Altered structure and function of fibrinogen after cleavage by Factor VII Activating Protease (FSAP)

Biochim Biophys Acta Mol Basis Dis. 2018 Oct;1864(10):3397-3406. doi: 10.1016/j.bbadis.2018.07.030. Epub 2018 Aug 1.

Abstract

Factor VII Activating Protease (FSAP) is a plasma protease affecting both coagulation and fibrinolysis. Although a role in hemostasis is still unclear, the identification of additional physiologic substrates will help to elucidate its role in this context. FSAP has been reported to cleave fibrinogen, but the functional consequences of this are not known. We have therefore undertaken this study to determine the implications of this cleavage for fibrin-clot formation and its lysis. Treatment of human fibrinogen with FSAP released an N-terminal peptide from the Bβ chain (Bβ1-53) and subsequently the fibrinopeptide B; within the Aα chain a partial truncation of the αC-region by multiple cleavages was seen. The truncated fibrinogen showed a delayed thrombin-catalyzed polymerization and formed fibrin clots of reduced turbidity, indicative of thinner fibrin fibers. Confocal laser scanning and scanning electron microscopy of these clots revealed a less coarse fibrin network with thinner fibers and a smaller pore size. A lower pore size was also seen in permeability studies. Unexpectedly, FSAP-treated fibrinogen or plasma exhibited a significantly faster tPA-driven lysis, which correlated exclusively with cleavage of fibrinogen and not with activation of plasminogen activators. Similar observations were also made in plasma after activation of endogenous zymogen FSAP, but not in plasma of carrier of the rare Marburg I single nucleotide polymorphism. In conclusion, altering fibrin clot properties by fibrinogenolysis is a novel function of FSAP in the vasculature, which facilitates clot lysis and may in vivo contribute to reduced fibrin deposition during thrombosis.

Keywords: Clot lysis; FSAP; Fibrin polymerization; Fibrinogen; Fibrinolysis; HABP2; Marburg I polymorphism; Thrombosis.

MeSH terms

  • Blood Coagulation
  • Fibrinogen / chemistry*
  • Fibrinogen / metabolism*
  • Fibrinolysis
  • Fibrinopeptide B / metabolism
  • Humans
  • Microscopy, Confocal
  • Microscopy, Electron, Scanning
  • Serine Endopeptidases / metabolism*

Substances

  • Fibrinopeptide B
  • Fibrinogen
  • HABP2 protein, human
  • Serine Endopeptidases