Selective inhibition by a synthetic hirudin peptide of fibrin-dependent thrombosis in baboons.
To determine the importance of the thrombin substrate recognition exosite for fibrinogen binding in the formation of both arterial and venous thrombi, we evaluated the antithrombotic effects of the tyrosine-sulfated dodecapeptide from residues 53-64 of hirudin (H peptide) in a nonhuman primate model. This peptide was studied because it inhibits thrombin cleavages of fibrinogen by simple competition without blocking enzyme catalytic-site function. When an exteriorized arteriovenous access shunt model was used in baboons (Papio anubis), thrombus formation was induced by placing a thrombogenic device made of (i) a segment of tubing coated covalently with type I collagen, which generated platelet-rich thrombi under arterial flow conditions, and (ii) two subsequent annular regions of flow expansion that produced fibrin-rich thrombi typically associated with venous valves and veins. Thrombus formation was quantified by measurements of 111In-labeled platelet and 125I-labeled fibrinogen deposition in both arterial-flow and venous-flow portions of the device. Continuous infusion of H peptide (0.5, 15, and 75 mg/kg) proximal to the device for 40 min interrupted, in a dose-response fashion, formation of fibrin-rich thrombus in the regions of disturbed flow and generation of fibrinopeptide A. In contrast, H peptide did not inhibit the capacity of platelets to deposit on the collagen surface (P greater than 0.2 at all doses) or to form hemostatic plugs (as assessed by measurements of bleeding time; P greater than 0.1 at all doses). These findings suggest that, by competitive inhibition of fibrinogen binding to thrombin, fibrin-rich venous-type thrombus formation may be selectively prevented. This strategy may be therapeutically attractive for preserving normal platelet function when conventional anticoagulant therapy is contraindicated.
Cadroy
Y
Y
Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322.
Maraganore
J M
JM
Hanson
S R
SR
Harker
L A
LA
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D005337:Fibrin / Q000502:physiology*; D006487:Hemostasis / Q000187:drug effects; D006629:Hirudins / Q000138:chemical synthesis / Q000494:pharmacology*; D007700:Kinetics; D010215:Papio; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D013927:Thrombosis / Q000517:prevention & control*; D013997:Time Factors
D006629:Hirudins; D010455:Peptides; D005337:Fibrin