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Thromb Haemost 2002; 88(01): 5-11
DOI: 10.1055/s-0037-1613145
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Schattauer GmbH

Effects of Hereditary and Acquired Risk Factors of Venous Thrombosis on a Thrombin Generation-Based APC Resistance Test

Joyce Curvers
1   Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
,
M. Christella L. G. D. Thomassen
1   Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
,
Janet Rimmer
2   Sheffield Hemophilia and Thrombosis Center, Royal Hallamshire Hospital, Sheffield, United Kingdom
,
Karly Hamulyak
3   Department of Haematology, University Hospital Maastricht, Maastricht University, Maastricht, Groningen, The Netherlands
,
Jan van der Meer
4   Division of Haemostasis, Thrombosis and Rheology, University Hospital Groningen, Groningen, The Netherlands
,
Guido Tans
1   Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
,
F. Eric Preston
2   Sheffield Hemophilia and Thrombosis Center, Royal Hallamshire Hospital, Sheffield, United Kingdom
,
Jan Rosing
1   Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 14 November 2002

Accepted 02 March 2002

Publication Date:
09 December 2017 (online)

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Summary

Background

Several hereditary and acquired risk factors for venous thromboembolism (VTE) are associated with impaired down-regulation of thrombin formation via the protein C pathway. To identify individuals at risk, functional tests are needed that estimate the risk to develop venous thrombosis.

Method

We determined the effects of hereditary and acquired risk factors of venous thrombosis on an APC resistance test that quantifies the influence of APC on the time integral of thrombin formation (the endogenous thrombin potential, ETP) initiated in plasma via the extrinsic coagulation pathway. APC sensitivity ratios (APCsr) were determined in plasma from carriers of factor VLeiden (n = 56) or prothrombin G20210A (n = 18), of individuals deficient in antithrombin (n = 9), protein C (n = 7) or protein S (n = 14) and of women exposed to acquired risk factors such as hormone replacement therapy (n = 49), oral contraceptive use (n = 126) or pregnancy (n = 35). We also analysed combinations of risk factors (n = 60).

Results

The thrombin generation-based APC resistance test was sensitive for the factor VLeiden and prothrombin G20210A mutation, to protein S deficiency, hormone replacement therapy, oral contraceptive use and pregnancy. The assay was not influenced by antithrombin-or protein C deficiency. The presence of more than one risk factor of venous thrombosis resulted in more pronounced APC resistance. The APCsr of individuals with a single or combined risk factors of VTE correlated well with reported risk increases.

Interpretation

The thrombin generation-based APC resistance test identifies individuals at risk for venous thrombosis due to acquired risk factors and/or hereditary thrombophilic disorders that affect the protein C pathway.

Keywords

Hereditary APC resistance - acquired APC resistance - thrombin generation-based test
 

  • References

  • 1 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-73.
    CrossrefPubMedSearch in Google Scholar
  • 2 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.
    CrossrefPubMedSearch in Google Scholar
  • 3 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 plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
    PubMedSearch in Google Scholar
  • 4 Bertina RM. Molecular risk factors for thrombosis. Thromb Haemost 1999; 82: 601-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 de Visser MC, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood 1999; 93: 1271-6.
    PubMedSearch in Google Scholar
  • 6 Rodeghiero F, Tosetto A. Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism. Ann Intern Med 1999; 130: 643-50.
    CrossrefPubMedSearch in Google Scholar
  • 7 Kraaijenhagen RA, in’t PSAnker, Koopman MM, Reitsma PH, Prins MH, van den Ende A, Buller HR. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000; 83: 5-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 van Hylckama AVlieg, van der Linden IK, Bertina RM, Rosendaal FR. High levels of factor IX increase the risk of venous thrombosis. Blood 2000; 95: 3678-82.
    PubMedSearch in Google Scholar
  • 9 Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med 2000; 342: 696-701.
    CrossrefPubMedSearch in Google Scholar
  • 10 Dahlback B, Carlsson M, Svensson PI. 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: 1004-8.
    CrossrefPubMedSearch in Google Scholar
  • 11 Rosing J, Tans G. Coagulation factor V: an old star shines again. Thromb Haemost 1997; 78: 427-33.
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Nicolaes GAF, Thomassen M, Tans G, Rosing J, Hemker HC. Effect of activated protein C on thrombin generation and on the thrombin potential in plasma of normal and APC-resistant individuals. Blood Coagul Fibrinolysis 1997; 08 (01) 28-38.
    CrossrefPubMedSearch in Google Scholar
  • 13 Koster T, Rosendaal FR, de Ronde H, Briet E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-6.
    CrossrefPubMedSearch in Google Scholar
  • 14 Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85: 1504-8.
    PubMedSearch in Google Scholar
  • 15 Lunghi B, Iacoviello L, Gemmati D, Dilasio MG, Castoldi E, Pinotti M, Castaman G, Redaelli R, Mariani G, Marchetti G, Bernardi F. Detection of new polymorphic markers in the factor V gene: association with factor V levels in plasma. Thromb Haemost 1996; 75: 45-8.
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Chan WP, Lee CK, Kwong YL, Lam CK, Liang R. A novel mutation of Arg306 of factor V gene in Hong Kong Chinese. Blood 1998; 91: 1135-9.
    PubMedSearch in Google Scholar
  • 17 Williamson D, Brown K, Luddington R, Baglin C, Baglin T. Factor V Cambridge: a new mutation (Arg306Thr) associated with resistance to activated protein C. Blood 1998; 91: 1140-4.
    PubMedSearch in Google Scholar
  • 18 Meinardi JR, Henkens CMA, Heringa MP, van der Meer J. Acquired APC resistance related to oral contraceptives and pregnancy and its possible implications for clinical practice. Blood Coagul Fibrinolysis 1997; 08 (02) 152-4.
    CrossrefPubMedSearch in Google Scholar
  • 19 Rosing J, Tans G, Nicolaes GAF, Thomassen M, van Oerle R, van derPloeg P, Heijnen P, Hamulyak K, Hemker HC. Oral contraceptives and venous thrombosis: Different sensitivities to activated protein C in women using second- and third-generation oral contraceptives. Br J Haematol 1997; 97 (01) 233-8.
    CrossrefPubMedSearch in Google Scholar
  • 20 Rosing J, Middeldorp S, Curvers J, Christella M, Thomassen LG, Nicolaes GA, Meijers JC, Bouma BN, Buller HR, Prins MH, Tans G. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet 1999; 354: 2036-40.
    CrossrefPubMedSearch in Google Scholar
  • 21 Vandenbroucke JP, Rosendaal FR. End of the line for “third-generation-pill” controversy?. Lancet 1997; 349: 1113-4.
    CrossrefPubMedSearch in Google Scholar
  • 22 Curvers J, Thomassen MCLGD, Nicolaes GAF, van Oerle R, Hamulyak K, Hemker HC, Tans G, Rosing J. Acquired APC resistance and oral contraceptives: differences between two functional tests. Br J Haematol 1999; 105: 88-94.
    CrossrefPubMedSearch in Google Scholar
  • 23 Nicolaes GAF, Thomassen M, vanOerle R, Hamulyak K, Hemker HC, Tans G, Rosing J. A prothrombinase-based assay for detection of resistance to activated protein C. Thromb Haemost 1996; 76 (03) 404-10.
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Makris M, Leach M, Beauchamp NJ, Daly ME, Cooper PC, Hampton KK, Bayliss P, Peake IR, Miller GJ, Preston FE. Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S. Blood 2000; 95: 1935-41.
    PubMedSearch in Google Scholar
  • 25 Tripodi A, Chantarangkul V, Mannucci PM. Hyperprothrombinemia may result in acquired activated protein C resistance. Blood 2000; 96: 3295-6.
    PubMedSearch in Google Scholar
  • 26 Smirnov MD, Safa O, Esmon NL, Esmon CT. Inhibition of activated protein C anticoagulant activity by prothrombin. Blood 1999; 94: 3839-46.
    PubMedSearch in Google Scholar
  • 27 Rosing J, Hoekema L, Nicolaes GAF, Thomassen MCLGD, Hemker HC, Varadi K, Schwarz HP, Tans G. Effects of protein S and factor Xa on peptide bond cleavages during inactivation of factor Va and factor VaR506Q by activated protein C. J Biol Chem 1995; 270: 27852-8.
    CrossrefPubMedSearch in Google Scholar
  • 28 Zoller B, Berntsdotter A, Garcia Pde Frutos, Dahlback B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995; 85: 3518-23.
    PubMedSearch in Google Scholar
  • 29 Wielders S, Mukherjee M, Michiels J, Rijkers DT, Cambus JP, Knebel RW, Kakkar V, Hemker HC, Beguin S. The routine determination of the endogenous thrombin potential, first results in different forms of hyper- and hypocoagulability. Thromb Haemost 1997; 77: 629-36.
    Thieme ConnectPubMedSearch in Google Scholar
  • 30 Koh KK, Home 3rd MK, Cannon 3rd RO. Effects of hormone replacement therapy on coagulation, fibrinolysis, and thrombosis risk in postmenopausal women. Thromb Haemost 1999; 82: 626-33.
    Thieme ConnectPubMedSearch in Google Scholar
  • 31 van der Meer FJ, Koster T, Vandenbroucke JP, Briet E, Rosendaal FR. The Leiden Thrombophilia Study (LETS). Thromb Haemost 1997; 78: 631-5.
    Thieme ConnectPubMedSearch in Google Scholar
  • 32 Tans G, Rosendaal FR, Curvers J, Thomassen MCLGD, Bertina RM, Rosing J. APC Resistance Determined with the Endogenous Thrombin Potential Is Associated with Venous Thrombosis: A Blinded Clinical Evaluation. Thromb Haemost 1999; Suppl: 202-3.
    PubMedSearch in Google Scholar
  • 33 Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996; 348: 981-3.
    CrossrefPubMedSearch in Google Scholar
  • 34 Prevention of venous thrombosis and pulmonary embolism. NIH Consensus Development. JAMA 1986; 256: 744-9.
    CrossrefPubMedSearch in Google Scholar
  • 35 Rosendaal FR. Risk factors for venous thrombotic disease. Thromb Haemost 1999; 82: 610-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 36 Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1995; 346: 1575-82.
    CrossrefPubMedSearch in Google Scholar
  • 37 Salomon O, Steinberg DM, Zivelin A, Gitel S, Dardik R, Rosenberg N, Berliner S, Inbal A, Many A, Lubetsky A, Varon D, Martinowitz U, Seligsohn U. Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment. Arterioscler Thromb Vasc Biol 1999; 19: 511-8.
    CrossrefPubMedSearch in Google Scholar
  • 38 Lowe G, Woodward M, Vessey M, Rumley A, Gough P, Daly E. Thrombotic variables and risk of idiopathic venous thromboembolism in women aged 45-64 years. Relationships to hormone replacement therapy. Thromb Haemost 2000; 83: 530-5.
    Thieme ConnectPubMedSearch in Google Scholar
  • 39 Vandenbroucke JP, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453-7.
    CrossrefPubMedSearch in Google Scholar
  • 40 Dilley A, Austin H, El-Jamil M, Hooper WC, Barnhart E, Evatt BL, Sullivan PS, Ellingsen D, Patterson-Barnett A, Eller D, Randall H, Philipp C. Genetic factors associated with thrombosis in pregnancy in a United States population. Am JObstet Gynecol 2000; 183: 1271-7.
    PubMedSearch in Google Scholar
  • 41 Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348: 977-80.
    CrossrefPubMedSearch in Google Scholar
  • 42 Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346: 1589-93.
    CrossrefPubMedSearch in Google Scholar
  • 43 Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Biiller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing third-generation progestagen. Lancet 1995; 346: 1593-6.
    CrossrefPubMedSearch in Google Scholar
  • 44 Grandone E, Margaglione M, Colaizzo D, D’Andrea G, Cappucci G, Brancaccio V, Di Minno G. Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations. Am J Obstet Gynecol 1998; 179: 1324-8.
    CrossrefPubMedSearch in Google Scholar
  • 45 Aznar J, Vaya A, Estelles A, Mira Y, Segui R, Villa P, Ferrando F, Falco C, Corella D, Espana F. Risk of venous thrombosis in carriers of the prothrombin G20210A variant and factor V Leiden and their interaction with oral contraceptives. Haematologica 2000; 85: 1271-6.
    PubMedSearch in Google Scholar
  • 46 Gerhardt A, Scharf RE, Beckmann MW, Starve S, Bender HG, Pillny M, Sandmann W, Zotz RB. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000; 342: 374-80.
    CrossrefPubMedSearch in Google Scholar