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• W2765780350 endingPage "141" @default.
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• W2765780350 abstract "Essentials•Factor XIII (FXIII)‐mediated fibrin crosslinking is delayed in hemophilia.•We determined effects of FXIII cotreatment with hemostatic agents on clot parameters.•FXIII cotreatment accelerated FXIII activation and crosslinking of fibrin and α2‐antiplasmin.•These data provide biochemical rationale for FXIII cotreatment in hemophilia.Summary: BackgroundHemophilia A results from the absence, deficiency or inhibition of factor VIII. Bleeding is treated with hemostatic agents (FVIII, recombinant activated FVII [rFVIIa], anti‐inhibitor coagulation complex [FEIBA], or recombinant porcine FVIII [rpFVIII]). Despite treatment, some patients have prolonged bleeding. FXIII‐A2B2 (FXIII) is a protransglutaminase. During clot contraction, thrombin‐activated FXIII (FXIIIa) crosslinks fibrin and α2‐antiplasmin, which promotes red blood cell retention and increases clot stability and weight. We hypothesized that FXIII cotreatment in hemophilia would accelerate FXIII activation, leading to increased fibrin crosslinking.MethodsFVIII‐deficient plasma and whole blood were clotted with or without hemostatic agents (FVIII, rFVIIa, FEIBA, or recombinant B‐domain‐deleted porcine FVIII [rpFVIII]) and/or FXIII. The effects on FXIII activation, thrombin generation, fibrin and α2‐antiplasmin crosslinking, clot formation and clot weight were measured by western blotting, calibrated automated thrombography, thromboelastography, and clot contraction assays.ResultsAs compared with FVIII‐treated hemophilic plasma, FVIII + FXIII cotreatment accelerated FXIIIa formation without increasing thrombin generation. As compared with buffer‐treated or FXIII‐treated hemophilic plasma, FVIII treatment and FVIII + FXIII cotreatment increased the generation and amount of crosslinked fibrin, including α‐chain‐rich high molecular weight species and crosslinked α2‐antiplasmin. In the presence of FVIII inhibitors, as compared with hemostatic treatments (rFVIIa, FEIBA, or rpFVIII) alone, FXIII cotreatment increased whole blood clot weight.ConclusionIn hemophilia A plasma and whole blood, FXIII cotreatment with hemostatic agents accelerated FXIIIa formation, increased the generation and amount of fibrin α‐chain crosslinked species, accelerated α2‐antiplasmin crosslinking, and increased clot weight. FXIII cotreatment with hemostatic therapy may augment hemostasis through increased crosslinking of fibrin and α2‐antiplasmin. Essentials•Factor XIII (FXIII)‐mediated fibrin crosslinking is delayed in hemophilia.•We determined effects of FXIII cotreatment with hemostatic agents on clot parameters.•FXIII cotreatment accelerated FXIII activation and crosslinking of fibrin and α2‐antiplasmin.•These data provide biochemical rationale for FXIII cotreatment in hemophilia. •Factor XIII (FXIII)‐mediated fibrin crosslinking is delayed in hemophilia.•We determined effects of FXIII cotreatment with hemostatic agents on clot parameters.•FXIII cotreatment accelerated FXIII activation and crosslinking of fibrin and α2‐antiplasmin.•These data provide biochemical rationale for FXIII cotreatment in hemophilia. Hemophilia A results from the absence, deficiency or inhibition of factor VIII. Bleeding is treated with hemostatic agents (FVIII, recombinant activated FVII [rFVIIa], anti‐inhibitor coagulation complex [FEIBA], or recombinant porcine FVIII [rpFVIII]). Despite treatment, some patients have prolonged bleeding. FXIII‐A2B2 (FXIII) is a protransglutaminase. During clot contraction, thrombin‐activated FXIII (FXIIIa) crosslinks fibrin and α2‐antiplasmin, which promotes red blood cell retention and increases clot stability and weight. We hypothesized that FXIII cotreatment in hemophilia would accelerate FXIII activation, leading to increased fibrin crosslinking. FVIII‐deficient plasma and whole blood were clotted with or without hemostatic agents (FVIII, rFVIIa, FEIBA, or recombinant B‐domain‐deleted porcine FVIII [rpFVIII]) and/or FXIII. The effects on FXIII activation, thrombin generation, fibrin and α2‐antiplasmin crosslinking, clot formation and clot weight were measured by western blotting, calibrated automated thrombography, thromboelastography, and clot contraction assays. As compared with FVIII‐treated hemophilic plasma, FVIII + FXIII cotreatment accelerated FXIIIa formation without increasing thrombin generation. As compared with buffer‐treated or FXIII‐treated hemophilic plasma, FVIII treatment and FVIII + FXIII cotreatment increased the generation and amount of crosslinked fibrin, including α‐chain‐rich high molecular weight species and crosslinked α2‐antiplasmin. In the presence of FVIII inhibitors, as compared with hemostatic treatments (rFVIIa, FEIBA, or rpFVIII) alone, FXIII cotreatment increased whole blood clot weight. In hemophilia A plasma and whole blood, FXIII cotreatment with hemostatic agents accelerated FXIIIa formation, increased the generation and amount of fibrin α‐chain crosslinked species, accelerated α2‐antiplasmin crosslinking, and increased clot weight. FXIII cotreatment with hemostatic therapy may augment hemostasis through increased crosslinking of fibrin and α2‐antiplasmin." @default.
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• W2765780350 date "2018-01-01" @default.
• W2765780350 modified "2023-10-05" @default.
• W2765780350 title "Factor XIII cotreatment with hemostatic agents in hemophilia A increases fibrin α‐chain crosslinking" @default.
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• W2765780350 doi "https://doi.org/10.1111/jth.13887" @default.
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