Active site-blocked factor IXa prevents intravascular thrombus formation in the coronary vasculature without inhibiting extravascular coagulation in a canine thrombosis model

C. R. Benedict, J. Ryan, B. Wolitzky, R. Ramos, M. Gerlach, P. Tijburg, David Stern

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Abstract

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 glutamylglyl-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 (> 180 min) at doses of 460 and 300 μg/kg, and partially blocked thrombus formation at 150 μg/kg. IXai attenuated the accumulation of 125I-fibrinogen/ fibrin at the site of the thrombus by ~ 67% (P < 0.001) and resulted in ~ 26% decrease in serotonin release from platelets in coronary sinus (P < 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.

Original languageEnglish (US)
Pages (from-to)1760-1765
Number of pages6
JournalJournal of Clinical Investigation
Volume88
Issue number5
DOIs
StatePublished - Jan 1 1991

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Factor IXa
Canidae
Catalytic Domain
Thrombosis
Factor IX
Heparin
Hemostasis
Fibrin
Blood Platelets
Coronary Thrombosis
Factor X
Intrinsic Factor
Coronary Sinus
Coronary Occlusion
Hemostatics
Fibrinogen
Needles
Serotonin
Coronary Vessels

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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Active site-blocked factor IXa prevents intravascular thrombus formation in the coronary vasculature without inhibiting extravascular coagulation in a canine thrombosis model. / Benedict, C. R.; Ryan, J.; Wolitzky, B.; Ramos, R.; Gerlach, M.; Tijburg, P.; Stern, David.

In: Journal of Clinical Investigation, Vol. 88, No. 5, 01.01.1991, p. 1760-1765.

Research output: Contribution to journalArticle

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