Hemolytic anemia pathophysiology

The pathophysiology of most hemolytic anemia involves complement-activated autoantibodies or non-complement-activated autoantibodies, which result in destruction of red blood cells.^[1] The underlying mechanisms is based on immune dysregulation between self and non-self.^[2] Numerous drugs including novel anti-cancer therapeutics, can result in immune-mediated hemolysis. On the other hand, the pathophysiology of non-immune-mediated hemolysis relates to structural factors, such as red blood cell membrane and enzyme defects which confer fragility towards red blood cells. In the setting of defects of red blood cell membranes or anti-oxidant enzymes, there is increased risk for red blood cell destruction.

Drug-induced hemolysis has large clinical relevance. It occurs when drugs actively provoke red blood cell destruction. Drug-induced hemolytic anemia can occur in an antibody-dependent or antibody-independent manner.

• Antibody-mediated hemolysis: This can occur via IgG or IgM binding to red blood cell membranes.^[3] Complement proteins then fix (or attach) onto IgG or IgM antibodies. This eventually results in recruitment of the membrane attack complex consisting of complement proteins C5-C9.
• Antibody-independent hemolysis: This occurs in the absence of IgG or IgM. It can occur via drug-induced protein adsorption on red blood cells.

Immune-mediated hemolysis is characterized by the presence of antibodies that bind to red blood cell membranes and trigger red blood cell destruction. In warm autoimmune hemolytic anemia, antibodies bind to the red blood cell membrane at 37 degrees Celcius (core body temperature for humans).^[2] The antibodies are usually polyclonal, meaning their specificity is for multiple antigens on red blood cells.^[2] Causes of immune-mediated hemolysis include:

• Drugs: This is one of the most common causes of immune-mediated hemolysis. Of note, there is overlap between drug-induced hemolysis and immune-mediated hemolysis. Specifically, drug-induced hemolysis can be immune-mediated or non-immune-mediated, while immune-mediated hemolysis can be drug-dependent or drug-independent.
  • Penicillin: Penicillin is an antibacterial medication that, in high doses, can induce immune-mediated hemolysis via the hapten mechanism in which antibodies are targeted against the combination of penicillin in association with red blood cells. Complement is activated by the attached antibody leading to the removal of red blood cells by the spleen.
  • Nivolumab: This is an antibody that binds to the PD-1 antigen found on lymphocytes. It is typically used to treat cancers like squamous cell carcinoma of the head and neck, melanoma, hepatocellular cancer, and lung cancer. Nivolumab can trigger significant autoimmune reactions. When the hematologic system is affected, hemolytic anemia can result.^[3]
  • Pembrolizumab: This is an antibody that binds to the PD-1 antigen found on lymphocytes. It is typically used to treat cancers like squamous cell carcinoma of the head and neck, melanoma, urothelial cancer, and lung cancer. Pembrolizumab can trigger significant autoimmune reactions. When the hematologic system is affected, hemolytic anemia can result.^[3]
  • Ipilimumab: This is an antibody that binds to cytotoxic T lymphocyte antigen-4 (CTLA-4) on T cells. CTLA-4 is normally an inhibitor molecule involved in the regulatory T cell response.^[2] CTLA-4 functions in maintaining normal homeostasis. Ipilimumab is commonly used to treat stage III melanoma in the adjuvant setting and stage IV melanoma.
  • Anti-RhD: This is a medication used to treat immune thrombocytopenia purpura (ITP). It works by saturating Fc receptors on splenic macrophages and also inducing a mild hemolysis.^[3]
• Infections: Amongst infectious agents, viruses are most likely to trigger hemolysis, compared to bacteria, parasites, or fungi.
• Autoimmune or rheumatologic disease: Activation of one’s own immune system can result in destruction of red blood cells in an antibody-dependent manner. Females are more likely to develop autoimmune hemolytic anemia.
• Lymphoproliferative disorders: These represent a group of primary bone marrow disorders characterized by rapid proliferation of T cells or B cells. Chronic lymphocytic leukemia (CLL), for example, is a lymphoproliferative disorder that is a known etiology of hemolytic anemia.
• Genetic polymorphisms: Mutations or genetic variants in certains genes, like CTLA-4, can cause hemolytic anemia. Mutations can contribute to autoimmunity.^[2]

Cold agglutinins usually bind to the the Ii carbohydrate antigen on red blood cells.^[2] Agglutination usually occurs in the peripheral vasculature in distal capillary beds, where temperature is cool. IgM antibody binds to red blood cells upon exposure to cold, and IgM fixes complement proteins like C1, initiating the classical complement pathway. Subsequent complement proteins include C4, C2, and C3. The membrane attack complex then forms and results in intravascular hemolysis.^[2]

Non-immune hemolysis is characterized by the absence of antibodies in the setting of red blood cell destruction.^[3] Non-immune drug-induced hemolysis can also arise from drug-induced damage to cell volume control mechanisms; for example drugs can directly or indirectly impair volume regulatory mechanisms, which become activated during hypotonic red blood cell swelling to return the cell to a normal volume. The consequence of the drugs actions are irreversible cell swelling and lysis (e.g. ouabain at very high doses). Alternatively, non-immune drug induced hemolysis can occur via oxidative mechanisms. This is particularly likely to occur when there is an enzyme deficiency in the antioxidant defense system of the red blood cells. Red blood cell enzymatic deficiencies are common causes of non-immune-mediated hemolysis.^[4]

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency: This is a red blood cell enzyme defect that results in oxidative stress and hemolysis. It is the most common red blood cell enzymatic defect. Antimalarial oxidant drugs like primaquine damages red blood cells in glucose-6-phosphate dehydrogenase deficiency in which the red blood cells are more susceptible to oxidative stress due to reduced NADPH production consequent to the enzyme deficiency. G6PD is the rate-limiting enzyme in the pentose phosphate pathway, or hexose monophosphate shunt. The normal function of G6PD is to confer reductive potential to erythrocytes via NADPH. Oxidation of NADPH to NADP+ in erythrocytes prevents oxidation of other molecules in these cells and thus prevents hemolysis.^[5] Intact G6PD allows for generation of reduced glutathione, which prevents oxidative stress and hemolysis.^[5] In the presence of G6PD deficiency, the stores of glutathione are depleted, and the sulfhydryl groups of hemoglobin and other proteins become oxidized. This creates precipitation of denatured hemoglobin known as Heinz bodies. This leads to irreversible membrane damage and thus hemolysis. Drugs that typically cause hemolysis in patients with G6PD deficiency include:
  • Primiquine and other anti-malarial agents
  • Fava beans
  • Sulfa drugs like trimethoprim-sulfamethoxazole
  • dapsone

• Pyruvate kinase deficiency: This is a red blood cell enzymatic defect that can result in oxidative stress and hemolysis. It is an autosomal recessive disorder. It is the second most common red blood cell enzymatic defect, after G6PD deficiency. Pyruvate kinase is the final enzyme in the glycolysis pathway and converts phosphoenolpyruvate to pyruvate.

• Glucose phosphate isomerase deficiency: This is a red blood cell enzymatic defect that can result in oxidative stress and hemolysis.

• Triose phosphate isomerase deficiency: This is a red blood cell enzymatic defect that can result in oxidative stress and hemolysis.^[6] This enzyme normally functions to convert dihydroxyacetone phosphate to glyceraldehyde-3-phosphate, which is a critical step in glycolysis. In addition to causing hemolytic anemia, this condition can cause neuromuscular disease and increased risk for infections.^[6]

Hemolytic anemia causes a compensatory increase in erythropoetin that in turn causes an increase in reticulocyte percentage and absolute reticulocyte count. This results in increased hemoglobin and red blood cell production.

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