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Fibrinogen γ′ chain carboxy terminal peptide selectively inhibits the intrinsic coagulation pathway
Author(s) -
Lovely Rehana S.,
Boshkov Lynn K.,
Marzec Ulla M.,
Hanson Stephen R.,
Farrell David H.
Publication year - 2007
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2007.06825.x
Subject(s) - fibrinogen , thrombin , peptide , chemistry , fibrin , partial thromboplastin time , coagulation , biochemistry , thromboplastin , thrombin time , microbiology and biotechnology , platelet , biology , immunology , medicine
Summary 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.