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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Figure 1

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Targeted disruption of the murine HCII gene. (a) Restriction map of the ...
Targeted disruption of the murine HCII gene. (a) Restriction map of the HCII locus and design of a replacement vector. The boxes represent exons 1–4 of the HCII gene. The thick lines represent genomic DNA; the thin lines, vector DNA. The targeting vector was constructed by insertion of the neomycin phosphotransferase gene (neo) between the EcoRI and BamHI sites of the HCII gene. (b) Southern blots of genomic DNA isolated from the tails of 4- to 6-week-old mice and digested with SacI. The restriction fragments were detected with probes (5′-probe and 3′-probe) that hybridized with sequences external to the genomic DNA present in the targeting vector. (c) Northern blot of total liver RNA obtained from adult mice. The blot was first hybridized with a cDNA probe containing sequences present in exons 2–4 of the HCII gene. It was then stripped and rehybridized with a probe containing sequences present in the neo cassette. (d) Western blot of mouse plasma probed with goat anti-human HCII IgG. The 68-kDa and 72-kDa bands represent two glycoforms of HCII that are present in normal mouse plasma (22). HCII genotypes (+/+, +/–, and –/–) are indicated in panels b–d.