[1] In acute liver failure, the net effect of all hemostatic chan

[1] In acute liver failure, the net effect of all hemostatic changes is not clear, partly because the changes in the hemostatic system in these patients have been less well defined compared with those in patients with cirrhosis. In an effort to elucidate this issue, we are systematically studying consequences of hemostatic defects in patients with acute liver failure. We recently demonstrated an intact selleck thrombin generating capacity in plasma from patients with acute liver injury and acute liver failure

(ALI/ALF) despite severely reduced plasma levels of coagulation factors and abnormal routine diagnostic tests of coagulation, such as the prothrombin time.[5] This intact thrombin generation has been ascribed to a concomitant decrease in both procoagulant and anticoagulant factors. In vivo, however, thrombin generation is not only a function of procoagulant and anticoagulant factors, but also of platelets.[6] The platelet surface provides a scaffold for the assembly of coagulation MLN0128 concentration factor complexes, and this assembly is an essential step in the thrombin generation pathway. Primary and secondary hemostasis, therefore, are

integrated physiologically to facilitate thrombin generation and fibrin formation. In view of the physiological importance of platelets in supporting coagulation, we now aim to better define changes in the primary hemostatic system of patients with ALI/ALF and their net effect on bleeding, thrombosis, and disease progression. Our group

initially studied parameters reflecting platelet function by thromboelastography using whole blood of patients with ALI/ALF.[7] We found evidence of normal to increased platelet activity in whole blood of patients with ALI/ALF when compared with normal controls despite reduced platelet numbers in a proportion of patients. The exact mechanisms underlying the observed increase in parameters reflecting platelet function and adhesion are unknown, but it may be attributed to increased levels of the adhesive protein von Willebrand factor (VWF). selleck compound Indeed, we have demonstrated that elevated levels of VWF may (over)compensate for abnormalities in platelet number and function in patients with cirrhosis.[8] These high VWF plasma levels result from disease-related overactivation of the reticulo-endothelial system in endothelial cells.[9, 10] VWF is a large, multimeric protein, and its interaction with platelet glycoprotein Ib is essential for platelet adhesion under conditions of flow, as evidenced by the bleeding tendency associated with qualitative or quantitative defects in VWF in von Willebrand disease. The functional capacity of VWF is normally strictly regulated in the blood by the VWF-cleaving protease, ADAMTS13, as VWF reactivity towards platelets is directly proportional to its multimeric size.

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