The Effects of Hormone Replacement Therapy on Hemostatic Variables in Women with Angiographically Verified Coronary Artery Disease

Høibraaten, Else; Os, Ingrid; Seljeflot, Ingebjørg; Andersen, Trine Opstad; Hofstad, A. E.; Sandset, Per Morten

doi:10.1016/s0049-3848(99)00233-9

Cited by 45 publications

(66 citation statements)

References 33 publications

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“…Randomized trials have shown that oral ERT increases plasma levels of prothrombin fragment F1ϩ2, 11,35 which is a marker for in vivo thrombin generation and which was recently related to the risk of recurrent VTE. 9 Consistent data reported that transdermal ERT had no detrimental effect on coagulation, 11,32,35 especially prothrombin fragment 1ϩ2 plasma level, and our findings are in accordance with these results. Thus, oral ERT might impair the balance between procoagulant factors and antithrombotic mechanisms, whereas transdermal ERT appears to have little or no effect on hemostasis.…”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

Differential Effects of Oral and Transdermal Estrogen/Progesterone Regimens on Sensitivity to Activated Protein C Among Postmenopausal Women

Oger

Alhenc‐Gelas

Lacut

et al. 2003

ATVB

158

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Objective-Activated protein C (APC) resistance not related to the factor V Leiden mutation is a risk factor for venous thrombosis. Oral estrogen replacement therapy (ERT) has been reported to induce APC resistance. Little is known about the effect of transdermal estrogen. Methods and Results-We enrolled 196 postmenopausal women who were randomly allocated to receive either 1 mg 17␤-estradiol orally (nϭ63) or 50 g 17␤-estradiol transdermally per day (nϭ68), both associated with 100 mg progesterone daily or placebo (nϭ65) for 6 months. An activated partial thromboplastin time (APTT)-based test and the effect of APC on thrombin potential (ETP) were used. Oral ERT induced an ETP-based APC resistance compared with both placebo (Pϭ0.006) and transdermal ERT (PϽ0.001), but there was no significant effect of transdermal ERT compared with placebo (Pϭ0.191). There was no significant effect of ERT on the APTT-based APC sensitivity ratio. Prothrombin fragment 1ϩ2 plasma levels were significantly higher after 6 months of treatment in women allocated to oral ERT compared with those on placebo and transdermal ERT and were positively and significantly correlated with changes in ETP-based APC sensitivity ratio. Conclusions-Our data show that oral, unlike transdermal, estrogen induces APC resistance and activates blood coagulation. These results emphasize the importance of the route of estrogen administration. Key Words: hormone replacement therapy Ⅲ APC resistance Ⅲ blood coagulation Ⅲ randomized trial Ⅲ factor V S everal observational studies [1][2][3][4][5][6][7] found that oral estrogen replacement therapy (ERT) was associated with a 2-fold increased risk of venous thromboembolism (VTE). This finding was confirmed in 2 randomized clinical trials. 8,9 Furthermore, consistent data provided evidence that oral ERT resulted in coagulation activation. 10 -14 However, studies investigating the effect of transdermal estrogen on the thrombotic process are scarce. 3,15 Activated protein C (APC) resistance has recently emerged as a risk factor for venous thrombosis. 16,17 In most cases, this defect is related to the presence of the R506Q mutation in factor V (FV) Leiden. 18 However, an APC-resistant phenotype detected in the absence of FV Leiden is also an independent risk factor for venous thrombosis. 19 Observational studies 20 -22 and 1 randomized trial 23 showed that oral ERT could induce an acquired APC resistance. Little is known about the effect of transdermal ERT on APC resistance. Therefore, we conducted a randomized, placebocontrolled trial that investigated the effect of both oral and transdermal estrogen/progesterone regimens on the anticoagulant response to APC and on coagulation activation. Methods Study Design and SettingThis study was a randomized, double-blind, placebo-controlled, parallel-group trial that took place at the Hôpital de la Cavale Blanche, Brest, France, between September 1999 and August 2001. Participants were followed up by regular visits, at randomization (baseline), and after 6 months. A medical revi...

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Section: Discussionsupporting

confidence: 92%

“…However, in agreement with several reports, we confirm that oral ERT significantly decreases TPS but does not change the FPS level. 32,33 The safety of HRT with regard to VTE is an important issue. Early studies of VTE risk among ERT users provided inconclusive results.…”

mentioning

confidence: 99%

Differential Effects of Oral and Transdermal Estrogen/Progesterone Regimens on Sensitivity to Activated Protein C Among Postmenopausal Women

Oger

Alhenc‐Gelas

Lacut

et al. 2003

ATVB

158

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“…The observed HRT-induced reduction in protein C activity is in agreement with the results obtained by Høibraaten et al 12,21 , while others have reported that the concentration of protein C remains unchanged 9,10,14,22 or is increased during HRT administration 11 . A reduction in protein C seems to be associated with the use of orally administered oestrogen/progestin combined, as used in the studies by Høibraaten et al 12,21 and in our study, while unaltered or increased concentration of protein C is observed in studies employing unopposed oestrogen 9,11,22 or transcutaneously administered HRT 10 . This apparent importance of unopposed oestrogen is also supported by the results we obtained on protein C in Group F. The concentrations of protein C in cycle 1 (2 months) and cycle 4 (11 months), representing unopposed oestrogen, were not significantly different from the baseline values.…”

Section: Discussionsupporting

confidence: 91%

“…We demonstrated that the effect of long cycle HRT on F 1þ2 was accompanied by a persistent reduction in the inhibitory potential of coagulation and an increase in the concentration of fibrin degradation products, but the latter exclusively after 12 months of treatment. This effect on fibrin turnover has been acknowledged in some studies 22,27,28 , while other studies report unaltered concentrations of fibrin degradation products 12,14,25,26 . Changes in the cumulative response 20 of the haemostatic variables indicate the most persistent effect of the treatment on the haemostatic balance.…”

Section: Discussionmentioning

confidence: 89%

Hormone replacement therapy and hypercoagulability. Results from the Prospective Collaborative Danish Climacteric Study

Sidelmann

2003

BJOG: An International Journal of Obstetrics and Gynaecology

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Objective To assess the influence of a variety of HRT regimens on the haemostatic balance using markers of fibrin turnover and inhibitors of coagulation. Design An open randomised study allocating women to either a control group or five different HRT treatment groups. Setting Gentofte Hospital, Hellerup, and Rigshospitalet, Copenhagen, Denmark.Population One hundred and forty-nine postmenopausal women without previous venous thromboembolic disease. Methods Prothrombin fragment 1þ2 (F 1þ2 ), fibrin degradation products, antithrombin, protein C, total protein S and activated protein C-normalised ratio were measured at baseline and after 6 and 12 months of HRT in six groups of healthy postmenopausal women: (A) no HRT (reference group), (B) continuous oestradiol valerate (E 2 V) plus cyproterone acetate, (C) cyclic E 2 V plus cyproterone acetate, (D) continuous combined oestrogen (E 2 ) plus norethindrone acetate, (E) E 2 combined with local delivery of levonorgestrel and (F) E 2 V plus medroxyprogesterone. Main outcome measures HRT-induced changes in the concentration of inhibitors of coagulation and markers of fibrin turnover during 12 months of treatment. Results Significant decreases of antithrombin and protein S were found in all treatment groups, of protein C in Groups C, D, E and F and of activated protein C-normalised ratio in Groups E and F. Fibrin degradation products increased after three months of treatment, whereas F 1þ2 was persistently increased after three months in Group F. The cumulative response of antithrombin was significantly lower in Groups D, E and F than in the reference group. The cumulative response of protein S and activated protein C-normalised ratio was lower, whereas that of F 1þ2 was significantly higher in Group F than in the reference group. Conclusion HRT reduces the inhibitory potential of coagulation significantly. The effect is related to the type of E 2 /progestin combination administered, but seems to be oestrogen-derived as the most pronounced effect is found with only quarterly progestin intake. Such procoagulant activity of HRT may well translate into clinical manifestations in thrombosis-prone individuals.

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“…38 In line with our results, it has been reported that free TFPI decreased with HRT use, and this was consistently true for oral regimens, 39 -41 whereas it was more debated for transdermal therapy. 42,43 Several groups of investigators were cautious in suggesting favorable effects of administered estrogen on PWV. 44 Here we show that the correlation between free TFPI and PWV remains significant even when excluding women currently on HRT, in particular those on oral HRT, indicating that this correlation is not dependent on HRT effects.…”

Section: Discussionmentioning

confidence: 99%

Tissue Factor Pathway Inhibitor

Régnault

Perret‐Guillaume

Kearney‐Schwartz

et al. 2011

ATVB

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Objective-To investigate in women older than 60 whether aortic stiffness or pulse pressure (PP) is associated with selected procoagulant or anticoagulant factors and to examine whether pulsatile stretch influences these factors in human vascular smooth muscle cells (VSMCs) in vitro. Methods and Results-Aortic pulse wave velocity (PWV) and carotid PP were studied in 123 apparently healthy postmenopausal women. PWV, PP, von Willebrand factor, and free tissue factor pathway inhibitor (TFPI), but not mean arterial pressure, increased with age. Free TFPI and PWV were positively correlated, even after adjustment for age and PP and other confounding parameters. In vitro, 5% or 10% pulsatile stretch (at 1 Hz) enhanced TFPI synthesis and secretion by VSMCs in a time-independent manner (1 to 48 hours) without changes in protein level of smooth muscle myosin heavy chain. Application of 5% static stretch had no effect. Conclusion-In postmenopausal women, free TFPI increases as vascular wall function deteriorates and PP increases.These findings are supported by the increase in TFPI synthesized by VSMCs in response to cyclic stress in vitro. They suggest that VSMCs require pulsatility to interfere with the coagulation process and highlight the relevance of plasma free TFPI levels to cardiovascular diseases. (Arterioscler Thromb Vasc Biol. 2011;31:1226-1232.)

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The Effects of Hormone Replacement Therapy on Hemostatic Variables in Women with Angiographically Verified Coronary Artery Disease

Cited by 45 publications

References 33 publications

Differential Effects of Oral and Transdermal Estrogen/Progesterone Regimens on Sensitivity to Activated Protein C Among Postmenopausal Women

Differential Effects of Oral and Transdermal Estrogen/Progesterone Regimens on Sensitivity to Activated Protein C Among Postmenopausal Women

Hormone replacement therapy and hypercoagulability. Results from the Prospective Collaborative Danish Climacteric Study

Tissue Factor Pathway Inhibitor

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