How to distinguish AHA

Acquired bleeding disorders can accompany haematological, neoplastic, autoimmune, cardiovascular or liver diseases, but can sometimes also arise spontaneously.

THEY CAN MANIFEST as single factor deficiencies or as complex haemostatic abnormalities. The following article addresses acquired haemophilia A, an autoimmune disorder characterised by inhibitory autoantibodies against coagulation factor VIII, and is based on an article recently published in

Haemophilia: The Official Journal of the World Federation of Haemophilia.

Patients with acquired bleeding disorders are often not seen first by haematologists or experts in bleeding disorders but rather by GPs, emergency or intensive care unit specialists, surgeons or any other specialty related to the site of first bleeding. For these physicians, it is often difficult to recognise a bleed as a first symptom of what truly is a bleeding disorder. Firstly, because the bleed may not seem unusual. Laboratory tests would probably be done only if bleeds occurred without identifiable cause, were difficult to control, or frequently recurring. Secondly, if laboratory tests have been ordered, their interpretation can be challenging because abnormalities may sometimes indicate a haemostasis disorder, but more often result from underlying disorders, medications, the bleed itself or poor sample quality.

Even more confusing for non-experts, laboratory abnormalities such as a prolonged activated partial thromboplastin time (APTT) may indicate a bleeding disorder (eg deficiency in factor VIII, IX or XI), a thrombogenic state (eg lupus anticoagulant) or neither of the two (eg deficiency in factor XII, prekallikrein or high molecular weight kininogen). Patients with liver disease, despite presenting with low platelet counts or a prolonged prothrombin time (PT) may eventually have a greater risk of thrombosis than a risk to bleed. While the fact that laboratory tests can’t predict bleeding has resulted in recommendations against routine testing in the general population, it is still important to raise awareness about the most important acquired bleeding disorders and to guide physicians towards proper interpretation of laboratory results in different clinical scenarios.

EPIDEMIOLOGY

Acquired haemophilia A (AHA) is a rare disorder. The UK surveillance study estimated in 2007 an incidence of 1.4 cases per million inhabitants per year. More recent estimates from Germany indicated an increase to up to six per million per year, possibly due to increased awareness of the disorder. Acquired haemophilia A affects men and women of all ages but is more frequent in the elderly. The mean age at diagnosis is approximately 70 years. About 30%-50% of patients have associated disorders, most often other autoimmune disorders or malignancy. About 5% of AHA cases occur in relation to pregnancy, usually postpartum. Due to its rarity, the disorder occurs almost always unexpectedly and is often not recognised.

PATHOPHYSIOLOGY

AHA is due to neutralising autoantibodies against factor VIII (FVIII). The residual FVIII activity is <1IU/dL in 50% of patients (<5IU/ dL in 75%, <40IU/dL in 100%).

FVIII-binding antibodies are often of the IgG4 subclass (>90% of patients), but other IgG subclasses, IgM and IgA can occur in various combinations. The differential impact of isotypes and subclasses to FVIII neutralisation is not known. The anti-FVIII antibody response is usually polyclonal in nature, and different FVIII domains are involved. The role of associated disorders in the pathophysiology of the anti-FVIII immune response is unknown. A mystery is also the striking difference in bleeding phenotype between AHA and congenital haemophilia A (HA) or HA with inhibitors against FVIII (HA-I). Patients with AHA frequently suffer from cutaneous and deep muscle bleeds, whereas joint bleeds are rarely seen.

ACQUIRED HAEMOPHILIA (AH)

BE AWARE OF THE SYMPTOMS OF A BLEEDING EPISODE DUE TO AH

Bleeding into the skin (purpura) and soft tissues1

Gastrointestinal bleeding1

Haematuria1

TREAT ACCORDINGLY

Prolonged postpartum bleeding1

• AH is often associated with other autoimmune conditions, malignant disease, certain drugs and pregnancy1 • AH is a potentially life threatening condition with mortality in range of 8-22%1 • Urgent Laboratory diagnosis is required when unexplained bleeding or bruising occurs.2

Consider AH in patients with: Recent onset of abnormal bleeding, isolated prolongation in aPTT, Normal PT.2

Stop the bleed with NovoSeven®3

90 µg/kg

NovoSeven®

Full administration in 2–5 minutes5 Peak coagulation ability in 10 minutes6

9 12

every 2-3

hours

6

NovoSeven® is easy to use, convenient and

portable with few reconstitution steps5 Con

3 Until clinical haemostasis is achieved4

9 12

every 4-12

hours

6 3 Successively increase dose interval to 4,6,8 or 12 hours for as long as treatment is judged to be indicated4

DIAGNOSIS

An isolated prolongation of the APTT (with normal PT) in a bleeding patient is the hallmark of AHA. Although APTT prolongation may result from many causes, it should never remain unexplained if observed in bleeding patients or before interventions with a high risk of bleeding.

In patients with AHA, FVIII activity will be found reduced, and the disorder is confirmed then by demonstrating the neutralising capacity of the autoantibody in the Bethesda assay. If FVIII activity testing and the Bethesda assay are not immediately available, an APTT mixing study may help to demonstrate the presence of an inhibitor in the patient plasma, which is at least suggestive of AHA in a bleeding patient. The mix of patient and normal plasma is recommended to be tested both immediately (a prolongation here would be suggestive of heparin or the lupus anticoagulant) and after incubation at 37°C for two hours (a progressive prolongation would be suggestive of inhibitors in AHA).

The differential diagnosis of an isolated APTT prolongation includes the following: • Low FVIII (AHA, HA, HA-I, von

Willebrand disease (VWD) or AVWS) • Low factor IX (haemophilia B) • Low factor XI (historically also called haemophilia C) • Conditions not associated with bleeding (eg LA, low factor XII, PKK, HMWK) • Pharmacological anticoagulants (eg heparin, dabigatran).

AHA and lupus anticoagulant (LA) are sometimes difficult to differentiate. Depending on its strength and the reagent used, LA can prolong the APTT to a variable degree and sometimes even interfere with APTT-based factor assays, including FVIII.

AHA can be excluded in this situation by demonstrating normal FVIII activity in chromogenic substrate assay or absence of FVIII-binding antibodies in immunoassays. Note that AHA and LA are both autoimmune disorders and can occur simultaneously in patients. Acquired von Willebrand syndrome is usually simple to differentiate from AHA, because the APTT mixing study and the Bethesda assay will be negative. FVIII is usually only low in acquired von Willebrand syndrome, if von Willebrand factor antigen assays are also low.

TREATMENT Haemostatic therapy

Patients with AHA should be referred to expert centres. At least, expert advice should be sought if referral is not possible. Surgical interventions can be life-threatening in patients with AHA and should be strictly avoided until haemostasis is secured by adequate treatment. The decision to treat bleeds, and the monitoring of treatment success, is based on clinical decision-making. Clinically relevant bleeds are treated with bypassing agents (recombinant factor VIIa [rFVIIa, eptacog alfa activated], activated prothrombin complex concentrate [APCC]) or recombinant porcine factor VIII (rpFVIII, susoctocog alfa). Human FVIII concentrates are only recommended if other options are not available because their efficacy is lower than that of the bypassing agents. Tranexamic acid can be used as an adjunct agent, for mucocutaneous bleeds, or as a single agent for minor bleeds. If rpFVIII is used, monitoring of the FVIII activity (by APTT-based one-stage assays) should be used to guide dosing. Such monitoring may help to prevent unnecessary and potentially harmful overdosing and to recognise patients with cross-reacting antibodies. Such antibodies were found in 44% of patients (usually of low titre) and will require higher doses of rpFVIII.

Immunosuppressive therapy

Immunosuppression is recommended to eradicate autoantibodies and induce remission of AHA. Regimens include corticosteroids (eg prednisone or prednisolone 1mg/kg body weight), rituximab (eg 375mg/m2 body surface area weekly for up to four doses) and/or cyclophosphamide (1-2mg/kg body weight daily). Caution should be exercised with old and fragile patients as registries show that mortality due to infection exceeds by far the risk of fatal bleeding. Prognostic factors have been determined in an observational registry and may be helpful to guide immunosuppressive therapy in the future.

CONCLUSION

Acquired bleeding disorders can be part of the pathophysiology of many diseases, including cardiovascular, hepatic, autoimmune and malignant disorders. Recognition of symptoms and laboratory signs is key to identification and proper management. The field is rapidly moving and, therefore, close cooperation is required among all specialties involved in patient management, including experts in haemostasis and thrombosis.

REFERENCE

Tiede, A, Zieger, B, Lisman, T. Acquired bleeding disorders. Haemophilia. 2021;27( suppl. 3):5–13. https://doi.org/10.1111/hae.14033.

References: 1) Giangrande P. Acquired Hemophilia. Revised ed. Montreal, Quebec, Canada: World Federation of Hemophilia; 2012. 2) Collins P, et al. BMC Res Notes 2010;3:161 3) Tengborn L et al. BJOG 2012;119:1529 – 1537. 4) NovoSeven® approved professional information. 5) Maahs J et al. Mixing and administration times of bypassing agents: observations from the Dosing Observational Study in Hemophilia (DOSE). J Blood Med 2014;5:153-156. 6) Fernández-Bello I, et al. The pharmacokinetics and pharmacodynamics of single-dose and multiple-dose recombinant activated factor VII in patients with haemophilia A or B. Haemophilia 2017;23(1):868–876. .

NovoSeven® 1 mg, 2 mg & 5 mg abbreviated Professional Information

Scheduling status: S4

Name of the medicine: NovoSeven® 1 mg, NovoSeven® 2 mg, NovoSeven® 5 mg; powder and solvent for solution for injection

Qualitative and quantitative composition: NovoSeven® 1 mg (corresponds to 50 KIU) contains 1 mg per vial activated recombinant coagulation factor VIIa (eptacog alfa); NovoSeven® 2 mg (corresponds to 100 KIU) contains 2 mg per vial activated recombinant coagulation factor VIIa (eptacog alfa); NovoSeven® 5 mg (corresponds to 250 KIU) contains 5 mg per vial activated recombinant coagulation factor VIIa (eptacog alfa).

Therapeutic indications:

• Treatment of patients with haemophilia with inhibitors to coagulation factor VIII and factor IX. The use of NovoSeven® is indicated for patients suffering life- or limb-threatening bleeds or requiring surgery and in home-treatment setting for early intervention to treat mild to moderate bleeding episodes. • Treatment of bleeding episodes and for the prevention of bleeding in patients with congenital FVII deficiency undergoing surgery or invasive procedures. • Treatment of bleeding episodes and for the prevention of bleeding in those patients undergoing surgery or invasive procedures with Glanzmann’s thrombasthenia with or without antibodies to GP

IIb-IIIa and/or HLA, and with past or present refractoriness to platelet transfusions, or where platelets are not readily available. • Treatment of bleeding episodes and for the prevention of bleeding in those patients with acquired haemophilia undergoing surgery or invasive procedures.

Posology and method of administration:

Haemophilia A or B with inhibitors or expected to have a high anamnestic response: Mild to moderate bleeding episodes (including home therapy): Early intervention has been shown to be efficacious in the treatment of mild to moderate joint, muscle and mucocutaneous bleeds. Two dosing regimens can be recommended: 1) Two to three injections of 90 μg per kg body weight administered at three-hour intervals. If further treatment is required, one additional dose of 90 μg per kg body weight can be administered. 2) One single injection of 270 μg per kg body weight. The duration of the home therapy should not exceed 24 hours. There is no clinical experience with administration of a single dose of 270 μg per kg body weight in elderly patients. Serious bleeding episodes: An initial dose of 90 μg per kg body weight is recommended. Dosing frequency should initially be every second hour until clinical improvement is observed. If continued therapy is indicated, the dose interval can then be increased to 3 hours for 1 - 2 days. Thereafter, the dose interval can be increased successively to every 4, 6, 8 or 12 hours for as long as treatment is judged as being indicated. A major bleeding episode may be treated for 2 - 3 weeks but can be extended beyond this if clinically warranted. Surgery/ invasive procedure: An initial dose of 90 μg per kg body weight should be given immediately before the procedure. The dose should be repeated after 2 hours and then at 2 - 3 hour intervals for the first 24 - 48 hours depending on the surgery performed and the clinical status of the patient. In major surgery, the dose should be continued at 2 - 4 hour intervals for 6 - 7 days. The dose interval may then be increased to 6 - 8 hours for another 2 weeks of treatment. Patients undergoing major surgery may be treated for up to 2 - 3 weeks until healing has occurred. Acquired Haemophilia: NovoSeven® should be given as early as possible after the start of a bleeding episode. The recommended initial dose, administered by intravenous bolus injection, is 90 μg per kg body weight. Following the initial dose of NovoSeven® further injections may be given if required. The duration of treatment and the interval between injections will vary with the severity of the haemorrhage, the invasive procedures or the surgery being performed. The initial dose interval should be 2 - 3 hours. Once haemostasis has been achieved, the dose interval can be increased successively to every 4, 6, 8 or 12 hours for as long as treatment is judged to be indicated. Factor VII deficiency: The recommended dose range is 15 - 30 μg per kg body weight every 4 - 6 hours until haemostasis is achieved. Dose and frequency of injections should be adapted to each individual. Limited clinical experience in long term prophylaxis in paediatric population has been gathered in the paediatric population below 12 years of age, with a severe clinical phenotype. Dose and frequency of injections for prophylaxis should be adapted to each individual. Glanzmann’s thrombasthenia: The recommended dose is 90 μg (range 80 - 120 μg) per kg body weight at intervals of two hours (1,5 – 2,5 hours). At least three doses should be administered to secure effective haemostasis. The recommended route of administration is bolus injection as lack of efficacy may appear in connection with continuous infusion. For those patients who are not refractory, platelets are the first line treatment for Glanzmann’s thrombasthenia. Contraindications: Hypersensitivity to the eptacog alfa, any of the excipients, or to mouse, hamster or bovine protein. Special warnings and precautions for use: When NovoSeven® is administered to patients outside current approved indications, arterial thromboembolic events are common. There may be a potential risk of development of thrombotic events or induction of disseminated intravascular coagulation (DIC) in association with NovoSeven® treatment in patients receiving NovoSeven® after major surgery or in pathological conditions in which tissue factor may be expressed more extensively than considered normal. Because of the risk of thromboembolic complications, caution should be exercised when administering NovoSeven® to patients with a history of coronary heart disease, to patients with liver disease, to neonates, or to patients at risk of thromboembolic phenomena or disseminated intravascular coagulation. As NovoSeven® may contain trace amounts of mouse IgG, bovine IgG and other residual culture proteins, the remote possibility exists that patients treated with NovoSeven® may develop hypersensitivity to these proteins. In such cases treatment with antihistamines IV should be considered. The duration of home treatment should not exceed 24 hours. Patients with factor VII deficiency treated with NovoSeven® should be monitored for factor VII antibodies. One case of angioneurotic oedema has been reported spontaneously in a patient with Glanzmann’s thrombasthenia after administration of NovoSeven®. NovoSeven® contains less than 1 mmol sodium per injection, indicating that it is essentially “sodium free”. Contains sucrose. Interaction with other medicines and other forms of interaction: The risk of a potential interaction between NovoSeven® and coagulation factor concentrates is unknown. Simultaneous use of prothrombin complex concentrates, activated or not, should be avoided. Anti-fibrinolytics have been reported to reduce blood loss in association with surgery in haemophilia patients, especially in orthopaedic surgery and surgery in regions rich in fibrinolytic activity, such as the oral cavity. Experience with concomitant administration of anti-fibrinolytics and NovoSeven® treatment is however limited. Based on a non-clinical study it is not recommended to combine NovoSeven® and rFXIII. There are no clinical data available on interaction between rFVIIa and rFXIII. Fertility, pregnancy and lactation: It is not known whether NovoSeven® can affect reproduction capacity. Safety in pregnancy has not been established. As a precautionary measure, it is preferable to avoid the use of NovoSeven® during pregnancy. It is not known whether NovoSeven® is excreted in human breast milk. Undesirable effects: Uncommon: venous thromboembolic events, rash, pruritus, urticaria, therapeutic response decreased, pyrexia; Rare: disseminated intravascular coagulation and related laboratory findings, coagulopathy, hypersensitivity, nausea, headache, arterial thromboembolic events, angina pectoris, injection site reaction including injection site pain, increased fibrin degradation products, increase of alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase and prothrombin levels; Frequency not known: anaphylactic reaction, intracardiac thrombus, flushing, angioedema. Overdose: Dose limiting toxicities of NovoSeven® have not been investigated in clinical trials. Cases of overdose have been reported in patients with haemophilia. No cases of overdose have been reported in patients with acquired haemophilia or Glanzmann’s thrombasthenia. In patients with factor VII deficiency, one episode of overdose has been associated with a thrombotic event in an elderly (> 80 year) male patient treated with 10 – 20 times the recommended dose. In addition, the development of antibodies against NovoSeven® and FVII has been associated with overdose in one patient with factor VII deficiency. The dose schedule should not be intentionally increased above the recommended doses due to the absence of information on the additional risk that may be incurred. Treatment is symptomatic and supportive.

Reg. No.: NovoSeven® 1 mg: 44/8.1/0550, NovoSeven® 2 mg: 44/8.1/0551, NovoSeven® 5 mg: 44/8.1/0552 For full prescribing information, refer to the Professional Information approved by the Regulatory Authority. Text revision date by SAHPRA: 2021/11/08

Applicant Address: Novo Nordisk (Pty) Ltd, 150 Rivonia Road, 10 Marion Street Office Park, Building C1, Sandton, Johannesburg, 2196, South Africa. Tel: 011 202 0500 Fax: 011 807 7989