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Thromb Haemost 1997; 78(02): 859-863
DOI: 10.1055/s-0038-1657642
Rapid Communication
Schattauer GmbH Stuttgart

The VITA Project: Phenotypic Resistance to Activated Protein C and FV Leiden Mutation in the General Population

Alberto Tosetto
The Hemophilia and Thrombosis Center, Department of Hematology, S. Bortolo Hospital, Vicenza, Italy
,
Francesco Rodeghiero
The Hemophilia and Thrombosis Center, Department of Hematology, S. Bortolo Hospital, Vicenza, Italy
,
Edoardo Missiaglia
The Hemophilia and Thrombosis Center, Department of Hematology, S. Bortolo Hospital, Vicenza, Italy
,
Elisabetta Gatto
The Hemophilia and Thrombosis Center, Department of Hematology, S. Bortolo Hospital, Vicenza, Italy
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Publikationsverlauf

Received 08. 1996

Accepted after revision 11. März 1997

Publikationsdatum:
12. Juli 2018 (online)

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Summary

Resistance to activated protein C (APC) has been recently identified as a common abnormality of the clotting system that significantly increases the risk of venous thromboembolism. The distribution of plasma response to APC in the general population and the variables potentially influencing it are however unknown. In this study, we analyzed the data from the first 4,000 subjects enrolled in the Vicenza Thrombophilia and Atherosclerosis (VITA) Project to identify the demographic and laboratory variables affecting the plasma response to APC. Plasma response to APC, expressed as APC-ratio, was significantly influenced not only by the presence of the FV Leiden mutation but also by the aPTT ratio, triglycerides, fibrinogen and cholesterol level and by pill use, ABO blood group, gender, smoke, body-mass index and age. The effect of these variables was independent of the presence of the FV Leiden mutation, and adjustment for their effect improved the discriminating efficiency of the APC-ratio for the presence of the FV Leiden mutation. Notwithstanding adjustment, the APC ratio was unsuitable for screening purposes in the general population (positive predictive value 82.7%).

 

  • References

  • 1 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-1008
    CrossrefPubMedSuche in Google Scholar
  • 2 Koster T, Rosendaal FR, de RondeH, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet 1993; 342: 1503-1506
    CrossrefPubMedSuche in Google Scholar
  • 3 Griffin JH, Evatt B, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 1993; 82: 1989-1993
    PubMedSuche in Google Scholar
  • 4 Svensson PJ, Dahlbäck B. Twenty novel families with thrombophilia and inherited resistance to activated protein C. Thromb Haemost 1993; 69: 1252
    PubMedSuche in Google Scholar
  • 5 Svensson PJ, Dahlbäck B. Novel mechanism for thrombosis characterised by poor anticoagulant response to activated protein C constitutes a major cause of thrombophilia. Thromb Haemost 1993; 69: 999
    PubMedSuche in Google Scholar
  • 6 Tosetto A, Gatto E, Masiero MT, Rodeghiero F. APC-Resistance in the general population. Relationship with other coagulation variables and with venous thrombotic history. Br J Haematol 1994; 87 (Suppl. 01) 188
    PubMedSuche in Google Scholar
  • 7 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de RondeH, van derVelden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67
    CrossrefPubMedSuche in Google Scholar
  • 8 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-1134
    CrossrefPubMedSuche in Google Scholar
  • 9 Rees DC. The population genetics of Factor V Leiden (Arg506Gln). Br J Haematol 1996; 95: 579-586
    CrossrefPubMedSuche in Google Scholar
  • 10 Dahlbäck B. Resistance to activated protein C, the Arg506 to Gin mutation in the Factor V gene, and venous thrombosis. Functional tests and DNA-based assay, pros and cons. Thromb Haemost 1995; 73: 739-742
    Thieme ConnectPubMedSuche in Google Scholar
  • 11 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: 2521-2524
    CrossrefPubMedSuche in Google Scholar
  • 12 Vasse M, Gaucher C, Beufe S, Van DredenP, Monconduit M, Mazurier C. Analysis of Factor VIII in a family with inherited resistance to activated protein C without factor V Leiden. Thromb Haemost 1995; 73: 1369
    PubMedSuche in Google Scholar
  • 13 Faioni EM, Franchi F, Asti D, Mannucci PM. Aquired resistance to activated protein C develops during pregnancy. Thromb Haemost 1995; 73: 1373
    PubMedSuche in Google Scholar
  • 14 Ehrenforth S, Radtke KP, Zwinge B, Siegert S, Scharrer I. Acquired APC-resistance in patients with lupus anticoagulants. Thromb Haemost 1995; 73: 1368
    Thieme ConnectPubMedSuche in Google Scholar
  • 15 Rodeghiero F, Tosetto A. Some remarks on the epidemiology of thrombotic disorders. Thromb Haemost 1993; 69: 527-528
    Thieme ConnectPubMedSuche in Google Scholar
  • 16 Kleinbaum DG, Kupper LL, Muller KE. Applied regression analysis and other multivariable methods. Boston: PWS-Kent Publishing Company; 1988
    Suche in Google Scholar
  • 17 Rodeghiero F, Tosetto A. The VITA Project: Population-based distribution of Protein C Antithrombin III Heparin Cofactor II and plasminogen. Relationship with physiological variables and establishment of reference ranges. Thromb Haemost 1996; 76: 226-233
    Thieme ConnectPubMedSuche in Google Scholar
  • 18 Frezzato M, Tosetto A, Rodeghiero F. Validated questionnaire for the identification of previous personal or familial venous thromboembolism. Am J Epidemiol 1996; 143: 1257-1265
    CrossrefPubMedSuche in Google Scholar
  • 19 Adell K, Ogbonna G. Rapid purification of human DNA from whole blood for potential application in clinical chemistry laboratories. Clin Chem 1990; 36: 261-264
    PubMedSuche in Google Scholar
  • 20 Siedel J, Hagele EO, Ziegerhom J, Wahlefeld AW. Reagent for the enzymatic determination of serum total cholesterol with improved lipolytic efficiency. Clin Chem 1983; 29: 1075-1080
    PubMedSuche in Google Scholar
  • 21 Wamick GR, Benderson J, Albers JJ. Dextran sulfate-Mg2+precipitation procedure for quantitation of high-density-lipoprotein cholesterol. Clin Chem 1982; 28: 1379-1388
    PubMedSuche in Google Scholar
  • 22 Fossati P, Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem 1982; 28: 2077-2080
    PubMedSuche in Google Scholar
  • 23 Tosetto A, Rodeghiero F. Diagnosis of APC resistance in patients on oral anticoagulant therapy. Thromb Haemost 1995; 73: 732-733
    Thieme ConnectPubMedSuche in Google Scholar
  • 24 Hosmer DW, Lemeshow S. Applied logistic regression. New York: John Wiley & Sons; 1989
    Suche in Google Scholar
  • 25 Galen RS, Gambino SR. The predictive value and efficiency of medical diagnoses. New York: John Wiley & Sons; 1975
    Suche in Google Scholar
  • 26 Daniel WW. Biostatistics: a foundation for analysis in the health sciences. New York: J. Wiley & Sons; 1987
    Suche in Google Scholar
  • 27 Tosetto A, Gatto E, Masiero MT, Rodeghiero F. Parallel line bioassay or single-point calibration for the establishment of reference ranges. Thromb Res 1994; 75: 479-483
    CrossrefPubMedSuche in Google Scholar
  • 28 Reed AH, Henry RJ, Mason WB. Influence of statistical method used on the resulting estimate of normal range. Clin Chem 1971; 17: 275-284
    PubMedSuche in Google Scholar
  • 29 StataCorp. Stata Statistical Software. 1995
    PubMedSuche in Google Scholar
  • 30 Cadroy Y, Sié P, Boneu B. Frequency of a defective response to activated protein C in patients with a history of venous thrombosis. Blood 1994; 83: 2008-2009
    PubMedSuche in Google Scholar
  • 31 Henkens CM, van der Meer J, van der Schaaf W, Pelsma PM, Geerards S, Seinen A, Bom VJ. Sensitivity to activated protein C (APC) related with sex, use of oral contraceptives and FVIII. Thromb Haemost 1995; 73: 1120
    Thieme ConnectPubMedSuche in Google Scholar
  • 32 Olivieri O, Friso S, Manzato F, Guella A, Bemardi F, Longhi B, Girelli D, Azzini M, Brocco G, Russo C, Corrocher R. Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol 1995; 91: 465-470
    CrossrefPubMedSuche in Google Scholar
  • 33 de RondeH, Bertina RM. Laboratory diagnosis of APC-Resistance: a critical evaluation of the test and the development of diagnostic criteria. Thromb Haemost 1994; 72: 880-886
    Thieme ConnectPubMedSuche in Google Scholar
  • 34 Lindberg UB, Crona N, Stigendal L, Teger-Nilsson AC, Silfverstolpe G. A comparison between effects of estradiol valerate and low dose ethinyl estradiol on haemostasis parameters. Thromb Haemost 1989; 61: 65-69
    Thieme ConnectPubMedSuche in Google Scholar
  • 35 Boschetti C, Cortellaro M, Nencioni T, Bertolli V, Della VolpeA, Zanussi C. Short-and long-term effects of hormone replacement therapy (transder-mal estradiol vs oral conjugate equine estrogens, combined with medroxyprogesterone acetate) on blood coagulation factors in postmenopausal women. Thromb Res 1991; 62: 1-8
    CrossrefPubMedSuche in Google Scholar
  • 36 Vasse M, Leduc O, Borg J, Chretien MH, Monconduit M. Resistance to activated protein C: evaluation of three functional assays. Thromb Res 1994; 76: 47-59
    CrossrefPubMedSuche in Google Scholar
  • 37 Rao AK, Elliott D, Stadnicki A, DeLa CadenaR. High levels of plasma FVIIIC impair anticoagulant response to activated protein C. Thromb Haemost 1995; 73: 1126
    Thieme ConnectPubMedSuche in Google Scholar
  • 38 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood 1987; 69: 454-459
    PubMedSuche in Google Scholar
  • 39 Solberg HE. Approved recommendation (1987) on the theory of reference values. Part 5. Determination of reference limits. J Clin Chem Clin Biochem 1987; 25: 645-656
    PubMedSuche in Google Scholar
  • 40 Jorquera JI, Montoro JM, Fernandez MA, Aznar JA, Aznar J. Modified test for activated protein C resistance. Lancet 1994; 344: 1162-1163
    PubMedSuche in Google Scholar
  • 41 Trossaert M, Conard J, Horellou HM, Samama MM, Ireland H, Bayston TA, Lane DA. Modified APC resistance assay for patients on oral anticoagulants. Lancet 1994; 344: 1709
    PubMedSuche in Google Scholar
  • 42 Svensson PJ, Zoller B, Dahlbäck B. Evaluation of original and modified APC-resistance test in unselected outpatients with clinically suspected thrombosis and in healthy controls. Thromb Haemost 1997; 77: 332-335
    Thieme ConnectPubMedSuche in Google Scholar
  • 43 Trossaert M, Conard J, Horellou HM, Elalamy I, Samama MM. The modified APC resistance test in the presence of Factor V deficient plasma can be used in patients without oral anticoagulant. Thromb Haemost 1996; 75: 521-522
    Thieme ConnectPubMedSuche in Google Scholar
  • 44 Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep vein thrombosis. Lancet 1995; 345: 152-155
    CrossrefPubMedSuche in Google Scholar
  • 45 Thompson SG, Kienast J, Pyke SDM, Haverkate F, van deLoo JCV. Hemostatic risk factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 332: 635-641
    CrossrefPubMedSuche in Google Scholar