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Harrison’s Hematology and Oncology 3rd Edition Dan L.
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Library of Congress Cataloging‐in‐Publication Data
Names: Hastings, Caroline, 1960– author. | Torkildson, Joseph C., author. | Agrawal, Anurag K. (Anurag Kishor), author. | Children’s Hospital & Research Center Oakland (Oakland, Calif.)
Title: Handbook of pediatric hematology and oncology : Children’s Hospital & Research Center Oakland / Dr Caroline A. Hastings, Dr Joseph C. Torkildson, Anurag K. Agrawal.
Description: Third edition. | Hoboken, NJ : Wiley-Blackwell, 2020. | Includes bibliographical references and index.
Identifiers: LCCN 2020023659 (print) | LCCN 2020023660 (ebook) | ISBN 9781119210740 (paperback) | ISBN 9781119210764 (adobe pdf) | ISBN 9781119210757 (epub)
Set in 9.25/11.5pt Minion Pro by SPi Global, Pondicherry, India
10 9 8 7 6 5 4 3 2 1
On a day‐to‐day basis, the patients and their families continue to show us how to live gracefully in even the most unbearable of times and inspire us to endeavor for improved outcomes. Our experiences have taught us the magnitude of remembering our roles: “to cure sometimes, to relieve often, to comfort always.” (anonymous, fifteenth century)
20 Sarcomas of the Soft Tissues and Bone, 253
21 Germ Cell Tumors, 265
22 Rare Tumors of Childhood, 275
23 Histiocytic Disorders, 287
24 Hematopoietic Stem Cell Transplantation, 295
25 Supportive Care of the Child with Cancer, 313
26 Central Venous Catheters, 323
27 Management of Fever in the Child with Cancer, 333
28 Acute Pain Management in the Inpatient Setting, 347
29 Palliative Care, 361
30 Chemotherapy Basics, 377
31 Guide to Procedures, 393
32 Treatment of Chemotherapy Extravasations, 403 Formulary, 409 Index, 489
Preface
The pace of change in the field of pediatric hematology, oncology, and hematopoietic cell therapies is staggering. Molecular biology, genomics, and biochemistry have accelerated the knowledge and understanding of disease states and further highlight the complex interplay of clinical, genetic, and social factors that constantly challenge us in the rapid application of novel findings to treat patients with the goal of improved outcomes. This translation of knowledge to the unique patient before us, the true art of the physician, encompassing experience, knowledge, intuition, and understanding of the individual needs and goals of patients and families, can be overwhelming. What is needed is a practical, tested approach to analyze and address these problems to ensure timely evaluation, competent clinical care, and avoidance of pitfalls that might negatively impact the patient or future treatment options. This practical approach is achieved by spending time with patients and families
and observing the myriad variations in disease and individual nuances that are not addressed in large studies or case reports, all the while expanding foundational knowledge.
This handbook represents the work of our colleagues at Children’s Hospital & Research Center Oakland toward this endeavor. The guidelines offered here have been used to instruct medical students, pediatric residents, nurses, pediatricians, and hematology/oncology fellows for over 25 years. This handbook provides clinical approaches for common problems in pediatric hematology, oncology, hematopoietic stem cell transplant, and newer cellular therapies; knowledge to organize and evaluate the care of your patients; and a framework to incorporate ever‐expanding psychosocial needs, clinical studies, medical treatments, and science. All of these are essential components that encompass the care of the child with blood disorders and cancer.
Acknowledgments
We are grateful to Yoram Unguru, MD, MS, MA, for submission of the expert case and teaching guide in Chapter 29. Dr. Unguru is an attending physician in the Division of Pediatric Hematology/Oncology at the Herman & Walter Samuelson Children’s Hospital at Sinai and Chairman of the Sinai Hospital Ethics Committee, as well as attending at the Johns Hopkins Berman Institute of Bioethics.
We are also extremely appreciative of patient cases submitted by Dr. Christina
Coleman Abadi, Assistant Professor of pediatrics at UCSF Benioff Children’s Hospital Oakland; Dr. Cheryl Peretz, senior research fellow and clinical instructor at UCSF Benioff Children’s Hospital Oakland; and Dr. Monica Davini, attending physician in the Division of Pediatric Hematology/ Oncology at Banner—University Medical Center, Tucson Campus in Tucson, Arizona. These cases appear in Chapters 18, 15, and 11, respectively.
1Approach to the Anemic Child
Anemia is the condition in which the concentration of hemoglobin or the red cell mass is reduced below normal. Anemia results in a physiological decrease in the oxygen‐carrying capacity of the blood and reduced oxygen supply to the tissues. Causes of anemia are increased loss or destruction of red blood cells (RBCs) or a significant decreased rate of production. When evaluating a child with anemia, it is important to determine if the problem is isolated to one cell line (e.g., RBCs) or multiple cell lines (i.e., RBCs, white blood cells [WBCs], or platelets). When two or three cell lines are affected, it may indicate bone marrow involvement (e.g., leukemia, metastatic disease, and aplastic anemia), sequestration (i.e., hypersplenism), immune deficiency, or an immune‐mediated process (e.g., hemolytic anemia and immune thrombocytopenic purpura).
Evaluation of anemia
The evaluation of anemia includes a complete medical history, family history, physical examination, and laboratory assessment (see Figure 1.1).
The diagnosis of anemia is made after reference to established normal controls for age (Table 1.1). The blood smear and red
cell indices are very helpful in the diagnosis and classification of anemia. They allow for classification by the cell size (mean corpuscular volume [MCV]), give the distribution of cell size (red cell distribution width [RDW]), and may give important diagnostic clues if specific morphological abnormalities are present (e.g., sickle cells, target cells, and spherocytes). The MCV, RDW, and reticulocyte count are helpful in the differential diagnosis of anemia. A high RDW, or anisocytosis, is seen in stress erythropoiesis and is often suggestive of iron deficiency or hemolysis. A normal or low reticulocyte count is an inappropriate response to anemia and suggests impaired red cell production. An elevated reticulocyte count suggests blood loss, hemolysis, or sequestration.
The investigation of anemia requires the following steps:
1. The medical history of the anemic child (Table 1.2), as certain historical points may provide clues as to the etiology of the anemia.
2. Detailed physical examination (Table 1.3), with particular attention to acute and chronic effects of anemia.
3. Evaluation of the complete blood count (CBC), RBC indices, and peripheral blood smear, with classification by MCV, reticulocyte count, and RBC morphology.
Figure 1.1 Diagnostic approach to the child with anemia (abbreviations: DBA, Diamond–Blackfan anemia; TEC, transient erythroblastopenia of childhood; RDW, red cell distribution width; FEP, free erythrocyte protoporphyrin; TIBC, total iron‐binding capacity; G6PD, glucose‐6‐phosphate dehydrogenase deficiency; DAT, direct antiglobulin test).
*Refer to Table 1.1 for age‐based normal values.
^Microcytosis with lead toxicity has been noted secondary to concomitant iron deficiency; see text.
Consideration should also be given to the WBC and platelet counts as well as their respective morphologies.
4. Determination of an etiology of the anemia by additional studies as needed (see Figures 1.1–1.3).
Interventions
Oral iron challenge
An oral iron challenge may be indicated in the patient with significant iron depletion, as documented by moderate‐to‐severe
*Compiled from the following sources: Dutcher TF. Lab Med 2:32–35, 1971; Koerper MA, et al. J Pediatr 89:580–583, 1976; Marner T. Acta Paediatr Scand 58:363–368, 1969; Matoth Y, et al. Acta Paediatr Scand 60:317–323, 1971; Moe PJ. Acta Paediatr Scand 54:69–80, 1965; Okuno T. J Clin Pathol 2:599–602, 1972; Oski F, Naiman J. Hematological Problems in the Newborn, 2nd ed., Philadelphia: WB Saunders, 1972, p. 11; Penttilä I, et al. Suomen Lääkärilehti 26:2173, 1973; and Viteri FE, et al. Br J Haematol 23:189–204, 1972. Cited in: Rudolph AM (ed). Rudolph’s Pediatrics, 16th ed., Norwalk, CT: Appleton & Lange, 1977.
Abbreviation: MCV, mean corpuscular volume.
anemia and deficiencies in circulating and storage iron forms (such as an elevated total iron‐binding capacity [TIBC], low serum iron, low transferrin saturation, and low ferritin). Iron absorption is impaired in certain chronic disorders (autoimmune diseases such as systemic lupus erythematosus, peptic ulcer disease, ulcerative colitis, and Crohn’s disease), by certain medications (antacids and histamine‐2 blockers), and by environmental factors such as lead toxicity.
Indications for an oral iron challenge include any condition in which a poor response to oral iron is being questioned, such as in: noncompliance, severe anemia secondary to dietary insufficiency (excessive milk intake), and ongoing blood loss.
Administration of an oral iron challenge is quite simple: first, draw a serum iron level; second, administer a dose of iron (3 mg/kg elemental iron) orally; third, draw another serum iron level 30–60 minutes later. The serum level is expected to increase by at least 100 mcg/dL if absorption is adequate. The oral iron challenge is a quick and easy method to assess appropriateness of oral iron to treat iron deficiency—a safer, cheaper, yet equally efficacious method of treatment as parenteral iron.
Parenteral iron therapy
Due to the potential risks of older parenteral iron preparations (specifically high‐molecular‐weight iron dextran), practitioners have moved to newer (and
Table 1.2 The medical history of the anemic child.
HEENTFrontal bossing, prominent malar and maxillary bones
Icteric sclerae
Angular stomatitis
Glossitis
Chest Rales, gallop rhythm, tachycardia
SpleenSplenomegaly
ExtremitiesRadial limb dysplasia
Spoon nails
Triphalangeal thumbs
perceived safer) formulations including ferric gluconate and iron sucrose. Three additional compounds have been approved, one only in Europe (iron isomaltoside) and two in the United States (ferumoxytol and ferric carboxymaltose). These newer agents have the potential benefit of total dose replacement in a very short and single infusion as compared to ferric gluconate and iron sucrose which require multiple doses. Low‐molecular‐weight (LMW) iron dextran is approved as a total dose infusion for adults in Europe but not the United States. Due to the smaller dose generally required
in pediatric patients, total iron replacement is feasible in 1–2 doses of LMW iron dextran and has been shown safe. Refer to the Formulary for calculation of LMW iron dextran dosing.
Severe allergic reactions can occur with iron dextran and therefore a LMW product should be preferentially utilized. A test dose (10–25 mg) should be given prior to the first dose with observation of the patient for 30–60 minutes prior to administering the remainder of the dose. A common side effect is mild to moderate arthralgias the day after drug administration, especially
Mild (Hemoglobin > 10 g/dL)
History and physical exam compatible with iron deficiency
Trial of oral iron
4–6 mg/kg/day
Dietary counseling
Reticulocyte count at 1 week
Continue oral iron
3-6 months
Blood Loss
Urinalysis
Stool guaiac
Meckel’s scan
Hemolysis
Assess degree of anemia
Moderate (Hemoglobin 7–10 g/dL)
Severe (Hemoglobin < 7 g/dL)
History, physical, iron studies, consider hemoglobin electrophoresis and family studies or
Iron Studies
FEP
Iron, TIBC, % iron
saturation
Review smear
Reticulocyte count
Stool guaiac
Consider
Coombs test (DAT)
Peripheral smear
Hemoglobinopathy/Thalassemia
Hemoglobin electrophoresis
Family studies
Lead poisoning
Iron malabsorption
Iron studies
Oral iron challenge
Consider parenteral iron
Bowel disease (Crohn’s, IBD)
Inflammatory disorder (lupus)
Hemoglobinopathy/Thalassemia
Hgb electrophoresis
Family studies
Lead toxicity
Consider
Hospitalization
Transfusion
IV or oral iron (if indicated)
Consider
Severe iron deficiency
Red cell aplasia
Malignancies
Infections
Hemolytic anemia with illness/infection
Thalassemia
β-thalassemia major
Hemoglobinopathy
Sickle cell disease
TEC
Figure 1.2 Evaluation of the child with microcytic anemia (abbreviations: FEP, free erythrocyte protoporphyrin; TIBC, total iron‐binding capacity; DAT, direct antiglobulin test; IBD, inflammatory bowel disease).
in patients with autoimmune disease. Acetaminophen frequently alleviates the arthralgias. Iron dextran is contraindicated in patients with rheumatoid arthritis.
Iron sucrose or ferric gluconate should be considered in patients for whom multiple doses are more feasible. Both are limited
by a maximum dose beyond which there is increased risk of adverse events. Ferumoxytol and ferric carboxymaltose have both received approval by the United States Food and Drug Administration for the treatment of iron deficiency anemia as well as renal insufficiency in adults. Both have
Low hemoglobin concentration
Elevated or normal reticulocyte count
Coombs test (DAT)
Positive
Negative
Normocytic Macrocytic
Low reticulocyte count
Infection
TORCH
Congenital hypoplastic anemia
Transcobalamin II deficiency
Immune hemolytic anemia
ABO incompatibility
Rh incompatibility
Minor blood group incompatibility
Peripheral smear
Abnormal
Membrane defect
Normal
Microcytic
α-thalassemia syndrome
Chronic intrauterine blood loss
Iron deficiency
Blood loss
Iatrogenic
Traumatic delivery
Internal hemorrhage
Twin-twin transfusion
Fetal-maternal transfusion
Infection
TORCH
Hereditary spherocytosis
Hereditary elliptocytosis
Red cell enzyme deficiency
G6PD
Pyruvate kinase
Figure 1.3 Approach to the full‐term newborn with anemia (abbreviations: DAT, direct antiglobulin test; G6PD, glucose‐6‐phosphate dehydrogenase deficiency; TORCH, toxoplasmosis, other, rubella, cytomegalovirus, herpes simplex virus).
the benefit of total dose replacement given as a rapid infusion due to slow release of elemental iron. Neither is immunogenic and therefore no test dose is required. Studies
regarding utilization in pediatric patients are limited regarding appropriate per kg dosage, although the infusions appear safe and therefore will likely replace use of iron
sucrose and ferric gluconate in the future due to the convenience of single dose replacement. Refer to the Formulary for dosing parameters for these products.
Erythropoietin
Recombinant human erythropoietin (EPO) stimulates proliferation and differentiation of erythroid precursors, with an increase in heme synthesis. This increased proliferation creates an increased demand in iron availability and can result in a functional iron deficiency if not given with iron therapy.
Indications for EPO include end‐stage renal disease, anemia of prematurity, anemia of chronic disease, anemia associated with treatment for AIDS, and autologous blood donation. EPO use for the treatment of chemotherapy‐induced anemia remains controversial and is not routinely recommended in pediatric patients (see Chapter 25). EPO has also been used in autoimmune hemolytic anemia with low production as well as in chemotherapy‐induced anemia when the family has religious beliefs that preclude transfusion. The use of EPO in this latter setting may reduce transfusion exposures but has not been validated.
The most common side effect of EPO administration is hypertension, which may be somewhat alleviated with changes in the dose and duration of administration.
Typical starting dose of EPO is 150 U/kg three times a week (IV) or subcutaneous (SC). CBCs and reticulocyte counts are checked weekly. Higher doses, and more frequent dosing, may be necessary. Response is usually seen within 1–2 weeks. Adequate iron intake (3 mg/kg/day orally or intermittent parenteral therapy) should be provided to optimize efficacy and prevent iron deficiency.
Transfusion therapy
Children with very severe anemia (i.e., hgb < 5 g/dL) may require treatment with red cell transfusion, depending on the underlying disease and baseline hemoglobin status, duration of anemia, rapidity of onset, and hemodynamic stability. The pediatric literature is scarce as to the best method of transfusing such patients. However, it appears to be common practice to give slow transfusions to children with cardiovascular compromise (i.e., gallop rhythm, pulmonary edema, excessive tachycardia, and poor perfusion) while being monitored in an ICU setting. Transfusions are given in multiple small volumes, sometimes separated by several hours, with careful monitoring of the vitals and fluid balance. For those children who have gradual onset of severe anemia, without cardiovascular compromise, continuous transfusion of 2 mL/kg/h has b een shown to be safe and result in an increase in the hematocrit of 1% for each 1 mL/kg of t ransfused packed RBCs (based on RBC storage method). The hemoglobin should be increased to a normal value to avoid further cardiac compromise (i.e., hgb 8–12 g/dL). Again, the final endpoint may be dependent on several factors including nature of anemia, ongoing blood loss or lack of production, baseline hemoglobin, and volume to be transfused. Care should be taken to avoid unnecessary exposure to multiple blood donors by maximal use of the unit of blood, proper division of units in the blood bank, and avoidance of opening extra units for small quantities to meet a total volume. See Chapter 5 for product preparation, ordering, and premedication. A posttransfusion hemoglobin can be checked if necessary at any point after the transfusion has been completed. Waiting for “reequilibration” is anecdotal and unnecessary.
Case studies for review
1. You are seeing a 1‐year‐old for their well‐child check in clinic. As part of routine screening, a fingerstick hemoglobin is recommended.
a. What questions in the history might help screen for anemia?
b. What about the physical examination? Multiple questions in the history can be helpful. Dietary screening for excessive milk intake is important in addition to asking about intake of iron‐rich foods such as green leafy vegetables and red meat. One should also ask about pica behavior such as eating dirt or ice and include questions regarding the age of the house to help screen for lead paint exposure and ingestion. Any sources of blood loss should also be explored including blood in the urine or stool as well as frequent gum or nose bleeding (more likely in an older child). Finally, family history should be explored regarding anemia during pregnancy, previous history of iron deficiency in siblings, and history of hemoglobinopathies.
Physical examination to search for anemia should be focused. Pallor, especially subconjunctival, perioral, and periungual, should be checked. Tachycardia, if present, would be more consistent with acute anemia rather than well‐compensated chronic anemia. Splenomegaly, scleral icterus, and jaundice may point to an acute or chronic hemolytic picture.
You do the fingerstick hemoglobin in clinic and it is 10.2 g/dL. The history is not suggestive of iron deficiency and the exam is unremarkable.
c. What are the reasonable next steps? Depending on the prevalence of iron deficiency in your population, it would be reasonable at this point to give a 1‐month trial of oral iron therapy. The family should be counseled that oral iron tastes bad and
should be given with vitamin C (i.e., orange juice) and not milk to improve absorption. If there is a low likelihood of iron deficiency, a family history of thalassemia or sickle cell disease, or a suggestive newborn screen, an empiric trial of oral iron supplementation should not be performed. Similarly, if there are signs that are consistent with a hemolytic process or a significant underlying disorder, further workup should be done. In these cases, it would be correct to next perform a CBC. If there are concerns for sickle cell disease or thalassemia, it would be reasonable to also perform hemoglobin electrophoresis. If there are concerns for hemolysis, labs including reticulocyte count, total bilirubin, lactate dehydrogenase, and a direct Coombs should be performed. Finally, if there is concern for a systemic illness such as leukemia, a manual differential should be requested. Further workup for iron deficiency (ferritin, TIBC) as well as lead toxicity (lead level) could be included or deferred until the anemia is better characterized utilizing the MCV and RDW on the CBC.
2. You are seeing a 15‐month‐old for a routine well‐child check visit. The family notes that the child has been well but appears pale to them. You ask the same questions as reviewed in case one, and the family notes a recent viral illness with no evidence of hemolysis, as there has been no history of dark‐colored urine or jaundice. The dietary history is unremarkable and on review, the 1‐year fingerstick hemoglobin was normal at 11.4 g/dL with a normal lead level at that time. There has been no noted diarrhea or blood loss, and the child is not on any medications. On exam, the child is pale but well appearing with a normal heart rate, respiratory rate, and blood pressure without scleral icterus or other signs of jaundice. There is no lymphadenopathy or hepatosplenomegaly. There are no petechiae or bruising.
a. What are some common diagnostic considerations?
b. What are the next laboratory steps?
Microcytic causes of anemia, notably iron deficiency anemia and secondary lead toxicity as well as thalassemia syndromes, have generally been ruled out with a history of a normal recent hemoglobin as well as a reassuring dietary history. Congenital causes of anemia, especially Diamond–Blackfan anemia, a pure red cell aplasia, have also been ruled out with a previous normal hgb. Megaloblastic anemias are also less likely to develop in the preceding 3 months after a normal hemoglobin. Hemolytic anemia, especially warm autoimmune hemolytic anemia (AIHA), remains a possibility even without a clinical history of jaundice in patients with slow hemolytic rates. Many other diagnostic possibilities remain at this point including viral suppression secondary to infections such as parvovirus, syndromes that may have bicytopenia or pancytopenia in addition to the clinical presentation of anemia including severe aplastic anemia and acute leukemias, as well as transient erythroblastopenia of childhood (TEC). Atypical hemolytic uremic syndrome (aHUS) is an unlikely possibility, but should be in the differential diagnosis in addition to occult blood loss.
The initial laboratory workup should include labs which will help make the diagnosis and potentially treat the patient: CBC/diff, reticulocyte count, Coombs test, complete metabolic panel (CMP), LDH, type and screen, fecal occult blood, parvovirus PCR, and urinalysis (UA). CBC will help evaluate the level of anemia noted clinically as well as determine if there are more cytopenias which will help direct the differential diagnosis. The reticulocyte count will be helpful in determining if the bone marrow is responding correctly to the anemia, as it should be high with a hemolytic process and suppressed if this is post
viral or secondary to TEC. Coombs is vital to help determine if this is an underlying warm autoimmune hemolytic anemia, noting that the Coombs will not be positive in all cases. Complete metabolic panel will look at many important aspects including renal function (to rule out aHUS), as well as bilirubin and AST which may be elevated along with the LDH if there is ongoing hemolysis. Similarly, the urinalysis will help rule out blood loss as well as hemolysis. Parvovirus PCR is not vital given the lack of clinical history, but this infection should remain in the differential diagnosis. Type and screen is important as the child may require blood transfusion depending on the level of anemia and the potential presence of hemolysis.
Lab results include the following:
Normal LDH, total, and indirect bilirubin
Normal UA
Negative direct Coombs
Normal CMP
c. What is the likely diagnosis?
The elevated reticulocyte count in the setting of a low hemoglobin should always make the practitioner first think of a hemolytic anemia, either a warm antibody or cold agglutinin. Yet, in this case, there are no other supporting laboratories for a hemolytic process. With a slow hemolytic process, it is possible that the UA, LDH, and indirect bilirubin could be normal but the direct Coombs should be helpful in the majority of warm antibody‐mediated cases. In the case of a cold agglutinin (usually associated with Mycoplasma infection), it is possible there would be no other positive lab findings. The most likely diagnosis here is TEC in recovery phase. TEC occurs due to unclear reasons and may present with concomitant neutropenia leading to workup for acute
lymphoblastic leukemia and aplastic anemia. Patients will have a decrease in erythroid precursors in the bone marrow and therefore a decrease in peripheral reticulocytes. TEC is an indolent process and thus patients will generally present with a well‐compensated but often severe normocytic anemia. Spontaneous recovery occurs with reticulocytosis, and thus TEC in the recovery phase can be mistaken for a hemolytic anemia.
Multiple choice questions
1. You are seeing a patient at their one year clinic visit and perform a finger stick hemoglobin. The hgb is 9.2 g/dl. The child has been well without any recent illnesses or significant findings on exam. What is the next best step?
a. Empirically start iron therapy
b. Obtain further history
c. Check a full CBC/diff
d. Plan to repeat in one month
e. Perform a lead level
Explanation: It is first important to understand underlying risk factors for anemia. These could include a dietary intake of significant milk consumption which would lead to iron deficiency or a family history of thalassemia. Also it is important to ask about a bleeding history to determine if there are ongoing losses. It important to ask about any history of jaundice or scleral icterus which would point to a hemolytic anemia as well as other inflammatory conditions which could lead to anemia of chronic disease. Choice a. would likely be correct after obtaining more history; choice c. is reasonable in cases where the history is not suggestive or the hgb does not increase with empiric iron therapy; choice d. would not be correct without other interventions; choice e. is important to do but lead toxicity itself does not lead to anemia, rather it is concomitant iron deficiency. The answer is b.
2. You are seeing a patient in the hospital admitted at two months of age for sepsis rule out secondary to high fever with associated decreased feeds and decreased urine output. The child has a urinary tract infection. A CBC is checked the hgb is 9.0 g/dl. There is no relevant family history, the mother received good prenatal care and was not anemic during pregnancy and the baby was born full term. What is the next best step?
a. Empirically start iron therapy
b. Plan to repeat the CBC prior to discharge
c. Plan to repeat the CBC in 1‐2 months as an outpatient
d. Provide reassurance to the family
Explanation: Although anemia in a young infant with an underlying infection can be due to bone marrow suppression, this level of hemoglobin is normal for age. The physiologic nadir of infancy occurs around 2‐3 months of age as fetal hemoglobin goes away (fetal hemoglobin lives 60‐90 days as compared to hemoglobin A which lives 90‐120 days). A certain level of anemia occurs prior to the bone marrow ramping up production of hemoglobin A red blood cells. Choice a. is incorrect as iron deficiency would be unlikely in this age although can occur in a very preterm infant or if the mother had severe anemia during pregnancy. Choice b. and c. are not necessary since the hb is normal for age. The answer is d.
3. You are seeing a patient in follow up. At the one year visit the finger stick hemoglobin was 9.4 g/dl. Given a nutritional history of significant milk intake you previously decided to empirically start iron therapy at a dose of 3 mg elemental iron daily and see the child today, one month later for a repeat finger stick hemoglobin. The repeat hemoglobin is now 10.2 g/dl. What is the next best step?
a. Stop iron therapy
b. Send a full CBC/diff
c. Continue iron therapy and see the patient back in one month
d. Continue iron therapy and see the patient back in 2‐3 months
Explanation: Given the level of hemoglobin and nutritional history, iron deficiency is the most likely diagnosis. Reticulocyte counts should increase in 1‐2 days after commencement of iron therapy and hemoglobin should rise within one week. A rise in hb in one month is reassuring that the diagnosis and treatment plan are correct. Choice a. is incorrect because it is important to continue iron therapy for 2‐3 months after resolution of anemia to replete liver iron stores; as this child is still anemic it is too early to stop iron therapy. Choice b. is unnecessary at this point since the hgb is appropriately increasing with therapy but may be necessary at a later point if the anemia persists on iron therapy. Choice c. is reasonable although given the amount of time of iron therapy required to replete stores and the improvement seen to date, it is not necessary to see the patient so frequently. The answer is d.
4. You are seeing a patient in follow up. At the one year visit the finger stick hemoglobin was 9.4 g/dl. Given a nutritional history of significant milk intake you previously decided to empirically start iron therapy at a dose of 3 mg elemental iron daily and see the child today, one month later for a repeat finger stick hemoglobin. The repeat hemoglobin is now 9.2 g/dl. The mother states that the child is taking the iron well, with vitamin C, and she has decreased milk intake to 16 oz (480 ml) on average in a 24 hour period. What is the next best step?
a. Continue iron therapy for another month and recheck hb at that time
b. Check a CBC/diff
c. Stop iron therapy and check a CBC/ diff
d. Stop iron therapy and check iron studies in addition to a CBC/diff
Explanation: As iron deficiency is the most likely cause of anemia, an empiric trial of iron is the correct first step. Assessing compliance with iron therapy and nutritional recommendations is very important in follow up especially if the hgb is not improved. In many cases the family is unable to give the iron well and the excessive milk intake continues. Assuming a reliable family as in the case above, it is important to now check a CBC/diff to further characterize the anemia. It would also be important to test for ongoing losses at this point with a urinalysis and fecal occult blood test. Choice a. is incorrect since iron therapy should show improvement in the hgb in 1 week and if that is not the case it is best to avoid iron overload by unnecessarily continuing iron. Choice b. though correct is not as good a choice as choice c. Choice d. is reasonable although it would be first important to check for microcytosis on the full CBC—if microcytic then it would be reasonable to test iron studies (ferritin, TIBC) in addition to checking hemoglobin electrophoresis for β‐thalassemia trait given the non‐responsiveness to iron therapy. The answer is c.
5. You are seeing a 15monthold for a routine clinic visit. The family notes the child has been more tired and pale recently. There was an antecedent viral illness about one month prior but the child is now otherwise well. The child had a normal finger stick hb at one year of age, eats a varied diet, has had no noted blood loss and had no signs of jaundice. The child is pale and tachycardic but otherwise well appearing without LAD or HSM. A finger stick hemoglobin is 5.4 g/ dl. Follow up CBC shows a normocytic anemia with normal WBC/diff and platelet count. The retic count is very low. What is the most likely diagnosis?
a. Transient erythroblastopenia of childhood
b. Iron deficiency anemia
c. Hemolytic anemia
d. Anemia of chronic disease
e. Aplastic anemia
Explanation: Transient erythroblastopenia of childhood (TEC) is a common etiology of normocytic anemia in infants and is due to unclear causes, possibly infection triggered bone marrow suppression. The normal MCV in addition to the low reticulocyte count in a well appearing child is suggestive of this diagnosis. TEC in recovery phase presents with a high reticulocyte and can be confused with hemolytic anemia. Choice b. is less likely since the anemia is normocytic and not microcytic. Choice c. is unlikely without a history of jaundice, scleral icterus or dark urine and with a low reticulocyte count. Choice d., although possible, is not suggested by a normal history without other medical diagnoses. Choice e. is also possible
with a normocytic anemia but typically pres ents with additional cytopenias. Often these patients have macrocytosis. The answer is a.
Suggested reading
Camaschella, C. (2015). Iron deficiency: new insights into diagnosis and treatment. Hematology Am. Soc. Hematol. Educ. Program 1: 8–13.
DeLoughery, T.G. (2014). Microcytic anemia. N Engl. J. Med. 371: 1324–1331.
Kaneva, K., Chow, E., Rosenfeld, C.G., and Kelly, M.J. (2017). Intravenous iron sucrose for children with iron deficiency anemia. J. Pediatr. Hematol. Oncol. 39: e259–e262.
Wang, M. (2016). Iron deficiency and other types of anemia in infants and children. Am. Fam. Physician 93: 270–278.
2Hemolytic Anemia
Red blood cells (RBCs) normally live for about 100–120 days in the circulation. Hemolytic anemia results from a reduced red cell survival due to increased destruction. To compensate for a reduced RBC life span, the bone marrow increases its output of red cells, a response mediated by erythropoietin. Destruction of red cells can be intravascular (within the circulation) or extravascular (by phagocytic cells of the bone marrow, liver, or spleen). Hemolytic anemia may be inherited (i.e., thalassemias, hemoglobinopathies, red cell enzyme deficiencies, or membrane defects) or acquired (immune‐mediated, associated with infection, or medication‐related). It can be chronic or acute. Some types of low‐grade chronic hemolytic anemias can have acute exacerbations, such as a child with glucose‐6‐phosphate dehydrogenase (G6PD) deficiency with an exposure to fava beans or other oxidative stress.
Red cell membrane disorders
Hereditary spherocytosis (HS) is the most common congenital red blood cell membrane disorder. The typical patient with HS has intermittent jaundice, and hemolytic or red cell aplastic episodes associated with viral infections, splenomegaly, and cholelithiasis. However, the clinical presentation
is quite variable, with most severe cases presenting in the newborn period or early childhood and milder cases presenting in adulthood.
Several membrane protein defects are responsible for HS, and most result in the instability of spectrin, one of the major red cell skeletal membrane proteins. Structural changes that result as a consequence of protein deficiency lead to membrane instability, loss of surface area, abnormal membrane permeability, and decreased red cell deformability. Metabolic depletion accentuates the defect in HS cells, which accounts for an increase in osmotic fragility after a 24‐hour incubation of whole blood at 37°C. The splenic sinusoids prevent passage of nondeformable spherocytic red cells. This explains the occurrence of splenomegaly in HS and the therapeutic effect of splenectomy.
Patients with HS have a mild‐to‐moderate chronic hemolytic anemia. Red cell indices reveal a normal to low mean corpuscular volume (MCV) depending on the number of microspherocytes. Cellular dehydration increases the mean corpuscular hemoglobin concentration (MCHC) characteristically >36%, which can be a helpful diagnostic clue. The red cell distribution width (RDW) is elevated because of the variable presence of microspherocytes and reticulocytes in proportion to the degree of hemolysis. The peripheral blood
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland, Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
smear can be highly suggestive with the presence of spherocytes, although this can be a normal finding in the patient with severe anemia and a resultant reticulocytosis. Osmotic fragility tests and ektacytometry studies show characteristic findings for HS, with increased red cell frag ility in hypotonic environments. Confirmatory testing is done with RBC band 3 protein reduction. Band 3 is the most abundant transmembrane protein found in the erythrocyte. This study is done by flow cytometry utilizing a fluorescent dye to bind the band 3 protein. It is 93% specific for the diagnosis of HS, though other diseases can test positive (i.e., congenital dyserythropoietic anemia type II, Southeast Asian ovalocytosis, hereditary pyropoikilocytosis).
As with other hemolytic anemias, affected individuals are susceptible to hypoplastic crises during viral infections. Human parvovirus B19, a frequent pathogen and the organism responsible for erythema infectiosum (fifth disease), selectively invades erythroid progenitor cells and may result in a transient arrest in red cell proliferation (see Chapter 1). Recovery begins within 7–10 days after infection and is usually completed by 4–6 weeks. If the initial presentation of a patient with HS is during an aplastic crisis, a diagnosis of HS might not be considered because the reticulocyte count will be low and the peripheral blood smear may be nondiagnostic. Anemia may also be more marked in patients with any underlying hemolytic disorder. A family history of HS should be explored; if it is positive, the patient should be evaluated for HS after recovery from the aplastic episode.
Splenectomy is often considered for patients who have severe hemolysis requiring transfusions or repeated hospitalization. In patients with mild hemolysis, the decision to perform splenectomy should be delayed; in many cases, it is not required.
For pediatric patients who have excessive splenic size, an additional consideration for splenectomy is to diminish the risk of traumatic splenic rupture. The risks of splenectomy must be considered before any clinical decision is made regarding the procedure.
Red cell survival returns to normal values after splenectomy unless an accessory spleen develops. Although an increased number of spherocytes can be seen in the peripheral blood after splenectomy and the osmotic fragility is more abnormal, the hemoglobin value is normal. Platelet counts frequently increase to more than 1000 × 109/l immediately after splenectomy, but return to normal levels over several weeks. No therapeutic interventions are required for postsplenectomy thrombocytosis in patients with HS.
To minimize the risk of sepsis due to Haemophilus influenza and Streptococcus pneumoniae, the splenectomy procedure (when necessary) is often postponed until after the child’s fifth or sixth birthday and when fully immunized. Patients should be immunized against these organisms in addition to Neisseria meningitidis prior to splenectomy and receive penicillin prophylaxis following the procedure. The increase in penicillin‐resistant strains of S. pneumoniae has raised questions regarding the use of prophylactic penicillin. No studies have determined the frequency of this problem in children receiving prophylactic penicillin after splenectomy. Dietary supplementation with folic acid (1 mg/day) is recommended due to high cellular turnover.
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia with periods of increased hemolysis in addition to risk of venous thrombosis and is associated with aplastic anemia. The red blood cell backbone has a deficiency in glycosylphosphatidylinositol (GPI) antigen structure leading to complement activation secondary to deficiency of CD55 or CD59.
Red cell enzyme deficiencies
Glucose is the primary metabolic substrate for the red cell. Because the mature red cell does not contain mitochondria, it can metabolize glucose only by anaerobic mechanisms. The two major metabolic pathways within the red cell are the Embden–Meyerhof pathway (EMP) and the hexose monophosphate shunt.
Red cell morphological changes are minimal in patients with red cell enzyme deficiency involving the EMP. Red cell indices are usually normocytic and normochromic. The reticulocyte count is elevated in proportion to the extent of hemolysis. Because many enzyme activities are normally increased in young red cells, a mild deficiency in one of the enzymes may be obscured by the reticulocytosis.
Pyruvate kinase (PK) deficiency is the most common enzyme deficiency in the EMP. The inheritance pattern of this disorder is autosomal recessive. Homozygotes usually have hemolytic anemia with splenomegaly, whereas heterozygotes are usually asymptomatic. The disorder is found worldwide, although it is most common in Caucasians of Northern European descent. The range of clinical expression is variable, from severe neonatal jaundice to a fully compensated hemolytic anemia. Anemia is usually normochromic and normocytic, but macrocytes may be present shortly after a hemolytic crisis, reflecting erythroid hyperplasia and early release of immature red cells. The osmotic fragility of red cells is normal to slightly reduced. Diagnosis is confirmed by a quantitative assay for PK, by the measurement of enzyme kinetics and glycolytic intermediates, and by family studies.
Splenectomy is a therapeutic option for PK‐deficient patients. As with HS, the decision should be made on the basis of the
patient’s clinical course. Unlike HS patients, PK‐deficient patients, although they improve after splenectomy, do not have complete correction of their hemolytic anemia. As with all hemolytic anemias, these patients should have dietary supplementation with folic acid (1 mg/day) to prevent megaloblastic complications associated with relative folate deficiency. Immunization against H. influenza, S. pneumonia, and N. meningitidis should be given, as well as lifelong penicillin prophylaxis in the splenectomized patient.
G6PD deficiency is the most common X‐linked red cell enzyme deficiency, with partial expression in the female population and full expression in the affected male population. The distribution of G6PD deficiency is worldwide, with the highest incidence in Africans and African‐Americans. Mediterraneans, American Indians, Southeast Asians, and Sephardic Jews are also affected. In African‐Americans, 12% of the male population has the deficiency, 18% of the female population is heterozygous, and 2% of the female population is homozygous. In Southeast Asians, G6PD deficiency is found in approximately 6% of the male population. Most likely, the prevalence of this enzyme abnormality confers resistance to malaria, thus its geographic distribution.
Many variants of G6PD deficiency are known and have been characterized at the biochemical and molecular levels. A variant found in Mediterraneans is associated with chronic hemolytic anemia. Other variants are associated with an unstable enzyme that has normal levels in young red cells. These variants result in hemolysis only in association with an oxidant challenge (as found in African‐Americans). In some cases of G6PD deficiency, hemolysis may be triggered by the oxidant intermediates generated during viral or bacterial infections or after ingestion of oxidant compounds. Shortly after exposure to the oxidant, hemoglobin is
oxidized to methemoglobin and eventually denatured, forming intracellular inclusions called Heinz bodies that attach to the red cell membrane. This portion of the membrane may be removed by reticuloendothelial cells resulting in a “bite” cell that has a shortened survival owing to its loss of membrane components. To compensate for hemolysis, red cell production is increased and thus the reticulocyte count is increased.
Individuals with the Mediterranean or Asian forms of G6PD deficiency, in addition to being sensitive to infections and certain drugs, often have a chronic, moderately severe anemia, with non‐spherocytic red cells and jaundice. Hemolysis usually starts in early childhood. Reticulocytosis is present and can increase the MCV.
When a hemolytic crisis occurs in G6PD deficiency (or favism), pallor, scleral icterus, hemoglobinemia, hemoglobinuria, and splenomegaly may be noted. Plasma haptoglobin and hemopexin concentrations are low with a concomitant rise in plasma‐free hemoglobin. The peripheral smear shows the fragmented bite cells and polychromatophilic cells. Red cell indices may be normal. Special stains can detect Heinz bodies in the cells during the first few days of hemolysis.
A diagnosis of G6PD deficiency should be suspected based on family history, ethnicity, laboratory features, physical findings, and recent exposure to oxidants with resultant acute hemolysis. The diagnosis is confirmed by a quantitative enzyme assay or by molecular analysis of the gene. Since reticulocytes may have a normal level of G6PD enzyme activity, screening tests during acute hemolysis may be falsely elevated; therefore, it is important to test once the hemolytic crisis has ended and the patient again has mature red blood cells. Treatment is directed toward supportive care during the acute event and counseling regarding prevention of future hemolytic crises. In patients with
chronic hemolysis, dietary supplementation with folic acid (1 mg/day) is recommended. Use of vitamin E, 500 mg/day, may improve red cell survival in patients with chronic hemolysis.
Autoimmune hemolytic anemia
In addition to intrinsic causes of hemolytic anemia, patients may develop an autoantibody or alloantibody toward their red blood cells. The underlying cause for this antibody formation is often idiopathic or precipitated by a secondary condition including drugs, infection, autoimmune diseases, or an oncologic process. A positive direct antiglobulin test (DAT, direct Coombs) is pathognomonic for immune‐mediated hemolysis with the appropriate clinical and laboratory findings (i.e., jaundice, scleral icterus, elevated bilirubin, and anemia with reticulocytosis). Fortunately, many pediatric cases of autoimmune hemolytic anemia (AIHA) are acute and self‐limited. However, AIHA may be a presenting feature in chronic immunologic or hematologic conditions including autoimmune lymphoproliferative disease, common variable immune deficiency, and systemic lupus erythematosus.
In the DAT, the patient’s erythrocytes are washed and then incubated with specific antiglobulin antisera (usually anti‐IgG and anti‐C3d). Agglutination indicates a positive test confirming the presence of antibodies or complement attached to the surface of the patient’s red blood cells. In patients with severe immune‐mediated hemolytic anemia, the DAT is often strongly positive, although the strength of the reaction does not always correlate to the severity of the disease. Similarly, up to 80% of patients will have antibodies in the serum as well, measured by the indirect Coombs (indirect antiglobulin test, IAT). In the IAT, test erythrocytes are incubated with donor
serum, washed, and then incubated with specific antiglobulin antisera. Agglutination again indicates a positive test indicating antibody in the patient’s sera against a foreign red cell antigen. Of note, patients without symptoms of hemolysis may have a positive DAT or IAT; therefore, screening is only recommended in the setting of clinical and laboratory signs of hemolysis. In approximately 5–10% of cases, patients may have an AIHA with a negative DAT.
The initiation of autoimmunity is poorly understood. Viral syndromes are often proposed as a culprit, although causation has been hard to prove. A majority of cases of AIHA in pediatrics are due to “warm” antibodies, so named because they react at 37 °C. These are often secondary to a viral syndrome, although patients with an underlying autoimmune disease or oncologic process can also present with a warm AIHA. Immune hemolytic anemia may also be seen after allogeneic transplant, generally secondary to autoantibodies formed by donor cells against donor RBCs. The formation of IgG antibodies leads to extravascular hemolysis in which pieces of the red cell membrane are sequentially removed during passages through the spleen. Patients may also develop DAT positive hemolytic anemia and immune‐mediated thrombocytopenia (Evans syndrome).
Patients may also develop AIHA secondary to cold agglutinins, often secondary to infection with Mycoplasma, and occurs secondary to IgM and complement (C3d) rather than IgG. IgM autoantibodies react with polysaccharide antigens on the RBC surface, specifically I/i heavy chains. IgM binding occurs at lower temperatures in the periphery leading to acrocyanosis. Intravascular hemolysis is rare with complement fixation leading to removal of RBCs in the liver. Corticosteroids are generally ineffective in cold agglutinin syndrome; intravenous immune globulin (IVIG) and avoidance of the cold are first‐line
therapies. Cold agglutinins are more likely in older patients though tend to be acute in children and chronic in adults.
Finally, also secondary to infection, children may develop paroxysmal cold hemoglobinuria, a transient condition which is often unrecognized with complement activation rather than IgG or IgM. This is specific to the P antigen on the RBC membrane. Diagnosis is made in the DAT negative patient with serum antibody demonstrated by the Donath–Landsteiner test. The majority of patients have self‐resolution though corticosteroids may be required.
Hemolytic disease of the newborn
Intrinsic causes of hemolytic anemia can present as jaundice in the newborn period. These syndromes must be differentiated from hemolytic disease of the newborn (HDN), in which alloimmunization in the mother occurs due to foreign RBC antigens from the fetus. RBC antigens can either be major (ABO) or minor (Rh, Kell, Duffy, etc.). For ABO hemolytic disease, typically the mother is type O and the fetus is type A; anti‐A antibodies subsequently produced by the mother then traverse the placenta leading to hemolytic anemia in the fetus. RhoGAM® (Rho[D] immune globulin) has virtually eliminated hemolytic disease in the Rh‐negative (D‐negative) mother with a Rh‐positive (D‐positive) fetus, although is still possible in the mother not receiving prenatal care. Many cases of HDN are now due to other minor RBC antigens with varying levels of clinical severity. AIHA in the mother can also lead to HDN. In this case, maternal IgG antibodies traverse the placenta and are transferred to the fetus. If the mother is DAT positive but does not have clinical signs of hemolytic anemia, there is usually no risk to the fetus.
Microangiopathic hemolytic anemia
Microangiopathic hemolytic anemias are due to extracorpuscular abnormalities and are not associated with antibody formation. Causes include disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), transplant‐associated microangiopathy, preeclampsia, malignant hypertension, valvular abnormalities, and march hemoglobinuria. In these cases, red blood cells travel through damaged blood vessels or heart valves or are damaged by the formation of an intravascular fibrin mesh due to hypercoagulability, leading to fragmentation (e.g., schistocytes) and intravascular hemolysis. In the case of TTP, ADAMTS13 is a useful evaluation as deficiency can occur in hereditary TTP secondary to mutation and in acquired TTP secondary to autoantibodies.
Transplant‐associated microangiopathy is increasingly being recognized, often secondary to calcineurin inhibitors in allogeneic transplant, though it has also been noted in patients after autologous transplantation, likely secondary to irradiation, multiagent chemotherapy, or viral reactivation leading to endothelial injury.
Evaluation
The evaluation of hemolytic anemia includes a thorough history assessing for evidence of chronic hemolytic anemia and possible precipitants of an acute event (see Figure 2.1).
The family history is equally important and questions to ask include:
● History of newborn jaundice
● Gallstones
● Splenomegaly or splenectomy
● Episodes of dark urine and/or yellow skin/sclerae
● Anemia unresponsive to iron supplementation
● Medications
● Environmental exposures
● Ethnicity
● Dietary history
The physical exam should be complete, but focused on:
● Skin color (pallor, jaundice, and icteric sclerae)
● Facial bone changes (extramedullary hematopoiesis)
● Abdominal fullness and splenomegaly
The laboratory evaluation includes:
● Complete blood count, RBC indices, and reticulocyte count
● Peripheral blood smear (assess for fragmented forms or evidence of inherited anemia with specific morphological abnormalities)
● Bilirubin, AST, lactate dehydrogenase (LDH)
● Coombs test, direct and indirect (to exclude antibody‐mediated red cell destruction)
● Urinalysis (for heme, bilirubin)
● Free plasma hemoglobin, haptoglobin
● Parvovirus PCR (if history is suspicious)
Specific tests for diagnosis may include:
● Osmotic fragility
● Ektacytometry
● RBC band 3
● Red cell enzyme defects (G6PD and PK)
● Red cell membrane defects (HS)
● CD 55/59
● ADAMTS13
The osmotic fragility test is used to measure the osmotic resistance of red cells. Red cells are incubated under hypotonic conditions, and their ability to swell before lysis is determined. The osmotic fragility of red cells is increased when the surface area to volume ratio of the red cells is decreased, as in hereditary spherocytosis, in which membrane instability results in membrane loss and decreased surface area. Conversely, osmotic fragility is decreased in liver disease, as the ratio of the red cell surface area to volume is
increased. Ektacytometry measures the deformability of red cells subjected simultaneously to shear stress and osmotic stress.
Treatment
Determination of a treatment plan relies on identification of the underlying cause of the anemia and the degree of acute hemolysis.
In chronic hemolysis, such as that associated with hereditary spherocytosis, splenectomy is often recommended to decrease the degree of splenic destruction and level of anemia and to decrease the incidence of bilirubin gallstones. This therapy must be now weighed against the potential long‐term complications of splenectomy including risk for infection, thrombosis, and pulmonary hypertension. In other forms of inherited
anemias in which the hemolysis is more significant and even life‐threatening, such as thalassemia or some forms of enzymopathies, chronic transfusion therapy is recommended. Other general measures include folic acid replacement due to high cell turnover, avoidance of oxidant chemicals and drugs, and iron chelation therapy as indicated for transfusion‐related iron overload.
Immune hemolytic anemias resulting in acute, symptomatic anemia require more immediate and aggressive therapy. The underlying disease, if present and identifiable, warrants treatment. Additionally, the use of corticosteroids in high doses is frequently necessary (starting with prednisone at 2–4 mg/kg/day). Very high doses for 2–4 days (up to 10 mg/kg/day [max 1 g]) may be necessary prior to decreasing back to 2 mg/kg/day. Splenectomy and immunosuppressive drugs (such as rituximab) have also been successful in steroid‐resistant disease. Immune globulin infusions do not contribute to resolution of the disease, but should be considered in patients with severe hemolysis who are requiring transfusion or are having a poor response to transfusion. Plasmapheresis can be considered in patients with severe IgG‐induced AIHA and should always be combined with an immune suppressive drug to ensure both antibody production and antibody titer reduction. Microangiopathic hemolytic anemias can also be severe and life‐threatening. Treatment should again first be directed toward the primary disorder to remove the cause of trauma, if possible. Transfusions are frequently necessary and splenectomy may be needed in some patients with severe hypersplenism.
Case studies for review
1. You are seeing a 6-year-old child in the emergency department. The family notes that the child has been jaundiced and
fatigued over the last few days with a red color to the urine. Fingerstick hemoglobin at the pediatrician’s office reveals a hemoglobin of 5 g/dl prior to transfer to the ED. On the basis of this history and hemoglobin, it appears that the child is suffering from a hemolytic anemia.
a. What initial lab studies will help confirm the diagnosis and also help with the initial treatment plan?
Initial lab studies should include a complete blood count with reticulocyte count. The reticulocyte count is an important first step to confirm that the patient is undergoing hemolysis, which should present with a low hemoglobin and a resultant increase in the reticulocyte count. A low reticulocyte count in this setting should lead to consideration of alternative diagnoses of decreased red cell production, such as viral suppression (although one would not expect hemolysis). A complete metabolic panel as well as lactate dehydrogenase (LDH) should be done to ensure that the patient is actually suffering from jaundice (elevated total bilirubin) and hemolysis (elevated LDH and AST). A DAT/IAT is an important first step to determine if the patient has an immune or nonimmune hemolytic anemia. If the DAT is positive, the blood bank should be asked to elute the antibody to determine if this is IgM, IgG, or possibly complement-mediated hemolysis.
The patient is noted to have a hemoglobin of 4.6 g/dl with 12.6% reticulocytes. One should first determine if the patient is having an appropriate bone marrow response to anemia by calculating the reticulocyte index (RI):
RI Reticulocyte count
current hemoglobin expected hemogl % o obin
In this case, the RI is 12.6% × (4.6/13) = 4.5.
An RI ≥ 3.0 is consistent with an appropriate bone marrow response to anemia, and therefore helps to rule out bone marrow dysfunction in this case. Modern blood cell analyzers have the ability to calculate the absolute reticulocyte count and the fraction of “immature” reticulocytes directly. Patients who are demonstrating an appropriate response to hemolysis will have an elevated absolute reticulocyte count and immature reticulocyte fraction; these will be low or normal in patients with an inadequate response.
Other labs include a total bilirubin of 6.7 mg/dl, LDH of 936 U/l (reference range 313–618 U/l), and AST of 161 U/l (reference range 8–43 U/l). DAT is noted to be positive for IgG and C3d.
b. What is the likely diagnosis?
With the positive DAT to IgG and complement and clinical and laboratory signs of hemolysis, warm antibody-mediated AIHA is the likely diagnosis. It should be noted that a positive DAT without clinical and laboratory signs of hemolysis is not sufficient for the diagnosis of AIHA.
c. What should be the initial treatment plan?
The patient is started on steroid therapy, intravenous (IV) methylprednisolone 1 mg/ kg twice a day (BID). After a couple of days, the hemoglobin has continued to decrease to 3 g/dl even though the methylprednisolone has been increased to 4 mg/kg BID and the patient is showing signs of symptomatic anemia and congestive heart failure.
d. How should your treatment change at this point?
Since the patient has a falling hemoglobin with clinical signs of cardiac instability and volume overload, the patient should be transfused. The term “least incompatible unit” has been used in the past but is a misnomer if phenotypically matched blood is given. The patient may not have a normal increase in hemoglobin with transfusion due to contin-
ued hemolysis and the potential for increased, bystander hemolysis with transfusion. Because of the cardiac instability, it is advisable to give the transfusion slowly and monitor for worsening cardiac function. Consideration can be given to IVIG infusion concurrently with the packed red blood cell (PRBC) transfusion. Finally, a change in therapy would be advisable at this point with an immunosuppressant drug such as rituximab (monoclonal antibody to CD20), cyclosporine, or cyclophosphamide.
2. You have been consulted on a now 4-dayold full-term neonate with profound jaundice (unconjugated hyperbilirubinemia) that has risen from 11 mg/dl at 72 hours to 20 mg/dl. The neonatology team has initiated phototherapy, but is asking for hematology recommendations.
a. What are some background questions that may be clarifying? It is important to consider questions which can help determine if the jaundice is physiologic or non-physiologic. A conjugated hyperbilirubinemia is never physiologic and should prompt early referral. An unconjugated hyperbilirubinemia in the first 14 days of life in the neonate can be physiologic secondary to liver immaturity and may be precipitated by prematurity, poor feeding, Asian ethnicity, infection, breastmilk jaundice, and drugs which impact liver metabolism. A family history of extended phototherapy may be indicative of physiologic or non-physiologic conditions. Family history of enlarged spleen, splenectomy, gallstones and/or cholecystectomy, or jaundice at an older age could by indicative of a membranopathy (i.e., hereditary spherocytosis or elliptocytosis), while jaundice at an older age could be indicative of an enzymopathy (i.e., G6PD, PK deficiency, or Gilbert syndrome). It is important to ensure that the mother received prenatal care and was tested for Rh incompatibility. ABO incompatibility
