Autoimmune hemolytic anemia

Background

Autoimmune hemolytic anemia (AIHA) is a disorder in which there is a generation of antibodies towards the Red Blood Cell membrane antigens, which leads to their destruction. AIHA can be primary (idiopathic), or secondary to many different disease processes (cancer, autoimmune diseases, etc.). The antibodies produced are either IgM or IgG, and the type that is produced greatly affects the prognosis as will be discussed below.

"Cold" Autoimmune Hemolytic Anemia

Cold AIHA refers to hemolytic disease caused by cold reacting autoantibodies, i.e. autoantibodies that agglutinate to RBCs at lower temperatures (usually 0°C-5°C). This is the less common than "warm" AIHA, and is typically mediated by IgM autoantibodies. When IgM autoantibodies attach to the RBCs, they cause an intravascular hemolysis, meaning that hemolysis and release of all intracellular contents occurs within the blood vessels. This results in elevated serum LDH, low haptoglobin, and presence of hemoglobinuria (due to the release of unprocessed hemoglobin into the blood stream. Causes "cold" AIHA" include:

1. Infection - most commonly ''Mycoplasma'' ''pneumoniae'' infection and infectious mononucleosis
   
2. Plasmacytomas - specifically Multiple Myeloma
   
3. Idiopathic

"Warm" Autoimmune Hemolytic Anemia

Warm AIHA referrs to hemolytic disease caused by warm reacting autoantibodies, i.e. autoantibodies that agglutinate to RBCs at higher temperatures (usually about 37°C). This is typically mediated by IgG autoantibodies, which results in extravascular hemolysis, meaning hemolysis occurs within the spleen. The IgG bound RBCs are detected by splenic macrophages, phagocytosed, and broken down intracellularly. The byproduct of hemoglobin digestion is unconjugated bilirubin, which is released into the blood stream bound to albumin, and excreted by the liver. Therefore, in warm AIHA, there is a unconjugated > conjugated hyperbilirubinemia, with a relative absence of elevated LDH and low haptoglobin. Causes of warm AIHA inlcude:

1. Lymphomas (specifically Non-Hodgkin's lymphoma)
   
2. Leukemias (specifically Chronic Lymphocytic Leukemia)
   
3. Collagen Vascular Diseases - Systemic Lupus Erethematosis, Rheumatoid Arthritis, Scleroderma, Temporal Arteritis, etc.
   
4. Drugs - methyldopa, quinidine, penicillin
   
5. Idiopathic

Clinical Features

-Signs and symptoms of anemia (fatigue, pallor, palpitations, etc.)
-Jaundice and scleral icteris from hyperbilirubinemia
-Features related to the patient's underlying disease process that is causing their AIHA

Diagnosis

Direct Coombs test - blood sample is removed of plasma and incubated with anti-human immunoglobulin (aka "Coombs reagent"). This detects if autoantibodies are attached to RBCs or compliment. If the RBCs are coated with IgG (positive direct Coombs test), this suggests the diagnosis of "warm AIHA. If the RBCs are coated with only compliment, this suggests the diagnosis of "cold" AIHA

Treatment

Warm AIHA
-Glucocorticoids are first-line
-Splenectomy for patient's with refractory disease to glucocorticoid therapy

Cold AIHA
-Typically no treatment is necessary as disease is self-limited and recommendations to avoid cold temperatures is typically sufficient
-RBC transfusion for significant and symptomatic disease
-Glucocorticoids are not indicated

Further Reading

Paroxysmal nocturnal hemoglobinuria (PNH)
Systemic lupus erythematosus
Rheumatoid arthritis
Scleroderma