Mechanisms of Venous and Arterial Thrombosis in Heparin-Induced Thrombocytopenia

Journal of Thrombosis and Thrombolysis (Impact Factor: 2.04). 10/2000; 10:13-20. DOI: 10.1023/A:1027372901367

ABSTRACT Since the reports by Weismann and Tobin in 1958 and Roberts et al. in 1964 called attention to paradoxical thrombosis in patients treated with heparin, the thrombotic aspect of the heparin-induced thrombocytopenia syndrome (HIT) has been emphasized. Yet to this day, the mechanism of thrombosis associated with HIT (HITT) is unclear. It is important to understand the etiology of HITT because of its devastating clinical consequences. We believe one rational approach to understand the mechanism underlying HITTS is to invoke Virchow's triad: stasis, vascular injury and a hypercoagulable state. A hypercoagulable state exists in all HIT patients due to platelet activation by heparin antibody binding. Thrombin generation from platelet microparticles and exposed platelet phospholipid, coupled with stasis (elderly bedridden or otherwise sedentary ill patients who comprise the majority of the HIT population), provide two risk factors that can lead to venous thrombosis. A hypercoagulable state coupled with endothelial cell dysfunction due to injury from heparin antibody, activated platelets, leukocytes, platelet microparticles, complement, atherosclerosis or medical intervention can lead to arterial thrombosis. Of patients with HIT, HITT occurs in about 25%, suggesting that a second set of patient specific risk factors, in addition to the generation of pathological heparin antibodies, determine whether HITT will develop. Interaction between activated platelets and other platelets, and with endothelial cells, leukocytes, neutrophils, monocytes and cytokines are areas of research that may provide more specific characterization of the hypercoagulable state and vascular damage. Nuances involving genetic variation in platelets, endothelial cells and immune function are also likely to be a major component of the observed variability of this disease spectrum. Virchow's triad may explain the different manifestations of HITTS.

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    ABSTRACT: Heparin is a natural agent with antithrombotic action, commercially available for therapeutic use as unfractionated heparin and low molecular weight heparin. Heparin-induced thrombocytopenia (HIT) is a serious adverse reaction to heparin that promotes antibody-mediated platelet activation. HIT is defined as a relative reduction in platelet count of 50% (even when the platelet count at its lowest level is above>150 x 10(9)/L) occurring within five to 14 days after initiation of the therapy. Thrombocytopenia is the main feature that directs the clinical suspicion of the reaction and the increased risk of thromboembolic complications is the most important and paradoxical consequence. The diagnosis is a delicate issue, and requires a combination of clinical probability and laboratory tests for the detection of platelet activation induced by HIT antibodies. The absolute risk of HIT has been estimated between 1% and 5% under treatment with unfractionated heparin, and less than 1% with low molecular weight heparin. However, high-quality evidence about the risk of HIT from randomized clinical trials is scarce. In addition, information on the frequency of HIT in developing countries is not widely available. This review aims to provide a better understanding of the key features of this reaction and updated information on its frequency to health professionals and other interested parties. Knowledge, familiarity, and access to therapeutic options for the treatment of this adverse reaction are mandatory to minimize the associated risks, improving patient safety.
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