Sarah Bos

39 Changes of in vitro potency of anticoagulant drugs 3 Introduction Cirrhosis may be associated with major changes in the hemostatic system. Although historically cirrhosis has been considered as the prototype of acquired bleeding disorders, it has become clear that the hemostatic balance in patients with cirrhosis is actually well preserved due to the concomitant decline in pro- and antihemostatic pathways.(1,2) The hemostatic balance in cirrhosis, however, is much more fragile compared to that of individuals with intact liver function. This likely explains why patients with cirrhosis may experience both bleeding and thrombotic complications.(1) Prevention or treatment of thrombotic complications in patients with cirrhosis is complicated by multiple factors involving the coagulopathy of cirrhosis. For example, vitamin K antagonists are difficult to dose, as patients with cirrhosis frequently have an elevated international normalized ration (INR) at baseline. As the INR is used to dose vitamin K antagonists, the desired target range in these particular patients is unclear. We and others have recently demonstrated that the potency of low molecular weight heparin (LMWH) is enhanced in cirrhosis.(3,4) These findings may imply that dose-adjustments may be required. Unfortunately, monitoring of LMWH in cirrhosis is complicated as the anti-Xa assay underestimates LMWH mass in cirrhotic plasma.(5) We also recently demonstrated that direct oral anticoagulants (DOACs) have an altered potency in cirrhotic plasma.(4,6) Confusingly, direct Xa inhibitors appear to have a decreased, and direct thrombin inhibitors an increased potency in cirrhosis. It is unknown whether the changes in potency of commonly used anticoagulant drugs differ according to the etiology of disease, as previous studies were performed with groups of patients of varying etiology.(3,4,6) One group of patients that appear to have an increased risk of thrombotic disease are patients with cirrhosis related to non-alcoholic fatty liver disease (NAFLD).(7) Hemostatic status in patients with NAFLD-related cirrhosis (i.e., cirrhosis as a result of non- alcoholic steatohepatitis [NASH]) may be governed by a combination of the hemostatic changes induced by cirrhosis and the hemostatic changes associated with obesity and the metabolic syndrome.(8) Given these findings, it is conceivable that the potency of anticoagulants is different in NASH-associated cirrhosis compared to cirrhosis of other etiologies. Insight in the effect of commonly use anticoagulant drugs in this growing patient population is of utmost importance for a more rational approach to prevention or treatment of thrombotic disease in this difficult-to-anticoagulate patient population.(9,10)Here, we will study the in vitro potency of three classes of anticoagulant drugs, previously tested by us in a group of patients with mixed cirrhosis (LMWH, the Xa inhibitor apixaban, and the thrombin inhibitor dabigatran). We will compare anticoagulant potency of these