Rebalanced Hemostasis, Bleeding, and Thrombosis in Liver Disease: A Comprehensive Review of Pathophysiology,...

Patients with liver disease exhibit complex changes in the hemostatic system that are often presumed to drive bleeding and thrombosis. Historically, liver disease was considered a bleeding disorder based on thrombocytopenia, prolonged routine coagulation tests, and reports of fulminant bleeding. Present evidence, however, indicates that antihemostatic changes are compensated for by simultaneous prohemostatic changes, resulting in a rebalanced hemostatic system. Further hemostatic changes may be induced by liver disease progression and extrahepatic factors, such as systemic inflammation, acute kidney injury, and cardiometabolic diseases. Despite extensive hemostatic changes in liver disease, current evidence does not consistently show that they increase bleeding risk, although this has been suggested repeatedly in published literature. Indeed, hemostatic changes appear largely unrelated to most bleeding complications, and specific thrombotic complications also appear unrelated to hemostatic changes. Major bleeding is common but predominantly reflects portal hypertension-related acute variceal bleeding and mechanical injury-related procedural bleeding. A proportion of bleedings, however, may be hemostasis-related, but the vast majority of such events do not require prohemostatic intervention. In contrast, a large proportion of thrombotic complications, including venous thromboembolism, portal vein thrombosis (PVT), and intrahepatic thrombosis, may in part be related to prohemostatic changes, although the role of hypercoagulability in PVT is increasingly questioned. Despite greater attention for thrombotic complications in liver disease, robust studies on optimal anticoagulant strategies are currently lacking. Studies evaluating the pharmacokinetics, pharmacodynamics, and efficacy for prevention of thrombosis and liver decompensation of direct oral anticoagulants and factor XIa inhibitors are therefore urgently needed.