Selective inhibition by a synthetic hirudin peptide of fibrin-dependent thrombosis in baboons

Journal Article · Fri Feb 15 04:00:00 EST 1991 · Proceedings of the National Academy of Sciences of the United States of America; (United States)

DOI:https://doi.org/10.1073/pnas.88.4.1177· OSTI ID:6045649

Cadroy, Y; Hanson, S R; Harker, L A ^[1]; Maraganore, J M ^[2]

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1. Emory Univ., Atlanta, GA (United States)
2. Biogen Inc., Cambridge, MA (United States)

To determine the importance of the thrombin substrate recognition exosite for fibrinogen binding in the formation of both arterial and venous thrombi the authors 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 {sup 111}In-labeled platelet and {sup 125}I-labeled fibrinogen deposition in both arterial-flow and venous-flow portions of the device. These finding 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.

• OSTI ID: 6045649
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (United States), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (United States) Vol. 88:4; ISSN 0027-8424; ISSN PNASA
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMALS
BABOONS
BIOCHEMISTRY
BLOOD COAGULATION
BLOOD COAGULATION FACTORS
BLOOD FLOW
CARDIOVASCULAR DISEASES
CHEMISTRY
COAGULANTS
DISEASES
DRUGS
ENZYMES
FIBRINOGEN
GLOBULINS
HEMATOLOGIC AGENTS
HEMOSTATICS
HYDROLASES
INHIBITION
MAMMALS
MONKEYS
ORGANIC COMPOUNDS
PEPTIDE HYDROLASES
PEPTIDES
PRIMATES
PROTEINS
RADIOASSAY
SERINE PROTEINASES
THROMBIN
THROMBOSIS
VASCULAR DISEASES
VERTEBRATES