What is the pathophysiology of heparin-induced thrombocytopenia (HIT)?

Updated: Apr 24, 2018
  • Author: Sancar Eke, MD, FASN; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
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Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder caused by antibodies to complexes of platelet factor 4 (PF4) and heparin. [5] Rauova and colleagues reported that heparin and PF4 form stable, ultralarge (>670 kDa) complexes (ULCs) composed of multiple PF4 tetramers arrayed in a lattice with several molecules of unfractionated heparin. Far fewer ULCs were formed when low-molecular weight heparin was used, and none were formed with the factor Xa inhibitor fondaparinux. [6]

Zheng and colleagues reported that healthy humans possess preexisting inactive/tolerant PF4/heparin-specific B cells, and that breakdown of tolerance can lead to production of PF4/heparin-specific antibodies. [7] These HIT antibodies can be found in plasma in more than 90% of patients with the clinical diagnosis of HIT. [5] However, HIT antibodies are also present in many patients (especially patients undergoing cardiac procedures) who have been exposed to heparin but who do not have clinical manifestations of HIT.

The antibodies bind to the PF4-heparin complexes on the platelet surface and induce platelet activation by cross-linking FcγIIA receptors. [8, 9, 10] The activated platelets increase the release and surface expression of PF4, creating a positive feedback loop in which further release of PF4 promotes further platelet activation. [11]

Alternatively, HIT antibodies may recognize PF4 bound to platelet chondroitin sulfate. These antibodies activate platelets even in the absence of heparin, thus explaining delayed-onset HIT, persistent HIT (in which recovery takes several weeks), spontaneous HIT syndrome (which resembles HIT clinically and serologically but occurs without proximate heparin exposure), and fondaparinux-associated HIT. [12]

Platelet activation results in the release of procoagulant platelet microparticles, platelet consumption, and thrombocytopenia. Marked generation of thrombin, activation of monocytes and other inflammatory cells, and endothelial injury and activation follow, producing the characteristic venous and arterial thromboses of HIT.

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