Autoimmune Hemolytic Anemia

Autoimmune Hemolytic Anemia: Excerpt from The 5-Minute Pediatric Consult

Michele P. Lambert, MD

Autoimmune Hemolytic Anemia - BASICS

Autoimmune Hemolytic Anemia - description

Autoimmune hemolytic anemia is characterized by shortened red cell survival that is caused by autoantibodies directed against RBCs, with or without the participation of complement on the red cell membrane.

Autoimmune Hemolytic Anemia - epidemiology

Autoimmune Hemolytic Anemia - incidence

• ~1:50,000–80,000 persons/year
• Peak incidence in childhood is in 1st 4 years of life with warm autoimmune hemolytic anemia.

Autoimmune Hemolytic Anemia - prevalence

• Less common in children and adolescents than in adults
• No apparent racial or sexual predisposition (in childhood)

Autoimmune Hemolytic Anemia - pathophysiology

Warm autoantibodies:

• Maximal activity of in vitro RBC binding at 37°C
• IgG-class antibody sometimes with relative specificity for Rh erythrocyte antigens
• IgG-coated RBCs cleared, predominantly in the spleen, by macrophages

Cold autoantibodies (cold agglutinins):

• Maximal activity of in vitro RBC binding at temperatures between 0°C and 30°C
• Almost always caused by IgM antibody with specificity for antigens of the i/I system on RBCs
• Anti-I antibodies characteristic of Mycoplasma pneumoniae–associated hemolysis
• Anti-i antibodies are usually found in infectious mononucleosis.
• Hemolysis is complement dependent.

Paroxysmal cold hemoglobinuria:

• IgG autoantibody binds RBC at cooler areas of the body (i.e., extremities), causing irreversible binding of complement components (C3 and C4). When coated RBCs enter warmer areas of the body, IgG falls off and complement causes hemolysis (Donath-Landsteiner biphasic hemolysin).
• Unusual IgG antibody with anti-P specificity
• Most frequently found in children with viral infections (30%)

Autoimmune Hemolytic Anemia - etiology

• Idiopathic
• Passive transfer of maternal antibodies
• Secondary to an underlying disorder
  • Infection: Viral (e.g., Mycoplasma, Epstein-Barr virus, cytomegalovirus, hepatitis, HIV) or bacterial (e.g., Streptococcus, typhoid fever, Escherichia coli septicemia)
  • Drugs: Antimalarials, antipyretics, sulfonamides, penicillin, rifampin
  • Hematologic disorders: Leukemia, lymphoma
  • Immunopathic/autoimmune disorders: Lupus, mixed connective tissue disorders, Wiskott-Aldrich syndrome, ulcerative colitis, rheumatoid arthritis, scleroderma, Evans syndrome/ALPS (autoimmune lymphoproliferative syndrome)
  • Tumors: Ovarian, carcinomas, thymomas, dermoid cysts

Autoimmune Hemolytic Anemia - DIAGNOSIS

Natural history:

• Acute disease:
  • Onset with rapid fall in hemoglobin level over hours to days
  • Usual course: Complete resolution of disease within 3–6 months
  • Resolution more likely in children who present between 2 and 12 years of age
• Chronic disease:
  • Slower onset of anemia over weeks to months, with some having persistence of hemolysis or intermittent relapses
  • More likely to be associated with underlying chronic Illness
  • More common in adults and children <2 years or >12 years of age

Autoimmune Hemolytic Anemia - signs & symptoms

Autoimmune Hemolytic Anemia - history

• Pallor
• Jaundice
• Dark urine
• Fever
• Weakness
• Dizziness
• Syncope
• Exercise intolerance

Autoimmune Hemolytic Anemia - physical exam

• Pallor
• Jaundice
• Splenomegaly
• Hepatomegaly
• Tachycardia, systolic flow murmur, S3 gallop
• Orthostasis in acute onset

Autoimmune Hemolytic Anemia - tests

Autoimmune Hemolytic Anemia - lab

CBC:

• Hemoglobin level decreased (occasionally, thrombocytopenia seen in Evans syndrome)
• Mean corpuscular volume may be normal.
• Reticulocyte count increased (although it may rarely be decreased)
• Peripheral smear: Spherocytes, polychromasia, macrocytes, rouleaux formation
• Direct antiglobulin test (Coombs)—positive:
  • Single most important test
  • Warm autoimmune hemolytic anemia will have IgG ± C3 positive.
  • Cold autoimmune hemolytic anemia and paroxysmal cold hemoglobinuria will have C3 positive.
• Haptoglobin level decreased
• Indirect hyperbilirubinemia
• Elevated lactate dehydrogenase
• Urinalysis: Hemoglobinuria, increased urobilinogen
• Bone marrow aspiration: Erythroid hyperplasia (to rule out leukemia or lymphoma associated with autoimmune hemolytic anemia)
• Cold agglutinin titer: Positive (usually >1:64)
• Donath-Landsteiner test should be performed in cases of suspected paroxysmal cold hemoglobinuria.

• A negative Coombs test can occur when small numbers of IgG or C3 molecules are present on the red cell membrane (i.e., in cases of less severe hemolysis, low-affinity antibodies, or in cases of very severe, rapid clearance). Radiolabeled Coombs test or enzyme immunoassays are more sensitive diagnostic tests in these circumstances.
• Reticulocytopenia may occur in most severe cases where the antibody coats and removes reticulocytes.

Autoimmune Hemolytic Anemia - differencial diagnosis

• Defects intrinsic to RBC:
  • Membrane defects
  • Enzyme defects
  • Hemoglobin defects
  • Congenital dyserythropoietic anemias
  • Paroxysmal nocturnal hemoglobinuria
• Defects extrinsic to RBC:
  • Immune mediated:
    • Isoimmune: Hemolytic disease of the newborn, blood group incompatibility
    • Autoimmune (see “Etiology”)
    • Drug-dependent RBC antibodies
  • Nonimmune-mediated:
    • Idiopathic
    • Secondary to an underlying disorder (i.e., hemolytic uremic syndrome, thrombotic thrombocytopenic purpura)
    • Mechanical: March hemoglobinuria, heart valves

Autoimmune Hemolytic Anemia - TREATMENT

Autoimmune Hemolytic Anemia - general measures

Blood transfusion:

• Indication: Physiologic compromise from the anemia (usually only in severe acute onset)
• Complications:
  • The blood bank may be unable to find compatible blood. In IgG-mediated disease, autoantibody is usually pan reactive; therefore, you must use the least incompatible unit of blood.
• In cold agglutinin disease, use a blood warmer for all infusions to decrease IgM binding and monitor for acute hemolysis during transfusion.

Autoimmune Hemolytic Anemia - medication

Corticosteroids:

• Indication:
  • In IgG-mediated disease, steroids have been shown to interfere with macrophage Fc and C3b receptors responsible for RBC destruction. They also have been shown to elute IgG Ab from the RBC surface (improving survival).
  • In chronic warm autoimmune hemolytic anemia, pulsed high-dose dexamethasone has been shown to be effective in some cases.
• Complications:
  • Both short- and long-term side effects
  • Generally not effective in cold agglutinin disease
• Dose:
  • Start prednisone PO/methylprednisolone IV at 2 mg/kg/d in divided doses.
  • Tapering of steroids should begin after a therapeutic response is achieved (may take several days to weeks).
• Goal:
  • Initially, to return to normal hemoglobin level with tolerable levels of steroid, or no steroids
  • In some patients, goal may be achieving decreased hemolysis and a clinically asymptomatic state with minimal steroid side effects.
  • Alternative treatments should be considered for patients unresponsive to steroids or who require high doses for maintenance of hemoglobin level.

Autoimmune Hemolytic Anemia - second line

• IV immunoglobulin:
  • Indication:
    • May be useful in selected cases of immune hemolytic anemia unresponsive to steroids
  • Mechanism of action is not entirely clear.
  • Complications:
    • Effect is usually temporary; retreatment may be required every 3–4 weeks.
  • Theoretical risk of transfusion transmitted viral infection
  • Expensive
  • Dose: Up to 1 g/kg/d for 5 days has been required to achieve a beneficial effect.
• Plasmapheresis/exchange transfusion:
  • Indication:
    • Will slow the rate of hemolysis in severe disease, especially if IgM mediated
  • Indicated if thrombotic thrombocytopenic purpura cannot be excluded
  • Complications:
    • Only of short-term benefit
  • Expensive
• Immunosuppressive agents (antimetabolites and alkylating agents):
  • Indication:
    • When there is a clinically unacceptable degree of hemolysis that is refractory to steroids and splenectomy
  • Some have been effective in cold agglutinin disease.
  • Complications:
    • There are varying side effects dependent on the agent used. Therefore, clinical indications must be strong and exposure to drug should be limited.
  • Dose:
    • Adjusted to maintain WBC >2,000, absolute neutrophil count (ANC) >1,000, and platelet count at 50,000–100,000 cells/mm³

Rituximab (an engineered anti-CD20 antibody)

Autoimmune Hemolytic Anemia - surgery

Splenectomy:

• Indication:
  • Patients unresponsive to medical management, who require moderate- to high-maintenance doses of steroids or who develop steroid intolerance may be candidates.
• Not effective in cold agglutinin disease
• Response rate is 50–70%, with many partial remissions.

Autoimmune Hemolytic Anemia - FOLLOW UP

Autoimmune Hemolytic Anemia - prognosis

Dependent on age, underlying disorder (if any), and response to therapy. See also “Diagnosis” section (“Natural History”).

Mortality in pediatric series ranged from 9–19%.

Autoimmune Hemolytic Anemia - patient monitoring

• Hemoglobin level q4h to q12h (depending on severity) until stable
• Reticulocyte count: Daily
• Spleen size: Daily
• Hemoglobinuria: Daily
• Coombs test: Weekly

Autoimmune Hemolytic Anemia - bibliography

1. Domen RE. An overview of immune hemolytic anemia. Cleve Clin J Med. 1998;65:89–99.
2. Engelfriet CP, Overbeeke MA Jr, von dem Borne AEG. Autoimmune hemolytic anemia. Semin Hematol. 1992;29:3–12.
3. King K, Ness, PM. Treatment of autoimmune hemolytic anemia. Semin Hematol. 2005;42(3):131–136.
4. Meyer O, Stahl D, Beckhove P, et al. Pulsed high-dose dexamethasone in chronic autoimmune hemolytic anemia. Br J Haematol. 1997;98:860–862.

Autoimmune Hemolytic Anemia - CODES

Autoimmune Hemolytic Anemia - icd9

283.0 Autoimmune hemolytic anemias

Autoimmune Hemolytic Anemia - FAQ

• Q: Will the anemia go away?
• A: Children with cold autoantibodies tend to have short-lived illness, whereas children with warm antibodies often have a chronic clinical course characterized by periods of remissions and relapses.
• Q: Is this contagious?
• A: No. Another child may acquire the same viral illness; however, the body’s response to produce an autoantibody is dependent on the individual patient.

Book Source Details

• Book Title: The 5-Minute Pediatric Consult
• Author(s): M. William Schwartz MD; et al.
• Year of Publication: 2008
• Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.

More About Autoimmune Hemolytic Anemia

• Back to disease: Autoimmune Hemolytic Anemia: Introduction
• Next Book Extract About Autoimmune Hemolytic Anemia: Acquired Hypothyroidism (The 5-Minute Pediatric Consult)
• More Book Extracts: All Online Books for Autoimmune Hemolytic Anemia

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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.

More About This Book: Title: The 5-Minute Pediatric Consult Authors: M. William Schwartz MD; et al. Publisher: Lippincott Williams & Wilkins Copyright: 2008 ISBN: 0-7817-7577-9

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