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Thromb Haemost 2002; 87(04): 614-621
DOI: 10.1055/s-0037-1613057
Review Article
Schattauer GmbH

No Association of Plasma Prothrombin Concentration or the G20210A Mutation with Incident Cardiovascular Disease

Results from the Cardiovascular Health Study
Adam M. Smiles
1   Department of Pathology, College of Medicine, University of Vermont, Burlington, VT
,
Nancy S. Jenny
1   Department of Pathology, College of Medicine, University of Vermont, Burlington, VT
,
Zhonghua Tang
1   Department of Pathology, College of Medicine, University of Vermont, Burlington, VT
,
Alice Arnold
2   Department of Biostatistics, University of Washington, Seattle, WA
,
Mary Cushman
1   Department of Pathology, College of Medicine, University of Vermont, Burlington, VT
3   Department of Medicine, College of Medicine, University of Vermont, Burlington, VT
,
Russell P. Tracy
1   Department of Pathology, College of Medicine, University of Vermont, Burlington, VT
4   Department of Biochemistry, College of Medicine, University of Vermont, Burlington, VT, USA
› Author Affiliations
Further Information

Publication History

Received 18 May 2001

Accepted after resubmission 29 November 2001

Publication Date:
08 December 2017 (online)

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Summary

Prothrombin is a key factor in blood clotting, a process intimately involved in thrombotic disease. We assessed prothrombin levels and G20210A genotype in a case-control study within the Cardiovascular Health Study. Cases included angina, myocardial infarction, stroke, and the presence of MRI-detectable infarcts (n ≈ 250 each). Populationbased controls free of clinical cardiovascular disease (CVD) (n ≈ 500) and a subset free of clinical and subclinical CVD (n ≈ 250) were used for comparison. The 20210 A allele, frequency 2.9%, was associated with higher mean prothrombin levels: 166.3 vs. 139.5 µg/ml (P <0.001). Significant correlates of prothrombin included gender, plasma lipids, other vitamin K-dependent proteins, and inflammatory markers, but not race, smoking, hypertension, diabetes, measures of subclinical CVD, or markers of procoagulant activity. Compared to controls, neither genotype nor prothrombin level was associated with any CVD case group. We conclude that, in the elderly, neither prothrombin level nor 20210 genotype were associated with either CVD risk factors or events. This is consistent with the lack of association of prothrombin levels with measures of underlying CVD or procoagulant markers.

Keywords

Prothrombin - elderly - nested case-control study - genetic polymorphism - cardiovascular disease
 

  • References

  • 1 Poort S, Rosendaal F, Reitsma P, Bertina R. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
    PubMedGoogle Scholar
  • 2 Ferraresi P, Marchetti G, Legnani E, Cavallari E, Castoldi E, Mascoli F, Ardissino D, Palareti G, Bernardi F. The heterozygous 20210 G/A prothrombin genotype is associated with early venous thrombosis in inherited thrombophilias and is not increased in frequency in artery disease. Arterioscler Thromb Vasc Biol 1997; 17: 2418-22.
    CrossrefPubMedGoogle Scholar
  • 3 Cumming A, Keeney S, Salden A, Bhavnani M, Shwe K, Hay C. The prothrombin gene G20210A variant: prevalence in a U.K. anticoagulant clinic population. Br J Haematol 1997; 98: 353-5.
    CrossrefPubMedGoogle Scholar
  • 4 Hillarp A, Zoller B, Svensson P, Dahlback B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost 1997; 78: 990-2.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Kapur R, Mills L, Spitzer S, Hultin M. A prothrombin gene mutation is significantly associated with venous thrombosis. Arterioscler Thromb Vasc Biol 1997; 17: 2875-9.
    CrossrefPubMedGoogle Scholar
  • 6 Arruda V, Annichino-Bizzacchi J, Goncalves M, Costa F. Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease. Thromb Haemost 1997; 78: 1430-3.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Arruda V, Siquiera L, Chiaparini L, Coelho O, Mansur A, Ramires A, Annichino-Bizzacchi J. Prevalence of the prothrombin gene variant 20210 G->A among patients with myocardial infarction. Cardiovasc Res 1998; 37: 42-5.
    CrossrefPubMedGoogle Scholar
  • 8 De Stefano V, Chiusolo P, Paciaroni K, Casorelli I, Rossi E, Molinari M, Servidei S, Tonali P, Leone G. Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients. Blood 1998; 91: 3562-5.
    PubMedGoogle Scholar
  • 9 Rosendaal F, Siscovick D, Schwartz S, Psaty B, Raghunathan T, Vos H. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women. Blood 1997; 90: 1747-50.
    PubMedGoogle Scholar
  • 10 Corral J, Gonzalez-Conejero R, Lozano M, Rivera J, Heras I, Vicente V. The venous thrombosis risk factor 20210 A allele of the prothrombin gene is not a major risk factor for arterial disease. Br J Haematol 1997; 99: 304-7.
    CrossrefPubMedGoogle Scholar
  • 11 Longstreth W, Rosendaal F, Siscovick D, Vos H, Schwartz S, Psaty B, Raghunathan T, Koepsell T, Reitsma P. Risk of stroke in young women and two prothrombotic mutations: factor V Leiden and prothrombin gene variant (G20210A). Stroke 1998; 29: 577-80.
    CrossrefPubMedGoogle Scholar
  • 12 Reuner K, Ruf A, Grau A, Rickmann H, Stolz E, Juttler E, Druschky K, Patscheke H. Prothrombin Gene G20210->A transition is a risk factor for cerebral vein thrombosis. Stroke 1998; 29: 1765-9.
    CrossrefPubMedGoogle Scholar
  • 13 Doggen C, Manger VCats, Bertina R, Rosendaal F. Interaction of coagulation defects and cardiovascular risk factors. Circulation 1998; 97: 1037-41.
    CrossrefPubMedGoogle Scholar
  • 14 Watzke H, Schuttrumpf J, Graf S, Huber K, Panzer S. Increased prevalence of a polymorphism in the gene coding for human prothrombin in patients with coronary heart disease. Thromb Res 1997; 87: 521-6.
    CrossrefPubMedGoogle Scholar
  • 15 Ridker P, Hennekens C, Miletich J. G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation 1999; 99: 999-1004.
    CrossrefPubMedGoogle Scholar
  • 16 Franco R, Trip M, ten Cate H, van den Ende A, Prins M, Kastelein J, Reitsma P. The 20210 G->A mutation in the 3’-untranslated region of the prothrombin gene and the risk for arterial thrombotic disease. Br J Haematol 1999; 104: 50-4.
    CrossrefPubMedGoogle Scholar
  • 17 Eikelboom J, Baker R, Parsons R, Taylor R, van Bockxmeer F. No association between the 20210 G/A prothrombin gene mutation and premature coronary artery disease. Thromb Haemost 1998; 80: 878-80.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Simioni P, Tormene D, Manfrin D, Gavasso S, Luni S, Stocco D. Girolami Prothrombin antigen levels in symptomatic and asymptomatic carriers of the 20210A prothrombin variant. Br J Haematol 1998; 103: 1045-50.
    CrossrefPubMedGoogle Scholar
  • 19 Hoffman C, Lawson W, Miller R, Hultin M. Correlation of vitamin Kdependent clotting factors with cholesterol and triglycerides in healthy young adults. Arterioscler Thromb 1994; 14: 1737-40.
    CrossrefPubMedGoogle Scholar
  • 20 Tracy R, Losito R, Howard P, Cushman M, Bovill E. The association of plasma lipids and vitamin K-dependent coagulation factors. In: Nutrition, genetics and heart disease. Vol. 6. Bray G, Ryan D. eds. Pennington Center Nutrition Series. Baton Rouge: LSU Press; 1996: 29-49.
    Google Scholar
  • 21 National Center for Health Statistics. Advance report of final mortality statistics, 1987. Public Health Service; Hyattsville, MD: 1989
    Google Scholar
  • 22 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. for the CHS Research Group. The Cardiovascular Health Study: design and rationale. Ann Epidemiol 1991; 01: 263-76.
    CrossrefPubMedGoogle Scholar
  • 23 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; 03: 358-66.
    CrossrefPubMedGoogle Scholar
  • 24 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.
    PubMedGoogle Scholar
  • 25 Gardin J, Wong N, Bommer W, Klopfenstein H, Smith V, Tabatznik B, Siscovick D, Lobodzinski S, Anton-Culver H, Manolio T. Echocardiographic design of a multi-center investigation of free-living elderly subjects: the Cardiovascular Health Study. J Am Soc Echocardiography 1992; 05: 63-72.
    CrossrefPubMedGoogle Scholar
  • 26 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.
    CrossrefPubMedGoogle Scholar
  • 27 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.
    CrossrefPubMedGoogle Scholar
  • 28 Bryan RNWS, Mill T, Elster A, Jungreis C, Poirier V, Lind B, Manolio T. Infarctlike lesions in the brain: prevalence and anatomic characteristics at MR imaging of the elderly: data from the Cardiovascular Health Study. Radiology 1997; 202: 17-19.
    CrossrefPubMedGoogle Scholar
  • 29 Ives D, Fitzpatrick A, Bild D, Psaty B, Kuller L, Crowley P, Cruise R, Theroux S. Surveillance and ascertainment of cardiovascular events. Ann Epidemiol 1995; 05: 278-85.
    CrossrefPubMedGoogle Scholar
  • 30 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.
    CrossrefPubMedGoogle Scholar
  • 31 American Diabetes Association. Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997; 07: 1183-97.
    PubMedGoogle Scholar
  • 32 Furberg C, Manolio T, Psaty B, Bild D, Borhani N, Newman A, Tabatznik B, Rautaharju P. Major electrocardiographic abnormalities in persons aged 65 years and older (the Cardiovascular Health Study). Am J Cardiol 1992; 69: 1329-35.
    CrossrefPubMedGoogle Scholar
  • 33 Kuller L, Shemanski L, Psaty B, Borhani N, Gardin J, Haan M, O’Leary D, Savage P, Tell G, Tracy R. Subclinical disease as an independent risk factor for cardiovascular disease. Circulation 1995; 92: 720-6.
    CrossrefPubMedGoogle Scholar
  • 34 Smiles A, Macy E, Sakkinen P, Bovill E, Mann K, Tracy R. Biological and analytical variability in plasma prothrombin concentration: implications for use in epidemiology. Blood Coagul Fibrinolysis 1998; 09: 525-31.
    CrossrefPubMedGoogle Scholar
  • 35 Bajaj M, Rana S, Wysolmerski R, Bajaj S. 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.
    CrossrefPubMedGoogle Scholar
  • 36 Rosenberg R. Chemistry of the hemostatic mechanism and its relationship to the action of heparin. Fed Proc 1977; 36: 10-18.
    PubMedGoogle Scholar
  • 37 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.
    PubMedGoogle Scholar
  • 38 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.
    PubMedGoogle Scholar
  • 39 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Diagnostica Stago. ST4 Operator’s Manual. Parsippany, NJ: American Bioproducts; 1992
    Google Scholar
  • 41 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 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.
    PubMedGoogle Scholar
  • 43 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 (suppl X) 3-9.
    PubMedGoogle Scholar
  • 44 Holvoet P, de Boer A, Verstreken M, Collen D. An enzyme-linked immunosorbent assay (ELISA) for the measurement of plasmin-alpha-2-antiplasmin complex in human plasma – application to the detection of in vivo activation of the fibrinolytic system. Thromb Haemost 1986; 56: 124-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 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.
    CrossrefPubMedGoogle Scholar
  • 46 Kuller L, Tracy R, Shaten J, Meilahn E. for the MRFIT Research Group. Relationship of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial. Am J Epidemiol 1996; 144: 537-47.
    CrossrefPubMedGoogle Scholar
  • 47 Howard P, Bovill E, Pike J, Church W, Tracy R. Factor VII antigen levels in a healthy blood donor population. Thromb Haemost 1994; 72: 21-7.
    PubMedGoogle Scholar
  • 48 SPSS for Windows Base 10.0. Chicago, SPSS, Inc. Chicago, IL: SPSS, Inc; 1999
  • 49 Kuller L, Fisher L, McClelland R, Fried L, Cushman M, Jackson S, Manolio T. Differences in prevalence of and risk factors for subclinical vascular disease among black and white participants in the cardiovascular health study. Arterioscler Thromb Vasc Biol 1998; 18: 283-93.
    CrossrefPubMedGoogle Scholar
  • 50 Moyer M, Tracy R, Tracy P, van’t Veer C, Sparks C, Mann K. Plasma lipoproteins support prothrombinase and other procoagulant enzymatic complexes. Arterioscler Thromb Vasc Biol 1998; 18: 458-65.
    CrossrefPubMedGoogle Scholar
  • 51 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. Amer J Epidemiol 1996; 143: 665-76.
    CrossrefPubMedGoogle Scholar
  • 52 Folsom A, Wu K, Davis C, Conlan M, Sorlie P, Szklo M. Population correlates of plasma fibrinogen and factor VII, putative cardiovascular risk factors. Atherosclerosis 1991; 91: 191-205.
    CrossrefPubMedGoogle Scholar
  • 53 Kyrle P, Mannhalter C, Beguin S, Stumpflen A, Hirschl M, Weltermann A, Stain M, Brenner B, Speiser W, Pabinger I, Lechner K, Eichinger S. Clinical studies and thrombin generation in patients homozygous or heterozygous for the G20210A mutation in the prothrombin gene. Arterioscler Thromb Vasc Biol 1998; 18: 1287-91.
    CrossrefPubMedGoogle Scholar