Autoimmune hemolytic anemia (AIHA)

A 42 year old woman presents with progressive fatigue, jaundice, and dark urine. Physical examination reveals pallor and splenomegaly. Laboratory studies show anemia, elevated LDH, elevated indirect bilirubin, decreased haptoglobin, and reticulocytosis. Peripheral blood smear demonstrates spherocytes, and the direct Coombs test is positive. Diagnosis?

Diagnosis is Autoimmune hemolytic anemia (AIHA).

1. Definition

Autoimmune hemolytic anemia (AIHA) is an acquired hemolytic anemia caused by autoantibodies directed against red blood cells, resulting in premature RBC destruction.

2. Types

2.1 Warm AIHA (Most Common Subtype)

  1. Caused by IgG antibodies against RBCs
  2. Antibodies react optimally at body temperature (37°C)
  3. Hemolysis is predominantly extravascular and occurs mainly in the spleen

Causes

Idiopathic

  • Most common overall cause

Autoimmune Disorders

  • Systemic lupus erythematosus (SLE)
  • Rheumatoid arthritis (RA)

Hematologic Malignancies

  • Chronic lymphocytic leukemia (CLL)

Drugs

  • Beta-lactams
  • Alpha-methyldopa

Classic Triad

  1. Anemia
  2. Jaundice
  3. Splenomegaly or hepatosplenomegaly

2.2 Cold AIHA (Cold Agglutinin Disease)

  1. Caused by IgM antibodies against RBCs
  2. Antibodies react optimally at colder temperatures
  3. Hemolysis is mainly complement-mediated and occurs predominantly in the liver

Causes

Infections

  • Mycoplasma pneumoniae
  • Infectious mononucleosis (EBV)

Lymphoproliferative Disorders

  • Lymphoma
  • Waldenström macroglobulinemia

3. Pathophysiology

3.1 Warm AIHA

  1. IgG-coated RBCs are recognized by splenic macrophages
  2. Partial phagocytosis of the RBC membrane produces spherocytes
  3. Spherocytes undergo splenic destruction leading to extravascular hemolysis

3.2 Cold AIHA

  1. IgM antibodies bind RBCs in cooler peripheral circulation
  2. IgM activates complement leading to RBC agglutination and hemolysis
  3. Hemolysis is predominantly complement-mediated

4. Clinical Features

4.1 General Features

  1. Fatigue and weakness
  2. Pallor
  3. Jaundice
  4. Dark urine
  5. Splenomegaly

4.2 Warm AIHA Features

  1. Chronic or acute hemolytic anemia
  2. Splenomegaly or hepatosplenomegaly common

4.3 Cold AIHA Features

  1. Acrocyanosis
  2. Raynaud phenomenon
  3. Symptoms worsen with cold exposure

5. Diagnosis

5.1 CBC

  1. Decreased hemoglobin
  2. Decreased hematocrit
  3. Increased reticulocyte count

5.2 Hemolysis Markers

  1. Increased LDH
  2. Increased indirect bilirubin
  3. Decreased haptoglobin

5.3 Peripheral Blood Smear

Warm AIHA

  1. Spherocytes

Cold AIHA

  1. RBC agglutination is characteristic
  2. Spherocytes may occasionally be present

5.4 Direct Coombs (Direct Antiglobulin) Test

Warm AIHA

  1. Positive for IgG ± C3

Cold AIHA

  1. Positive mainly for complement (C3)

6. Management

6.1 Warm AIHA

First-Line Therapy

  1. Corticosteroids
    • Prednisone is first-line treatment

Supportive Therapy

  1. RBC transfusion if severe or symptomatic anemia occurs
    • Cross-matching may be difficult
    • “Least incompatible” blood may be required in emergencies

Second-Line Therapy

  1. Rituximab (Anti-CD20 monoclonal antibody)
  2. Immunosuppressive agents:
    • Mycophenolate mofetil
    • Azathioprine
    • Cyclophosphamide
  3. Splenectomy

Refractory Cases

  1. Hematopoietic stem cell transplantation (rarely used)

Additional Management

  1. Treat the underlying cause

6.2 Cold AIHA

General Measures

  1. Avoid cold exposure
  2. Keep the patient warm

Medical Therapy

  1. Rituximab
  2. Chemotherapy agents:
    • Fludarabine
    • Bendamustine

Important Point

  1. Steroids and splenectomy are generally ineffective and not routinely recommended

Additional Management

  1. Treat the underlying disorder

7. Complications

7.1 Warm AIHA

  1. Deep vein thrombosis (DVT)
  2. Pulmonary embolism (PE)

7.2 Cold AIHA

  1. Raynaud phenomenon
  2. Acrocyanosis

8. Key Clinical Insight

Hemolytic anemia with spherocytes and a positive direct Coombs test strongly suggests warm autoimmune hemolytic anemia

9. Exam Level Pearls

  1. Warm AIHA is the most common type of AIHA
  2. Warm AIHA is mediated by IgG antibodies
  3. Cold AIHA is mediated by IgM antibodies
  4. Spherocytes are characteristic of warm AIHA
  5. RBC agglutination is characteristic of cold AIHA
  6. Direct Coombs test confirms autoimmune hemolysis
  7. Warm AIHA causes predominantly extravascular hemolysis
  8. Cold AIHA is associated with Mycoplasma pneumoniae and EBV infection
  9. Steroids are first-line therapy for warm AIHA
  10. Steroids are usually ineffective in cold AIHA
  11. Rituximab is effective in both warm and cold AIHA
  12. Splenectomy is useful in refractory warm AIHA but generally ineffective in cold AIHA
By Prabin Duwadee at

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