of coagulation: Protein C, its cofactor Protein S, Antithrombin (AT), and Tissue Factor Pathway Inhibitor (TFPI). Deficiencies of Protein C (2), Protein S (3), and AT (4), are clearly associated with increased risk of venous thromboembolism; however associations between the levels of these proteins and atherosclerotic cardiovascular disease (CVD) have not been consistent (5-10), pos- sibly due to the different mechanisms involved in venous versus arterial thrombus formation, as well as the effect of the atherosclerotic disease process on the measured variables. TFPI deficiency has not been widely reported in association with thromboembolic disease, although TFPI has been established as a direct inhibitor of Factor Xa and Factor VIIa/TF complex (11). Recent experiments indicate TFPI may block the interaction of lipopolysaccharide with its receptor, and thus block the induction of tissue factor by inflammatory and endo- thelial cells (12). The Cardiovascular Health Study (CHS) is a cohort study of 5,888 community dwelling persons over 65 years of age (13). Because of the known age-related increased risk of arterial thrombosis, we measured the four anticoagulant proteins in a subgroup (n = 400) free of prevalent clinical CVD at baseline to limit the influence of clinical events. The data were used to establish the cross-sectional correlates of the anticoagulant proteins, and to develop hypotheses regarding their associations in this elderly population. Methods Population. The original CHS cohort (n = 5,201) was recruited from random samples of Medicare eligibility lists at four field centers, located in Forsyth County, North Carolina; Washington County, Maryland; Sacramento County, California; and Pittsburgh County, Pennsylvania. Recruitment details have been reported previously (14). Baseline examination was performed over one year beginning in May 1989. Medication and lifestyle histories, physical examinations and phlebotomy samples were obtained. Blood samples were analyzed at the Central CHS Laboratory at the University of Vermont. Data were transmitted to the Coordinating Center at the University of Washington. General quality assurance procedures and laboratory methods have been published (15). Subjects were classified at baseline according to the presence or absence of clinical cardiovascular disease (13). All subjects underwent duplex ultra- sonography of carotid arteries (16), echocardiography (17), blood pressure measurements including the ankle-brachial index (18), and twelve lead resting ECG. Definitions. Baseline coronary heart disease was defined by 1) self-reported myocardial infarction, angina or use of nitroglycerin; 2) definite myocardial infarction on resting ECG by Minnesota code (19); 3) or self-reported history 134 Thromb Haemost 1998; 80: 134 – 9 © 1998 Schattauer Verlag, Stuttgart Correlates of Antithrombin, Protein C, Protein S, and TFPI in a Healthy Elderly Cohort Pamela A. Sakkinen 1 , Mary Cushman 2 , Bruce M. Psaty 3 , Lewis H. Kuller 4 , S. Paul Bajaj 5 , Arun K. Sabharwal 6 , Robin Boineau 7 , Elizabeth Macy 8 , Russell P. Tracy 1 From the 1 Depts of Pathology and Biochemistry, the 2 Depts of Medicine and Pathology, University of Vermont, the 3 Depts of Medicine, Epidemilogy and Health Services, University of Washington, Seattle, Washington, the 4 Dept of Epidemiology, University of Pittsburgh, the 5 Depts of Medicine and Biochemistry, 6 Dept of Biochemistry, St. Louis University, the 7 Division of Epidemiology and Clinical Applications, NHLBI, NIH, Bethesda, MD, the 8 Dept of Pathology, University of Vermont, USA Summary The majority of fatal acute myocardial infarctions occur in the elderly. Since these events are predominantly thrombotic, we studied the cross-sectional associations of the anticoagulant proteins Anti- thrombin, Protein C, Protein S, and Tissue Factor Pathway Inhibitor (TFPI) in a subgroup (n = 400) of the Cardiovascular Health Study (a study of healthy men and women ≥ 65 years) free of clinical cardio- vascular disease (CVD). We did not observe any strong age-associated trends, although Protein C was lower in older women (p ≤ 0.001), and TFPI was higher in older men (p ≤ 0.01). The inhibitors were highly intercorrelated, and were associated with increased levels of inflammation-sensitive proteins (e.g., fibrinogen, plasminogen), lipids (especially total and LDL-cholesterol), and coagulation factors, such as Factors VIIc, IXc, and Xc. None was associated with the procoagulant markers Prothrombin Fragment F1-2 or Fibrinopeptide A. Only TFPI was associated with subclinical atherosclerosis: ankle-arm index and inter- nal carotid artery stenosis, p trend ≤ 0.01; and carotid wall thickness, p trend ≤ 0.05. In multivariate analysis the independent predictors of TFPI were levels of fibrinogen; the fibrinolytic marker plasmin- antiplasmin complex; LDL-cholesterol; and carotid wall thickness (R 2 for the model = 0.35). In summary, the inhibitors did not appear to increase with age, and were predominantly associated with inflammation markers and lipids. Since markers of thrombin production do increase with age, we hypothesize that an age-related hemostatic imbalance may ensue, with associated increased thrombotic risk. Only TFPI was associated with subclinical CVD, suggesting that it may more closely reflect endo- thelial damage. (250) Introduction Acute myocardial infarctions are usually caused by coronary throm- bosis. Even though greater than 80% of fatal acute myocardial infarc- tions have been reported to occur in men and women over the age of 65 (1), little is known about the regulation of the anticoagulant proteins in this age group. There are four major proteins involved in the regulation Correspondence to: Dr. Russell P. Tracy, University of Vermont, Aquatec Bldg, T205, 55A S. Park Drive, Colchester, VT 05446, USA – Tel.: +1 802 656 8961; FAX Number: +1 802 656 8965; E-mail: rtracy@salus.med. uvm.edu For personal or educational use only. No other uses without permission. All rights reserved. Downloaded from www.thrombosis-online.com on 2018-05-19 | ID: 1001066444 | IP: 54.70.40.11