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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:863.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Inferior Vena Cava Ligation Rapidly Induces Tissue Factor Expression and Venous Thrombosis in Rats

Ji Zhou; Linda May; Peng Liao; Peter L. Gross; Jeffrey I. Weitz

From the Departments of Medicine (J.Z., L.M., P.L., P.L.G., J.I.W.) and Biochemistry and Medical Sciences (J.I.W.), McMaster University, and Henderson Research Centre (J.Z., L.M., P.L., P.L.G., J.I.W.), Hamilton, Ontario, Canada.

Correspondence to Dr Ji Zhou, Henderson Research Centre, 711 Concession Street, Hamilton, Ontario, L8V 1C3, Canada. E-mail jzhou{at}thrombosis.hhscr.org

Objective— Although stasis is important in the pathogenesis of deep vein thrombosis (DVT), how it contributes to thrombogenesis is largely unknown. To gain mechanistic insight, we used a rat model of inferior vena cava (IVC) ligation.

Methods and Results— Rats were subjected to IVC ligation for 15 to 60 minutes. Ligation resulted in rapid IVC dilatation and by 60 minutes, thrombi were detected in all rats. Small thrombi were detected in the IVC of most rats after 15 minutes of ligation. Thrombi were rich in fibrin, contained aggregated platelets as well as trapped leukocytes and red cells, and most originated at sites of localized endothelial denudation. Immunohistochemical analysis revealed tissue factor (TF)-expressing leukocytes within the thrombi and adherent to the vessel wall. Despite a largely intact vessel wall, endothelial cells also stained for TF. The expression of TF colocalized with that of protein disulfide isomerase (PDI), an enzyme implicated in TF decryption.

Conclusions— These findings suggest that the rapid development of DVT after IVC ligation reflects a combination of stasis-induced vein wall injury and enhanced TF expression in endothelial cells and leukocytes. Because TF expression occurs so soon after ligation, new synthesis is unlikely. Instead, stasis-induced venous dilatation with or without exposure of subendothelial TF, may be responsible for vessel wall TF expression. Colocalization of TF and PDI raises the possibility that PDI-mediated TF decryption plays a role in the pathogenesis of DVT.

Vena cava ligation in rats results in rapid formation of venous thrombi. Most thrombi develop at sites of endothelial denudation. Tissue factor expression by endothelial cells and leukocytes may also trigger thrombosis. Tissue factor colocalizes with protein disulfide isomerase, suggesting that tissue factor decryption may play a role in venous thrombosis.

Key Words: deep vein thrombosis • inferior vena cava ligation • tissue factor • P-selectin • protein disulfide isomerase