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 TAFI-related 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.