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

Abstract

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.

Natural anticoagulants: A missing link in mild to moderate bleeding tendencies

“…Along the same lines, paradoxically increased levels of TAFI were found in the analyses of fibrinolysis parameters in patients with menorrhagia, hereditary mucocutaneous bleeding, and BUC 27 . Increased TAFI‐levels have also been associated with a more severe bleeding phenotype in haemophilia patients 28 . To what extend increased levels of TM underlie increased TAFI levels found in independent bleeding cohorts needs to be elucidated in further studies.…”

Evaluation of Thrombin and Plasmin Generation Velocity Ratios during Progressive Plasma Dilution

“…In severe hemophilia A patients, impaired TAFI generation is associated with a several-fold higher bleeding rate compared to patients with near-normal TAFI generation. 10 Our data show that in normal plasma, V PG exceeds V TG at 1:2 dilution, but elevated FVIII sustains higher VR. Conversely, in FVIII-deficient plasma, V PG remained about 2-fold greater than V TG pre-and postdilution.…”

Elucidating the molecular mechanisms of fibrinolytic shutdown after severe injury: The role of thrombin-activatable fibrinolysis inhibitor

“…The majority (70%) were male, and the average age was 33.5 years (interquartile range [IQR], 25.7-48.3 years). Fifty-seven percent (32) presented after blunt mechanism injury, and the cohort was severely injured, with a median New Injury Severity Score of 27 (IQR, [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]. While the median SBP was 126 mm Hg (IQR, 99-140), Data are presented as n (%) or median (IQR) as relevant.…”

“…13 Both large and small animal models with thrombosis and thrombolytic therapy demonstrate that TAFI levels correlate with response to lytic therapy and TAFI inhibition results in enhanced tPA-mediated fibrinolysis. [14][15][16][17] An extensive body of literature on hemophilia and other factor deficiencies has highlighted the integral role of TAFI in fibrinolysis cessation and an antifibrinolytic phenotype; for example, in hemophilia A patients, TAFI levels are inversely related to bleeding and factor consumption, 18 and TAFI is known to be protective against bleeding events in congenital hemophilia A, factor VIII knockout mice. 19 Furthermore, inhibition of factor XI also results in increase in endogenously provoked fibrinolysis, suggesting that intrinsic pathway inhibition results in lack of thrombin-activated TAFI activity.…”