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Mechanisms of thrombosis related to hormone therapy
Thrombosis Research (2009) 123 Suppl. 2, S70–S73
intl.elsevierhealth.com/journals/thre
Mechanisms of thrombosis related to hormone therapy Per Morten Sandseta,b, *, Else Høibraatena , Anette Løken Eilertsena,b , Anders Dahma a
Oslo University Hospital at Ullev˚ al, Department of Hematology, and b Faculty of Medicine, University of Oslo, Oslo, Norway
KEYWORDS Oral contraceptives Hormone therapy Coagulation factors Coagulation inhibitors Activated protein C resistance
Abstract Combined oral contraceptives and combined oral postmenopausal hormone therapy are associated with a weak, but clinically significant risk of arterial and venous thrombosis (VT). The effects are related to dose of estrogen and type of progestin. The main effects are increase in markers of activated coagulation, reduction in coagulation inhibitors, and acquired activated protein C resistance. Reduction in tissue factor pathway inhibitor (TFPI) is probably an important mechanism, which predicts activation of coagulation and acquired resistance to activated protein C. Coagulation markers should be used as intermediate or surrogate markers in early pharmacodynamic studies to evaluate the risk associated with new formulations. © 2009 Elsevier Ltd. All rights reserved.
Introduction It is now well established that combined oral hormone therapy containing estrogen and progestin is associated with a small, but clinically significant increased risk of both arterial and venous thrombosis. The risk is increased both with combined oral contraceptives and with combined oral postmenopausal hormone therapy [1]. The prothrombotic effects are mainly related to exposure and dose of estrogen, whereas progestins seem to reverse the prothrombotic effects of estrogen. This mini-review concerns the specific mechanisms that may be involved in triggering thrombosis, and is mainly based on our own studies on the effects of combined oral postmenopausal hormone therapy in healthy women [2] and in women with a history of venous * Corresponding author. Professor Per Morten Sandset, MD, PhD. Oslo University Hospital Ullev˚ al, Department of Hematology, N-0407 Oslo, Norway. Tel.: +47 22119240; fax: +47 2119040. E-mail address: [email protected] (P.M. Sandset).
thrombosis (VT) [3] as a model for the effect of hormone therapy on coagulation. Early studies investigated the effects of hormone therapy on selected components of the coagulation and the fibrinolytic systems. These studies identified marginal changes of several such components, but since the values rarely deviated outside normal ranges, the clinical implications of these changes were controversial. More recent experimental and mathematical model studies have shown that blood coagulation is very delicately balanced, and that even minor disturbances, e.g., marginal increases in clotting factors and/or marginal decreases of coagulation inhibitors, may induce significant thrombin generation and thereby potentially trigger thrombosis [4]. It is therefore possible that the relatively small changes in coagulation factors induced by hormone therapy, even when retained within their normal reference ranges, can be of importance for the risk of thrombosis. Retrospectively, data on such intermediate or surrogate end-points were actually available years
0049-3848/ $ – see front matter © 2009 Elsevier Ltd. All rights reserved.
Mechanisms of thrombosis related to hormone therapy ahead of the later randomized clinical studies to predict the excess risk of thrombosis associated with postmenopausal hormone therapy [5,6].
S71 combined oral contraceptives and combined oral postmenopausal hormone therapy.
Effects of hormone therapy on coagulation
Effects of estrogen dose and mode of administration
To address the risk of VT associated with postmenopausal hormone therapy, we chose to investigate women with a high risk of VT. Using a sequential design, we included 140 women with a history of VT, and they were randomized to treatment with once daily combined oral postmenopausal hormone therapy containing conventional dose estrogen (2 mg 17-b-estradiol) and progestin (1 mg norethisterone acetate) or placebo [3]. The study was discontinued prematurely due to publication of new data from a randomized clinical study that strongly suggested excess risk of thrombotic complications with conventional dose oral combined hormone therapy [7]. Eight of 71 women in the hormone group and only one of 69 women in the placebo group had developed recurrent VT [3]. Biochemical markers displayed marked thrombin generation with increased levels of prothrombin fragments 1+2, thrombin antithrombin complexes, and D-dimer, and the increase in these markers was higher in those women who subsequently developed recurrent VT [8]. The effects on fibrinogen and factor VIII were neutral. Factor VII antigen was unchanged but with reduced levels of activated factor VII suggesting less activation of factor VII. The most important changes occurred with coagulation inhibitors. Antithrombin and protein C decreased by approximately 10%, tissue factor pathway inhibitor (TFPI) activity by 15%, and TFPI free antigen by nearly 30%. In multivariate analysis, the decrease in TFPI levels was predictive for the increase in markers of activated coagulation. The strong effect of hormone therapy on TFPI has also been demonstrated in women taking oral contraceptives [9], and this effect may be an important mechanism for thrombotic risk in women taking hormone therapy. Acquired resistance to activated protein C (APC) has proven to be an important effect both of oral contraceptives [10,11] and with postmenopausal hormone therapy [12]. This effect is best demonstrated using the sensitive thrombin generation assay [13]. Changes in free TFPI and free protein S are important predictors for the APC resistant phenotype [12,14]. The marked changes in TFPI may therefore a major mechanism for the increased risk of thrombosis in women taking
Reduction of ethinylestradiol from >50 mg in first-generation oral contraceptives to 30 mg in second- and third-generation oral contraceptives significantly reduced the risk of thrombotic complications [15,16]. However, further reduction in estrogen dose from 30 mg to 15 20 mg has only marginally reduced the risk of thrombosis [15], which suggests a treshold effect for estrogen dose. Less is known about the role of the estrogen component in women taking oral combined postmenopausal hormone therapy. As with oral contraceptives, proper testing of the doseresponse effects on relevant clinical end-points and biochemical markers, including coagulation and inflammatory markers, was not performed when these drugs were first introduced in the market. Both in clinical practice and in epidemiological and randomized clinical studies a conventional dose of estrogen, either 2 mg 17-bestradiol or 0.625 mg conjugated equine estrogen, have been used [5,6]. These doses far exceed the dose needed for climacteric relief in most women, and formulations containing lower doses of estrogen have now been introduced. In a recent randomized open label study we have tested the hypothesis that a low-dose estrogen formulation containing half the dose of estrogen (1 mg 17-b-estradiol) as compared with conventional-dose estrogen (2 mg 17-bestradiol) is associated with less activation of coagulation and with less effect on coagulation and inflammatory markers. We have found that the low-dose formulation induced much less activation of coagulation [2], and was associated with less alterations in coagulation markers including TFPI [17]. The low-dose formulation also had slightly less effect on the acquisition of the APC resistant phenotype [18]. However, the low-dose and conventional-dose formulations had similar effects on C-reactive protein [19]. It is therefore a possibility that formulations with lower estrogen doses may be associated with less risk of thrombosis, but this needs verification in randomized clinical studies. Most studies have found that postmenopausal transdermal estrogen is not associated with activation of coagulation, which may be attributed to lack of “first-pass” hepatic effects of estrogen after transdermal administration [6].
S72 These findings are consistent with recent clinical data suggesting that transdermal estrogen does not increase the risk of VT [20]. Contrary to postmenopausal transdermal estrogen therapy, transdermal contraception is associated with a significant risk of VT [21], which possibly implies that the “first-pass” hepatic effect is not avoided with ethinylestradiol. Effects of progestins There is so far no evidence that progestin therapy alone is associated with increased risk for thrombotic complications. However, circumstantial evidence suggests that progestins differentially counter the prothrombotic effects of estrogens [15]. Epidemiological studies first identified that second- and third-generation oral contraceptives containing the same estrogen component but with different progestins had markedly differential risks of VT [22]. It was therefore of great interest that a differential effect on acquired APC resistance [11] and on other coagulation markers [23] was detected. Recently, it was shown that second- and third-generation oral contraceptives differentially reduce the levels of protein C and TFPI, which again may explain the effects on acquired APC resistance [14]. Less is known about differential impacts of progestins in combined oral postmenopausal hormone therapy, but a recent study suggests differential effects of two progestins on fibrinolytic markers [24]. Concluding remarks The compiled literature on the effects of combined oral contraceptives and combined oral postmenopausal hormone therapy on coagulation is confusing, with differential effects of different formulations on various coagulation markers. These effects may in part be explained by estrogen dose and type of progestin. However, all formulations more or less induce a prothrombotic phenotype with increased levels of coagulation activation markers, such as prothrombin fragments 1+2, reduced levels of natural anticoagulants, and an acquired resistance to APC. Reduction in free TFPI seems to be a very important mechanism for thrombosis. Finally, a weak proinflammatory effect with increased C-reactive protein may also be involved. The authors’ opinion is that these coagulation and inflammatory markers should be used as intermediate or surrogate markers to estimate the risk of thrombotic complications. Well designed pharmacodynamic studies in a limited number of
P.M. Sandset et al. subjects using such end-points can be an important tool for the selection of new formulations of oral contraceptives and postmenopausal hormone therapy in the future. Conflicts of interest: Our studies on postmenopausal hormone therapy were supported by unconditional grants from NovoNordisk, Oslo, Norway. EH is currently the Medical Director of EliLilly S.p.a., Florence, Italy.
References [1] Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Female hormones and thrombosis. Arterioscler Thromb Vasc Biol 2002;22:201 10. [2] Eilertsen AL, Qvigstad E, Andersen TO, Sandvik L, Sandset PM. Conventional-dose hormone therapy (HT) and tibolone, but not low-dose HT and raloxifene, increase markers of activated coagulation. Maturitas 2006;55: 278 87. [3] Hoibraaten E, Qvigstad E, Arnesen H, Larsen S, Wickstrom E, Sandset PM. Increased risk of recurrent venous thromboembolism during hormone replacement therapy results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET). Thromb Haemost 2000;84:961 7. [4] Mann KG. Biochemistry and physiology of blood coagulation. Thromb Haemost 1999;82:165 74. [5] Lowe GDO. Hormone replacement therapy and cardiovascular disease: increased risks of venous thromboembolism and stroke, and no protection from coronary heart disease 248. J Intern Med 2004;256:361 74. [6] Sandset PM, Høibraaten E, Eilertsen AE. Hormone replacement therapy and coagulation. In: Erkkola R, editor. The Menopause (European Practice in Gynecology and Obstetrics Series Vol. 9). Edinburgh: Elsevier; 2006, Chapter 6. [7] Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. J Am Med Assoc 1998;280:605 13. [8] Hoibraaten E, Qvigstad E, Andersen TO, Mowinckel MC, Sandset PM. The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism results from a randomized, double-blind, clinical trial. Thromb Haemost 2001;85: 775 81. [9] Dahm A, Van Hylckama Vlieg A, Bendz B, Rosendaal F, Bertina RM, Sandset PM. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 2003;101:4387 92. [10] Rosing J, Middeldorp S, Curvers J, Christella M, Thomassen LG, Nicolaes GA, et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet 1999;354:2036 40. [11] Rosing J, Tans G, Nicolaes GA, Thomassen MC, Van Oerle R, van der Ploeg PM, 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 8.
Mechanisms of thrombosis related to hormone therapy [12] Hoibraaten E, Mowinckel MC, de Ronde H, Bertina RM, Sandset PM. Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double-blind, placebo-controlled trial. Br J Haematol 2001;115:415 20. [13] Nicolaes GA, Thomassen MC, Van Oerle R, Hamulyak K, Hemker HC, Tans G, et al. A prothrombinase-based assay for detection of resistance to activated protein C. Thromb Haemost 1996;76:404 10. [14] van Vliet HA, Bertina RM, Dahm AE, Rosendaal FR, Rosing J, Sandset PM, et al. Different effects of oral contraceptives containing different progestogens on protein S and tissue factor pathway inhibitor. J Thromb Haemost 2008;6:346 51. [15] Rosendaal FR, Van Hylckama Vlieg A, Tanis BC, Helmerhorst FM. Estrogens, progestogens and thrombosis. J Thromb Haemost 2003;1:1371 80. [16] Middeldorp S. Oral contraceptives and the risk of venous thromboembolism. Gend Med 2005;2(Suppl A):S3 9. [17] Eilertsen AL, Sandvik L, Mowinckel MC, Andersen TO, Qvigstad E, Sandset PM. Differential effects of conventional and low dose oral hormone therapy (HT), tibolone, and raloxifene on coagulation and fibrinolysis. Thromb Res 2007;120:371 9. [18] Eilertsen AL, Liestol S, Mowinckel MC, Hemker HC, Sandset PM. Differential impact of conventional and lowdose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system. Thromb Haemost 2007;97:938 43.
S73 [19] Eilertsen AL, Sandvik L, Steinsvik B, Sandset PM. Differential impact of conventional-dose and low-dose postmenopausal hormone therapy, tibolone and raloxifene on C-reactive protein and other inflammatory markers. J Thromb Haemost 2008;6:928 34. [20] Scarabin PY, Oger E, Plu-Bureau E. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362: 428 32. [21] Burkman RT. Transdermal hormonal contraception: benefits and risks. Am J Obstet Gynecol 2007;197: 134 6. [22] Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: metaanalysis. Br Med J 2001;323:131 4. [23] Middeldorp S, Meijers JC, van den Ende AE, van Enk A, Bouma BN, Tans G, et al. Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study. Thromb Haemost 2000;84:4 8. [24] Norris LA, Brosnan J, Bonnar J, Conard J, Kluft C, Hellgren M. Inhibitors and activation markers of the haemostatic system during hormone therapy: a comparative study of oral estradiol (2 mg)/dydrogesterone and estradiol (2 mg)/trimegestone. Thromb Haemost 2008; 100:253 60.
intl.elsevierhealth.com/journals/thre
Mechanisms of thrombosis related to hormone therapy Per Morten Sandseta,b, *, Else Høibraatena , Anette Løken Eilertsena,b , Anders Dahma a
Oslo University Hospital at Ullev˚ al, Department of Hematology, and b Faculty of Medicine, University of Oslo, Oslo, Norway
KEYWORDS Oral contraceptives Hormone therapy Coagulation factors Coagulation inhibitors Activated protein C resistance
Abstract Combined oral contraceptives and combined oral postmenopausal hormone therapy are associated with a weak, but clinically significant risk of arterial and venous thrombosis (VT). The effects are related to dose of estrogen and type of progestin. The main effects are increase in markers of activated coagulation, reduction in coagulation inhibitors, and acquired activated protein C resistance. Reduction in tissue factor pathway inhibitor (TFPI) is probably an important mechanism, which predicts activation of coagulation and acquired resistance to activated protein C. Coagulation markers should be used as intermediate or surrogate markers in early pharmacodynamic studies to evaluate the risk associated with new formulations. © 2009 Elsevier Ltd. All rights reserved.
Introduction It is now well established that combined oral hormone therapy containing estrogen and progestin is associated with a small, but clinically significant increased risk of both arterial and venous thrombosis. The risk is increased both with combined oral contraceptives and with combined oral postmenopausal hormone therapy [1]. The prothrombotic effects are mainly related to exposure and dose of estrogen, whereas progestins seem to reverse the prothrombotic effects of estrogen. This mini-review concerns the specific mechanisms that may be involved in triggering thrombosis, and is mainly based on our own studies on the effects of combined oral postmenopausal hormone therapy in healthy women [2] and in women with a history of venous * Corresponding author. Professor Per Morten Sandset, MD, PhD. Oslo University Hospital Ullev˚ al, Department of Hematology, N-0407 Oslo, Norway. Tel.: +47 22119240; fax: +47 2119040. E-mail address: [email protected] (P.M. Sandset).
thrombosis (VT) [3] as a model for the effect of hormone therapy on coagulation. Early studies investigated the effects of hormone therapy on selected components of the coagulation and the fibrinolytic systems. These studies identified marginal changes of several such components, but since the values rarely deviated outside normal ranges, the clinical implications of these changes were controversial. More recent experimental and mathematical model studies have shown that blood coagulation is very delicately balanced, and that even minor disturbances, e.g., marginal increases in clotting factors and/or marginal decreases of coagulation inhibitors, may induce significant thrombin generation and thereby potentially trigger thrombosis [4]. It is therefore possible that the relatively small changes in coagulation factors induced by hormone therapy, even when retained within their normal reference ranges, can be of importance for the risk of thrombosis. Retrospectively, data on such intermediate or surrogate end-points were actually available years
0049-3848/ $ – see front matter © 2009 Elsevier Ltd. All rights reserved.
Mechanisms of thrombosis related to hormone therapy ahead of the later randomized clinical studies to predict the excess risk of thrombosis associated with postmenopausal hormone therapy [5,6].
S71 combined oral contraceptives and combined oral postmenopausal hormone therapy.
Effects of hormone therapy on coagulation
Effects of estrogen dose and mode of administration
To address the risk of VT associated with postmenopausal hormone therapy, we chose to investigate women with a high risk of VT. Using a sequential design, we included 140 women with a history of VT, and they were randomized to treatment with once daily combined oral postmenopausal hormone therapy containing conventional dose estrogen (2 mg 17-b-estradiol) and progestin (1 mg norethisterone acetate) or placebo [3]. The study was discontinued prematurely due to publication of new data from a randomized clinical study that strongly suggested excess risk of thrombotic complications with conventional dose oral combined hormone therapy [7]. Eight of 71 women in the hormone group and only one of 69 women in the placebo group had developed recurrent VT [3]. Biochemical markers displayed marked thrombin generation with increased levels of prothrombin fragments 1+2, thrombin antithrombin complexes, and D-dimer, and the increase in these markers was higher in those women who subsequently developed recurrent VT [8]. The effects on fibrinogen and factor VIII were neutral. Factor VII antigen was unchanged but with reduced levels of activated factor VII suggesting less activation of factor VII. The most important changes occurred with coagulation inhibitors. Antithrombin and protein C decreased by approximately 10%, tissue factor pathway inhibitor (TFPI) activity by 15%, and TFPI free antigen by nearly 30%. In multivariate analysis, the decrease in TFPI levels was predictive for the increase in markers of activated coagulation. The strong effect of hormone therapy on TFPI has also been demonstrated in women taking oral contraceptives [9], and this effect may be an important mechanism for thrombotic risk in women taking hormone therapy. Acquired resistance to activated protein C (APC) has proven to be an important effect both of oral contraceptives [10,11] and with postmenopausal hormone therapy [12]. This effect is best demonstrated using the sensitive thrombin generation assay [13]. Changes in free TFPI and free protein S are important predictors for the APC resistant phenotype [12,14]. The marked changes in TFPI may therefore a major mechanism for the increased risk of thrombosis in women taking
Reduction of ethinylestradiol from >50 mg in first-generation oral contraceptives to 30 mg in second- and third-generation oral contraceptives significantly reduced the risk of thrombotic complications [15,16]. However, further reduction in estrogen dose from 30 mg to 15 20 mg has only marginally reduced the risk of thrombosis [15], which suggests a treshold effect for estrogen dose. Less is known about the role of the estrogen component in women taking oral combined postmenopausal hormone therapy. As with oral contraceptives, proper testing of the doseresponse effects on relevant clinical end-points and biochemical markers, including coagulation and inflammatory markers, was not performed when these drugs were first introduced in the market. Both in clinical practice and in epidemiological and randomized clinical studies a conventional dose of estrogen, either 2 mg 17-bestradiol or 0.625 mg conjugated equine estrogen, have been used [5,6]. These doses far exceed the dose needed for climacteric relief in most women, and formulations containing lower doses of estrogen have now been introduced. In a recent randomized open label study we have tested the hypothesis that a low-dose estrogen formulation containing half the dose of estrogen (1 mg 17-b-estradiol) as compared with conventional-dose estrogen (2 mg 17-bestradiol) is associated with less activation of coagulation and with less effect on coagulation and inflammatory markers. We have found that the low-dose formulation induced much less activation of coagulation [2], and was associated with less alterations in coagulation markers including TFPI [17]. The low-dose formulation also had slightly less effect on the acquisition of the APC resistant phenotype [18]. However, the low-dose and conventional-dose formulations had similar effects on C-reactive protein [19]. It is therefore a possibility that formulations with lower estrogen doses may be associated with less risk of thrombosis, but this needs verification in randomized clinical studies. Most studies have found that postmenopausal transdermal estrogen is not associated with activation of coagulation, which may be attributed to lack of “first-pass” hepatic effects of estrogen after transdermal administration [6].
S72 These findings are consistent with recent clinical data suggesting that transdermal estrogen does not increase the risk of VT [20]. Contrary to postmenopausal transdermal estrogen therapy, transdermal contraception is associated with a significant risk of VT [21], which possibly implies that the “first-pass” hepatic effect is not avoided with ethinylestradiol. Effects of progestins There is so far no evidence that progestin therapy alone is associated with increased risk for thrombotic complications. However, circumstantial evidence suggests that progestins differentially counter the prothrombotic effects of estrogens [15]. Epidemiological studies first identified that second- and third-generation oral contraceptives containing the same estrogen component but with different progestins had markedly differential risks of VT [22]. It was therefore of great interest that a differential effect on acquired APC resistance [11] and on other coagulation markers [23] was detected. Recently, it was shown that second- and third-generation oral contraceptives differentially reduce the levels of protein C and TFPI, which again may explain the effects on acquired APC resistance [14]. Less is known about differential impacts of progestins in combined oral postmenopausal hormone therapy, but a recent study suggests differential effects of two progestins on fibrinolytic markers [24]. Concluding remarks The compiled literature on the effects of combined oral contraceptives and combined oral postmenopausal hormone therapy on coagulation is confusing, with differential effects of different formulations on various coagulation markers. These effects may in part be explained by estrogen dose and type of progestin. However, all formulations more or less induce a prothrombotic phenotype with increased levels of coagulation activation markers, such as prothrombin fragments 1+2, reduced levels of natural anticoagulants, and an acquired resistance to APC. Reduction in free TFPI seems to be a very important mechanism for thrombosis. Finally, a weak proinflammatory effect with increased C-reactive protein may also be involved. The authors’ opinion is that these coagulation and inflammatory markers should be used as intermediate or surrogate markers to estimate the risk of thrombotic complications. Well designed pharmacodynamic studies in a limited number of
P.M. Sandset et al. subjects using such end-points can be an important tool for the selection of new formulations of oral contraceptives and postmenopausal hormone therapy in the future. Conflicts of interest: Our studies on postmenopausal hormone therapy were supported by unconditional grants from NovoNordisk, Oslo, Norway. EH is currently the Medical Director of EliLilly S.p.a., Florence, Italy.
References [1] Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Female hormones and thrombosis. Arterioscler Thromb Vasc Biol 2002;22:201 10. [2] Eilertsen AL, Qvigstad E, Andersen TO, Sandvik L, Sandset PM. Conventional-dose hormone therapy (HT) and tibolone, but not low-dose HT and raloxifene, increase markers of activated coagulation. Maturitas 2006;55: 278 87. [3] Hoibraaten E, Qvigstad E, Arnesen H, Larsen S, Wickstrom E, Sandset PM. Increased risk of recurrent venous thromboembolism during hormone replacement therapy results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET). Thromb Haemost 2000;84:961 7. [4] Mann KG. Biochemistry and physiology of blood coagulation. Thromb Haemost 1999;82:165 74. [5] Lowe GDO. Hormone replacement therapy and cardiovascular disease: increased risks of venous thromboembolism and stroke, and no protection from coronary heart disease 248. J Intern Med 2004;256:361 74. [6] Sandset PM, Høibraaten E, Eilertsen AE. Hormone replacement therapy and coagulation. In: Erkkola R, editor. The Menopause (European Practice in Gynecology and Obstetrics Series Vol. 9). Edinburgh: Elsevier; 2006, Chapter 6. [7] Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. J Am Med Assoc 1998;280:605 13. [8] Hoibraaten E, Qvigstad E, Andersen TO, Mowinckel MC, Sandset PM. The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism results from a randomized, double-blind, clinical trial. Thromb Haemost 2001;85: 775 81. [9] Dahm A, Van Hylckama Vlieg A, Bendz B, Rosendaal F, Bertina RM, Sandset PM. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 2003;101:4387 92. [10] Rosing J, Middeldorp S, Curvers J, Christella M, Thomassen LG, Nicolaes GA, et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet 1999;354:2036 40. [11] Rosing J, Tans G, Nicolaes GA, Thomassen MC, Van Oerle R, van der Ploeg PM, 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 8.
Mechanisms of thrombosis related to hormone therapy [12] Hoibraaten E, Mowinckel MC, de Ronde H, Bertina RM, Sandset PM. Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double-blind, placebo-controlled trial. Br J Haematol 2001;115:415 20. [13] Nicolaes GA, Thomassen MC, Van Oerle R, Hamulyak K, Hemker HC, Tans G, et al. A prothrombinase-based assay for detection of resistance to activated protein C. Thromb Haemost 1996;76:404 10. [14] van Vliet HA, Bertina RM, Dahm AE, Rosendaal FR, Rosing J, Sandset PM, et al. Different effects of oral contraceptives containing different progestogens on protein S and tissue factor pathway inhibitor. J Thromb Haemost 2008;6:346 51. [15] Rosendaal FR, Van Hylckama Vlieg A, Tanis BC, Helmerhorst FM. Estrogens, progestogens and thrombosis. J Thromb Haemost 2003;1:1371 80. [16] Middeldorp S. Oral contraceptives and the risk of venous thromboembolism. Gend Med 2005;2(Suppl A):S3 9. [17] Eilertsen AL, Sandvik L, Mowinckel MC, Andersen TO, Qvigstad E, Sandset PM. Differential effects of conventional and low dose oral hormone therapy (HT), tibolone, and raloxifene on coagulation and fibrinolysis. Thromb Res 2007;120:371 9. [18] Eilertsen AL, Liestol S, Mowinckel MC, Hemker HC, Sandset PM. Differential impact of conventional and lowdose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system. Thromb Haemost 2007;97:938 43.
S73 [19] Eilertsen AL, Sandvik L, Steinsvik B, Sandset PM. Differential impact of conventional-dose and low-dose postmenopausal hormone therapy, tibolone and raloxifene on C-reactive protein and other inflammatory markers. J Thromb Haemost 2008;6:928 34. [20] Scarabin PY, Oger E, Plu-Bureau E. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362: 428 32. [21] Burkman RT. Transdermal hormonal contraception: benefits and risks. Am J Obstet Gynecol 2007;197: 134 6. [22] Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: metaanalysis. Br Med J 2001;323:131 4. [23] Middeldorp S, Meijers JC, van den Ende AE, van Enk A, Bouma BN, Tans G, et al. Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study. Thromb Haemost 2000;84:4 8. [24] Norris LA, Brosnan J, Bonnar J, Conard J, Kluft C, Hellgren M. Inhibitors and activation markers of the haemostatic system during hormone therapy: a comparative study of oral estradiol (2 mg)/dydrogesterone and estradiol (2 mg)/trimegestone. Thromb Haemost 2008; 100:253 60.