• Clinical science

Hemolytic anemia


Hemolytic anemias are a group of conditions characterized by the breakdown of red blood cells. Hemolysis is caused by either abnormalities of the RBCs themselves (abnormalities in hemoglobin, the RBC membrane or intracellular enzymes), also called corpuscular anemia, or by external causes (immune-mediated or mechanical damage), which is referred to as extracorpuscular anemia. All hemolytic anemias feature varying degrees of fatigue, pallor, and weakness (from asymptomatic disease to life-threatening hemolytic crisis), although some diseases have more specific findings (e.g., venous thrombosis in paroxysmal nocturnal hemoglobinuria). They also share common laboratory findings, such as elevated indirect bilirubin and lactate dehydrogenase, reticulocytosis, and decreased haptoglobin levels. The Coombs test helps to distinguish autoimmune (positive Coombs test) from non-autoimmune anemias (negative Coombs test). Treatment includes RBC transfusions as required but otherwise depends on the specific type of hemolytic anemia and its causes.


Laboratory signs of hemolysis

Coombs test

This test detects antibodies and/or complement proteins on RBCs surface; (direct test) or in patient's serum (indirect test). The test uses a special Coombs serum that contains anti-human globulins. A positive result in a patient with hemolysis supports the diagnosis of antibody-mediated, extracorpuscular anemia.

  • Direct Coombs test
    • After taking a patient's blood sample, it is purified so that only the erythrocytes remain.
    • Coombs serum containing anti-human globulins (antigens) is added.
    • The examiner visually analyzes the sample and looks for erythrocyte agglutination.
  • Indirect Coombs test
    • After taking a patient's blood sample, it is purified so that only the serum remains.
    • A donor's blood sample containing erythrocytes is added.
    • Coombs serum containing anti-human globulins (antigens) is added as well.
    • The examiner visually analyzes the sample and looks for erythrocyte agglutination.
      • In the case of erythrocyte agglutination → positive test → confirmation of preexisting circulating, free antibodies within patient's serum that bound to donor's RBC surfaces
      • In the case of absent erythrocyte agglutination → negative test


Corpuscular hemolytic anemias

Erythrocytic membrane defects

Think of PNH if a patient presents with hemolytic anemia, venous thrombosis, and pancytopenia!

Enzyme defects



Extracorpuscular hemolytic anemia

Isoimmune hemolytic anemia

Autoimmune hemolytic anemia (AIHA)

Microangiopathic hemolytic anemia

Macroangiopathic hemolytic anemia

  • Etiology
    • Moderate and severe aortic stenosis; : heart valve replacement resolves the anemia
    • Prosthetic heart valve
    • Extracorporeal circulation (e.g., dialysis)
    • Exertional hemoglobinuria (“March hemoglobinuria”): destruction of RBCs in the feet during strenuous exercise (especially running and walking on hard surfaces)
  • Pathophysiology
    • RBC destruction in the systemic circulation due to mechanical forces applied to the erythrocyte membrane
  • Clinical features


Extra- vs intravascular hemolysis

Intravascular hemolysis Extravascular hemolysis
Coombs test
  • Usually normal
Urine hemosiderin
  • Present
  • Usually absent
Urine hemoglobin
  • Present
  • Usually absent
Peripheral smear