Differential impact of conventional and low-dose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system

Anette L. Eilertsen; Sigurd Liestøl; Marie-Christine Mowinckel; H. Coen Hemker; Per-Morten Sandset

doi:10.1160/TH06-11-0632

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2007; 97(06): 938-943
DOI: 10.1160/TH06-11-0632

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Differential impact of conventional and low-dose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system

Authors

Anette L. Eilertsen

¹Department of Haematology Ullevål University Hospital Trust, Oslo, Norway

²Medical Clinic, Faculty Division Ullevål University Hospital, Oslo, Norway
Sigurd Liestøl

¹Department of Haematology Ullevål University Hospital Trust, Oslo, Norway
Marie-Christine Mowinckel

¹Department of Haematology Ullevål University Hospital Trust, Oslo, Norway
H. Coen Hemker

³Synapse BV, Cardiovascular Research Institute, Maastricht, The Netherlands
Per-Morten Sandset

¹Department of Haematology Ullevål University Hospital Trust, Oslo, Norway

²Medical Clinic, Faculty Division Ullevål University Hospital, Oslo, Norway

Abstract

Summary

Recent studies have shown that hormone therapy (HT) is associated with an acquired resistance to activated protein C (APC). The aims of the present study were to evaluate a possible dose-response relationship and differential effects of different HT regimens on functionality of the APC system. Two hundred two healthy women were randomly assigned to receive treatment for 12 weeks with tablets containing either low-dose HT containing 1 mg 17β-oestradiol + 0.5 mg norethisterone acetate (NETA) (n=50), conventional-dose HT containing 2 mg 17β-oestradiol and 1 mg NETA (n=50), 2.5 mg tibolone (n=51), or 60 mg raloxifene (n=51). Normalized APC system sensitivity ratios (nAPCsr) were determined in plasma collected at baseline and after 12 weeks using a thrombin generation-based APC resistance test probed with either recombinant APC (rAPC) or thrombomodulin (rTM). NAPCsr increased in both the conventional- and low-dose HT groups, consistent with reduced sensitivity to APC. The increase was slightly more pronounced in the conventional-dose group, but the difference between the two HT groups was not statistically significant. The sensitivity to APC was only marginally altered in those allocated to tibolone. Consequently, tibolone showed a different phenotype as compared with the low-dose HT group. A small increase in nAPCsr with both rAPC and rTM was seen in the raloxifene-group, but the increase was less than in the low-dose HT group. Our findings indicate that oestrogen-progestin therapy induces an APC resistant phenotype, which may be related to dose, whereas tibolone and raloxifene only marginally alter the sensitivity to APC.

Keywords

Activated protein C - hormone therapy - tibolone - raloxifene - coagulation

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Referenzen

References
1 Lowe GDO. Hormone replacement therapy and cardiovascular disease: increased risks of venous thromboembolism and stroke, and no protection from coronary heart disease. J Intern Med 2004; 256: 361-374.
2 Blumenthal RS, Baranowski B, Dowsett SA. Cardiovascular effects of raloxifene: the arterial and venous systems. Am Heart J 2004; 147: 783-789.
3 Peverill RE. Hormone therapy and venous thromboembolism. Best Pract Res Clin Endocrinol Metab 2003; 17: 149-164.
4 Koh KK, Horne III MK, Cannon III RO. Effects of hormone replacement therapy on coagulation, fibrinolysis, and thrombosis risk in postmenopausal women. Thromb Haemost 1999; 82: 626-633.
5 Mann KG, Brummel K, Butenas S. What is all that thrombin for?. J Thromb Haemost 2003; 1: 1504-1514.
6 Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-522.
7 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.
8 Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Female hormones and thrombosis. Arterioscler Thromb Vasc Biol 2002; 22: 201-210.
9 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.
10 Post MS, Rosing J, van der Mooren MJ. et al. Increased resistance to activated protein C after shortterm oral hormone replacement therapy in healthy post-menopausal women. Br J Haematol 2002; 119: 1017-1023.
11 Oger E, Alhenc-Gelas M, Lacut K. et al. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: A randomized trial. Arterioscler Thromb Vasc Biol 2003; 23: 1671-1676.
12 Duschek EJ, Neele SJ, Thomassen MC. et al. Effect of raloxifene on activated protein C (APC) resistance in postmenopausal women and on APC resistance and homocysteine levels in elderly men: two randomized placebo-controlled studies. Blood Coagul Fibrinolysis 2004; 15: 649-655.
13 Winkler UH, Altkemper R, Kwee B. et al. Effects of tibolone and continuous combined hormone replacement therapy on parameters in the clotting cascade: a multicenter, double-blind, randomized study. Fertil Steril 2000; 74: 10-19.
14 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.
15 Eilertsen AL, Qvigstad E, Andersen TO. et al. Conventional- dose hormone therapy (HT) and tibolone, but not low-dose HT and raloxifene, increase markers of activated coagulation. Maturitas 2006; 55: 278-287.
16 Hemker HC, Giesen P, Al Dieri R. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4-15.
17 Regnault V, Hemker HC, Wahl D. et al. Phenotyping the haemostatic system by thrombography--potential for the estimation of thrombotic risk. Thromb Res 2004; 114: 539-545.
18 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.
19 Post MS, Christella M, Thomassen LG. et al. Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: a randomized, placebo-controlled study in postmenopausal women. Arterioscler Thromb Vasc Biol 2003; 23: 1116-1121.
20 Demirol A, Baykal C, Kirazli S. et al. Effects of hormone replacement on hemostasis in spontaneous menopause. Menopause 2001; 8: 135-140.
21 Lowe G, Woodward M, Vessey M. et al. Thrombotic variables and risk of idiopathic venous thromboembolism in women aged 45–64 years. Relationships to hormone replacement therapy. Thromb Haemost 2000; 83: 530-535.
22 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.
23 Alhenc-Gelas M, Plu Bureau, Guillonneau S. et al. Impact of progestagens on activated protein C (APC) resistance among users of oral contraceptives. J Thromb Haemost 2004; 2: 1594-1600.
24 Henkens CM, Bom VJ, Seinen AJ. et al. Sensitivity to activated protein C; influence of oral contraceptives and sex. Thromb Haemost 1995; 73: 402-404.
25 Toorians AWFT, Thomassen MCLG, Zweegman S. et al. Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people. J Clin Endocrinol Metab 2003; 88: 5723-5729.
26 Cosman F, Baz-Hecht M, Cushman M. et al. Shortterm effects of estrogen, tamoxifen and raloxifene on hemostasis: a randomized-controlled study and review of the literature. Thromb Res 2005; 116: 1-13.
27 Azevedo GD, Franco RF, Baggio MS. et al. Effects of raloxifene therapy on the anticoagulant system in postmenopausal women. Climacteric 2003; 6: 140-145.
28 Eilertsen AL, Sandvik L, Mowinckel MC. et al. Differential effects of conventional and low dose oral hormone therapy (HT), tibolone, and raloxifene on coagulation and fibrinolysis. Thromb Res 2006;
29 de Visser MC, van Hylckama V, Tans G. et al. Determinants of the APTT- and ETP- based APC sensitivity tests. J Thromb Haemost 2005; 3: 1488-1494.