Differential Roles for the Coagulation Factors XI and XII in Regulating the Physical Biology of Fibrin

Joanna L. Sylman, Uranbileg Daalkhaijav, Ying Zhang, Elliot M. Gray, Parsa A. Farhang, Tiffany T. Chu, Jevgenia Zilberman-Rudenko, Cristina Puy, Erik I. Tucker, Stephanie A. Smith, James H. Morrissey, Travis W. Walker, Xiaolin L. Nan, András Gruber, Owen J.T. McCarty

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

In the contact activation pathway of the coagulation, zymogen factor XII (FXII) is converted to FXIIa, which triggers activation of FXI leading to the activation of FIX and subsequent thrombin generation and fibrin formation. Feedback activation of FXI by thrombin has been shown to promote thrombin generation in a FXII-independent manner and FXIIa can bypass FXI to directly activate FX and prothrombin in the presence of highly negatively charged molecules, such as long-chain polyphosphates (LC polyP). We sought to determine whether activation of FXII or FXI differentially regulate the physical biology of fibrin formation. Fibrin formation was initiated with tissue factor, ellagic acid (EA), or LC polyP in the presence of inhibitors of FXI and FXII. Our data demonstrated that inhibition of FXI decreased the rate of fibrin formation and fiber network density, and increased the fibrin network strength and rate of fibrinolysis when gelation was initiated via the contact activation pathway with EA. FXII inhibition decreased the fibrin formation and fibrin density, and increased the fibrinolysis rate only when fibrin formation was initiated via the contact activation pathway with LC polyP. Overall, we demonstrate that inhibition of FXI and FXII distinctly alter the biophysical properties of fibrin.

Original languageEnglish (US)
Pages (from-to)1328-1340
Number of pages13
JournalAnnals of Biomedical Engineering
Volume45
Issue number5
DOIs
StatePublished - May 1 2017

Keywords

  • Coagulation
  • FXI-deficiency
  • FXII-deficiency
  • Fibrin
  • Stability
  • Structure

ASJC Scopus subject areas

  • Biomedical Engineering

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    Sylman, J. L., Daalkhaijav, U., Zhang, Y., Gray, E. M., Farhang, P. A., Chu, T. T., Zilberman-Rudenko, J., Puy, C., Tucker, E. I., Smith, S. A., Morrissey, J. H., Walker, T. W., Nan, X. L., Gruber, A., & McCarty, O. J. T. (2017). Differential Roles for the Coagulation Factors XI and XII in Regulating the Physical Biology of Fibrin. Annals of Biomedical Engineering, 45(5), 1328-1340. https://doi.org/10.1007/s10439-016-1771-7