Heparin-induced thrombocytopenia pathophysiology
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Heparin-induced thrombocytopenia |
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Differentiating Heparin-induced thrombocytopenia from other Diseases |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.B.B.S. [2]
Overview
Heparin-induced thrombocytopenia is diagnosed when the platelet count falls by > 50% typically after 5-10 days of heparin therapy. It is caused by antibodies to complexes between heparin and platelet factor 4 (PF4). These antibody complexes stimulates the procoagulant pathways due to activation of platelet and endothelium.
Pathophysiology
An understanding of the pathophysiology of HIT requires an understanding of normal physiology:
- Under normal circumstances, platelet factor 4 (PF4) is found in the alpha granules of platelets. It is a positively charged protein that functions to antagonize the effects of heparin-like proteins like heparin sulfate and chondroitin sulfate on the cell surface.[1] PF4 is located intracellularly, but upon platelet activation, PF4 is released, and it contributes to the release of antithrombin from the cell surface, promoting clotting (platelet plugging).
- Under normal circumstances, there are no endogenous antibodies to PF4.
The pathophysiology of HIT begins with heparin or heparinoid exposure:
- Heparin exposure can trigger the release of PF4 from endothelial surfaces. Heparin can then form ultra-large complexes with PF4 via electrostatic forces.
- These complexes of heparin and PF4 can induce production of antibodies, and this large complex serves as an unfamiliar antigen to the body.[1] IgG antibodies are typically produced.
- Immune complexes eventually form, consisting of heparin, PF4 and IgG.[1] The crystallized fragment domain, or (Fc) domain of IgG can bind to Fc receptors, such as FC gamma R II, on the surface of a variety of immune cells, including platelets, neutrophils, and monocytes.
- Binding of IgG from the large complexes triggers activation of the target cells and eventual production of thrombin, which is highly thrombogenic and contributes to clot formation.[1]
- Widespread systemic thrombosis can lead to significant morbidity and mortality.