Sarah Bos

11 General introduction 1 Fibrinolysis Fibrinolysis is the process that ensures the breakdown of a clot formation. This process is triggered by tissue-type plasminogen activator (tPA), which converts plasminogen into plasmin. Plasmin degrades the fibrin mesh at various places, leading to the production of soluble fibrin degradation products. The conversion of plasminogen to plasmin is down regulated via plasminogen activator inhibitor-1 (PAI-1), an inhibitor of tPA, plasmin inhibitor (PI) and activated thrombin-activatable fibrinolysis inhibitor (TAFI). TAFI inhibits fibrinolysis by cleaving parts from partially degraded fibrin, thereby inhibiting t-PA–mediated plasminogen activation.(7)The balance in fibrinolysis prevents unwanted plasmin generation. Disruption of this balance may cause either hyper- or hypo-fibrinolysis. Hemostatic changes in liver disease Cirrhosis is the end stage of chronic liver disease. Cirrhosis is defined as a diffuse hepatic process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules.(8) The liver is the site of synthesis for many proteins involved in hemostasis. Consequently, patients with cirrhosis acquire multiple and complex alterations in their hemostatic system. Recent insights in consequences of the hemostatic changes in patients with cirrhosis have indicated a balanced, but unstable hemostatic system in these patients.(9,10) Primary hemostasis in patients with cirrhosis is characterized by thrombo- cytopenia. The decrease in platelet count is mainly due to congestive splenomegaly and decreased production of thrombopoietin in the liver. In contrast, the decrease of ADAMTS13 in cirrhosis promotes primary hemostasis. ADAMTS13 inhibits the activity of von Willebrand factor (VWF), a large protein partly responsible for clot formation. Several studies showed the increase of VWF levels and decrease in levels of ADAMTS13.(11,12) These changes in protein activity appear to compensate for thrombocytopenia, leading to a new balance in primary hemostasis. Patients with cirrhosis have a decreased synthesis of proteins involved in coagulation. The change in proteins promoting bleeding seems to be counterbalanced by the change in proteins that promote thrombosis. On one hand there is the decreased level of coagulation factors, II,V, VII, IX, X, XI, vitamin K deficiency and dysfibrinogenemia and on the other hand there is an elevated level of FVIII, decreased level of protein C, protein S, antithrombin, α 2-macroglobuline and heparin cofactor II.(9,10,13). The net effect of these changes in patients with cirrhosis result in a hypercoagulable state.(14,15) The fibrinolytic system also seems to be in balance in patients with cirrhosis, due to the concomitant decline of antifi-brinolytics (antiplasmin, thrombin activatable fibrinolysis inhibitor), and plasminogen. However, current literature is not