Endotoxemia as a trigger of thrombosis in cirrhosis

Cirrhosis is associated with a so called “coagulopathy”, which is underscored by the prolongation of global clotting tests, hyperfibrinolysis and thrombocytopenia.1 These laboratory changes have been suggested to predispose to bleeding complications, but recent data have challenged this hypothesis.2

Analysis of the interplay between bleeding and cirrhosis revealed that spontaneous and provoked bleeding events are not always associated with clotting changes; of note, apart from gastrointestinal bleeding, which is unrelated to clotting changes, spontaneous (serious) bleeding such as cerebral hemorrhage is infrequent amongst patients with cirrhosis.3

In contrast with the putative association between “coagulopathy” and bleeding in cirrhosis, recent data indicate that the clinical history of cirrhosis may be complicated by thrombotic events in the peripheral and portal circulation, which worsens clinical outcomes of cirrhotic patients.3

Cirrhosis is the underlying cause of portal vein thrombosis (PVT) in 22–28% of all cases.3 In studies using angiography or surgery, the prevalence of PVT ranged from 0.6% to 16%, whilst ultrasonography studies reported a prevalence as high as 10–25%.3 The prevalence of PVT increases with the severity of cirrhosis, being approximately 1% in patients with compensated cirrhosis and rising to 8–25% in candidates for liver transplantation.3 For example, one study reported that the 5-year cumulative incidence of PVT was 10.7% in 1,243 patients with mild to moderate cirrhosis (Child-Pugh classes A and B); prothrombin time and esophageal varices were the only variables associated with PVT.4

The detection of a hypercoagulable or prothrombotic state in cirrhosis may account for the increased risk of venous thrombosis associated with this condition. Thus, using highly sensitive tests of a hypercoagulable state, such as pro-thrombin fragment F1+2, D-dimer, high-molecular weight fibrin/fibrinogen complexes or soluble fibrin, clotting activation with secondary hyperfibrinolysis has been detected in about 30% of cirrhotic patients.3 The concept that cirrhosis is associated with an ongoing pro-thrombotic state has been supported by experiments suggesting that an enhanced ratio of factor VIII/natural anticoagulants is implicated in clotting activation.1 However, the precise mechanism accounting for hypercoagulation status and eventually venous thrombosis in cirrhosis has not been elucidated.