Basics
Description
- Autoimmune hemolytic anemia (AIHA) 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.
- 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
Epidemiology
- Less common in children and adolescents than in adults
- No apparent racial or sexual predisposition (in childhood)
Incidence
- ~1-3:100,000 persons/year
- Peak incidence in childhood is in first 4 years of life with warm AIHA.
Pathophysiology
- Warm autoantibodies (~80% cases)
- Maximal activity of in vitro antibody RBC binding at 37 °C
- IgG-class antibody usually
- IgG-coated RBCs cleared, predominantly in the spleen, by macrophages.
- Cold autoantibodies (cold agglutinins) (7-25%)
- 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%)
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
- Autoimmune disorders: lupus, mixed connective tissue disorders, Wiskott-Aldrich syndrome, ulcerative colitis, rheumatoid arthritis, common variable immunodeficiency, scleroderma, Evans syndrome, ALPS (autoimmune lymphoproliferative syndrome), 22q11.2 deletion syndrome
- Tumors: ovarian, carcinomas, thymomas, dermoid cysts
Diagnosis
History
- Pallor
- Jaundice
- Dark urine
- Fever
- Weakness
- Dizziness
- Syncope
- Exercise intolerance
Physical Exam
- Pallor
- Jaundice
- Splenomegaly
- Hepatomegaly
- Tachycardia, systolic flow murmur, S3 gallop
- Orthostasis in acute onset
Diagnostic Tests & Interpretation
Lab
CBC
- Hemoglobin level decreased (occasionally, thrombocytopenia seen in Evans syndrome).
- Mean corpuscular volume may be normal.
- Reticulocyte count increased (although may also be decreased if reticulocytes bear the target antigen).
- Peripheral smear: spherocytes, polychromasia, macrocytes, agglutination
- Direct antiglobulin test (Coombs)-positive (usually)
- Single most important test
- Warm AIHA will have IgG ± C3-positive.
- Cold AIHA 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 AIHA)
- Cold agglutinin titer: positive (usually >1:64)
- Donath-Landsteiner test should be performed in cases of suspected paroxysmal cold hemoglobinuria.
Alert
- A negative Coombs test can occur when small numbers of IgG or C3 molecules are present on the red cell membrane or if most of the coated red cells are cleared from circulation (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 some cases where the antibody coats and removes reticulocytes.
Differential Diagnosis
- Defects intrinsic to RBC:
- Membrane defects such as hereditary spherocytosis
- Enzyme defects including hemolytic episode due to G6PD deficiency
- 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
- Hemolytic transfusion reaction
- Non-immune-mediated
- Idiopathic
- Secondary to an underlying disorder (i.e., hemolytic uremic syndrome, thrombotic thrombocytopenic purpura)
- Mechanical: march hemoglobinuria, heart valves
Treatment
Medication
First Line
Corticosteroids
- Indication:
- In IgG-mediated disease, steroids have been shown to interfere with macrophage Fc and C3b receptors responsible for RBC destruction. In addition, they have been shown to elute IgG Ab from the RBC surface (improving survival).
- In chronic, warm, AIHA, 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/24 h 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 doses of steroid or off steroids entirely
- 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.
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.
- Effect is usually temporary; retreatment may be required every 3-4 weeks.
- Complications:
- Red cell antibodies in IVIG preparations may be a confounder.
- Aseptic meningitis
- Theoretical risk of transfusion-transmitted viral infection
- Expensive
- Dose: Up to 1 g/kg/24 h for 5 days has been required to achieve a beneficial effect.
- Large doses of IVIG have been associated with causing hemolytic anemia.
- 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
- Rituximab: monoclonal anti-CD20 antibody likely works through depletion of B cells
- Indicated in refractory AIHA (375 mg/m2 weekly for 2-4 weeks)
- Response 40-100%
- Particularly useful in warm AIHA
- Adverse effects: fever, chills, rigors, hypertension, bronchospasm; rare risk of viral infections
- 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
- Alemtuzumab (anti-CD52): may be effective very refractory AIHA particularly secondary to B-cell chronic lymphocytic leukemia (B-CLL)
Additional Treatment
General Measures
Blood transfusion: should only be used with great caution in this setting in patients with very low hemoglobin/brisk hemolysis because of difficulty with appropriate cross-matching
- 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.
Surgery/Other Procedures
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.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Hemoglobin level q4h-q12h (depending on severity) until stable
- Reticulocyte count: daily
- Spleen size: daily
- Hemoglobinuria: daily
- Coombs: weekly
Prognosis
- Dependent on age, underlying disorder (if any), and response to therapy. See also "Description" section (natural history).
- Mortality in pediatric series ranged from 9 to 19%.
Complications
- May be increased risk of venous thrombosis in patients with AIHA
- May be associated with a predisposition to lymphoproliferative disorders
- Gallstones related to chronic hemolysis
Additional Reading
- Barros MMO, Blajchman MA, Borde JO. Warm autoimmune hemolytic anemia: recent progress in understanding the immunobiology and treatment. Transfus Med Rev. 2010;24(3):195-210. [View Abstract]
- Hoffman PC. Immune hemolytic anemia-select topics. Hematology. 2009:80-86. [View Abstract]
- King K, Ness PM. Treatment of autoimmune hemolytic anemia. Semin Hematol. 2005;42(3):131-136. [View Abstract]
- Petz LD. Cold antibody autoimmune hemolytic anemia. Blood Rev. 2008;22(1):1-15. [View Abstract]
Codes
ICD09
- 283.0 Autoimmune hemolytic anemias
ICD10
- D59.1 Other autoimmune hemolytic anemias
- D59.0 Drug-induced autoimmune hemolytic anemia
SNOMED
- 413603009 Autoimmune hemolytic anemia (disorder)
- 309742004 Drug-induced autoimmune hemolytic anemia (disorder)
- 3978000 Warm autoimmune hemolytic anemia (disorder)
- 398937006 Cold autoimmune hemolytic anemia (disorder)
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.