE BOTH INTERNALLY ALLY EXPECTANCY AND EXTERNALLY Andrea M. Panggalo Ennia Y. B. Bancin Revina R. Gunawan

REFERENCE: 208

T

Death

Share this info through your social media account!

H

TRACING OF HAEMOPHILIA HEREDITARY MOSTLY OCCUR ILLNESS BEFORE IN MALE, BUT MARRIAGE CAN ALSO OCCUR IS HIGHLY FEMALES IN SUGGESTED

World Federation of Hemophilia. WFH has spearheaded a scientific study updating the prevalence of hemophilia to higher numbers than preciously estimated. [Internet]. 2019 [cited March 19th 2021].

Available from: https://news.wfh.org/wfh-has-spearheaded-a-scientific-study-updating-theprevalence-of-hemophilia-to-higher-numbers-than-previously-est

World Haemophilia Day: Play Your Part in Fighting Haemophilia Stigma

Haemophilia is an inherited bleeding disorder in which the blood does not clot properly1. That is caused by a lack of clotting factor proteins in the blood1. There are 2 types of Haemophilia, which are Haemophilia A and Haemophilia B. Haemophilia A (the most common type of haemophilia) affects 1 in 5,000 male births1.

The range of disabilities and comorbidities that accompany the disorders, and the challenges that patients and caregivers face in dealing with these diseases while striving to lead a normal life4. The aim of treatment should not be just to survive but to achieve a high quality of life.

Moreover, the physiological effects of haemophilia affect either the haemophiliacs or their families. They got stigmatized and subject to social discrimination. It is such an irony that people with haemophilia still have the social barriers that are born within unrespectful social stigma about hemophilia4.

Treating this lifelong disease requires teamwork between the patients, health-care provider, and importantly also the whole society. This might be a very small step, but abolishing stigma is the very first step if we dream about haemophiliacs living in a way they actually should be. Thus, let's fight the stigma.

209

Bibliography

1. What is Haemophilia [Internet]. Centers for Disease Control and Prevention. Centers for Disease Control

and

Prevention;

2020

[cited

2021

Mar15].

Available

from:

https://www.cdc.gov/ncbddd/hemophilia/facts.html 2. 10 Myths and Facts about Haemophilia [Internet]. HemAware. 2018 [cited 2021Mar14].

Available from: https://hemaware.org/mind-body/what-10-myths-and-facts-about-hemophilia 3. Mehta P, Reddivari AKR. Haemophilia. [Updated 2021 Jan 16]. In: StatPearls [Internet].

Treasure

Island

(FL):

StatPearls

Publishing;

2021

Jan-.

Available

from:

https://www.ncbi.nlm.nih.gov/books/NBK551607/ 4. De Prince [Internet]. 2006. Report on the current situation of Chinese Haemophiliacs Beijing Aizhixing

Institute,.

[Cited

2021Mar18].

Available

from:

https://lib.ohchr.org/HRBodies/UPR/Documents/Session4/CN/BAI_CHN_UPR_S4_2009_anx_ Hemo-Report_Annex_ENG.pdf

210

#WorldHaemophiliaDay

PLAY YOUR PART

HAEMOPHILIA STIGMA #FightToProtect

Haemophilia Can Cause...(1)

Who’s Affected?

1 IN 5000 MALE BIRTHS

(1)

The estimated frequency of haemophilia is around 1 in

Haemophilia is a bleeding disorder in which the blood does not clot properly.(1)

Bleeding within joints that can lead to chronic joint disease and pain

Bleeding in the head and sometimes in the brain which can cause long term problems

Death can occur if the bleeding cannot be stopped

10000 live births (3)

The most famous

HAEMOPHILIA STIGMA (2)

#1 People with haemophilia are fragile and cannot be active

This is far from reality! There are amazing athletes with hemophilia.

LET’S FIGHT THE STIGMA!

LEARN S TAKE ACTION SPEAK UP Know the facts

Know That Everyone is Worthy #2 Many communities assume that it is “witchcraft” or a “curse.

This is just a disease, which is common in men although women can also experience this disease. #3 A woman with a bleeding disorder can’t have children

Women with bleeding disorders certainly can have children. Still, a woman should consult with her hematologist and obstetrician.

Share accurate informations about hemophilia Speak Up Towards Any Discriminations or Other Negative Behaviors “You do it all the time, constantly. Day after day. It’s tough. It’s tough because ordinary people don’t have to go through the same things.”

A 48 year old male haemophilia survivor

References: 1. What is Hemophilia [Internet]. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention; 2020 [cited 2021Mar15]. Available from: https://www.cdc.gov/ncbddd/hemophilia/211 facts.html 2. 10 Myths and Facts About Hemophilia [Internet]. HemAware. 2018 [cited 2021Mar14]. Available from: https://hemaware.org/mind-body/what-10-myths-and-facts-about-hemophilia 3. Mehta P, Reddivari AKR. Hemophilia. [Updated 2021 Jan 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551607/

This study aims to reduce the prevalence of hemophilia, also to make the public more aware and concerned about hemophilia. Hemophilia is a X-Linked congenital bleeding disorder caused by blood clotting factor defects. Based on World Federation of Hemophilia (WFH) annual globlay surveys, the number of men with hemophilia is quite high in world. A female could be a carrier of hemophilia. The symptoms such as hemorrghages, bruising, tachycardia, and other could occur in hemophilia. If hemophilia is not treated immediately, fatal consequences such as internal bleeding, joint pain, and infection may be a complication. Based on the results of studies from various sources, pre-marital and routine screening are way for preventing hemophilia but the people still overlook frequently. Through pre-marital checkups, people can find out what factors are in their bodies that can cause abnormalities in the future.

Meanwhile, the screening test will carry out examinations including measurement of complete blood cells, evaluation of hemostasis, radiographic tests, identification of relatives' conditions, and others. Overall, with the public knowing about symptoms and the importance of the premarital checkups, the public can be more alert, cconcern, and are willing to do both tests to reduce the prevalence of this disease.

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Battle the FLOOD, Settle Our BLOOD Abstract Introduction Hemophilia is a bleeding disorder.1 It hampers daily activities.2 Hemophilia affects 1 in 5,000 male births.3 There is no cure available and treatments are costly.4 People’s awareness on prevention is still low.

Method We gathered information from CDC and journals.

Results We propose a solution to educate people through a simple tagline, Battle the FLOOD, Settle Our BLOOD. “FLOOD” emphasizes the bleeding and represents the impacts while “BLOOD” represents preventive actions.

Discussion By implementing our solution, we hope that hemophilia burdens could be reduced.

References 1.

Centers for Disease Control and Prevention. Hemophilia [Internet]. 2021. Available from: https://www.cdc.gov/ncbddd/hemophilia/index.html

2.

D’Angiolella LS, Cortesi PA, Rocino A, Coppola A, Hassan HJ, Giampaolo A, et al.

The socioeconomic burden of patients affected by hemophilia with inhibitors. Eur J Haemathology

[Internet].

2018;

Available

from:

https://onlinelibrary.wiley.com/doi/full/10.1111/ejh.13108 3.

Inserro A. Prevalence of Hemophilia Worldwide Is Triple That of Previous Estimates, New

Study

Says

[Internet].

2019.

Available

from:

https://www.ajmc.com/view/prevalence-of-hemophilia-worldwide-is-triple-that-ofprevious-estimates-new-study-says-

214

4.

Andreia Café, Manuela Carvalho, Miguel Crato, Miguel Faria, Paula Kjollerstrom, Cristina Oliveira, Patrícia R. Pinto, Ramón Salvado AA dos S& CS. Haemophilia A: health and economic burden of a rare disease in Portugal. Orphanet J Rare Dis. 2019;14(211).

215

216

Background : According to the report on the Annual Global Survey (2019), there are 195.263 out of 358.749 people identified with bleeding disorder. The ratio of haemophilia is 1 in 10.000 in developing countries with 400 cases haemophilia A each year. This number occurred red due to several reasons, such as the unawareness of mothers on being a carrier. In this public poster, we aim to raise awareness of haemophilia carriers, in hopes that the soon to-be mother will be well aware and prepared for the possibilities, and help to relieve burdens for haemophilia patients, especially those who are expecting a baby.

Methods : We searched the following electronic databases for the datas regarding this matter : PubMed. Results : We found that through raising awareness of haemophilia carriers will help them to be more prepared and plan their pregnancy safely.

Discussion : There are tests they should take before planning on having a baby, such as maternal blood test or DNA testing. If the mother weren’t aware of being a carrier, those test should be taken as soon as possible. It is also expected for the pregnant couple to consult plans for the baby to an obstetrician.

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218

THE GIVEN THRONE: Act Like a Royal to be Treated Like a Royal

Introduction Haemophilia is a bleeding disorder which interferes with the blood clotting process caused by the low level of various clotting factors.1,5 In most cases, haemophilia is an inherited disorder but it is possible to develop haemophilia later in life.2,5 Haemophilia occurs in about five in every 100,000 male births.3 Although information about haemophilia is widely spread, there are still many misconceptions.

Method Articles on haemophilia’s epidemiology, diagnosis and prevention were collected and critically appraised to assess the validity, importancy and applicability.

Result and Discussion The title ‘The Given Throne’ illustrates that most haemophilia cases are usually a hereditary disorder.7 The Royal theme in the subtitle is used because haemophilia patients must be protected like royals and they should implement the ROYAL behaviours in their daily life to prevent bleeding episodes.4,6 Regular exercise is a must to build muscle strength.8,9,10 Obtain clotting factor test to get a diagnosis of haemophilia.8,9,10 Your daily diet has to be maintained and Always guarantee your dental hygiene to prevent and reduce bleeding.8,9,10 Limit small injuries that can cause bleeding.8,9,10

Conclusion Haemophilia cannot be cured, but persons who suffered from haemophilia can improve their quality of life by reminding themselves to implement the ROYAL behaviours.3,5

219

Bibliography

1. Konkle, BA., Huston, H., Fletcher, S.N. Hemophilia A. 2000 Sep 21 [Updated 2017 Jun 22] In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet].

Seattle (WA): University of Washington, Seattle.

Bookshelf URL: https://www.ncbi.nlm.nih.gov/books/ 2. Swami, A., Kaur, V. Von Willebrand Disease: A Concise Review and Update for the Practicing Physician. Clinical and Applied Thrombosis/Hemostasis. 2017; 23(8):900-910.

3. Coffin, D. Hemophilia World News. Available from: https://news.wfh.org/wfh-hasspearheaded-a-scientific-study-updating-the-prevalence-of-hemophilia-to-highernumbers-than-previously-estimated/ [Accessed 17 March 2021].

4. Centers for Disease Control and Prevention. Diagnosis: Hemophilia. Available from: https://www.cdc.gov/ncbddd/hemophilia/diagnosis.html [Accessed 17 March 2021].

5. Pusat Data dan Informasi, Kementerian Kesehatan Republik Indonesia. Hari Hemofilia Sedunia. Available from: https://pusdatin.kemkes.go.id/article/view/15042000001/harihemofilia-sedunia.html [Accessed 17 March 2021].

6. Yoshua, V. Angliadi, E. Rehabilitasi Medik pada Hemofilia. Available from: https://docobook.com/rehabilitasi-medik-pada-hemofilia.html [Accessed 17 March 2021].

7. Harper, D. Hemofilia. Available from: http://www.etymonline.com/index.php [Accessed 17 March 2021].

8. Kizilocak, H., Young, G. Dignosis and Treatment of Hemophilia. Clinical Advances in Hematology and Oncology. 2019; 17(6): 344-351.

9. Strike, K., Mulder, K., Michael, R. Exercise for haemophilia (Review). Cochrane Database of Systematic Reviews.

2016(12).

Art.No.:CD011180.

DOI: 10.1002/14651858.CD011180.pub2.

10. Ljung, R.C.R. Prevention and Management of Bleeding Episodes in Children with Hemophilia. Pediatric Drugs. 2018; 20:455–464.

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World Haemophilia Day 2021

T h e i v e n h r o n e T h e G G i v e n T T h r o n e

Act Like a Royal, to be Treated Like a Royal

WHAT IS HAEMOPHILIA?

FACTS YOU SHOULD KNOW 5 in 100,000 men are are born born with with haemophilia haemophilia It mostly affects men but

women can be carriers.

Haemophilia is a hereditary disorder where blood cannot clot normally.

It can cause spontaneous bleeding and also posttraumatic or surgery bleeding.

HOW TO DIAGNOSE? SCREENING TEST

CBC Activated Partial Thromboplastin Time (APTT) Test Prothrombin Time (PT) Test Fibrinogen Test

HOW TO MANAGE? The best way to treat haemophilia is to replace the missing clotting factor, which can help the blood to clot properly.

CLOTTING FACTOR TEST

START YOUR ROYAL BEHAVIOUR!

Level of factor VIII & IX in the blood

R

O

Y

A

L

Regular exercise is a must, such as swimming

Obtain clotting factor test immediately

Your daily diet has to be maintained

Always guarantee your dental hygiene

Limit small injuries, such as papercuts, bruises, etc.

References 1. Konkle, BA., Huston, H., Fletcher, S.N. Hemophilia A. 2000 Sep 21 [Updated 2017 Jun 22] In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle. Bookshelf URL: https://www.ncbi.nlm.nih.gov/books/ 2. Swami, A., Kaur, V. Von Willebrand Disease: A Concise Review and Update for the Practicing Physician. Clinical and Applied Thrombosis/Hemostasis. 2017; 23(8):900-910.

3. Coffin, D. Hemophilia World News. Available from: https://news.wfh.org/wfh-has-spearheaded-a-scientific-study-updating-the-prevalence-of-hemophilia-to-higher-numbers-than-previously-estimated/ [Accessed 17 March 2021].

4. Centers for Disease Control and Prevention. Diagnosis: Hemophilia. Available from: https://www.cdc.gov/ncbddd/hemophilia/diagnosis.html [Accessed 17 March 2021].

5. Pusat Data dan Informasi, Kementerian Kesehatan Republik Indonesia. Hari Hemofilia Sedunia. Available from: https://pusdatin.kemkes.go.id/article/view/15042000001/hari-hemofilia-sedunia.html [Accessed 17 March 2021].

6. Yoshua, V. Angliadi, E. Rehabilitasi Medik pada Hemofilia. Available from: https://docobook.com/rehabilitasi-medik-pada-hemofilia.html [Accessed 17 March 2021].

7. Harper, D. Hemofilia. Available from: http://www.etymonline.com/index.php [Accessed 17 March 2021].

221 8. Kizilocak, H., Young, G. Dignosis and Treatment of Hemophilia. Clinical Advances in Hematology and Oncology.

2019; 17(6): 344-351.

9. Strike, K., Mulder, K., Michael, R. Exercise for haemophilia (Review). Cochrane Database of Systematic Reviews. 2016(12). Art.No.:CD011180. DOI: 10.1002/14651858.CD011180.pub2.

10. Ljung, R.C.R. Prevention and Management of Bleeding Episodes in Children with Hemophilia. Pediatric Drugs. 2018; 20:455–464.

DON’T DISRESPECT, SIMPLY ACCEPT Alicia Gani, Venna Bella Sabatina, Christyara Karyadi Haemophilia, which means love (philia) of blood (hemo), manifests with prolonged and excessive bleeding spontaneously or after insignificant trauma.1 In 2019 the incidence of haemophilia in 115 countries was 195,263 and still continues to increase. By gender, haemophilia is more common in men than women. People with haemophilia are often labeled as scary, weak, not masculine, and so on.2 A study by Reinicke K, et al. assessing nine Danish men (40-54 years old) with severe haemophilia stated that their greatest difficulty was meeting social expectations as a man and father.3 Because of this stigma, we are interested in making a public poster entitled "Don't Disrespect, Simply ACCEPT". We hope this poster can help reduce or even eliminate the stigma in society towards haemophilia patients.

In this poster, we present the definition and a brief epidemiology overview of haemophilia. Furthermore, we also illustrate the various stigmas that exist in society towards haemophilia patients. In the middle of the poster, we portray a haemophilia patient who looks sad because of the stigma. Finally, we try to provide a solution which is presented with the acronym "ACCEPT", it means as a community, we have to accept and should not disrespect them.

References: 1. Salen P, Babiker HM. Hemophilia A. [Updated 2020 Nov 19]. In: StatPearls [Internet].

Treasure

Island

(FL):

StatPearls

Publishing;

2021

Jan-.

Available

from:

https://www.ncbi.nlm.nih.gov/books/NBK470265/ 2. World Federation of Hemophilia. Report on The ANNUAL GLOBAL SURVEY 2019.

World Federation of Hemophilia. 2020; (4) 3. Reinicke, K., Søgaard, I. S., & Mentzler, S. Masculinity Challenges for Men With Severe Hemophilia. American journal of men's health. 2019; 13(4), 1557988319872626. https://doi.org/10.1177/1557988319872626

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WORLD HAEMOPHILIA DAY

Alicia Gani Venna Bella Sabatina Christyara Karyadi

Don’t DisrEspeCt, SimpLy

Acce P t

What is Haemophilia?

Haemophilia is usually an inherited bleeding disorder in which the blood does not clot properly.

If yOu wAnt tO kNow mOre, sCan tHis Qr cOde.

How Common is Haemophilia?

Approximately 20,000 people with haemophilia are to be born worldwide each year.

If you can t play with your kids, you re not a fun dad.

We are scared of you, you keep bleeding!

THEY SAY...

“Sorry, we couldn t hire you, this job requires a lot of strength.

Why do you have a helmet on?

You are so weird!

Hey be careful with them.

You ll get infected too!

You re so boring! You can t do sports.

What Should We Do?

A C C E P T

223 References : 1. CDC. What is Hemophilia [Internet]. Centers for Disease Control and Prevention. 2020 [cited 2021 Feb 26]. Available from: https://www.cdc.gov/ncbddd/hemophilia/facts.html 2. World Federation of Hemophilia. Report on The ANNUAL GLOBAL SURVEY 2019. World Federation of Hemophilia. 2020; (4) 3. Reinicke, K., Søgaard, I. S., & Mentzler, S. Masculinity Challenges for Men With Severe Hemophilia. American journal of men's health. 2019; 13(4), 1557988319872626. https://doi.org/10.1177/1557988319872626

Model Methods in Justifying Misconceptions of Haemophilia Bleeding is normal for any living organism, but what if it doesn't stop like it normally does? There is a condition of a rare disorder called Haemophilia in which your blood doesn't clot normally due to the lack of sufficient blood-clotting proteins. The people who suffers Haemophilia may bleed for a longer time after an injury occurs as the clotting factors bind slower to platelets in order to stop bleeding. The two types of Haemophilia are Haemophilia A with a clotting factor VIII deficiency and haemophilia B with a clotting factor IX deficiency.

Nevertheless, the society has its own perspective and myths about Haemophilia. For instance, If a person with haemophilia gets a minor cut, they will bleed to death, sports are forbidden for people with Haemophilia, and children with haemophilia will grow out of it.

In fact, minor cuts are not a cause for concern as it heals on their own. Also, exercise is extremely important to strengthen muscles as it reduces the risk of being overweight. Lastly, haemophilia has no cure.

Proper education and accurate sources guides the general public to sort out the right and wrongs in collecting information. Thus, any misconceptions and myths can be avoided.

Word Count: 200 Reference: 1. Mayoclinic.org. 2021. Mayo Clinic - Mayo Clinic. [online] Available at: <https://www.mayoclinic.org> [Accessed 17 March 2021].

2. 2021. [online] Available at: <https://www.researchgate.net/publication/284761902_Hemophilia> [Accessed 17 March 2021].

3. 2021. [online] Available at: <https://www.researchgate.net/publication/284761902_Hemophilia> [Accessed 17 March 2021].

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Model methods in justifying misconceptions of Haemophilia

BLOOD BLOOD

Haemophilia is a rare disorder in which your blood doesn't clot normally

T I U O L N O S

Be careful of injuries l ook out for any hemophilia symptomps o o

oBTAIN OFFICIAL SOURCES

D

ccasionally check if your family has bleeding disorder

ften consult to the doctor for any bleeding abnormalities

on't hesitate to make list of vitamins and medication

Exercise strengthens muscle

People with haemophilia shouldn’t do sports

W

orld

H ae m ophi

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MAYOCLINIC.ORG. 2021. MAYO CLINIC - MAYO CLINIC. [ONLINE] AVAILABLE AT: <HTTPS://WWW.MAYOCLINIC.ORG> [ACCESSED 17 MARCH 2021].

225 2021. [ONLINE] AVAILABLE AT: <HTTPS://WWW.RESEARCHGATE.NET/PUBLICATION/284761902_HEMOPHILIA> [ACCESSED 17 MARCH 2021].

2021. [ONLINE] AVAILABLE AT: <HTTPS://WWW.RESEARCHGATE.NET/PUBLICATION/284761902_HEMOPHILIA> [ACCESSED 17 MARCH 2021].

ABSTRACT Hemophilia Makes Bandage

INTRODUCTION : Hemophilia A is seen in about 1 in every 4,000–5,000 males worldwide, compared with hemophilia B, which is estimated to be in 1 in every 20,000 men. Hemophilia C, a much rarer form of the disease, is estimated to occur in about 1 case per 100,000 people in the U.S.1Alongside with that facts, many people in this world still don’t know and underestimate this hemophilia, so we make this poster to create awareness to many people in many social layers & groups.

METHOD

: We search from CDC (Centers for Disease Control Control and Prevention),

NHS, HEMOPHILIA NEWS TODAY & Kementrian Kesehatan Republik Indonesia.

DISCUSSION

: Hemophilia is a bleeding disorder that have 3 types, hemophilia A (lack of

factor VIII), Hemophilia B (lack of factor IX) ,Hemophilia C (lack of factor XI) 2 and all of them have the same diagnose which is bleeding in the same kind of part of places arm, nose, head, ankle, finger, and urine.3 RESULT

: Of all cases, males are dominantly affected by this disease. Also, because

hemophilia is a serious disease and can’t be cured, so people need to know about this treatment, such as First aid that we know as RICE (rest, ice, compression and elevation)4, infusing blood clotting factor that can clot & also we suggest to get annual medical checkup to know the right treatment.3

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SOURCE : 1. Margarida Azevedo, M., 2021. What Is Hemophilia?. [online] Hemophilia News Today.

Available at: <https://hemophilianewstoday.com/what-is-hemophilia/> [Accessed 19 March 2021].

2. Types [Internet]. Stanfordhealthcare.org. 2021 [cited 19 March 2021]. Available from: https://stanfordhealthcare.org/medical-conditions/cancer/hemophilia/hemophilia-types.html 3. What is Hemophilia? | CDC [Internet]. Centers for Disease Control and Prevention. 2021 [cited 19 March 2021]. Available from: https://www.cdc.gov/ncbddd/hemophilia/facts.html 4. [Internet]. Hemophilia.ca. 2021 [cited 19 March 2021]. Available from: https://www.hemophilia.ca/files/Chapter%2004.pdf

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