Correlates of Antithrombin, Protein C, Protein S, and TFPI in a Healthy Elderly Cohort

Pamela A. Sakkinen; Mary Cushman; Bruce M. Psaty; Lewis H. Kuller; S. Paul Bajaj; Arun K. Sabharwal; Robin Boineau; Elizabeth Macy; Russell P. Tracy

doi:10.1055/s-0037-1615152

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1998; 80(01): 134-139
DOI: 10.1055/s-0037-1615152

Rapid Communication

Schattauer GmbH

Correlates of Antithrombin, Protein C, Protein S, and TFPI in a Healthy Elderly Cohort

Authors

Pamela A. Sakkinen

¹Depts of Pathology and Biochemistry
Mary Cushman

²Depts of Medicine and Pathology, University of Vermont
Bruce M. Psaty

³Depts of Medicine, Epidemilogy and Health Services, University of Washington, Seattle, Washington
Lewis H. Kuller

⁴Dept of Epidemiology, University of Pittsburgh
S. Paul Bajaj

⁵Depts of Medicine and Biochemistry
Arun K. Sabharwal

⁶Dept of Biochemistry, St. Louis University
Robin Boineau

⁷Division of Epidemiology and Clinical Applications, NHLBI, NIH, Bethesda, MD
Elizabeth Macy

⁸Dept of Pathology, University of Vermont, USA
Russell P. Tracy

¹Depts of Pathology and Biochemistry

Abstract

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 cardiovascular 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 internal 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 plasminantiplasmin 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. (250)

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References

References
1 National Center for Health Statistics.. Advance Report of Final Mortality Statistics. 1984. Public Health Service; Hyattsville, MD: 1986
2 Miletich J. Laboratory diagnosis of protein C deficiency. Semin Thromb Hemost 1990; 16: 169-76.
3 Bertina R. Hereditary protein S deficiency. Haemostasis 1985; 15: 241-6.
4 Hirsh J, Piovella F, Pini M. Congenital antithrombin III deficiency: incidence and clinical features. Am J Med 1989; 87 (Suppl 3B): 34S-8S.
5 van der Bom JG, Bots ML, van Vliet HHDM, Pols HAP, Hofman A, Grobbee DE. Antithrombin and atherosclerosis in the Rotterdam study. Arterioscler Thromb Vasc Biol 1996; 16: 864-7.
6 Thompson SG, Fechtrup C, Squire E, Heyse U, Breithardt JCW, van de Loo JK. Antithrombin III and fibrinogen as predictors of cardiac events in patients with angina pectoris. Arterioscler Thromb Vasc Biol 1996; 16: 357-62.
7 Wu K, Folsom A, Heiss G, Davis C, Conlon M, Barnes R. Association of coagulation factors and inhibitors with carotid artery atherosclerosis. Early results of the Atherosclerosis Risk in Communities (ARIC) study. Ann Epidemiol 1992; 2: 471-80.
8 Gensini GF, Rostagno C, Abbate R, Favilla S, Mannucci PM, Serneri GGN. Increased protein C and fibrinopeptide A concentration in patients with angina. Thromb Res 1988; 50: 517-25.
9 Cortellaro M, Boschetti C, Cofrancesco E, Zanussi C, Catalano M, de Gaetano G, Gabrielli L, Lombardi B, Specchia G, Tavazzi L, Tremoli E, della Volpe A, Polli E. for the PLAT Study Group. The PLAT study: hemostatic function in relation to atherothrombotic ischemic events in vascular disease patients. Principal results. Arteriosclerosis Thrombosis 1992; 12: 1063-70.
10 Meade T. Epidemiology of atheroma, thrombosis and ischaemic heart disease. In: Haemostasis and Thrombosis. Bloom A, Thomas D. eds. Churchill Livingstone; Edinburgh, Scotland,: 1987. pp 697-720.
11 Broze GJ. Tissue factor pathway inhibitor. Thromb Haemost 1995; 74: 90-3.
12 Park CT, Creasey AA, Wright SD. Tissue factor pathway inhibitor blocks cellular effects of endotoxin by binding to endotoxin and interfering with transfer to CD14. Blood 1997; 89: 4268-74.
13 Fried L, Borhani N, Enright P, Furberg C, Gardin J, Kronmal R, Kuller L, Manolio T, Mittelmark M, Newman A, O’Leary D, Psaty B, Rautaharju P, Tracy R, Weiler P. ftCRG. The Cardiovascular Health Study: design and rationale. Ann Epidemiol 1991; 1: 263-76.
14 Tell G, Fried L, Hermanson B, Manolio T, Newman A, Borhani N. Recruitment of adults 65 years and older as participants in the Cardiovascular Health Study. Ann Epidemiol 1993; 3: 360-8.
15 Cushman M, Bovill E, Tracy R. Activated protein C resistance and inherited thrombosis. Am J Clin Pathol 1995; 104: 357 (letter).
16 O’Leary D, Polak J, Wolfson S, Bond M, Bommer W, Sheth S, Psaty B, Sharrett A, Manolio T. for CHS Investigators. Use of sonography to evaluate carotid atherosclerosis in the elderly: the Cardiovascular Health Study. Stroke 1991; 22: 1155-63.
17 Gardin J, Wong N, Bommer W, Klopfenstein H, Smith V, Tabatznik B, Siscovic D, Lobodzinski S, Anton-Culver H, Manolio T. Echocardio-graphic design of a multi-center investigation of free-living elderly subjects: the Cardiovascular Health Study. J Am Soc Echocardiogr 1992; 5: 63-72.
18 Newman A, Siscovick D, Manolio T, Polak J, Fried L, Borhani N, Wolfson S. for the CHS Investigators. Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Circulation 1993; 88: 837-45.
19 Blackburn H, Keys A, Simonson E, Rautaharju P, Punsar S. The electrocardiogram in population studies: a classification system. Circulation 1960; 21: 1160-75.
20 Cushman M, Psaty B, Macy E, Bovill E, Cornell E, Kuller L, Tracy R. Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease. Arterioscler Thromb Vasc Biol 1996; 16: 1163-9.
21 Cushman M, Cornell E, Howard P, Bovill E, Tracy R. Laboratory methods and quality assurance in the Cardiovascular Health Study. Clin Chem 1995; 41: 264-70.
22 Tracy R, Bovill E, Stump D, Lin T, Gomol T, Collen D, Mann K. Reduction of in vitro artifact during blood collection in TIMI II. Blood 1988; 78 (Suppl. 01) 376 (Abstract).
23 Bajaj MS, Rana SV, Wysolmerski RB, Bajaj SP. Inhibitor of the VIIa-tissue factor complex is reduced in patients with disseminated intravascular coagulation but not in patients with hepatocellular disease. J Clin Invest 1987; 79: 1874-8.
24 Rosenberg R. Chemistry of the hemostatic mechanism and its relationship to the action of heparin. Fed Proc 1977; 36: 10-8.
25 Howard P, Bovill E, Mann K, Tracy R. A monoclonal antibody-based immunoassay for measurement of protein C in plasma. Clin Chem 1988; 34: 324-30.
26 Bovill E, Landesman M, Busch S, Fregeau G, Mann K, Tracy R. Studies on the measurement of protein S in plasma. Clin Chem 1991; 37: 1708-14.
27 Declerck P, Mombaerts P, Holvoet P, De Mol M, Collen D. Fibrinolytic response and fibrin fragment D-dimer levels in patients with deep vein thrombosis. Thromb Haemost 1987; 58: 1024-9.
28 Diagnostica Stago.. ST4 Operator‘s Manual. Parsippany, NJ: American Bioproducts; 1992
29 Holvoet P, Cleemput H, Collen D. Assay of human tissue-type plasminogen activator (t-PA) with an enzyme-linked immunosorbent assay (ELISA) based on three murine monoclonal antibodies to t-PA. Thromb Haemost 1985; 54: 684-97.
30 DeClerck P, Alessi M, Verstreken M, Kruithof E, Juhan-Vague I, Collen D. Measurement of plasminogen activator inhibitor 1 (PAI-1) in biological fluids with a murine monoclonal antibody based enzyme-linked immunosorbent assay. Blood 1988; 71: 220-5.
31 Holvoet P, de Boer A, Verstreken M, Collen D. An enzyme-linked immunosorbent assay (ELISA) for the measurement of plasmin-alpha-2-anti-plasmin complex in human plasma – application to the detection of in vivo activation of the fibrinolytic system. Thromb Haemost 1986; 56: 124-7.
32 Alessi M, Juhan-Vague I, Declerck P, Anfosso F, Gueunoun E, Collen D. Correlations between t-PA and PAI-1 antigen and activity and t-PA/PAI-1 complexes in plasma of control subjects and of patients with increased t-PA or PAI-1 levels. Thromb Res 1990; 60: 509-16.
33 Declerck P, Collen D. Measurement of plasminogen activator inhibitor 1 (PAI-1) in plasma with various monoclonal antibody-based enzyme-linked immunosorbent assays. Thromb Res 1990; (Supplement X): 3-9.
34 Cushman M, Yanez D, Psaty B, Fried L, Heiss G, Lee M, Polak J, Savage P, Tracy R. for the CHS Investigators. Association of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: the Cardiovascular Health Study. Am J Epidemiol 1996; 143: 665-76.
35 SPSS/PC+ V2.0. Chicago: SPSS Inc.; 1988
36 Cushman M, Cornell E, Macy E, Psaty B, Tracy R. Correlates of the fibrin fragment D-dimer, a measure of fibrinolysis, in an elderly cohort free of prevalent cardiovascular disease (Abstract). Circulation 1995; 92: I-624.
37 Tracy R, Losito R, Howard P, Cushman M, Bovill E. The association of plasma lipids and vitamin K dependent coagulation factors. In: Pennington Center Nutrition Series. Nutrition, genetics and heart disease. Bray G, Ryan D. eds. Louisiana State University Press; Baton Rouge,: 1996. pp 29-49.
38 Novotny W, Girard T, Miletich J, Broze G. Purification and characterization of Lipoprotein-associated coagulation inhibitor from human plasma. J Biol Chem 1989; 264: 18832-7.
39 Callas PW, Bovill EG, Mann KG, Braunwald E, Thompson B, Tracy RP. The association of anticoagulant protein concentrations with acute myocardial infarction in the thrombolysis in myocardial infarction phase II (TIMI II) trial. Journal of Thrombosis and Thrombolysis. in Press.
40 Dahlbäck B, Stenflo J. High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein. Proc Natl Acad Sci USA 1981; 78: 2512-6.
41 Jenkins G, Seiffert D, Parmer R, Miles L. Regulation of plasminogen gene expression by Interleukin-6. Blood 1997; 89: 2394-403.
42 Suzuki K, Deyashiki Y, Nishioka J, Toma K. Protein C Inhibitor: structure and function. Thromb Haemost 1989; 61: 337-42.
43 Oates A, Salem H. The binding and regulation of protein S by neutrophils. Blood Coagul Fibrinolysis 1991; 2: 601-7.
44 Tracy R, Macy E, Bovill E, Cushman M, Psaty B, Cornell E, Kuller L. Smoking status affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arterioscler Thromb Vasc Biol 1997; 17: 2167-76.
45 Jang IK, Lassila R, Fuster V. Atherogenesis and inflammation. Eur Heart J (suppl K) 1994; 14: 2-6.
46 Folsom AR, Wu KK, Rosamond WD, Sharret AR, Chambless LE. Hemostatic factors and incidence of coronary heart disease in the Atherosclerosis Risk in Communities (ARIC) study (Abstract). Circulation 1996; 93: 622.
47 Conlan M, Folsom A, Finch A, Davis C, Marcucci G, Sorlie P, Wu K. Antithrombin III: associations with age, race, sex and cardiovascular disease risk factors. Thromb Haemost 1994; 72: 551-6.