Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ' as thrombomobulin II

Matrix Biol. 2017 Jul;60-61:8-15. doi: 10.1016/j.matbio.2016.09.010. Epub 2016 Oct 23.


Fibrin is an important matrix protein that provides the backbone to the blood clot, promoting tissue repair and wound healing. Its precursor fibrinogen is one of the most heterogeneous proteins, with an estimated 1 million different forms due to alterations in glycosylation, oxidation, single nucleotide polymorphisms, splice variation and other variations. Furthermore, ligation by transglutaminase factor XIII (cross-linking) adds to the complexity of the fibrin network. The structure and function of the fibrin network is in part determined by this natural variation in the fibrinogen molecule, with major effects from splice variation and cross-linking. This mini-review will discuss the direct effects of fibrinogen αEC and fibrinogen γ' splice variation on clot structure and function and also discuss the additional role of fibrinogen γ' as thrombomodulin II. Furthermore, the effects of cross-linking on clot function will be described. Splice variation and cross-linking are major determinants of the structure and function of fibrin and may therefore impact on diseases affecting bleeding, thrombosis and tissue repair.

Keywords: Cross-linking; Fibrin clot; Fibrinogen; Splice-variant.

Publication types

  • Review

MeSH terms

  • Alternative Splicing
  • Blood Coagulation / physiology
  • Cross-Linking Reagents
  • Factor XIII / chemistry
  • Factor XIII / genetics
  • Factor XIII / metabolism*
  • Fibrin / chemistry
  • Fibrin / genetics
  • Fibrin / metabolism*
  • Fibrinogens, Abnormal / chemistry
  • Fibrinogens, Abnormal / genetics
  • Fibrinogens, Abnormal / metabolism*
  • Gene Expression
  • Glycosylation
  • Humans
  • Polymorphism, Genetic
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Processing, Post-Translational*
  • Thrombomodulin / chemistry
  • Thrombomodulin / genetics
  • Thrombomodulin / metabolism*
  • Wound Healing / physiology


  • Cross-Linking Reagents
  • Fibrinogens, Abnormal
  • Protein Isoforms
  • THBD protein, human
  • Thrombomodulin
  • fibrinogen gamma'
  • Fibrin
  • Factor XIII