Hemolytic anemia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Shyam Patel [2]

Overview

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.

Pathophysiology

Drug-Induced Hemolysis

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.

Immune-Mediated Hemolysis

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:

Cold Agglutinin-Mediated Hemolysis

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-Mediated Hemolysis

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]

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 red blood cell production.

References

  1. Salama A (2015). "Treatment Options for Primary Autoimmune Hemolytic Anemia: A Short Comprehensive Review". Transfus Med Hemother. 42 (5): 294–301. doi:10.1159/000438731. PMC 4678315. PMID 26696797.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Berentsen S, Sundic T (2015). "Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy". Biomed Res Int. 2015: 363278. doi:10.1155/2015/363278. PMC 4326213. PMID 25705656.
  3. 3.0 3.1 3.2 3.3 3.4 Mintzer DM, Billet SN, Chmielewski L (2009). "Drug-induced hematologic syndromes". Adv Hematol. 2009: 495863. doi:10.1155/2009/495863. PMC 2778502. PMID 19960059.
  4. Wiback SJ, Palsson BO (2002). "Extreme pathway analysis of human red blood cell metabolism". Biophys J. 83 (2): 808–18. doi:10.1016/S0006-3495(02)75210-7. PMC 1302188. PMID 12124266.
  5. 5.0 5.1 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.
  6. 6.0 6.1 Celotto AM, Frank AC, Seigle JL, Palladino MJ (2006). "Drosophila model of human inherited triosephosphate isomerase deficiency glycolytic enzymopathy". Genetics. 174 (3): 1237–46. doi:10.1534/genetics.106.063206. PMC 1667072. PMID 16980388.

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