VWF/ADAMTS13 Imbalance, But Not Global Coagulation or Fibrinolysis, Is Associated With Outcome and Bleeding in Acute Liver Failure

Abstract

Background and Aims Recent studies of acute liver failure (ALF) in man and animals have suggested that rebalanced hemostasis occurs, with distinct hypercoagulable features clinically evidenced by a low risk of bleeding. Rodent models have shown a link between intrahepatic microthrombus formation and progression of ALF. We sought to confirm these earlier findings in a large series of well‐characterized ALF patients from the Acute Liver Failure Study Group (ALFSG). Patients and Methods Citrated plasma samples taken on admission from 676 patients with ALF or acute liver injury (ALI; INR ≥ 2.0 without hepatic encephalopathy) were used to determine levels of VWF, ADAMTS13 activity, thrombomodulin‐modified thrombin generation, and clot lysis time (CLT) and compared with levels in 40 healthy controls. Results Patients had 3‐fold increased VWF levels, 4‐fold decreased ADAMTS13 activity, similar thrombin generating capacity, and 2.4‐fold increased CLT, compared with controls. Increasing disease severity was associated with progressively more elevated VWF levels as well as hypofibrinolysis. Patients who died or underwent liver transplantation within 21 days of admission had higher VWF levels, lower ADAMTS13 activity, but similar thrombin generation and a similar proportion of patients with severe hypofibrinolysis, when compared to transplant‐free survivors. Likewise, patients with bleeding complications had higher VWF levels and lower ADAMTS13 activity compared to those without bleeding. Thrombin generation and CLT did not differ significantly between bleeding and non‐bleeding patients. Conclusion Rebalanced hemostatic status was confirmed in a large cohort of patients with ALI/ALF demonstrating that VWF/ADAMTS13 imbalance is associated with poor outcome and bleeding. The association between VWF/ADAMTS13 imbalance and bleeding suggest that bleeding in ALF relates more to systemic inflammation than a primary coagulopathy.