Autoimmune Hemolytic Anemia

Hematology > Autoimmune Hemolytic Anemia

Summary
Description

Autoimmune hemolytic anemia (AIHA) is caused by autoantibody-induced hemolysis (the premature destruction of circulating red blood cells); usually idiopathic, it is also associated with infection, lymphoproliferative disorders, autoimmune diseases, and some drugs Hallmark findings include: anemia with elevated reticulocyte count in the absence of blood loss; a positive direct antiglobulin (Coombs) test; and spherocytes or RBC aggregates on the peripheral blood smear Autoimmune hemolytic anemia is classically divided into two groups: warm and cold disease In warm autoimmune hemolytic anemia: autoantibody immunoglobin G (IgG) attacks red blood cells (RBCs); patients are usually over age 50; typically treated with corticosteroids and therapies for underlying diseases In chronic cold agglutinin disease: cold-activated immunoglobin M (IgM) and complement (C3d) coat RBCs and trigger hemolysis; patients usually over age 50; sometimes resolves with cold avoidance; rarely progresses to renal failure Paroxysmal cold hemoglobinuria (PCH): rare disease induced most often by postviral Donath-Landsteiner autoantibody at cold temperatures in children; often acute and severe, though usually short-lived and self-limited; rarely progresses to renal failure, frank lymphoma, or death

Synonyms Immediate action

If severe anemia suspected - e.g. extreme pallor, somnolence, obtundation, tachycardia, breathlessness at rest, postural hypotension, angina - advise hospitalization for potential transfusion.

Order complete blood count and start intravenous line Draw blood for type and cross-match If patient's hemoglobin is low (<4g/dL), pulmonary edema is present, or cardiac or cerebral function is threatened, this is a medical emergency and transfusion is necessary If cross-match is problematic, transfuse best possible match; transfused RBCs will not hemolyze faster than the patient's own RBCs

If rare aplastic crisis is suspected (hemoglobin low, reticulocyte count near zero) advise hospitalization for potential transfusion as this is a medical emergency.

Urgent action

A hematocrit of <20, rapidly developing anemia, declining functional status, or evidence of end-organ damage requires urgent action Admit patient to hospital for observation and potential transfusion Evaluate patient for underlying infection, medication history

Key points

The diagnosis of AIHA must meet two criteria: evidence of hemolysis (anemia plus elevated reticulocyte count in the absence of blood loss); and evidence of RBC autoantibodies/complement (usually indicated by a positive direct Coombs test). Note: the direct Coombs test is falsely negative in a small percentage of AIHA Though usually idiopathic, AIHA is commonly associated with infection, autoimmune disease, lymphoproliferative disorders, and some drugs Warm AIHA and cold agglutinin disease are most common among adults over age 50, in whom the diseases are usually chronic and relapsing; PCH, a rare disorder occurring most commonly in children, usually resolves on its own Medical intervention is usually not necessary in the many patients who present with a mild hemolytic anemia; therapy becomes necessary when anemia is significant

Background
Cardinal features
Autoimmune hemolytic anemia (AIHA):

RBC destruction is caused by autoantibodies and/or complement that coat the membrane of the cell, activate macrophages, and induce phagocytosis Low hematocrit: <37% (female) to <40% (male) Elevated reticulocyte count: >2.4% (female) to >2.6% (male) Elevated reticulocyte index: >3% Spherocytes or RBC aggregates are visible on the peripheral blood smear The most clinically important AIHAs are warm AIHA, chronic cold agglutinin disease, and paroxysmal cold hemoglobinuria

Warm AIHA:

Direct Coombs test is positive for immunoglobulin G (IgG), complement (C3d), or both Spherocytes present on the peripheral blood smear Phagocytized RBCs are typically sequestered in the spleen Most patients quickly respond to corticosteroids, though the disorder is chronic and often relapsing Refractory cases require prolonged immunosuppression or may undergo splenectomy; life-threatening cases may require transfusion

Chronic cold agglutinin disease:

Positive direct Coombs test rarely detects cold-reactive IgM, but always detects C3d bound to RBC membrane

RBC aggregates seen on peripheral blood smear Typically, cold agglutinin titer is very high Idiopathic form of disease is frequently recurrent condition and often responds to cold avoidance; exacerbations are intermittent Critical to explore diagnosis of B-cell lymphoma, which will determine therapy Corticosteroids are usually not helpful Splenectomy is rarely beneficial (unless splenic lymphoma) because RBCs destroyed primarily by C3d activation are sequestered in the liver, not spleen In presence of B-cell neoplasm, chemotherapy or immunotherapy may help Exposure to cold can prompt sudden drop in hematocrit and induce renal failure

Paroxysmal cold hemoglobinuria:

Diagnosis generally relies on clinical presentation; routine tests do not pick up pathological Donath-Landsteiner autoantibody Most often appears postviral in children and young adults Symptoms may include fever, chills, abdominal distress, nausea, leg/back pain Signs may include jaundice and hemoglobinuria IgG detected in serum Direct Coombs test is usually negative for pathological IgG and complement Indirect Coombs test is negative Diagnosis is confirmed with test for hallmark Donath-Landsteiner autoantibody Often acute and severe, but usually short-lived and self-limited Treatment includes: cold avoidance; supportive care; transfusions to alleviate symptoms; corticosteroids rarely useful In rare cases can progress to renal failure

Causes
Common causes Warm AIHA:

Idiopathic: warm autoantibody IgG, its complement (C3d), or both, coat the red cell membrane and at 37C induce phagocytosis Secondary: warm antibodies produced by lymphoproliferative disorders (e.g. nonHodgkin's lymphoma, chronic lymphocytic leukemia (CLL); collagen vascular/autoimmune diseases (e.g. systemic lupus erythematosus (SLE); and HIV infection

Cold agglutinin disease:

Idiopathic: the IgM autoantibody has an affinity for RBCs at cold temperatures (0C18C); at warmer temperatures (37C, or 98.6F), when the two have no particular affinity, the IgM antibody can come off the RBC, but the remaining complement sticks. Hemolysis occurs as the liver and spleen remove complement-coated RBCs Secondary: cold autoantibodies produced by infections such as Epstein-Barr virus, Mycoplasma pneumoniae, and infectious mononucleosis; and lymphoproliferative

disorders, such as non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL) Paroxysmal cold hemoglobinuria:

Idiopathic: Donath-Landsteiner autoantibody Secondary: viral infections (particularly in children and young adults), which produce the Donath-Landsteiner antibody

Rare causes Secondary Warm AIHA:

Certain drugs that induce hemolysis as a side effect (e.g. the antineoplastics cladribine and fludarabine) Evans' syndrome (concomitant immune thrombocytopenic purpura and warm antibody AIHA) Immunologic diseases such as agammaglobinuria, hypogammaglobulinemia, dysglobulinemias, and immune deficiency syndromes Monoclonal gammopathy of undetermined significance (MGUS) Gastrointestinal diseases, including ulcerative colitis

Secondary chronic cold agglutinin disease:

B-cell malignancies such as CLL, lymphomas, or Waldenstrm macroglobinuria Certain prescription medications, including alpha-methyldopa, high-dose penicillin, and certain second and third generation cephalosporins Mumps

Secondary paroxysmal cold hemoglobinuria:

Syphilis Measles or measles vaccination

Serious causes Secondary warm AIHA:

Connective tissue/autoimmune diseases, such as SLE Lymphoproliferative disorders, such as non-Hodgkin's lymphoma, CLL

Secondary chronic cold agglutinin disease:

B-cell malignancies such as CLL, lymphomas, or Waldenstrm macroglobinuria

Secondary paroxysmal cold hemoglobinuria:

Viral infection (particularly in children and young adults) Syphilis

Contributory or predisposing factors

B-cell malignancy (produces hemolysis-inducing autoantibodies) Family or personal history of autoimmune disease (produces hemolysis-inducing autoantibodies) Viral infection in children (produces the Donath-Landsteiner autoantibody, which induces PCH) Cold temperature (induces IgM activation in cold agglutinin disease)

Epidemiology
Incidence and prevalence
Incidence

Figures are unreliable and, for all AIHAs, range from one new case per 75,000-80,000 in the general population per year to one per 300,000.
Prevalence

Warm AIHA: 1-2 cases per 100,000 in the general population.

Frequency

Warm AIHA is the most common, representing 50-70% of all AIHAs It is estimated that chronic cold agglutinin disease makes up 16-32% of all AIHAs Paroxysmal cold hemoglobinuria occurs rarely, in perhaps 1% of all AIHAs

Demographics
Age

Warm AIHA afflicts people of all ages, but its incidence increases with age and peaks in midlife Chronic cold agglutinin disease predominates among patients in their 50s and 60s Paroxysmal cold hemoglobinuria is usually a disorder of children or young adults; spontaneous remission occurs in most children

Gender

More women than men suffer with warm AIHA and chronic cold agglutinin disease.
Race

No particular racial group appears more prone to AIHA than any other.
Genetics

There is no known genetic predisposition to AIHA, though risk factors for AIHA include a family history of autoimmune diseases, such as SLE, rheumatoid arthritis, and glomerulonephritis.

Socioeconomic status

No socioeconomic group appears more prone to AIHA than any other.

Codes
ICD-9 code 283.0 Autoimmune hemolytic anemia.

Read more about Autoimmune hemolytic anemia from this First Consult monograph:
Diagnosis | Differential diagnosis | Treatment | Summary of evidence | Outcomes | Prevention | Resources

More Key Resources

Overview
Anemia, Autoimmune Hemolytic (Quick Reference) Ferri: Ferri's Clinical Advisor 2013, 1st ed. Autoimmune Hemolytic Anemia (includes Table) Bope and Kellerman: Conn's Current Therapy 2012, 1st ed.

Epidemiology
Epidemiology of AIHA Ferri: Ferri's Clinical Advisor 2013, 1st ed.

Etiology
Etiology and Pathophysiology of AIHA McPherson & Pincus: Henry's Clinical Diagnosis and Management by Laboratory Methods, 22nd ed. Etiology of AIHA (includes Table) Kliegman: Nelson Textbook of Pediatrics, 19th ed.

Diagnosis
Clinical Findings of Warm AIHA Hoffman: Hematology: Basic Principles and Practice, 5th ed. Clinical Manifestations of AIHA Kliegman: Nelson Textbook of Pediatrics, 19th ed.

Treatment & Management

Clinical Management of Warm-Antibody AIHA Bope and Kellerman: Conn's Current Therapy 2012, 1st ed. Therapy for AIHA Hoffman: Hematology: Basic Principles and Practice, 5th ed.

Patient Education Drugs

Prednisone
http://emedicine.medscape.com/article/955266-treatment#a1128

Kliegman: Nelson Textbook of Pediatrics, 19th ed.