Incorporation of fibrin molecules containing fibrinopeptide A alters clot ultrastructure and decreases permeability

Veronica H. Flood, Chandrasekaran Nagaswami, Irina N. Chernysh, Hamid A. Al-Mondhiry, John W. Weisel, David H. Farrell

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Previous studies have shown that a heterozygous mutation in the fibrinogen Aα chain gene, which results in an Aα R16C substitution, causes fibrinolytic resistance in the fibrin clot. This mutation prevents thrombin cleavage of fibrinopeptide A from mutant Aα R16C chains, but not from wild-type Aα chains. However, the mechanism underlying the fibrinolytic resistance is unclear. Therefore, this study investigated the biophysical properties of the mutant fibrin that contribute to fibrinolytic resistance. Fibrin clots made from the mutant fibrinogen incorporated molecules containing fibrinopeptide A into the polymerised clot, which resulted in a 'spiky' clot ultrastructure with barbed fibrin strands. The clots were less stiff than normal fibrin and were cross-linked slower by activated FXIII, but had an increased average fiber diameter, were more dense, had smaller pores and were less permeable. Protein sequencing showed that unclottable fibrinogen remaining in the supernatant consisted entirely of homodimeric Aα R16C fibrinogen, whereas both cleaved wild-type α chains and uncleaved Aα R16C chains were in the fibrin clot. Therefore, fibrinolytic resistance of the mutant clots is probably a result of altered clot ultrastructure caused by the incorporation of fibrin molecules containing fibrinopeptide A, resulting in larger diameter fibers and decreased permeability to fibrinolytic enzymes.

Original languageEnglish (US)
Pages (from-to)117-124
Number of pages8
JournalBritish Journal of Haematology
Volume138
Issue number1
DOIs
StatePublished - Jul 1 2007

Keywords

  • Biochemistry
  • Coagulation factors
  • Fibrinolysis
  • Genetics of thrombosis and haemostasis
  • Thrombin

ASJC Scopus subject areas

  • Hematology

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