PDF herunterladen
Thromb Haemost 2000; 84(03): 396-400
DOI: 10.1055/s-0037-1614034
Commentary
Schattauer GmbH

Prothrombin Activation Is Increased among Asymptomatic Carriers of the Prothrombin G20210A and Factor V Arg506Gln Mutations

Kenneth A. Bauer
1   From the Department of Medicine, Beth Israel Deaconess Medical Center and Boston VA Healthcare System, Harvard Medical School, Boston; the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; the Division of Cardiovascular Genetics, University College London Medical School, the MRC Epidemiology and Medical Care Unit, St. Bartholomew’s and Royal London Medical College, London, UK
,
Steve Humphries
1   From the Department of Medicine, Beth Israel Deaconess Medical Center and Boston VA Healthcare System, Harvard Medical School, Boston; the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; the Division of Cardiovascular Genetics, University College London Medical School, the MRC Epidemiology and Medical Care Unit, St. Bartholomew’s and Royal London Medical College, London, UK
,
Belinda Smillie
1   From the Department of Medicine, Beth Israel Deaconess Medical Center and Boston VA Healthcare System, Harvard Medical School, Boston; the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; the Division of Cardiovascular Genetics, University College London Medical School, the MRC Epidemiology and Medical Care Unit, St. Bartholomew’s and Royal London Medical College, London, UK
,
Lily Li
1   From the Department of Medicine, Beth Israel Deaconess Medical Center and Boston VA Healthcare System, Harvard Medical School, Boston; the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; the Division of Cardiovascular Genetics, University College London Medical School, the MRC Epidemiology and Medical Care Unit, St. Bartholomew’s and Royal London Medical College, London, UK
,
Jacqueline A. Cooper
1   From the Department of Medicine, Beth Israel Deaconess Medical Center and Boston VA Healthcare System, Harvard Medical School, Boston; the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; the Division of Cardiovascular Genetics, University College London Medical School, the MRC Epidemiology and Medical Care Unit, St. Bartholomew’s and Royal London Medical College, London, UK
,
Samad Barzegar
1   From the Department of Medicine, Beth Israel Deaconess Medical Center and Boston VA Healthcare System, Harvard Medical School, Boston; the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; the Division of Cardiovascular Genetics, University College London Medical School, the MRC Epidemiology and Medical Care Unit, St. Bartholomew’s and Royal London Medical College, London, UK
,
Robert D. Rosenberg
1   From the Department of Medicine, Beth Israel Deaconess Medical Center and Boston VA Healthcare System, Harvard Medical School, Boston; the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; the Division of Cardiovascular Genetics, University College London Medical School, the MRC Epidemiology and Medical Care Unit, St. Bartholomew’s and Royal London Medical College, London, UK
,
George J. Miller
1   From the Department of Medicine, Beth Israel Deaconess Medical Center and Boston VA Healthcare System, Harvard Medical School, Boston; the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; the Division of Cardiovascular Genetics, University College London Medical School, the MRC Epidemiology and Medical Care Unit, St. Bartholomew’s and Royal London Medical College, London, UK
› InstitutsangabenSupported in part by National Institutes of Health (HL33014), the British Heart Foundation (RG95007, PG/95190 and RG93008), the Medical Research Service of the Department of Veterans Affairs, and DuPont Pharma (Wilmington, DE).
Weitere Informationen

Publikationsverlauf

Received 03. Januar 2000

Accepted after revision 14. April 2000

Publikationsdatum:
14. Dezember 2017 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Summary

The risk of venous thrombosis is increased in individuals who carry specific genetic abnormalities in blood coagulation proteins. Among Caucasians, the prothrombin G20210A and factor V Arg506Gln (FV R506Q) mutations are the most prevalent defects identified to date. We evaluated their influence on markers of coagulation activation among participants in the Second Northwick Park Heart Study, which recruited healthy men (aged 50–61 years) from nine general medical practices in England and Wales. They were free of clinical vascular disease and malignancy at the time of recruitment. Genotypes for the two mutations were analyzed using microplate array diagonal gel electrophoresis, and coagulation markers (factor XIIa; activation peptides of factor IX, factor X, and prothrombin; fibrinopeptide A) were measured by immunoassay. Factor VII coagulant activity and factor VIIa levels were determined by a functional clotting assay. Among 1548 men genotyped for both mutations, 28 (1.8%) and 52 (3.4%) were heterozygous for prothrombin G20210A and FV R506Q, respectively. The only coagulation marker that was significantly associated with the two mutations was prothrombin activation fragment F1+2 [mean ± SD, 0.88 ± 0.32 nmol/L in men with prothrombin G20210A (p = 0.002) and 0.89 ± 0.30 in men with FV R506Q (p = 0.0001) versus 0.72 ± 0.24 among non-carriers for either mutation]. This data provides conclusive evidence that heterozygosity for the prothrombin G20210A as well as the FV R506Q mutations in the general population leads to an increased rate of prothrombin activation in vivo.

Key words

Prothrombin G20210A - factor V-Arg506Gln - coagulation activation markers - prothrombin activation fragment F1+2
 

  • References

  • 1 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
    CrossrefPubMedSuche in Google Scholar
  • 2 Greengard JS, Sun X, Xu X, Fernandez JA, Griffin J, Evatt B. Activated protein C resistance caused by Arg506Gln mutation in factor Va. Lancet 1994; 343: 1361-2.
    PubMedSuche in Google Scholar
  • 3 Voorberg J, Roelse J, Koopman R, Buller H, Berends F, ten Cate JW, Mertens K, van Mourik JA. Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V. Lancet 1994; 343: 1535-6.
    CrossrefPubMedSuche in Google Scholar
  • 4 Zöller B, Svensson PJ, He X, Dahlbäck B. Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest 1994; 94: 2521-4.
    CrossrefPubMedSuche in Google Scholar
  • 5 Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332: 912-7.
    CrossrefPubMedSuche in Google Scholar
  • 6 Kalafatis M, Bertina RM, Rand MD, Mann KG. Characterization of the molecular defect in Factor VR506Q . J Biol Chem 1995; 270: 4053-7.
    CrossrefPubMedSuche in Google Scholar
  • 7 Heeb MJ, Kojima Y, Greengard JS, Griffin JH. Activated protein C resistance: molecular mechanisms based on studies using purified Gln506-factor V. Blood 1995; 85: 3405-11.
    PubMedSuche in Google Scholar
  • 8 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
    PubMedSuche in Google Scholar
  • 9 Rosendaal FR, Doggen CJM, Zivelin A, Arruda VR, Aiach M, Siscovick DS, Hillarp A, Watzke HH, Bernardi F, Cumming AM, Preston FE, Reitsma PH. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998; 79: 706-8.
    Thieme ConnectPubMedSuche in Google Scholar
  • 10 Miller GJ, Bauer KA, Barzegar S, Foley AJ, Mitchell JP, Cooper JA, Rosenberg RD. The effects of quality and timing of venepuncture on markers of blood coagulation in healthy middle-aged men. Thromb Haemost 1995; 73: 82-6.
    Thieme ConnectPubMedSuche in Google Scholar
  • 11 Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215.
    CrossrefPubMedSuche in Google Scholar
  • 12 Day IN, Humphries SE. Electrophoresis for genotyping: microtiter array diagonal gel electrophoresis on horizontal polyacrylamide gels, hydrolink or agarose. Anal Biochem 1994; 222: 389-95.
    CrossrefPubMedSuche in Google Scholar
  • 13 Day IN, Humphries SE, Richards S, Norton D, Reid M. High-throughput genotyping using horizontal polyacrylamide gels with wells arranged for microplate array diagonal gel electrophoresis (MADGE). Biotechniques 1995; 19: 830-5.
    PubMedSuche in Google Scholar
  • 14 Miller GJ, Stirling Y, Esnouf MP, Heinrich J, van de Loo J, Kienast J, Wu KK, Morrissey JH, Meade TW, Martin JC, Imeson JD, Cooper JA, Finch A. Factor VII-deficient substrate plasmas depleted of protein C raise the sensitivity of the factor VII bio-assay to activated factor VII: an international study. Thromb Haemost 1994; 71: 38-48.
    Thieme ConnectPubMedSuche in Google Scholar
  • 15 Morrissey JH, Macik BG, Neuenschwander PF, Comp PC. Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 1993; 81: 734-44.
    PubMedSuche in Google Scholar
  • 16 Ford RP, Esnouf MP, Burgess AI, Sarphie A. An enzyme-linked immunosorbent assay (ELISA) for the measurement of activated factor XII (Hageman factor) in human plasma. J Immunoassay 1996; 17: 119-31.
    PubMedSuche in Google Scholar
  • 17 Teitel JM, Bauer KA, Lau HK, Rosenberg RD. Studies of the prothrombin activation pathway utilizing radioimmunoassays for the F2/F1+2 fragment and thrombin-antithrombin complex. Blood 1982; 59: 1086-97.
    PubMedSuche in Google Scholar
  • 18 Bauer KA, Kass BL, ten Cate H, Hawiger JJ, Rosenberg RD. Factor IX is activated in vivo by the tissue factor mechanism. Blood 1990; 76: 731-6.
    PubMedSuche in Google Scholar
  • 19 Bauer KA, Kass BL, ten Cate H, Bednarek MA, Hawiger JJ, Rosenberg RD. Detection of factor X activation in humans. Blood 1989; 74: 2007-15.
    PubMedSuche in Google Scholar
  • 20 Miller GJ, Bauer KA, Cooper JA, Rosenberg RD. Activation of the coagulant pathway in cigarette smokers. Thromb Haemost 1998; 79: 549-53.
    Thieme ConnectPubMedSuche in Google Scholar
  • 21 Kyrle PA, Mannhalter C, Béguin S, Stümpflen A, Hirschl M, Weltermann A, Stain M, Brenner G, 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.
    CrossrefPubMedSuche in Google Scholar
  • 22 Butenas S, van’t Veer C, Mann KG. “Normal” thrombin generation. Blood 1999; 94: 2169-78.
    PubMedSuche in Google Scholar
  • 23 Martinelli I, Bottasso B, Duca F, Faioni E, Mannucci PM. Heightened thrombin generation in individuals with resistance to activated protein C. Thromb Haemost 1996; 75: 703-5.
    Thieme ConnectPubMedSuche in Google Scholar
  • 24 Zöller B, Holm J, Svensson P, Dahlbäck B. Elevated levels of prothrombin activation fragment 1+2 in plasma from patients with heterozygous Arg506 to Gln mutation in the factor V gene (APC-resistance) and/or inherited protein S deficiency. Thromb Haemost 1996; 75: 270-4.
    Thieme ConnectPubMedSuche in Google Scholar
  • 25 Simioni P, Scarano L, Gavasso S, Sardella C, Girolami B, Scudeller A, Girolami A. Prothrombin fragment 1+2 and thrombin-antithrombin complex levels in patients with inherited APC resistance due to factor V Leiden mutation. Br J Haematol 1996; 92: 435-41.
    CrossrefPubMedSuche in Google Scholar
  • 26 van’t Veer C, Kalafatis M, Bertina RM, Simioni P, Mann KG. Increased tissue factor-initiated prothrombin activation as a result of the Arg506→Gln mutation in factor VLEIDEN . J Biol Chem 1997; 272: 20721-9.
    CrossrefPubMedSuche in Google Scholar
  • 27 Bauer KA, Broekmans AW, Bertina RM, Coanrd J, Horellou MH, Samama MM, Rosenberg RD. Hemostatic enzyme generation in the blood of patients with hereditary protein C deficiency. Blood 1988; 71: 1418-26.
    PubMedSuche in Google Scholar
  • 28 Mannucci PM, Tripodi A, Bottasso B, Baudo F, Finazzi G, De Stefano V, Palareti G, Manotti C, Mazzucconi MG, Castaman G. Markers of procoagulant imbalance in patients with inherited thrombophilic syndromes. Thromb Haemost 1992; 67: 200-2.
    Thieme ConnectPubMedSuche in Google Scholar
  • 29 Conard J, Bauer KA, Gruber A, Griffin JH, Schwarz HP, Horellou MH, Samama MM, Rosenberg RD. Normalization of markers of coagulation activation with a purified protein C concentrate in adults with homozygous protein C deficiency. Blood 1993; 82: 1159-64.
    PubMedSuche in Google Scholar
  • 30 Lowe GDO, Rumley A, Woodward M, Reid E, Rumley J. Activated protein C resistance and the FV:R506Q mutation in a random population sample. Associations with cardiovascular risk factors and coagulation variables. Thromb Haemost 1999; 81: 918-24.
    Thieme ConnectPubMedSuche in Google Scholar
  • 31 Miletich JP, Prescott SM, White R, Majerus PW, Bovill EG. Inherited predisposition to thrombosis. Cell 1993; 72: 477-80.
    CrossrefPubMedSuche in Google Scholar
  • 32 Schafer AI. Hypercoagulable states: molecular genetics to clinical practice. Lancet 1994; 344: 1739-42.
    CrossrefPubMedSuche in Google Scholar
  • 33 Seligsohn U, Zivelin A. Thrombophilia as a multigenic disorder. Thromb Haemost 1997; 78: 297-301.
    Thieme ConnectPubMedSuche in Google Scholar
  • 34 Pelzer H, Schwart A, Stuber W. Determination of human prothrombin activation fragment 1+2 in plasma with an antibody against a synthetic peptide. Thromb Haemost 1991; 65: 153-9.
    Thieme ConnectPubMedSuche in Google Scholar
  • 35 Bauer KA, Weiss LM, Sparrow D, Vokonas PS, Rosenberg RD. Agingassociated changes in indices of thrombin generation and protein C activation in humans. Normative aging study. J Clin Invest 1987; 80: 1527-34.
    CrossrefPubMedSuche in Google Scholar
  • 36 Doggen CJM, Manger VCats, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors. Increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation 1998; 97: 1037-41.
    CrossrefPubMedSuche in Google Scholar
  • 37 Ardissino D, Peyvandi F, Merlini PA, Colombi E, Mannucci PM. Factor V (Arg506→Gln) mutation in young survivors of myocardial infarction. Thromb Haemost 1996; 75: 701-2.
    Thieme ConnectPubMedSuche in Google Scholar
  • 38 Corral J, Gonzalez-Conejero R, Lozano ML, 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 thrombotic disease. Br J Haematol 1997; 99: 304-7.
    CrossrefPubMedSuche in Google Scholar
  • 39 Ridker PM, Miletich JP, Hennekens CH. G20210A mutation in the prothrombin gene and the risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of American men. Circulation 1999; 99: 999-1004.
    CrossrefPubMedSuche in Google Scholar
  • 40 Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Longstreth Jr WT, Raghunathan TE, Koepsell TD, Reitsma PH. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997; 89: 2817-21.
    PubMedSuche in Google Scholar
  • 41 Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos HL. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women. Blood 1997; 90: 1747-50.
    PubMedSuche in Google Scholar