LAUSR

When first reading the article by Raparelli et al. in this issue of HEPATOLOGY, we came away with quite different perspectives, as we suspect many readers will depending on their own experience and background in this field. In a laborious series of experiments on human blood samples, the authors have explored the relationship between circulating gut-derived endotoxin and evidence of platelet activation that could contribute to a relative hypercoagulable state in patients with cirrhosis and possibly to disease-related complications and progression. In many ways, this study offers important insight into platelet function in the pathophysiology of cirrhosis-related coagulopathy. From another perspective, the study points out the need for more research in this challenging area, further refinements in bench methodology, and dynamic studies that take into account the clinically unstable patient with cirrhosis. Most of those involved with clinical care and/or laboratory assessment of bleeding and clotting in liver disease patients are aware of the emergence of newer concepts of a rebalanced but fragile hemostatic system in cirrhosis. Hence, there is a broad consensus on the status of the coagulation system in cirrhosis (normoto hypercoagulable in most published studies). However, the status of the other two components of hemostasis, platelet function and fibrinolysis, is the subject of ongoing clinical controversy. It should also be noted that although key studies in this field (including the Raparelli et al. study) have included and compared Child-Turcotte-Pugh class A, B, and C patients—the latter of which may justifiably include some patients with “decompensated” cirrhosis—most of the patients have been relatively stable judging from the narrow creatinine ranges and from exclusion of bacterial infection and clinical sepsis. Thus, none of these studies clearly excluded or focused on the recently recognized and distinct entity of acute on chronic liver failure (ACLF), a very unstable condition in which the hemostatic pathways are likely to be especially unstable. Historically, platelet hypofunction has been thought to contribute to cirrhotic bleeding. In their article, Raparelli et al. provide additional evidence for enhanced in vitro and in vivo platelet activity in patients with cirrhosis. The authors performed classical platelet aggregation studies using light transmission aggregometry in patients and control subjects in which platelet counts in the control subjects were adjusted to obtain the same platelet count in both groups. Because platelet aggregation studies are highly dependent on platelet count, this adjustment is mandatory for a meaningful comparison; however, as outlined by the authors, many prior studies did not account for the difference in platelet count between patients and control subjects. Raparelli et al. show that when platelets are weakly activated by a “subthreshold” concentration of activator, platelet aggregatory potential is substantially increased in patients with cirrhosis compared with control subjects. Using a higher activator concentration, an experimental setup employed by routine Abbreviations: ACLF, acute on chronic liver failure; LPS, lipopolysaccharide.