Mechanisms of Venous and Arterial Thrombosis in Heparin-Induced Thrombocytopenia
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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- "Microparticles have been found in increased numbers in normal pregnancy (Bretelle et al., 2003), and have been associated with several prothrombotic conditions such as thrombotic thrombocytopenic purpura (Galli et al., 1996), myocardial infarction (Mallat et al., 2000), sepsis (Joop et al., 2001), heparin-induced thrombocytopenia (Hughes et al., 2000; Walenga et al., 2000) and even pre-eclampsia (Greer, 1999; Bretelle et al., 2003). Laude et al. (2001) have measured total microparticles in women with a history of recurrent pregnancy loss compared with controls, and found microparticle levels to be above the upper limit of normal in 59% of patients. "
ABSTRACT: Circulating microparticles are markers of cell activation associated with various prothrombotic states. As hypoxia due to uteroplacental thrombosis is considered to be one of the causes of pregnancy loss, microparticles may be associated with pregnancy loss, in addition to, or as part of, other procoagulant states such as antiphospholipid syndrome or hereditary thrombophilias. The objective of this study was to examine the prevalence of circulating microparticles in women with recurrent pregnancy loss. A total of 96 women with recurrent pregnancy losses were enrolled in a case-control study and compared with 90 parous women. Microparticles were measured by flow cytometry using fluorescent anti-CD51/CD31 antibodies. Microparticle levels >2 SD above the mean of controls (57,700/ml) were detected in 12 out of 96 women with recurrent miscarriages (12.5%), compared with two of the 90 control women (2.2%), P<0.008. The titre of microparticles did not correlate with age, number of pregnancy losses, primary secondary or tertiary aborters status, or with pregnancy losses in the 1st or 2nd trimesters. A proportion of women with pregnancy loss have elevated endothelial microparticles suggesting that endothelial damage or activation might be associated with the pathogenesis of pregnancy loss.Human Reproduction 02/2004; 19(1):191-5. DOI:10.1093/humrep/deg512 · 4.57 Impact Factor