Factor XIII cotreatment with hemostatic agents in hemophilia A increases fibrin α-chain crosslinking

Joan D Beckman, L. A. Holle, A. S. Wolberg

Research output: Contribution to journalArticle

2 Citations (Scopus)

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: Background 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. Methods 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. Results 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. Conclusion 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.

Original languageEnglish (US)
Pages (from-to)131-141
Number of pages11
JournalJournal of Thrombosis and Haemostasis
Volume16
Issue number1
DOIs
StatePublished - Jan 1 2018

Fingerprint

Factor XIII
Hemophilia A
Hemostatics
Fibrin
Antifibrinolytic Agents
Thrombin
Weights and Measures
Swine
Factor XIIIa
Hemorrhage
Thrombelastography

Keywords

  • factor XIII
  • fibrin
  • hemophilia
  • hemostasis
  • α-antiplasmin

PubMed: MeSH publication types

  • Comparative Study
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Factor XIII cotreatment with hemostatic agents in hemophilia A increases fibrin α-chain crosslinking. / Beckman, Joan D; Holle, L. A.; Wolberg, A. S.

In: Journal of Thrombosis and Haemostasis, Vol. 16, No. 1, 01.01.2018, p. 131-141.

Research output: Contribution to journalArticle

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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: Background 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. Methods 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. Results 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. Conclusion 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.",
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AU - Wolberg, A. S.

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N2 - 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: Background 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. Methods 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. Results 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. Conclusion 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.

AB - 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: Background 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. Methods 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. Results 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. Conclusion 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.

KW - factor XIII

KW - fibrin

KW - hemophilia

KW - hemostasis

KW - α-antiplasmin

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