28-0.64-μm size range in mediating ALF syndrome. The direct correlation between MP number and factor VIII levels also suggests that MPs may play a role in vascular endothelial cell activation/injury of ALF, the severity of which directly correlates with mortality.10, 33 Whether MPs serve as mediators of the systemic complications of ALF or are simply biomarkers of inflammation cannot be determined KU-60019 chemical structure conclusively from our data; however, it appears likely that they represent both the cause and the effect of systemic inflammation. Recent studies have

also incriminated MPs in the pathogenesis of chronic liver diseases (CLDs).30 Patients with cirrhosis have increased circulating MPs derived from leukocytes, ECs, and hepatocytes, compared to healthy controls, and concentrations of MPs increase with increasing severity of cirrhosis.20 MPs isolated from PPP of subjects with cirrhosis were shown in vitro and in experimental animals to impair Aloxistatin supplier vasoconstrictor response and may thereby cause the vasoplegia of end-stage liver disease. Similarly, T-lymphocyte-derived CD4+ and CD8+

MP numbers were higher in patients with nonalcoholic fatty liver disease and chronic hepatitis C than healthy controls and correlated with disease activity.34, 35 In contrast to the present work, the number of CD41+ (platelet-derived) MPs in these populations with CLD were not significantly higher than healthy controls nor were they proportional to the severity of disease. However, both of these studies were performed using flow cytometry and

may have thereby missed a possible effect of platelet-derived MPs, most of which (as shown herein) are below the limit of detection by flow cytometry. These studies and the present work suggest that increased production of platelet MPs may be restricted to acute conditions characterized by a prominent SIRS. In addition to systemic effects of MPs implied by the association of MP concentrations and systemic complications of ALF, procoagulant MPs may also 上海皓元医药股份有限公司 serve to exacerbate the primary liver injury. In a mouse model of APAP hepatotoxicity, activation of coagulation within the necrotic liver increases the primary APAP-induced injury and is greatly ameliorated by heparin administration.7 Furthermore, the prothrombotic effect of APAP is also greatly ameliorated in mice expressing low levels of TF, providing indirect evidence that liver-derived TF may mediate the activation of coagulation.7 Other experimental models also support a role for secondary activation of coagulation within the acutely injured liver in the pathogenesis of liver failure.36, 37 Because thrombin generation requires exposure of anionic phospholipids on cellular and/or MP surfaces, intrahepatic MPs would be reasonable candidate platforms on which coagulation occurs. MP-TF assays have also shown that the population of circulating MPs is highly procoagulant in a TF-dependent manner.