@article {1570, title = {Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort.}, journal = {Thromb Haemost}, volume = {80}, year = {1998}, month = {1998 Jul}, pages = {134-9}, abstract = {

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 Antithrombin, 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 > or = 65 years) free of clinical cardiovascular disease (CVD). We did not observe any strong age-associated trends, although Protein C was lower in older women (p < or = 0.001), and TFPI was higher in older men (p < or = 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 internal carotid artery stenosis, p trend < or = 0.01; and carotid wall thickness, p trend < or = 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 (R2 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 endothelial damage.

}, keywords = {Aged, Aged, 80 and over, Analysis of Variance, Anticoagulants, Antithrombin III, Biomarkers, Cross-Sectional Studies, Disease Susceptibility, Female, Humans, Lipoproteins, Male, Prevalence, Protein C, Protein S, Reference Values, Risk Factors, Thrombosis}, issn = {0340-6245}, author = {Sakkinen, P A and Cushman, M and Psaty, B M and Kuller, L H and Bajaj, S P and Sabharwal, A K and Boineau, R and Macy, E and Tracy, R P} } @article {659, title = {Post-menopausal hormone therapy and concentrations of protein C and antithrombin in elderly women.}, journal = {Br J Haematol}, volume = {114}, year = {2001}, month = {2001 Jul}, pages = {162-8}, abstract = {

The effects of post-menopausal hormone therapy (HRT) on blood coagulation in elderly women are not well defined. We studied associations of HRT use with levels of natural anticoagulant proteins in a cross-sectional study of 3393 women > or = 65 years of age participating in the Cardiovascular Health Study. Protein C antigen and antithrombin were measured in all users (n = 230 unopposed oestrogen; 60 oestrogen/progestin) and a comparison group of 196 age- and race-matched non-users. Compared with non-users, oestrogen use was associated with higher protein C (4.80 vs. 4.30 microg/ml, P < 0.01). Results were similar for oestrogen/progestin (P > 0.05). In both user groups, antithrombin was lower than in non-users (109\% for each vs. 115\% in non-users, P < 0.001). Adjustment for factors related to prescription of HRT and to anticoagulant protein levels had little impact on the results. For antithrombin, associations with HRT were larger for thinner Caucasian women and black women. Venous thrombosis from HRT may be mediated partly by alterations in antithrombin, but not protein C concentrations. This study extends previous observations to older women, the group at highest risk of venous thromboembolism. Studies of HRT-induced alterations in anticoagulant function in relation to the occurrence of thrombosis with HRT are required.

}, keywords = {Aged, Antithrombins, Black People, Body Mass Index, Cross-Sectional Studies, Estrogen Replacement Therapy, Female, Humans, Logistic Models, Postmenopause, Progestins, Protein C, Risk Factors, Venous Thrombosis, White People}, issn = {0007-1048}, doi = {10.1046/j.1365-2141.2001.02911.x}, author = {Cushman, M and Psaty, B M and Meilahn, E N and Dobs, A S and Kuller, L H} } @article {1047, title = {PROC, PROCR and PROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study.}, journal = {J Thromb Haemost}, volume = {6}, year = {2008}, month = {2008 Oct}, pages = {1625-32}, abstract = {

BACKGROUND AND OBJECTIVES: Genes encoding protein C anticoagulant pathways are candidates for atherothrombotic and other aging-related disorders.

METHODS: Using a tagSNP approach, and data from the Cardiovascular Health Study (CHS), we assessed associations of common polymorphisms of PROC, PROS1 and PROCR with: (i) plasma protein C, soluble protein C endothelial receptor (sEPCR) and protein S levels measured in a subsample of 336 participants at study entry; and (ii) risk of incident clinical outcomes [coronary heart disease (CHD), stroke, and mortality] in 4547 participants during follow-up. Secondarily, we explored associations between plasma protein C, protein S and sEPCR levels and other candidate genes involved in thrombosis, inflammation, and aging.

RESULTS: The PROCR Ser219Gly polymorphism (rs867186) was strongly associated with higher sEPCR levels, explaining 75\% of the phenotypic variation. The PROCR Ser219Gly variant was also associated with higher levels of circulating protein C antigen. An IL10 polymorphism was associated with higher free protein S levels. The minor alleles of PROC rs2069901 and PROS1 rs4857343 were weakly associated with lower protein C and free protein S levels, respectively. There was no association between PROCR Ser219Gly and risk of CHD, stroke, or mortality. The minor allele of another common PROCR tagSNP, rs2069948, was associated with lymphoid PROCR mRNA expression and with increased risk of incident stroke and all-cause mortality, and decreased healthy survival during follow-up.

CONCLUSIONS: A common PROCR variant may be associated with decreased healthy survival in older adults. Additional studies are warranted to establish the role of PROCR variants in ischemic and aging-related disorders.

}, keywords = {Aged, Aged, 80 and over, Aging, Antigens, CD, Blood Coagulation Factor Inhibitors, Cardiovascular Diseases, Coronary Disease, Endothelial Protein C Receptor, Female, Humans, Inflammation, Male, Middle Aged, Mortality, Polymorphism, Genetic, Protein C, Protein S, Receptors, Cell Surface, Risk, Stroke, Thrombosis}, issn = {1538-7836}, doi = {10.1111/j.1538-7836.2008.03118.x}, author = {Reiner, A P and Carty, C L and Jenny, N S and Nievergelt, C and Cushman, M and Stearns-Kurosawa, D J and Kurosawa, S and Kuller, L H and Lange, L A} }