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.
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.
- Under normal circumstances, heparin administration results in activation of antithrombin III, which in turn inhibits factors II, IX, X, XI, XII, and XIII. The allows for adequate anticoagulation for patients.
Pathophysiology:
- This begins with heparin exposure, which 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.