Platelet protease nexin-1 limits fibrinolysis in patients with cirrhosis.

Background & Aims: The role of protease nexin 1 (PN-1), a serine protease inhibitor that regulates both coagulation and fibrinolysis, is unknown in patients with cirrhosis. This study aimed to provide a comprehensive assessment of the role of PN-1 in cirrhosis. Methods: Plasma PN-1 concentration in 212 patients with advanced chronic liver disease and 30 healthy individuals was measured by ELISA. The role of PN-1 was investigated using thrombin generation assay, rotational thromboelastometry, and clot lysis assay in platelet-rich plasma and platelet-free plasma from 10 patients with stable decompensated cirrhosis and 10 healthy individuals. Results: Plasma PN-1 concentration was higher in patients with advanced chronic liver disease than in healthy individuals (0.21 vs. 0 ng/ml, p = 0.0001), strongly increased with liver disease severity and portal hypertension, and was associated with 1-year mortality. In patients with stable decompensated cirrhosis, the synergy between platelet PN-1 and thrombomodulin to inhibit thrombin generation, observed in healthy individuals, was lost. Importantly, platelet PN-1 inhibition induced a much greater acceleration of fibrinolysis in patients with cirrhosis than in healthy individuals (1.6 and 2.8 times greater reduction in lysis onset time and lysis index 30, respectively, without tPA). Unlike platelet PN-1, plasma PN-1 plays a negligible role in coagulation and fibrinolysis. Conclusions: Platelet-derived PN-1 was found to markedly limit fibrinolysis in decompensated cirrhosis, although its impact on coagulation appeared minimal. Although elevated plasma PN-1 concentrations were observed in patients with advanced chronic liver disease, they did not contribute to hemostasis regulation. Overall, PN-1 should be added to the list of hemostasis factors that are dysregulated in cirrhosis. Impact and implications: The role of PN-1, a serpin that regulates both coagulation and fibrinolysis, is unknown in cirrhosis. PN-1 appears as an important regulator of fibrinolysis in patients with cirrhosis. The role of PN-1 (and platelets more broadly) should be taken into account when assessing fibrinolysis in patients with cirrhosis.