Sarah Bos

30 CHAPTER 2 PSC/PBC NASH ALD Viral Controls PAI-1 (ng/ml) 3.5 (1.7-6.5) b 2.6 (2.0-9.9) b 1.6 (0.9-3.2) 1.4 (0.5-1.8) 1.8 (1.1-2.7) tPA (ng/ml) 13.4 (8.5-19.7) c 14.1 (10.3-25.2) c 17.1 (10.6-23.2) c 11.4 (7.2-20.5) c 2.8 (1.5-4.2) Table 4. Plasma levels of proteins involved in fibrinolysis Abbreviations: ALD, alcoholic liver disease, viral comprises hepatitis B and hepatitis C; NASH, non- alcoholic steatohepatitis; PAI-1, plasminogen activator inhibitor-1; PBC, primary biliary cholangitis; tPA, tissue plasminogen activator. Note: Data are expressed as median (interquartile range). a p < 0.05 vs. control, b p < 0.01 vs. Control, c p < 0.001 vs. control. Discussion We performed in-depth hemostatic profiling of primary hemostasis, secondary hemostasis and fibrinolysis and found that in general patients with cirrhosis have a hypercoagulable profile with no overt differences between etiologies of cirrhosis. Specifically, high levels of the platelet adhesive protein VWF, hypercoagulability by thrombomodulin-modified TGA, a prothrombotic fibrin structure, and hypofibrinolysis in our cohort of patients with predominantly CTP A/B cirrhosis were found. These results are in line with previous studies(6–8), with the exception of the hypofibrinolytic state. In summary, our results suggest that patients with CTP A/B cirrhosis, regardless of etiology, have a prohemostatic state that increases the risk for thrombotic complications, reinforcing the recent change in the historical dogma that cirrhosis is an acquired bleeding disorder. Indeed, it has now been firmly established that cirrhosis increases the risk for thrombotic events, notably venous thrombosis and portal vein thrombosis.(5,25,26) Within our primary hemostasis analyses we found increased VWF levels in all etiologies, but slightly non-significantly decreased ADAMTS13 levels only in patients with cholestatic disease and viral cirrhosis. Although ADAMTS13 is synthesized in the liver,(28) and therefore levels are expected to decrease similar to levels of other hemostatic factors (e.g. those shown in Table 3), ADAMTS13 is synthesized also in stellate cells,(27,28) whichmay explain themainly preserved ADAMTS13 levels in our patients. Although multiple studies have demonstrated decreased plasma levels of ADAMTS13 in cirrhosis, previous studies from our group found ADAMTS13 to be relatively preserved,(3,15) which is in line with our current data. The preserved levels of ADAMTS13 might also be related to the disease severity of our study population, which in mainly mild to moderate. Although the VWF/ADAMTS13 unbalance is potentially thrombogenic, we did not find evidence for ongoing platelet activation as evidenced by a lack of increase in the platelet activation marker P-selectin, which is also in line with previously published work.(15)