• Clinical science

Hemolytic anemia

Summary

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

Overview

Types and etiologies of hemolytic anemia

Hemolytic anemias are characterized by an excessive breakdown of red blood cells (RBCs). They can be classified according to the cause of hemolysis (intrinsic or extrinsic) and by the location of hemolysis (intravascular or extravascular).

Type Definition Causes
By RBC pathology
Intrinsic hemolytic anemia
  • Increased destruction of RBCs due to a defect within the RBC
Extrinsic hemolytic anemia
  • Abnormal breakdown of normal RBCs
By location of RBC breakdown
Intravascular hemolytic anemia
  • Increased destruction of RBCs within the blood vessels
Extravascular hemolytic anemia
  • Increased destruction of RBCs by the reticuloendothelial system (primarily the spleen)

Clinical features

References: [3][4]

Diagnostics

Serum studies [5][6][7]

General findings

Specific workup for hemolytic anemia [5][6]

Coombs test [9]

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

Direct Coombs test

Indirect Coombs test

  • The patient's blood sample is purified so that only serum remains.
  • A donor's blood (RBC) sample is added.
  • Coombs serum is added as well.
  • The sample is analyzed for erythrocyte agglutination.
    • Erythrocyte agglutination indicates the test is positive: Preexisting, circulating, freeantibodies within patient's serum bind to the surface of the donor's RBCs, causing agglutination.
    • Absence of erythrocyte agglutination indicates the test is negative.
  • Indicated for detecting antibodies in:

The direct Coombs test detects antibodies attached directly to the RBC surface. The indirect (or not direct) Coombs test detects serum antibodies not bound to RBCs.

Peripheral blood smear [5][10]

Additional findings [11][12]

Intrinsic hemolytic anemias

Erythrocytic membrane defects

Paroxysmal nocturnal hemoglobinuria (PNH)

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

Other examples

Enzyme defects

Pyruvate kinase deficiency [20][21][22]

Other examples

Hemoglobinopathies

Hemoglobin C disease [23]

Hemoglobin Zurich [25]

  • Pathophysiology: Replacement of the distal histidine in the beta globin chain with arginine enlargement of the ligand binding space around iron increased affinity for carbon monoxide increased carboxyhemoglobin levels (≥ 3%)
  • Clinical symptoms:
    • Often asymptomatic
    • Hemolysis upon exposure to certain chemicals and diet (e.g., sulfonamides, fava beans), stress, and infection
    • Binding of carbon monoxide stabilizes the hemoglobin chain; hence, smokers have less prominent hemolysis.
  • Diagnosis: newborn screening
  • Treatment

Other examples

In hemoglobin C disease, there is an excess of lyCine (lysine) which substitutes the amino acid glutamic acid.

Extrinsic hemolytic anemia

Isoimmune hemolytic anemia

Autoimmune hemolytic anemia (AIHA)

Cold agglutinin disease [26][27][28]

Cold weather is MMMMiserable: Cold (IgM) AIHA is seen in Malignancy (CLL), Mycoplasma pneumoniae, and Mononucleosis.

Warm agglutinin disease [32][33][34][28][29]

Warm weather is Great”: Warm AIHA is IgG mediated.

Microangiopathic hemolytic anemia [37][10]

Macroangiopathic hemolytic anemia