Hemolytic anemia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]
Overview
Pathophysiology
Drug-Induced Hemolysis
Drug induced hemolysis has large clinical relevance. It occurs when drugs actively provoke red 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.[1]
- 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
Penicillin 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.
The drug itself can be targeted by the immune system, e.g. by IgE in a Type I hypersensitivity reaction to penicillin, rarely leading to anaphylaxis.
Non-immune
Non-immune hemolysis is characterized by the absence of antibodies.[1] 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 regulatory volume decrease mechanisms, which become activated during hypotonic RBC 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).
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency: 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 defence system of the red blood cells. An example is where 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.[2] Intact G6PD allows for generation of reduced glutathione, which prevents oxidative stress and hemolysis.[2] 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
Some drugs cause RBC (red blood cell) lysis even in normal individuals. These include dapsone and sulfasalazine.
Compensatory response
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 RBC production.
References
- ↑ 1.0 1.1 Mintzer DM, Billet SN, Chmielewski L (2009). "Drug-induced hematologic syndromes". Adv Hematol. 2009: 495863. doi:10.1155/2009/495863. PMC 2778502. PMID 19960059.
- ↑ 2.0 2.1 Luzzatto L, Seneca E (2014). "G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications". Br J Haematol. 164 (4): 469–80. doi:10.1111/bjh.12665. PMC 4153881. PMID 24372186.