Atherosclerosis 157 (2001) 309 – 314 Cross-sectional association of soluble thrombomodulin with mild peripheral artery disease; the ARIC study Veikko Salomaa a, *, Carmen Matei b , Nena Aleksic b , Leticia Sansores-Garcia b , Aaron R. Folsom c , Harinder Juneja b , Eunsik Park d , Kenneth K. Wu b a KTL-National Public Health Institute, Department of Epidemiology and Health Promotion, Mannerheimintie 166, FIN-00300, Helsinki, Finland b Diision of Hematology, Uniersity of Texas Medical School, Houston, TX, USA c Diision of Epidemiology, School of Public Health, Uniersity of Minnesota, Minneapolis, MN, USA d Collaboratie Studies Coordinating Center, Department of Biostatistics, UNC, Chapel Hill, NC, USA Received 19 June 2000; received in revised form 20 October 2000; accepted 31 October 2000 Abstract Thrombomodulin, an endothelial membrane glycoprotein, is an essential part of the protein C anti-coagulant pathway. It may also have a role in the regulation of fibrinolysis. We carried out a cross-sectional study to assess the association of soluble thrombomodulin (sTM) with peripheral artery disease (PAD) in a stratified random sample (n =863) of otherwise healthy black and white participants of the Atherosclerosis Risk in Communities (ARIC) Study. PAD was more common in black than in white participants and associated with classical risk factors in an expected manner; positively with age, smoking, hypertension, diabetes (P =0.05), and LDL-cholesterol, and inversely with HDL-cholesterol. Significant positive associations were observed also with fibrinogen and white blood cell count. Overall, the sTM concentration was not a significant predictor of PAD. The association was, however, modified by the level of factor VIII:C in whites (P =0.002 for the interaction), but not in blacks. Protein C was inversely associated with PAD prevalence (odds ratio 0.33, 95% CI 0.18 – 0.61, P =0.0004). sTM was inversely associated with plasminogen, but no associations with t -PA, PAI-1, or D-dimer were seen. In conclusion, the present results provide some additional evidence on the role of thrombomodulin-protein C pathway in atherosclerotic disease and support our earlier observation on interaction between sTM and factor VIII:C. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Thrombomodulin; Atherosclerosis; Peripheral artery disease www.elsevier.com/locate/atherosclerosis 1. Introduction Thrombomodulin (TM), an endothelial membrane glycoprotein, is an essential part of the protein C anticoagulant pathway [1,2]. It acts as a thrombin receptor and facilitates protein C activation by thrombin. Activated protein C, in the presence of protein S, degrades activated factors V and VIII, thereby, inhibiting further thrombin formation and lim- iting blood coagulation. Intact TM is associated with cell membrane, but some cleaved TM fragments exist as soluble TM (sTM) in circulating blood [3]. The physio- logic role of sTM is unknown, but its concentration has been considered to reflect endothelial damage [4]. Its association with atherosclerosis remains unclear. Only a few studies exist on sTM and atherosclerosis. Most of them have examined peripheral artery disease (PAD), but the results have been conflicting. Some studies have reported a positive association [5,6], while others have failed to find any association [7,8]. We recently reported an inverse association between sTM and incident coro- nary heart disease (CHD) in a prospective study of initially healthy participants of the Atherosclerosis Risk in Communities (ARIC) Study [9]. Cross-sectionally, however, sTM showed no overall association with the intima-media thickness of the carotid arteries [9]. More- over, the association of sTM with both these manifesta- tions of atherosclerosis was dependent on the factor VIII:C level, so that in persons with a high level of factor VIII:C, high sTM levels were associated with lower risk of disease. * Corresponding author. Tel.: +358-9-47448620; fax: +358-9- 47448338. E-mail address: veikko.salomaa@ktl.fi (V. Salomaa). 0021-9150/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII:S0021-9150(00)00729-2