Autoimmune Hemolytic Anemia The 5 Minute Pediatric Consult


	Autoimmune Hemolytic Anemia

Deborah L. Kramer

Database
Differential Diagnosis
Data Gathering
Physical Examination
Laboratory Aids
Therapy
Common Questions and Answers
Bibliography

DATABASE

DEFINITION

Autoimmune hemolytic anemia (AIHA) is characterized by shortened red-cell survival that is caused by autoantibodies directed against red blood cells, with or without the participation of complement on the red-cell membrane.

CAUSES

Idiopathic
Passive transfer of maternal antibodies
Secondary to an underlying disorder
- Infection: viral (e.g., Mycoplasma, Epstein-Barr virus [EBV], cytomegalovirus [CMV], 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, Wiskott-Aldrich syndrome, ulcerative colitis, rheumatoid arthritis, scleroderma
- Tumors: ovarian, carcinomas, thymomas, dermoid cysts

PATHOPHYSIOLOGY

Warm autoantibodies
- Maximal activity of in vitro red-cell binding at 37°C
- IgG-class antibody usually with relative specificity for Rh erythrocyte antigens
- IgG-coated RBCs cleared predominantly in the spleen by macrophages
- Complement not required for clearance, although complement fixation may contribute to clearance
Cold autoantibodies (cold agglutinins)
- Maximal activity of in vitro red-cell binding at temperatures between 0°C and 30°C
- Almost always caused by IgM antibody with specificity for antigens of the i/T system on RBCs
- Anti-i antibodies characteristic of Mycoplasma pneumoniae-associated hemolysis
- Anti-i antibodies usually found in infectious mononucleosis
- IgM-coated RBCs are cleared primarily in the liver by hepatic macrophage C3b receptors.
- Hemolysis is complement-dependent.
Paroxysmal cold hemoglobinuria (PCH)
- 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%)

EPIDEMIOLOGY

Occurs at an incidence of about 1:50,000 to 80,000 persons per year
Less common in children and adolescents than in adults
No apparent racial or sexual preponderance (in childhood)
Peak incidence in childhood is in first 4 years of life with warm AIHA.
Mortality in pediatric series ranged from 9% to 19%.

COMPLICATIONS

Heart failure may be seen in severe anemia; requires aggressive supportive care.
Morbidity is usually secondary to treatment (see Therapy section).

PROGNOSIS

Dependent on age, underlying disorder (if any), and response to therapy. See also in Data Gathering section, Natural History.

DIFFERENTIAL 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 in Database section, Causes
- Drug-dependent red-cell antibodies
- Nonimmune mediated
  - Idiopathic
  - Secondary to an underlying disorder (i.e., hemolytic uremic syndrome [HUS], thrombotic thrombocytopenic purpura [TTP])
  - Mechanical: march hemoglobinuria, heart valves

DATA GATHERING

NATURAL HISTORY

Acute disease
- Onset with rapid fall in hemoglobin level over hours to days
- Usual course: complete resolution of disease within 3 to 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 disorder
- More common in adults and children <2 years or >12 years of age

HISTORY

Pallor
Jaundice
Dark urine
Fever
Weakness
Dizziness
Syncope
Exercise intolerance

PHYSICAL EXAMINATION

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

LABORATORY AIDS

CBC: Hb level decreased (occasionally, thrombocytopenia seen in Evan syndrome); MCV may be normal
Reticulocyte count increased
Peripheral smear: spherocytes, polychromasia, macrocytes, rouleaux formation
Direct antiglobulin test (Coombs): positive
- Single most important test
- Warm AIHA will have IgG ± C3 positive
- Cold AIHA and PCH will have C3 positive
Haptoglobin level decreased
Indirect hyperbilirubinemia
Elevated LDH
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 PCH.

PITFALLS

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). 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.

THERAPY

PATIENT MONITORING

Hemoglobin level q4h to q12h (depending on severity)
Reticulocyte count: daily
Spleen size: daily
Hemoglobinuria: daily
Coombs test: weekly

BLOOD TRANSFUSION

Indication
- Blood transfusion is indicated in cases of physiologic compromise from the anemia (usually only in severe acute onset) or with continued blood loss.
Complications
- The blood bank may be unable to find compatible blood. In IgG-mediated disease, autoantibody is usually panreactive; therefore, you must use the least incompatible unit of blood. In cold agglutinin disease, you must prewarm all infusions to decrease IgM binding and must monitor for acute hemolysis during transfusion.
Dose
- Use only a volume of blood sufficient to relieve compromise from anemia.

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 AIHA, pulsed high-dose dexamethasone has been shown to be effective in some cases.
Complications
- There are both short- and long-term side effects of steroids. Corticosteroids are 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 once a therapeutic response is achieved (may take several weeks to months). Alternative treatments should be considered for patients unresponsive to steroids or who require high doses for maintenance of hemoglobin level.
Goal
- The goal is initially to return to normal hemoglobin level with nontoxic levels of steroid, or no steroids. However, in some patients, the goal may be achieving decreased hemolysis and a clinically asymptomatic state with minimal steroid side effects.

INTRAVENOUS IMMUNE GLOBULIN (IVIG)

Indication
- IVIG may be useful in selected cases of immune hemolytic anemia unresponsive to steroids. The mechanism of action is not entirely clear.
Complications
- The effect is usually temporary; retreatment may be required q3 to q4 weeks. There may be a risk of hepatitis C. IVIG is expensive.
Dose
- Up to 1 g/kg/d for 5 days has been required to achieve a beneficial effect.

PLASMAPHERESIS/EXCHANGE TRANSFUSION

Indication
- This treatment will slow the rate of hemolysis in severe disease.
Complications
- It is only of short-term benefit and is expensive.
Dose
- The frequency and duration depend on response.

SPLENECTOMY

Indication
- Patients unresponsive to medical management, who require moderate to high maintenance doses of steroids or who develop steroid intolerance may be candidates for splenectomy. It is not effective in cold agglutinin disease.
The response rate is about 50% to 70%, with the majority only partial remissions.
Complications
- There is a high morbidity rate for the surgical procedure and during the postoperative period.
- There is an increased risk of sepsis.

IMMUNOSUPPRESSIVE AGENTS (ANTIMETABOLITES, ALKYLATING AGENTS)

Indication
- When there is a clinically unacceptable degree of hemolysis that is refractory to steroids and splenectomy, immunosuppressive agents are indicated. 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>2000, ANC>1000, and platelet count at 50,000 to 100,000 cells/mm³

PROGNOSIS

Dependent on age, underlying disorder (if any), and response to therapy. See also in Data Gathering section, Natural History.

COMMON QUESTIONS AND ANSWERS

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.

ICD-9-CM 283.0

BIBLIOGRAPHY

Domen RE. An overview of immune hemolytic anemias. Cleve Clin J Med 1998;65(2):89–99.

Engelfriet CP, Overbeeke MAM, Kr. von dem Borne AEG. Autoimmune hemolytic anemia. Semin Hematol 1992;29(1):3–12.

Lanzkowsky P. Hemolytic anemia. In: Lanzkowsky P, ed. Manual of pediatric hematology and oncology. New York: Churchill Livingstone, 1989:83–122.

Mathew P, Chen G, Wang W. Evans syndrome; results of a national survey. J Pediatr Hematol Oncol 1997;19(5):433–437.

Meyer O, Stahl D, Beckhove P, Huhn D, Salama A. Pulsed high-dose dexamethasone in chronic autoimmune hemolytic anemia of warm type. Br J Haematol 1997;98(4):860–862.

Ware RE, Rosse WF. Autoimmune hemolytic anemia. In: Nathan DG, Oski FA, eds. Hematology of infancy and childhood, 5th ed., Philadelphia: WB Saunders, 1998: 499–522.

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