Fibrinogen gamma' chain carboxy terminal peptide selectively inhibits the intrinsic coagulation pathway.
The minor gammaA/gamma' isoform of fibrinogen contains a high affinity binding site for thrombin exosite II that is lacking in the major fibrinogen isoform, gammaA/gammaA fibrinogen. The biological consequences of gamma' 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 gamma' 410-427 peptide. The gamma' 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 gamma' peptide inhibited thrombin cleavage of larger proteinaceous substrates, including fibrinogen and factor VIII. The gamma' 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 gamma' 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 gamma' peptide has selective effects on the intrinsic pathway.
Lovely
Rehana S
RS
Department of Pathology, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
Boshkov
Lynn K
LK
Marzec
Ulla M
UM
Hanson
Stephen R
SR
Farrell
David H
DH
D000818:Animals; D000925:Anticoagulants / Q000378:metabolism / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D010215:Papio; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D011517:Prothrombin Time; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000517:prevention & control
D000925:Anticoagulants; D010446:Peptide Fragments; C027539:fibrinopeptides gamma; D005169:Factor VIII; D005340:Fibrinogen; D013917:Thrombin