Heparin cofactor II (HCII) is a plasma glycoprotein that inactivates thrombin rapidly in the presence of dermatan sulfate or heparin. 1 Although the presence of thrombin–HCII complexes in normal human plasma indicates that HCII inhibits thrombin in vivo, 2 the physiological function of HCII remains unknown. Homozygous HCII-deficient mice develop thrombotic occlusion of the carotid artery faster than wild-type mice after photochemically-induced damage to the endothelium, 3 suggesting that HCII might play a role in inhibiting thrombosis after arterial injury. Numerous clinical studies, however, have failed to demonstrate a convincing association between HCII deficiency and arterial or venous thrombosis. 4 More recent studies suggest that individuals with higher than average HCII levels are less likely to develop carotid atherosclerosis or in-stent restenosis. 5–7

To further investigate the association between plasma HCII and coronary heart disease (CHD), we measured HCII antigen levels in stored plasma samples from the Atherosclerosis Risk in Communities (ARIC) study. 8 In this study, 16 000 middle-aged subjects have been followed for the development of atherosclerotic disease and its sequelae with an average follow-up of 11.7 years. A detailed description of the study population, HCII immunoassay, and statistical methods is available at http://atvb. ahajournals. org. HCII levels were determined in a total of 760 subjects. Of these, 378 were subjects who developed CHD during follow-up (185 definite or probable myocardial infarction, 36 silent myocardial infarction, 24 definite fatal CHD, and 133 revascularization procedure), and 382 were non-cases selected by stratified sampling. CHD cases and non-cases were similar in age, gender, and race. CHD cases were more likely than non-cases to have diabetes or hypertension, greater cigarette use, lower HDL cholesterol, or higher fibrinogen or white blood cell counts.