Acquired APC resistance and oral contraceptives: differences between two functional tests

Curvers, Joyce; Thomassen, M. Christella L. G. D.; Nicolaes, Gerry A. F.; Oerle, René van; Hamulyák, Karly; HEMKER, Coenraad; Tans, Guido; Rosing, Jan

doi:10.1046/j.1365-2141.1999.01302.x

Cited by 39 publications

(77 citation statements)

References 33 publications

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“…A lack of sensitivity of the APTT-based assay to detect ERT-induced modifications could explain these negative findings. 24 In the EVTET trial, 23 oral ERT significantly increased the ETP-based nAPCsr at 6 months. Our results confirm this finding.…”

Section: Discussionmentioning

confidence: 99%

“…The activated partial thromboplastin time (APT-T)-based APC resistance assay was performed on an ST888 analyzer (Diagnostica Stago) with use of a commercially available kit (Coatest APC resistance, Biogenics). The response to APC was also determined with a thrombin generation test initiated by the extrinsic coagulation pathway, as described before, 23,24 with some modifications. Before the assay, plasma was defibrinated by incubation with reptilase (final concentration, 0.2 UB/mL; Diagnostica Stago) for 30 minutes at 37°C followed by 15 minutes at 0°C, after which the clot was removed with a plastic spatula.…”

Section: Laboratory Investigationsmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

Section: Laboratory Investigationsmentioning

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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“…Pregnancy and oral contraceptive usage reduce the anticoagulant response to APC. 8,38,39 Estradiol lowers GlcCer synthase, the primary enzyme that synthesizes GlcCer, and it also raises glucosidase activity, 40 suggesting that plasma GlcCer levels might be reduced by pregnancy or oral contraceptive use. Some anticancer drugs are also known to reduce GlcCer synthesis, 41,42 and tamoxifen decreases GlcCer synthesis in cultured cells.…”

Section: Discussionmentioning

confidence: 99%

Plasma glucosylceramide deficiency as potential risk factor for venous thrombosis and modulator of anticoagulant protein C pathway

Deguchi

Fernández

Pabinger

et al. 2001

Blood

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To assess the relationship between venous thrombosis and plasma glucosylceramide (GlcCer) or phosphatidylethanolamine (PE), plasma levels of GlcCer and PE were determined for 70 venous thrombosis patients referred for evaluation and 70 healthy blood donors. The mean GlcCer level, but not the PE level, was lower in patients versus controls (4.9 vs 6.5 g/mL [P ‫؍‬ .0007] and 66 vs 71 g/mL [P ‫؍‬ .48], respectively). As a measure of relative risk, the odds ratio for deep vein thrombosis in subjects with GlcCer levels below the 10th percentile of controls was 5.7 (95% CI, 2.3-14). To assess the influence of glycolipids on anticoagulant response to activated protein C (APC):protein S in modified prothrombin time assays, the effects of depleting endogenous plasma GlcCer by glucocerebrosidase treatment or of adding exogenous purified GlcCer or other neutral glycolipids to plasma were tested. Glucocerebrosidase treatment reduced plasma sensitivity to APC: protein S in parallel with GlcCer reduction. Exogenously added GlcCer and the homologous Glc-containing globotriaosylceramide (Gb3Cer), but not galactosylceramide, dose-dependently prolonged clotting times of normal plasma in the presence, but not absence, of APC:protein S, which suggests that GlcCer or Gb3Cer can enhance protein C pathway anticoagulant activity. In studies using purified proteins, inactivation of factor Va by APC:protein S was enhanced by GlcCer alone and by GlcCer in multicomponent vesicles containing phosphatidylserine and phosphatidylcholine. These results suggest that the neutral glycolipids GlcCer and Gb3Cer may directly contribute to the anticoagulant activity of the protein C pathway and that deficiency of plasma GlcCer may be a risk factor for venous thrombosis. (Blood. 2001;97: 1907-1914

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“…In the present study, resistance to APC was measured with an assay that is particularly sensitive to changes in the hormonal status of women, 12,16,24,27,28 ie, with a test that quantifies the effect of APC on thrombin generation initiated via the extrinsic coagulation pathway (endogenous thrombin potential-based test). 21 nAPCsr determined with this test correlates remarkably well with the risk increase of venous thromboembolism reported in oral contraceptive users and in carriers of the factor V Leiden mutation.…”

Section: Post Et Al Estrogen Replacement Therapy and Resistance To Apcmentioning

confidence: 99%

Effect of Oral and Transdermal Estrogen Replacement Therapy on Hemostatic Variables Associated With Venous Thrombosis

Post

Christella

Thomassen

et al. 2003

ATVB

Self Cite

124

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Objective-The purpose of this study was to investigate whether the effect of transdermal estrogen therapy in postmenopausal women differs from that of oral therapy with regard to resistance to activated protein C (APC), an important risk factor for venous thrombosis, and levels of related proteins, such as protein S, protein C, and prothrombin. Methods and Results-In a randomized, double-blind, placebo-controlled study, 152 healthy hysterectomized postmenopausal women received daily either placebo (nϭ49), transdermal 17␤-estradiol (E 2 ) 50 g (tE 2 group, nϭ33), oral E 2 1 mg (oE 2 group, nϭ37), or oral E 2 1 mg combined with gestodene 25 g (oE 2 ϩG group, nϭ33) for 13 28-day treatment cycles, followed by 4 cycles of placebo for each group. Plasma samples were collected at baseline and in cycles 4, 13, and 17. In cycle 13, significant increases versus baseline and placebo were found in normalized APC sensitivity ratios (nAPCsr) in all treated groups (tE 2 , ϩ26.9%; oE 2 , ϩ102.7%; oE 2 ϩG, ϩ69.9%). Increases in nAPCsr were significantly higher in the oral treatment groups than in the tE 2 group. In addition, compared with baseline and placebo, after 13 cycles, decreases were observed in total protein S (tE 2 , Ϫ4.1%; oE 2 , Ϫ7.9%; oE 2 ϩG, Ϫ5.8%), free protein S (tE 2 , Ϫ7.1%; oE 2 , Ϫ8.4%; oE 2 ϩG, Ϫ5.2%), and protein C in the oE 2 ϩG group (Ϫ6.4%), but these changes did not explain the increase in nAPCsr. Changes in prothrombin were small and also did not affect the nAPCsr. Conclusions-Increases were observed in resistance to APC, which were more pronounced in the oral treatment groups than in the transdermal group. The increase in resistance to APC was not explained by changes in protein S, protein C, or prothrombin and may contribute to the increased incidence of venous thrombosis in users of hormone replacement therapy. Key Words: resistance to activated protein C Ⅲ protein S Ⅲ protein C Ⅲ estrogen replacement therapy Ⅲ venous thrombosis W omen using oral estrogen containing hormone replacement therapy 1-3 or oral contraceptives 4 have an increased risk of developing venous thrombosis. The risk for oral contraceptive users is higher in women who use ethynylestradiol in combination with so-called third-generation progestogens (desogestrel or gestodene) than among women using ethynylestradiol in combination with the secondgeneration progestogen levonorgestrel. 4 This difference might be explained by a differential effect of the progestogens on resistance to activated protein C (APC), 5,6 a risk factor for venous thrombosis. 7,8 It is plausible that the observed increased risk of venous thrombosis in hormone replacement users can also, at least in part, be explained by an increase in resistance to APC.The effect of hormone replacement therapy on resistance to APC, on protein S, and on protein C has been investigated in several studies. However, only few had a randomized, placebo-controlled design. 9 -16 Only uncontrolled 17,18 and cross-sectional 19 studies on the effect of transdermal estradiol on resistance...

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Acquired APC resistance and oral contraceptives: differences between two functional tests

Cited by 39 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

Plasma glucosylceramide deficiency as potential risk factor for venous thrombosis and modulator of anticoagulant protein C pathway

Effect of Oral and Transdermal Estrogen Replacement Therapy on Hemostatic Variables Associated With Venous Thrombosis

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