Sarah Bos

123 General discussion 7 We used ex-vivo thrombin generation tests and d-dimer levels to assess the anticoagulant potency of edoxaban. Specifically, we used thrombomodulin- modified thrombin generation tests, which gives an accurate balance between pro- and anticoagulant mechanisms, and confirmed enhanced thrombin generating capacity in patients. Several clinical characteristics, however, may affect the thrombin generation test. For example, it is known that an age related increase in thrombin generation exists which might be a indicator of the increase in thromboembolic events with higher age.(29–31) Our patients and controls had a mean age difference of approximately 10 years, but the difference in ETP between patients and controls far exceeds the increase in thrombin generating capacity due to ageing. Importantly, we have assessed both absolute and relative effects of edoxaban exposure on thrombin generation, and found impaired anticoagulant capacity in patients in both approaches. Although plasma levels of edoxaban were similar in patients and in controls, the inhibition of coagulation was less effective in patients compared to healthy controls. The absolute level of ETP potential of patients on anticoagulation was twice as high compared to healthy controls. This might suggest an insufficient anticoagulant effect. However, there are no standardized levels of endogenous thrombin potential (ETP) of patients on anticoagulation which should be targeted to achieve optimal anticoagulant treatment. Another finding which might support an insufficient anticoagulant effect is that the d-dimer levels, an indirect reflection of coagulation, of patients did not alter during the study period whereas the d-dimer levels of healthy controls slowly decreased over time. Earlier in vitro studies corroborate these findings as they showed that the Xa inhibitors rivaroxaban and apixaban also exert a decreased anticoagulant effect in plasma of patients with CTP A/B/C cirrhosis.(16,25) The data shown in chapter 4 clearly shows no evidence of accumulation of edoxaban due to decreased hepatic clearance in patient with CTP A cirrhosis. Since our study group mainly consisted of patients CTP A cirrhosis, we have no data on the clearance in CTP B/C cirrhosis. Edoxaban has a 30-50% renal clearance. The remainder of the drug is cleared by biliary/intestinal excretion with a minimal through metabolism ( < 4%) by CYP450 enzymes.(27,32) Theoretically, patients with cirrhosis and impaired renal function are more prone for drug accumulation since DOACs are partially cleared by metabolic inactivation in the liver, and in part by renal excretion. Extrapolation of our results to the other Xa inhibitors, rivaroxaban and apixaban, should be done carefully. Even though the clearance of both these drugs are somewhat similar to edoxaban (65% hepatic and 35% renal for rivaroxaban, 75% hepatic and 25% renal for apixaban) studies must determine whether accumulation occurs with these drugs in patients with CTP A cirrhosis.