Fibrinogen γ′ chain carboxy terminal peptide selectively inhibits the intrinsic coagulation pathway

Rehana S. Lovely, Lynn Boshkov, Ulla M. Marzec, Stephen R. Hanson, David Farrell

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

The minor γA/γ′ isoform of fibrinogen contains a high affinity binding site for thrombin exosite II that is lacking in the major fibrinogen isoform, γA/γA fibrinogen. The biological consequences of γ′ chain binding to thrombin were therefore investigated. Coagulation assays, thrombin activity assays, and a primate thrombosis model were used to characterize the biological effects of the γ′ 410-427 peptide. The γ′ peptide had little effect on thrombin cleavage of the small peptidyl substrate tosyl-glycyl-prolyl-arginine-4-nitranilide acetate. However, in vitro assays demonstrated that the γ′ peptide inhibited thrombin cleavage of larger proteinaceous substrates, including fibrinogen and factor VIII. The γ′ peptide inhibited the activated partial thromboplastin time in plasma and showed greater inhibition of activated partial thromboplastin time assays than prothrombin time assays, consistent with the inhibition of factor VIII cleavage. Studies in a baboon thrombosis model showed that the γ′ 410-427 peptide inhibited fibrin-rich thrombus formation (typical of venous thrombi) and, to a lesser extent, platelet-rich thrombus formation (typical of arterial thrombi). These results indicate that binding of thrombin exosite II by the γ′ peptide has selective effects on the intrinsic pathway.

Original languageEnglish (US)
Pages (from-to)494-503
Number of pages10
JournalBritish Journal of Haematology
Volume139
Issue number3
DOIs
StatePublished - Nov 2007

Fingerprint

Thrombin
Fibrinogen
Thrombosis
Peptides
Partial Thromboplastin Time
Factor VIII
glycyl-prolyl-arginine
Protein Isoforms
Papio
Prothrombin Time
Fibrin
Primates
Acetates
Blood Platelets
Binding Sites

Keywords

  • Animal model
  • Anticoagulants
  • Blood coagulation
  • Factor VIII
  • Thrombin
  • Thrombosis

ASJC Scopus subject areas

  • Hematology

Cite this

Fibrinogen γ′ chain carboxy terminal peptide selectively inhibits the intrinsic coagulation pathway. / Lovely, Rehana S.; Boshkov, Lynn; Marzec, Ulla M.; Hanson, Stephen R.; Farrell, David.

In: British Journal of Haematology, Vol. 139, No. 3, 11.2007, p. 494-503.

Research output: Contribution to journalArticle

Lovely, Rehana S. ; Boshkov, Lynn ; Marzec, Ulla M. ; Hanson, Stephen R. ; Farrell, David. / Fibrinogen γ′ chain carboxy terminal peptide selectively inhibits the intrinsic coagulation pathway. In: British Journal of Haematology. 2007 ; Vol. 139, No. 3. pp. 494-503.
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