Thrombin activatable fibrinolysis inhibitor pathway alterations correlate with bleeding phenotype in patients with severe hemophilia A

Background: Patients with severe hemophilia A display varied bleeding phenotypes despite similar factor VIII (FVIII) activity levels. Objective: We investigated different thrombin activatable fibrinolysis inhibitor (TAFI)‐related variables in patients with severe hemophilia A and their possible correlation with bleeding tendency. Patients/Methods: Sixty‐one patients with severe hemophilia A (FVIII:C <1%], treated on demand, were included. Patients were categorized as mild, moderate, and severe bleeders according to number of bleeds per year (≤2, 3‐24, ≥25, respectively). Thirty healthy males served as controls. Clot lysis time was assessed by turbidimetric assay, TAFI activation by two‐stage functional assay, and response to TAFIa as the prolongation of fibrinolysis time upon addition of purified TAFIa. Circulating levels of activated TAFI (TAFIa/ai) were measured by specific enzyme‐linked immunosorbent assay. Results: As compared to controls, hemophilic patients displayed shorter lysis time, less TAFIa generation, and reduced response to TAFIa, but similar TAFIa/ai levels. Clot lysis time was similar in mild, moderate, and severe bleeders, whereas TAFIa generation and response to TAFIa decreased with the increase in bleeding tendency; moreover, circulating TAFIa/ai levels were highest in severe bleeders. Patients with markedly impaired TAFIa generation or TAFIa response (below median) displayed 3‐ fold to 4‐fold higher bleeding rate and factor consumption than patients whose TAFIrelated values approached the control ones. Conclusion: The TAFI pathway impairment correlates with bleeding phenotype in severe hemophilia and may represent a promising tool to stratify the bleeding risk