Increased anticoagulant response to drugs targeting thrombin, but not to drugs targeting FXa, in plasma from patients with cirrhosis

Background: Chronic liver disease was previously considered as the prototype of acquired coagulopathy responsible for bleeding because of a decreased number and function of platelets, decreased synthesis of coagulation factors by the diseased liver, and hyperfibrinolysis. Recently, laboratory studies and clinical observations have provided evidence for a rebalanced hemostatic status in patients with chronic liver disease due to a concomitant decline in pro- and antihemostatic proteins. However, this balance can be easily tipped over to a hypercoagulable or a hypocoagulable state with the risk of both bleeding complications and clinical thrombotic events. In fact, treatment and prevention for thrombotic complications is frequently required. Nevertheless, patients with liver disease are often withheld from anticoagulant therapy, because of the perceived bleeding diathesis and as a result of the limited clinical experience the anticoagulant of choice for the various indications is still not known. A recent study demonstrated an increased anticoagulant response to low molecular weight heparin in plasma from patients with cirrhosis. This potentially increased response of cirrhotic patients to anticoagulant drugs may require dose adjustments to prevent unwanted bleeding complications. Aims: Here the in vitro effect of clinically approved anticoagulant drugs in plasma from cirrhotic patients at different stages of liver disease was evaluated. Methods: The anticoagulant potency of antithrombotic drugs was studied by performing thrombin generation tests (Calibrated Automated Thrombinography) in the presence of thrombomodulin, which allows the evaluation of the balance between pro- and anticoagulant factors in plasma. Twenty-five patients with cirrhosis (10 with mild, 10 with moderate, and 5 with severe disease) and 30 healthy controls were studied. The study was approved by the local medical ethical committee (METc 2012/122 Nl40435.042.12) and informed consent was obtained from all subjects. Thrombin generation was determined before and after addition of unfractionated heparin (0.1 U/mL), low molecular weight heparin (0.2 U/ml), fondaparinux (0.5 µg/ml), dabigatran (300 ng/ml), and rivaroxaban (25 ng/ml). Results: An increased anticoagulant response in plasma from cirrhotic patients to anticoagulants targeting thrombin was observed. The endogenous thrombin potential was reduced by 85.5% by heparin in patients, and an 83.0% reduction was observed in controls (P=0.038). Addition of dabigatran led to a much more pronounced reduction in peak thrombin generation in patients compared to controls (73.0% reduction in patients vs. 0.2% reduction in controls, P