ANEMIA, AUTOIMMUNE HEMOLYTIC

ANEMIA, AUTOIMMUNE HEMOLYTIC - Kerry J. Murphy, MD
BASICS
DESCRIPTION
• Acquired anemia induced by binding of autoantibodies to RBC membrane antigens
• 3 main types defined by maximal binding temperature of the autoantibodies
- Warm (37C [98.6F]) reacting IgG antibody
- Cold (0-4C [32-39.2F]) reacting IgM antibody
- Mixed type: Both warm IgG and cold C3 reacting antibodies
- Drug induced: Mostly warm IgG reacting antibodies
- System(s) Affected Hematopoietic/lymphatic/immunologic
GENERAL PREVENTION
None known
EPIDEMIOLOGY
• Predominant age: 50 years
• Predominant sex: Female > Male
ALERT
Geriatric Considerations
Unusual in this age group; rule out neoplasia.
Pediatric Considerations
May occur in pediatric age group
Incidence
4/100,000 per year
RISK FACTORS
• Malignancy
• Autoimmune disorders
• Infection
• Medications
• Prior blood transfusion
• Prior hematopoietic cell transplant
Genetics
Unknown
PATHOPHYSIOLOGY
• Warm autoimmune hemolytic anemia (AIHA)
- IgG attaches to RBCs, which are then ingested by macrophages of the spleen.
• Cold AIHA
- IgM binds RBC surface temporarily, activates complement, deposits C3 on cell surface, and RBCs are ingested by macrophages of the liver.
- Rarely, complete complement cascade activated with membrane attack complex insertion causing intravascular hemolysis.
• Mixed antibody AIHA: Both warm IgG and cold C3 involved.
• Drug induced
- Hapten induced: Drug attaches to rbc membrane inducing IgG production.
- Immune complex: Drug-IgM immune complex binds RBC membrane, activating complement.
- Autoantibody: Drug induces production of anti-RBC IgG.
ETIOLOGY
• Warm antibody (48-70% cases)
- Primary cause: Idiopathic
- Secondary causes
 Lymphoproliferative disorders (CLL, Hodgkin disease, NHL)
 Autoimmune disorders
 Viral infection (especially in children)
• Cold antibody
- Cold agglutinin syndrome (CAS) (16-32%):
 Acute: Infection (mycoplasma, mononucleosis, viral)
 Chronic: Lymphoproliferative disorders (lymphoma)
- Paroxysmal cold hemoglobinuria
 Infection
• Mixed type
- Idiopathic
- Secondary to lymphoproliferative or autoimmune disorders
• Drug induced
- Penicillin: Hapten induced
- Quinine: Immune complex
- -Methyldopa: Autoantibody induced
ASSOCIATED CONDITIONS
• Evans syndrome
• Systemic lupus erythematosus
• Chronic lymphocytic leukemia
• Diffuse lymphomas

DIAGNOSIS
SIGNS AND SYMPTOMS
History
• Weakness/fatigue
• Exertional dyspnea
• Dizziness
• Palpitations
• Malaise
• Association with cold (CAS)
Physical Exam
• Pallor
• Jaundice
• Splenomegaly
• Hepatomegaly
• Tachycardia
• Flow murmur
• Blue gray discoloration of acral surfaces (CAS)
TESTS
Lab
• Direct Coombs' (DAT direct antiglobulin test)
- Positive test indicates presence of antibodies or complement on RBC surface.
• CBC
- Anemia (normocytic, normochromic); may be sudden and life threatening
- Mild to moderate increase in mean corpuscular volume (MCV) depending on level of reticulocytosis
- Increased mean cell hemoglobin concentration (MCHC)
- Spherocytosis
- Poikilocytosis
- Anisocytosis
- Rouleaux
- Reticulocytosis
- Nucleated RBC
- Large polychromatophilic reticulocytes
• Hyperbilirubinemia (unconjugated)
• Decreased haptoglobin
• Elevated LDH
• Hemoglobinemia
• Serology
- IgG antibody (warm, mixed, drug-induced, paroxysmal hemoglobinuria)
- IgM antibody (cold)
• Urinalysis
- Hemoglobinuria, hemosiderinuria
Pathological Findings
• Peripheral blood smear
- Spherocytes, schistocytes
• Bone marrow biopsy
- Bone marrow hyperplasia, increased marrow hemosiderin
DIFFERENTIAL DIAGNOSIS
• Other hemolytic anemias
• Autoimmune thrombocytopenic purpura (ITP)
• Evans syndrome
• Microangiopathic hemolytic disorders
• Aplastic anemia
• Megaloblastic anemia
TREATMENT
GENERAL MEASURES
• Warm antibody
- Folic acid supplementation
- Mild and moderate: See "Medications"
- Severe
 Plasmapheresis as a temporizing measure for refractory or life threatening anemia (1)[C]
 Packed RBC transfusion for life-threatening anemia (difficult to cross-match; need special blood bank techniques; in emergency, use most compatible cross-match (2)[C]
• Cold antibody
- Cold agglutinin syndrome
 Avoid cold, maintain high temperatures indoors, wear additional clothing outdoors
 Folic acid supplementation
 Plasmapheresis as a temporizing measure for refractory or life-threatening anemia (1)[C]
 Packed RBC transfusion for life-threatening anemia (2)[C]
• Paroxysmal cold hemoglobinuria
- Supportive care
• Mixed
- Steroids, splenectomy, and immunosuppressives as in warm AIHA
• Drug-induced
- Stop the offending drug.
- Plasmapheresis/exchange transfusion for severe life-threatening cases
Diet
No special diet
Activity
• Rest until asymptomatic.
• Avoid contact sports if splenomegaly is present.
MEDICATION (DRUGS)
First Line
• Warm antibody
- Glucocorticoids: Prednisone 1 mg/kg/d PO in divided doses
 70-80% patients improve within 3 weeks
 Taper gradually to 20 mg/d over 2 weeks
 May require maintenance dose 10 mg every other day (1)[A]
- Precautions: Significant side effects with long-term use
• Cold antibody
- Malignancy induced: Chemotherapy
- Rituximab for cold AIHA due to chronic lymphoproliferative disorders (1)[C]
• Mixed antibody
- Prednisone as in warm AIHA
Second Line
• Warm antibody
- Immunosuppressive drugs: Recommended for patients who fail splenectomy, relapse after splenectomy, cannot tolerate corticosteroids, and nonsurgical candidates
 Cyclophosphamide 50 mg/kg/d for 4 days followed by GCSF for those with refractory anemia (2)[C]
 Precautions: Monitor for marrow suppression
 Azathioprine (Imuran) 1-2 mg/kg/d within 2 weeks of starting steroids if not responding (3)[C]
 Cyclosporine 5-10 mg/kg/d in 2 divided doses
 Rituximab (anti-CD20 monoclonal Ab) 375 mg/m2 once weekly for 2-4 weeks for children and refractory cases
 Mycophenolate mofetil 500-1000 mg/d in 2 divided doses; increase to 1-2 g daily (2)[C]
- Other medical therapies for refractory cases
 Danazol 600-800 mg/d PO
 IVIG (1)[C]
• Mixed antibody
- Immunosuppressives if refractory to steroids and splenectomy
SURGERY
• Warm antibody
- Splenectomy is the preferred second-line treatment for warm AIHA for those who have failed steroids.
 50% initial response rate
 Patients may require low-dose maintenance prednisone 15 mg daily
 Post splenectomy: Vaccinate against encapsulated organisms such as pneumonococcus and meningococcus (2)[A]
• Cold antibody
- Surgery not recommended
• Mixed antibody
- Splenectomy
FOLLOW-UP
PROGNOSIS
• Good with appropriate treatment
• Determined by course of the primary disease If secondary to an underlying disorder
COMPLICATIONS
• Shock (severe anemia)
• Venous thromboembolism
• Thrombocytopenic purpura (Evans syndrome)
• Lymphoproliferative disorders in warm AIHA
• Post splenectomy sepsis syndrome
PATIENT MONITORING
• Monitor carefully if transfusion essential
• Use only warm IV fluids and blood products for cold AIHA
• Avoid hypothermic surgical procedures for cold AIHA
REFERENCES
1. Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Amer J Hematol, 2002;69:258-271.
2. King KE, Ness PM. Treatment of autoimmune hemolytic anemia. Sem in Hematology, 2005; 42:131-136.
3. Pruss A, Salama A, Ahrens N, Hansen A, Kiesewetter H, Koscielny J, Dorner T. Immune hemolysis-serological and clinical aspects. Clin Exp Med, 2003;3:55-64.