Heparin cofactor II inhibits arterial thrombosis after endothelial injury
Li He, … , Daniel T. Eitzman, Douglas M. Tollefsen
Li He, … , Daniel T. Eitzman, Douglas M. Tollefsen
Published January 15, 2002
Citation Information: J Clin Invest. 2002;109(2):213-219. https://doi.org/10.1172/JCI13432.
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Article

Heparin cofactor II inhibits arterial thrombosis after endothelial injury

Abstract

Heparin cofactor II (HCII) is a plasma protein that inhibits thrombin rapidly in the presence of dermatan sulfate, heparan sulfate, or heparin. HCII has been proposed to regulate coagulation or to participate in processes such as inflammation, atherosclerosis, and wound repair. To investigate the physiologic function of HCII, about 2 kb of the mouse HCII gene, encoding the N-terminal half of the protein, was deleted by homologous recombination in embryonic stem cells. Crosses of F1HCII+/– animals produced HCII–/– offspring at the expected mendelian frequency. Biochemical assays confirmed the absence of dermatan sulfate–dependent thrombin inhibition in the plasma of HCII–/– animals. Crosses of HCII–/– animals produced litters similar in size to those obtained from heterozygous matings. At 1 year of age, HCII-deficient animals were grossly indistinguishable from their wild-type littermates in weight and survival, and they did not appear to have spontaneous thrombosis or other morphologic abnormalities. In comparison with wild-type animals, however, they demonstrated a significantly shorter time to thrombotic occlusion of the carotid artery after photochemically induced endothelial cell injury. This abnormality was corrected by infusion of purified HCII but not ovalbumin. These observations suggest that HCII might inhibit thrombosis in the arterial circulation.

Authors

Li He, Cristina P. Vicente, Randal J. Westrick, Daniel T. Eitzman, Douglas M. Tollefsen

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Effect of HCII deficiency on thrombotic occlusion of the carotid artery....
Effect of HCII deficiency on thrombotic occlusion of the carotid artery. Blood flow in the common carotid artery was monitored continuously with an ultrasonic flow probe. Local endothelial injury was induced by application of a 540-nm laser beam to the carotid artery followed by injection of rose bengal dye (50 mg/kg) into the lateral tail vein. (a) Mice with a mixed C57BL/6-129/SvJ genetic background. (b) Mice backcrossed for six generations into the C57BL/6 background. Five minutes before the injection of rose bengal dye, some of these mice were injected intravenously with purified human HCII or ovalbumin as indicated to achieve a plasma level of about 1 μM.