Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography

Svetlana N. T. chaikovski; Huib A. A. M. van Vliet; M.Christella L. G. D. Thomassen; Rogier M. Bertina; Frits R. Rosendaal; Per-Morten Sandset; Frans M. Helmerhorst; Guido Tans; Jan Rosing

doi:10.1160/TH07-07-0439

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 98(06): 1350-1356
DOI: 10.1160/TH07-07-0439

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography

Authors

Svetlana N. T. chaikovski

¹Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
Huib A. A. M. van Vliet

²Department of Gynecology, Division of Reproductive Medicine, Leiden University Medical Center, Leiden, The Netherlands
M.Christella L. G. D. Thomassen

¹Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
Rogier M. Bertina

³Department of Hematology, Haemostasis and Thrombosis Research Center, Leiden University Medical Center, Leiden, the Netherlands
Frits R. Rosendaal

³Department of Hematology, Haemostasis and Thrombosis Research Center, Leiden University Medical Center, Leiden, the Netherlands

⁴Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
Per-Morten Sandset

⁵Department of Hematology, Faculty Division, Ullevål University Hospital, Oslo, Norway
Frans M. Helmerhorst

²Department of Gynecology, Division of Reproductive Medicine, Leiden University Medical Center, Leiden, The Netherlands

⁴Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
Guido Tans

¹Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
Jan Rosing

¹Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands

Abstract

Summary

In a study population consisting of healthy men (n=8), women not using oral contraceptives (OC) (n=28) and women using different kinds of OC (n=187) we used calibrated automated thrombography (CAT) in the absence and presence of added activated protein C (APC) to compare parameters that can be obtained from thrombin generation curves, i.e. lag time, time to peak, peak height and endogenous thrombin potential (ETP). Both with and without APC, plasmas of OC users exhibited the shortest lag time and time to peak, and the highest peak height and ETP. In the absence of APC none of these parameters differed between users of OC containing different progestogens. In contrast, in the presence of APC shorter lag times and time to peak, and higher peak height and ETP were observed in plasma of users of gestodene-,desogestrel-,drospirenone- and cyproterone acetate-containing OC than in plasma of users of levonorgestrel-containing OC. The ETP determined in the absence of APC (ETP-APC) had no predictive value for the APCsr (r=0.11; slope 0.9×10^–3; 95%CI: –0.1×10^–3 to 2.0×10^–3) whereas the ETP measured in the presence of APC (ETP+APC) showed an excellent correlation with the APCsr (r=0.95; slope 6.6×10^–3; 95%CI: 6.3×10^–3 to 6.9×10^–3) indicating that the APCsr is entirely determined by the ETP_+APC. In conclusion, OC use increases thrombin generation, but differential effects of second and third generation OCs on the protein C system likely determine the differences in the risk of venous thrombosis between these kinds of OC.

Keywords

APC resistance - oral contraceptives - thrombin generation

Full Text

References

References
1 Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Female hormones and thrombosis. Arterioscler Thromb Vasc Biol 2002; 22: 201-210.
2 Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. Br Med J 2001; 323: 131-134.
3 Dargaud Y, Trzeciak MC, Bordet JC. et al. Use of calibrated automated thrombinography +/- thrombomodulin to recognise the prothrombotic phenotype. Thromb Haemost 2006; 96: 562-567.
4 Hemker HC, Al Dieri R, De Smedt E. et al. Thrombin generation, a function test of the haemostaticthrombotic system. Thromb Haemost 2006; 96: 553-561.
5 Rotteveel RC, Roozendaal KJ, Eijsman L. et al. The influence of oral contraceptives on the time-integral of thrombin generation (thrombin potential). Thromb Haemost 1993; 70: 959-962.
6 Nicolaes GA, Thomassen MC, Tans G. et al. Effect of activated protein C on thrombin generation and on the thrombin potential in plasma of normal and APCresistant individuals. Blood Coagul Fibrinolysis 1997; 8: 28-38.
7 Curvers J, Thomassen MC, Nicolaes GA. et al. Acquired APC resistance and oral contraceptives: differences between two functional tests. Br J Haematol 1999; 105: 88-94.
8 Rosing J, Middeldorp S, Curvers J. et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet 1999; 354: 2036-2040.
9 Dahlback 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.
10 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
11 Tripodi A, Chantarangkul V, Mannucci PM. Hyperprothrombinemia may result in scquired activated protein C reistance. Blood 2000; 96: 3295-3296.
12 Laffan MA, Manning R. The influence of factor VIII on measurement of activated protein C resistance. Blood Coagul Fibrinolysis 1996; 7: 761-765.
13 Curvers J, Thomassen MC, Rimmer J. et al. Effects of hereditary and acquired risk factors of venous thrombosis on a thrombin generation-based APC resistance test. Thromb Haemost 2002; 88: 5-11.
14 Shu H, Wramsby M, Bokarewa M. et al. Decrease in protein C inhibitor activity and acquired APC resistanceduring normal pregnancy. J Thromb Thrombolysis 2000; 9: 277-281.
15 Olivieri O, Friso S, Manzato F. et al. Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol 1995; 91: 465-470.
16 Rosing J, Tans G, Nicolaes GA. et al. 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: 233-238.
17 Hoibraaten E, Mowinckel MC, de Ronde H. et al. Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, doubleblind, placebo-controlled trial. Br J Haematol 2001; 115: 415-420.
18 Ehrenforth S, Radtke KP, Scharrer I. Acquired activated protein C-resistance in patients with lupus anticoagulants. Thromb Haemost 1995; 74: 797-798.
19 Koster T, Rosendaal FR, de Ronde H. et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-1506.
20 Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-522.
21 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: 1271-1276.
22 Tans G, van Hylckama Vlieg A, Thomassen MC. et al. Activated protein C resistance determined with a thrombin generation-based test predicts for venous thrombosis in men and women. Br J Haematol 2003; 122: 465-470.
23 Hemker HC, Giesen P, Al Dieri R. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4-15.
24 Koenen RR, Christella M, Thomassen LG. et al. Effect of oral contraceptives on the anticoagulant activity of protein S in plasma. Thromb Haemost 2005; 93: 853-859.
25 van Vliet HA, Frolich M, Christella M. et al. Association between sex hormone-binding globulin levels and activated protein C resistance in explaining the risk of thrombosis in users of oral contraceptives containing different progestogens. Hum Reprod 2005; 20: 563-568.
26 van Vliet HA, Winkel TA, Noort I. et al. Prothrombotic changes in users of combined oral contraceptives containing drospirenone and cyproterone acetate. J Thromb Haemost 2004; 2: 2060-2062.
27 Bertina RM, van der Marel-van Nieuwkoop W, Loeliger EA. Spectrophotometric assays of prothrombin in plasma of patients using oral anticoagulants. Thromb Haemost 1979; 42: 1296-1305.
28 Dahm A, Van Hylckama Vlieg A, Bendz B. et al. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 2003; 101: 4387-4392.
29 Koster T, Rosendaal FR, Briet E. et al. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood 1995; 85: 2756-2761.
30 Giri TK, Hillarp A, Hardig Y. et al. A new direct, fast and quantitative enzyme-linked ligandsorbent assay for measurement of free protein S antigen. Thromb Haemost 1998; 79: 767-772.
31 Brugge JM, Tans G, Rosing J. et al. Protein S levels modulate the activated protein C resistance phenotype induced by elevated prothrombin levels. Thromb Haemost 2006; 95: 236-242.
32 Kemmeren JM, Algra A, Meijers JC. et al. Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor VLeiden mutation: a randomized trial. Blood 2004; 103: 927-933.
33 Newton JR. Classification and comparison of oral contraceptives containing new generation progestogens. Hum Reprod Update 1995; 1: 231-263.
34 de Visser MC, van Hylckama Vlieg A, Tans G. et al. Determinants of the APTT- and ETP-based APC sensitivity tests. J Thromb Haemost 2005; 3: 1488-1494.
35 Gris JC, Jamin C, Benifla JL. et al. APC resistance and third-generation oral contraceptives: Acquired resistance to activated protein C, oral contraceptives and the risk of thromboembolic disease. Hum Reprod 2001; 16: 3-8.
36 Gris JC, Nouvellon-Cochery E, Mares P. Increased resistance to activated protein C in women taking thirdgeneration oral contraceptives?. Blood 2004; 104. 1907 author reply 1908–1909.
37 Tans G, Curvers J, Middeldorp S. et al. A randomized cross-over study on the effects of levonorgestreland desogestrel-containing oral contraceptives on the anticoagulant pathways. Thromb Haemost 2000; 84: 15-21.
38 Middeldorp S, Meijers JC, van den Ende AE. et al. Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a crossover study. Thromb Haemost 2000; 84: 4-8.
39 Hezard N, Bouaziz-Borgi L, Remy MG. et al. Utility of thrombin-generation assay in the screening of factor V G1691A (Leiden) and prothrombin G20210A mutations and protein S deficiency. Clin Chem 2006; 52: 665-670.