Mechanisms of venous and arterial thrombosis in heparin-induced thrombocytopenia

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 (H IT) has been emphasized. Yet to this day, the mechanism of thrombosis assoc iated with HIT (HITT) is unclear. It is important to understand the etiolog y 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 hy percoagulable state exists in all HIT patients due to platelet activation b y heparin antibody binding. Thrombin generation from platelet microparticle s and exposed platelet phospholipid, coupled with stasis (elderly bedridden or otherwise sedentary ill patients who comprise the majority of the HIT p opulation), provide two risk factors that can lead to venous thrombosis. A hypercoagulable state coupled with endothelial cell dysfunction due to inju ry from heparin antibody, activated platelets, leukocytes, platelet micropa rticles, complement, atherosclerosis or medical intervention can lead to ar terial thrombosis. Of patients with HIT, HITT occurs in about 25%, suggesti ng that a second set of patient specific risk factors, in addition to the g eneration of pathological heparin antibodies, determine whether HITT will d evelop. Interaction between activated platelets and other platelets, and wi th endothelial cells, leukocytes, neutrophils, monocytes and cytokines are areas of research that may provide more specific characterization of the hy percoagulable state and vascular damage. Nuances involving genetic variatio n in platelets, endothelial cells and immune function are also likely to be a major component of the observed variability of this disease spectrum. Vi rchow's triad may explain the different manifestations of HITTS.