Antithrombotic efficacy of recombinant tick anticoagulant peptide. A potent inhibitor of coagulation factor Xa in a primate model of arterial thrombosis.
BACKGROUND
Tick anticoagulant peptide is a specific, potent inhibitor of blood coagulation factor Xa. The effects of recombinant tick anticoagulant peptide (rTAP) and standard heparin (SH) were compared in an anesthetized baboon model of arterial thrombosis where platelet deposition onto a Dacron vascular graft segment of an arteriovenous (AV) shunt was studied.


RESULTS
Animals were randomized to receive systemic administration of SH (10 or 100 U/kg i.v. bolus followed by 0.4 or 1.0 U/kg/min i.v. infusion, respectively) or rTAP (6.25, 12.5, or 25.0 micrograms/kg/min i.v. infusion). rTAP, but not SH, caused a significant (p less than 0.05), dose-dependent reduction of indium-111 labeled platelet and iodine-125 labeled fibrin (ogen) deposition onto the graft. Deposition was not significantly increased from baseline values during infusion of 12.5 or 25.0 micrograms/kg/min of rTAP. Blood flow was maintained at 64 +/- 9, 95 +/- 2, or 97 +/- 2% of baseline following infusion of 6.25, 12.5, or 25.0 micrograms/kg/min of rTAP, respectively. Both SH and rTAP significantly (p less than 0.05) decreased the systemic fibrinopeptide A (FPA) elevation during exposure to the Dacron graft. rTAP was fully antithrombotic at APTT values of 42.6 +/- 2.4 seconds (less than twofold basal value), while SH had no antithrombotic efficacy despite APTT values greater than 150 seconds (greater than fivefold basal value).


CONCLUSIONS
The demonstrated antithrombotic effect of rTAP in the absence of alterations in primary hemostasis suggests that controlling thrombin generation through inhibition of factor Xa may be a novel and effective pharmacological approach in the prevention of high-shear arterial thrombosis.
Schaffer
L W
LW
Department of Pharmacology, Merck Sharp and Dohme Research Laboratories, West Point, PA 19486.
Davidson
J T
JT
Vlasuk
G P
GP
Siegl
P K
PK
D000818:Animals; D060829:Arthropod Proteins; D001807:Blood Vessel Prosthesis; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006083:Graft Occlusion, Vascular / Q000188:drug therapy; D006493:Heparin / Q000627:therapeutic use; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D010215:Papio; D010455:Peptides / Q000627:therapeutic use*; D010973:Platelet Adhesiveness / Q000187:drug effects; D011093:Polyethylene Terephthalates; D011994:Recombinant Proteins / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy*; D013987:Ticks
D060829:Arthropod Proteins; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D011093:Polyethylene Terephthalates; D011994:Recombinant Proteins; C063967:tick anticoagulant peptide; D006493:Heparin