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
› Author Affiliations
Further Information

Publication History

Received 08 1996

Accepted after revision 11 March 1997

Publication Date:
12 July 2018 (online)

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
  • 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
  • 3 Griffin JH, Evatt B, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 1993; 82: 1989-1993
  • 4 Svensson PJ, Dahlbäck B. Twenty novel families with thrombophilia and inherited resistance to activated protein C. Thromb Haemost 1993; 69: 1252
  • 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
  • 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
  • 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
  • 8 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-1134
  • 9 Rees DC. The population genetics of Factor V Leiden (Arg506Gln). Br J Haematol 1996; 95: 579-586
  • 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
  • 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
  • 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
  • 13 Faioni EM, Franchi F, Asti D, Mannucci PM. Aquired resistance to activated protein C develops during pregnancy. Thromb Haemost 1995; 73: 1373
  • 14 Ehrenforth S, Radtke KP, Zwinge B, Siegert S, Scharrer I. Acquired APC-resistance in patients with lupus anticoagulants. Thromb Haemost 1995; 73: 1368
  • 15 Rodeghiero F, Tosetto A. Some remarks on the epidemiology of thrombotic disorders. Thromb Haemost 1993; 69: 527-528
  • 16 Kleinbaum DG, Kupper LL, Muller KE. Applied regression analysis and other multivariable methods. Boston: PWS-Kent Publishing Company; 1988
  • 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
  • 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
  • 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
  • 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
  • 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
  • 22 Fossati P, Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem 1982; 28: 2077-2080
  • 23 Tosetto A, Rodeghiero F. Diagnosis of APC resistance in patients on oral anticoagulant therapy. Thromb Haemost 1995; 73: 732-733
  • 24 Hosmer DW, Lemeshow S. Applied logistic regression. New York: John Wiley & Sons; 1989
  • 25 Galen RS, Gambino SR. The predictive value and efficiency of medical diagnoses. New York: John Wiley & Sons; 1975
  • 26 Daniel WW. Biostatistics: a foundation for analysis in the health sciences. New York: J. Wiley & Sons; 1987
  • 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
  • 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
  • 29 StataCorp. Stata Statistical Software. 1995
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 38 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood 1987; 69: 454-459
  • 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
  • 40 Jorquera JI, Montoro JM, Fernandez MA, Aznar JA, Aznar J. Modified test for activated protein C resistance. Lancet 1994; 344: 1162-1163
  • 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
  • 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
  • 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
  • 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
  • 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