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

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

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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 2018
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by research funding from the National Institutes of Health (R01HL126974 to A. S. Wolberg and T32HL007149 to the University of North Carolina and J. D. Beckman) and a 2016 Mentored Research Award from the Hemostasis and Thrombosis Research Society by CSL Behring to J. D. Beckman.

Funding Information:
This study was supported by research funding from the National Institutes of Health (R01HL126974 to A. S. Wolberg and T32HL007149 to the University of North Carolina and J. D. Beckman) and a 2016 Mentored Research Award from the Hemostasis and Thrombosis Research Society by CSL Behring to J. D. Beckman. The authors thank J. R. Byrnes, S. Kattula, J. Mickelson and D. M. Monroe for helpful discussions, and A. Ma, N. S. Key and the staff of the University of North Carolina Hemophilia Treatment Center for their assistance in obtaining patient samples.

Publisher Copyright:
© 2017 International Society on Thrombosis and Haemostasis

Keywords

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

Fingerprint

Dive into the research topics of 'Factor XIII cotreatment with hemostatic agents in hemophilia A increases fibrin α-chain crosslinking'. Together they form a unique fingerprint.

Cite this