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] Shyam Patel [3]
Overview
Heparin-induced thrombocytopenia is diagnosed when the platelet count falls by > 50% typically after 5-10 days of heparin therapy. Heparin exposure triggers the release of PF4 from endothelial surfaces. Complexes of heparin and PF4 serve as neoepitopes, or new antigens, and can induce production of antibodies, since this large complex serves as an unfamiliar antigen to the body. Binding of IgG from the large complexes into the Fc gamma RII receptors triggers activation of the target cells containing the receptors and eventual release of platelet microparticles. This results in production of thrombin, which is highly thrombogenic and contributes to clot formation. Ultimately, this leads to thrombotic complications in the venous and arterial systems.
Pathophysiology
An understanding of the pathophysiology of HIT requires an understanding of normal physiology.
Normal physiology:
- Under normal circumstances, platelet factor 4 (PF4) is synthesized by platelet precursors called megakaryocytes.[1] It is stored 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.[2] PF4 is located intracellularly, but upon platelet activation, PF4 is released. Since is it a positively charged protein, it binds to negatively charged glycosaminoglycans, such as heparan sulfate.
- Under normal circumstances, antithrombin is then displaced from heparan sulfate, resulting in the normal desired coagulation.[1] PF4 thus 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, exogenous 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 multimolecular complexes with PF4 via electrostatic forces.[3] The epitopes of PF4 that are known to bind to heparin include proline-37 and proline-34.[4][5]
- These complexes of heparin and PF4 serve as neoepitopes, or new antigens, and can induce production of antibodies, since this large complex serves as an unfamiliar antigen to the body.[2] IgG antibodies are typically produced to the multimolecular complexes.[3][6]
- Immune complexes eventually form within a few days of exposure to heparin. The immune complexes consist of heparin, PF4 and IgG.[2] The crystallized fragment domain, or (Fc) domain of IgG can bind to Fc receptors, such as FC gamma RII, on the surface of a variety of immune cells, including platelets, neutrophils, and monocytes.
- Binding of IgG from the large complexes into the Fc gamma RII receptors triggers activation of the target cells containing the receptors and eventual release of platelet microparticles. This results in production of thrombin, which is highly thrombogenic and contributes to clot formation.[2] It also leads to production of platelet-fibrin thrombi.[4][7]
- Widespread systemic thrombosis can lead to significant morbidity and mortality.
Reference
- ↑ 1.0 1.1 Arepally GM, Ortel TL (2010). "Heparin-induced thrombocytopenia". Annu Rev Med. 61: 77–90. doi:10.1146/annurev.med.042808.171814. PMC 4153429. PMID 20059332.
- ↑ 2.0 2.1 2.2 2.3 Lee GM, Arepally GM (2013). "Diagnosis and management of heparin-induced thrombocytopenia". Hematol Oncol Clin North Am. 27 (3): 541–63. doi:10.1016/j.hoc.2013.02.001. PMC 3668315. PMID 23714311.
- ↑ 3.0 3.1 Linkins LA, Dans AL, Moores LK, Bona R, Davidson BL, Schulman S; et al. (2012). "Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): e495S–e530S. doi:10.1378/chest.11-2303. PMC 3278058. PMID 22315270.
- ↑ 4.0 4.1 McKenzie SE, Sachais BS (2014). "Advances in the pathophysiology and treatment of heparin-induced thrombocytopenia". Curr Opin Hematol. 21 (5): 380–7. doi:10.1097/MOH.0000000000000066. PMC 4232774. PMID 24992313.
- ↑ Chong BH (July 2003). "Heparin-induced thrombocytopenia". J. Thromb. Haemost. 1 (7): 1471–8. PMID 12871282.
- ↑ Ahmed I, Majeed A, Powell R (September 2007). "Heparin induced thrombocytopenia: diagnosis and management update". Postgrad Med J. 83 (983): 575–82. doi:10.1136/pgmj.2007.059188. PMC 2600013. PMID 17823223.
- ↑ Warkentin TE (May 2003). "Heparin-induced thrombocytopenia: pathogenesis and management". Br. J. Haematol. 121 (4): 535–55. PMID 12752095.