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Thromb Haemost 1996; 76(02): 226-233
DOI: 10.1055/s-0038-1650559
Original Article
Schattauer GmbH Stuttgart

The VITA Project: Population-based Distributions of Protein C, Antithrombin III, Heparin-cofactor II and Plasminogen -Relationship with Physiological Variables and Establishment of Reference Ranges

Francesco Rodeghiero
The Hemophilia and Thrombosis Center, Department of Hematology, S. Bortolo Hospital, Vicenza, Italy
,
Alberto Tosetto
The Hemophilia and Thrombosis Center, Department of Hematology, S. Bortolo Hospital, Vicenza, Italy
› Author Affiliations
Further Information

Publication History

Received 21 November 1995

Accepted after resubmission 26 April 1996

Publication Date:
10 July 2018 (online)

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Summary

A proper laboratory diagnosis of inherited thrombophilia due to defects of the coagulation system may be obtained only by a stringent definition of the diagnostic reference ranges taking into account the influence exerted by major physiological variables. To this purpose, we analyzed the data for Protein C, Antithrombin III, Heparin-Cofactor II and plasminogen coming from the first 4,000 subjects enrolled in the VITA Project. This is the first study that allows the establishment of reference ranges in a non-selected, active population using stringent standardization of clinical and laboratory measurements and multivariable regression techniques for data analysis.

Serum triglycerides and total cholesterol, together with plasma fibrinogen were found to influence the functional plasma level of the four considered proteins. Menopause increased AT-III concentration, while pill use increased Heparin-Cofactor II and plasminogen. PT and PTT ratio, gender, age, smoking, body-mass index, HDL cholesterol and blood group had minor effects. The effect of these variables should be taken into account for both clinical and epidemiologic purposes, using appropriate reference ranges or covariance analysis for adjustment.

 

  • References

  • 1 Mannucci PM, Tripodi A. Laboratory screening of inherited thrombotic syndromes. Thromb Haemost 1987; 57: 247-251
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Tosetto A, Frezzato M, Rodeghiero F. Family history and inherited thrombophilia. Br J Haematol 1995; 89: 227-228
    CrossrefPubMedGoogle Scholar
  • 3 Allaart CF, Poort SR, Rosendaal FR, Reitsma PH, Bertina RM, Briet E. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet 1993; 341: 134-138
    CrossrefPubMedGoogle Scholar
  • 4 Miletich JP, Prescott SM, White R, Majerus PW, Bovill EG. Inherited predisposition to thrombosis. Cell 1993; 72: 477-480
    CrossrefPubMedGoogle Scholar
  • 5 Tait RC, Walker ID, Islam SIAM, McCall F, Conkie JA, Wight M, Mitchell R, Davidson JF. Protein C activity in healthy volunteers. Influence of age, sex, smoking and oral contraceptives. Thromb Haemost 1993; 70: 281-285
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Tait RC, Walker ID, Islam SIAM, McCall F, Conkie JA, Mitchell R, Davidson JF. Influence of demographic factors on antithrombin III activity in a healthy population. Br J Haematol 1993; 84: 476-480
    CrossrefPubMedGoogle Scholar
  • 7 Tait RC, Walker ID, Conkie JA, Islam SIAM, McCall F, Mitchell R, Davidson JF. Plasminogen levels in healthy volunteers. Influence of age, sex, smoking and oral contraceptives. Thromb Haemost 1992; 68: 506-510
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Dolan G, Neal K, Cooper P, Brown P, Preston FE. Protein C, antithrombin III and plasminogen: effect of age, sex and blood group. Br J Haematol 1994; 86: 798-803
    CrossrefPubMedGoogle Scholar
  • 9 Rodeghiero F, Tosetto A. Some remarks on the epidemiology of thrombotic disorders. Thromb Haemost 1993; 69: 527-528
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Kleinbaum DG, Kupper LL, Muller KE. Applied regression analysis and other multivariable methods. Boston: PWS-Kent Publishing Company 1988
    PubMedGoogle Scholar
  • 11 Ben-Tal O, Zivelin A, Seligsohn U. The relative frequency of hereditary thrombotic disorders among 107 patients with thrombophilia in Israel. Thromb Haemost 1989; 61: 50-54
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Gladson CL, Scharrer I, Hach V, Beck KH, Griffin JH. The frequency of type I heterozygous protein S and protein C deficiency in 141 unrelated young patients with venous thrombosis. Thromb Haemost 1988; 59: 18-22
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Pabinger I, Brucker S, Kyrle PA, Schneider B, Kominger HC, Niessner H, Lechner K. Hereditary deficiency of antithrombin III, protein C and protein S: prevalence in patients with a history of venous thrombosis and criteria for rational patient screening. Blood Coagul Fibrinolysis 1992; 3: 547-553
    CrossrefPubMedGoogle Scholar
  • 14 Vikydal R, Kominger C, Kyrle PA, Niessner H, Pabinger I, Thaler E, Lechner K. The prevalence of hereditary antithrombin-III deficiency in patients with a history of venous thromboembolism. Thromb Haemost 1985; 54: 744-745
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Miletich J, Sherman L, Broze Jr G. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 991-996
    CrossrefPubMedGoogle Scholar
  • 16 Frezzato M, Tosetto A, Rodeghiero F. Validation of a questionnaire for the diagnosis of previous venous thromboembolism. Br J Haematol 1994; 87 (Suppl. 01) 79
    PubMedGoogle Scholar
  • 17 Rose GA. The diagnosis of ischemic heart pain and intermittent claudication in field surveys. Bull WHO 1962; 27: 645-658
    PubMedGoogle Scholar
  • 18 The ARIC Investigators. The Atherosclerosis Risk In Communities (ARIC) study: design and objectives. Am J Epidemiol 1989; 129: 687-702
    CrossrefPubMedGoogle Scholar
  • 19 Rossi E, Mondonico P, Lombardi A, Preda L. Method for the determination of functional (clottable) fibrinogen by the new family of ACL coagulometers. Thromb Res 1988; 52: 453-468
    CrossrefPubMedGoogle Scholar
  • 20 Palareti G, Maccaferri M, Manotti C, Tripodi A, Chantarangkul V, Rodeghiero F, Ruggeri M, Mannucci PM. on behalf of C.I.S.M.E.L. Fibrinogen assays: a collaborative study of six different methods. Clin Chem 1991; 37: 714-719
    PubMedGoogle Scholar
  • 21 Teien AN, Abildgaard U, Hook M. The anticoagulant effect of heparan sulfate and dermatan sulfate. Thromb Res 1976; 8: 859-867
    CrossrefPubMedGoogle Scholar
  • 22 Walker PA, Bauer KA, McDonagh J. A simple, automated functional assay for protein C. Am J Clin Pathol 1989; 92: 210-213
    CrossrefPubMedGoogle Scholar
  • 23 Abildgaard U, Lie M, Odegard OR. Antithrombin (heparin cofactor) assay with new chromogenic substrate (S2238 and Chromozyn TH). Thromb Res 1977; 11: 549-553
    CrossrefPubMedGoogle Scholar
  • 24 Vinazzer H, Stocker K. Heparin cofactor II: experimental approach to a new assay and clinical results. Thromb Res 1991; 61: 235-241
    CrossrefPubMedGoogle Scholar
  • 25 Friberger P, Knos M, Gustavsson S, Aurell L, Claeson G. Methods for the determination of plasmin, antiplasmin and plasminogen by means of substrate S-2251. Haemostasis 1978; 7: 138-145
    PubMedGoogle Scholar
  • 26 Finney DJ. Statistical methods in biologic assay. London: C. Griffin: 1978
  • 27 Tosetto A, Gatto E, Masiero MT, Rodeghiero F. Parallel line bioassay or singlepoint calibration for the establishment of reference ranges. Thromb Res 1994; 75: 479-483
    CrossrefPubMedGoogle Scholar
  • 28 Tosetto A, Rodeghiero F. Parallel line bioassay in coagulation laboratory. A program for personal computer use and an example application to ristocetin cofactor assay. Clin Lab Haematol 1991; 13: 371-377
    PubMedGoogle Scholar
  • 29 Hubbard AR. Standardization of protein C in plasma: establishment of an international standard. Thromb Haemost 1988; 59: 464-467
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Siedel J, Hagele EO, Ziegerhorn J, Wahlefeld AW. Reagent for the enzymatic determination of serum total cholesterol with improved lipolytic efficiency. Clin Chem 1983; 29: 1075-1080
    PubMedGoogle Scholar
  • 31 Abell LL, Levy BB, Brodie BB, Kendall FE. A simplified method for estimation of total cholesterol in serum and demonstration of its specificity. J Biol Chem 1952; 195: 357-366
    PubMedGoogle Scholar
  • 32 Warnick GR, Benderson J, Albers JJ. Dextran sulfate-Mg2+ precipitation procedure for quantitation of high-density-lipoprotein cholesterol. Clin Chem 1982; 28: 1379-1388
    PubMedGoogle Scholar
  • 33 Fossati P, Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem 1982; 28: 2077-2080
    PubMedGoogle Scholar
  • 34 Conlan MG, Folsom AR, Finch A, Davis CE, Marcucci G, Sorlie P, Wu KK. Antithrombin III: association with age, race, sex and cardiovascular risk factors. Thromb Haemost 1994; 72: 551-556
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Conlan MG, Folsom AR, Finch A, Davis CE, Sorlie P, Wu KK. Correlation of plasma protein C levels with cardiovascular risk factors in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) study. Thromb Haemost 1993; 70: 762-767
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Daniel WW. Biostatistics: a foundation for analysis in the health sciences. New York: J. Wiley & Sons: 1987
  • 37 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
    PubMedGoogle Scholar
  • 38 Reed AH, Henry RJ, Mason WB. Influence of statistical method used on the resulting estimate of normal range. Clin Chem 1971; 17: 275-284
    PubMedGoogle Scholar
  • 39 Norusis MJ. SPSS/PC+ Statistics 4.0. Chicago: SPSS, Inc. 1990
    PubMedGoogle Scholar
  • 40 Solberg HE. Establishment and use of reference values. In: Fundamentals of Clinical Chemistry Tietz NW. ed. W. B. Saunders Co.,; Philadelphia: 1987: 197-212
  • 41 Miller GJ, Walter SJ, Stirling Y, Thompson SG, Esnouf MP, Meade TW. Assay of factor VII activity by two techniques: evidence for increased conversion of VII to alpha Vila in hyperlipidaemia, with possible implications for ischaemic heart disease. Br J Haematol 1985; 59: 249-258
    CrossrefPubMedGoogle Scholar
  • 42 Tait RC, Walker ID, Islam SIAM, Mitchell R, Conkie JA, McCall F, Davidson JF. Age related changes in protein C activity in healthy adult males. Thromb Haemost 1991; 65: 326-327
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Mackie IJ, Segal H, Burren T, Gallimore M, Walsh KJ, Robinson G, Machin SJ. Heparin cofactor II levels are increased by the use of combined oral contraceptives. Blood Coagul Fibrinolysis 1990; 1: 647-651
    PubMedGoogle Scholar
  • 44 Massouh M, Jatoi A, Gordon EM, Ratnoff OD. Heparin cofactor II activity in plasma during pregnancy and oral contraceptive use. J Lab Clin Med 1989; 114: 697-699
    PubMedGoogle Scholar
  • 45 Andersson TR, Larsen ML, Handeland GF, Abildgaard U. Heparin cofactor II activity in plasma: application of an automated assay method to the study of a normal adult population. Scand J Haematol 1986; 36: 96-102
    PubMedGoogle Scholar