Active site-blocked factor IXa prevents intravascular thrombus formation in the coronary vasculature without inhibiting extravascular coagulation in a canine thrombosis model.
To assess the contribution of Factor IX/IXa, to intravascular thrombosis, a canine coronary thrombosis model was studied. Thrombus formation was initiated by applying current to a needle in the circumflex coronary artery. When 50% occlusion of the vessel developed, the current was stopped and animals received an intravenous bolus of either saline, bovine glutamyl-glycyl-arginyl-Factor IXa (IXai), a competitive inhibitor of Factor IXa assembly into the intrinsic Factor X activation complex, bovine Factor IX, or heparin. Animals receiving saline or Factor IX developed coronary occlusion due to a fibrin/platelet thrombus in 70 +/- 11 min. In contrast, infusion of IXai prevented thrombus formation completely (greater than 180 min) at doses of 460 and 300 micrograms/kg, and partially blocked thrombus formation at 150 micrograms/kg. IXai attenuated the accumulation of 125I-fibrinogen/fibrin at the site of the thrombus by approximately 67% (P less than 0.001) and resulted in approximately 26% decrease in serotonin release from platelets in coronary sinus (P less than 0.05). Hemostatic variables in animals receiving IXai, remained within normal limits. Animals given heparin in a concentration sufficient to prevent occlusive thrombosis had markedly increased bleeding, whereas heparin levels that maintained extravascular hemostasis did not prevent intracoronary thrombosis. This suggests that Factor IX/IXa can contribute to thrombus formation, and that inhibition of IXa participation in the clotting mechanism blocks intravascular thrombosis without impairing extravascular hemostasis.
Benedict
C R
CR
Department of Internal Medicine, University of Texas Medical School, Houston 77225.
Ryan
J
J
Wolitzky
B
B
Ramos
R
R
Gerlach
M
M
Tijburg
P
P
Stern
D
D
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D003328:Coronary Thrombosis / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004285:Dogs; D015949:Factor IXa / Q000494:pharmacology*; D005340:Fibrinogen / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology
D005340:Fibrinogen; D006493:Heparin; D015949:Factor IXa