Livedoid Vasculopathy: A French Observational Study Including Therapeutic Options.

Livedoid vasculopathy is a rare thrombotic cutaneous disease. This observational study aimed to assess the clinical and biological features of livedoid vasculopathy and the efficacy of treatments. Patients enrolled had typical livedoid vasculopathy both clinically and histologically. Investigation of thrombophilia was performed. Electromyography was undertaken in the presence of symptoms suggesting peripheral neuropathy. Eighteen women and 8 men were included, with a mean age of 35.5 years at onset. Twenty patients had at least one thrombophilia factor. Ten patients had a peripheral neuropathy with 2 of these patients demonstrating a specific thrombo-occlusive vasculopathy on muscle biopsy. Anticoagulation with low molecular weight heparin was the most prescribed therapy and was associated with the best outcome (effective in 14 patients). Eight patients had severe disease refractory to anticoagulation and required intravenous immunoglobulins, producing a good response in 6 patients.

Thrombophilic risk of individuals with rare compound factor V Leiden and prothrombin G20210A polymorphisms: an international case series of 100 individuals.

The risk of thrombosis in individuals with rare compound thrombophilias, homozygous factor V Leiden (FVL) plus heterozygous prothrombin G20210A (PTM), homozygous PTM plus heterozygous FVL, and homozygous FVL plus homozygous PTM, is unknown. We identified, worldwide, individuals with these compound thrombophilias, predominantly through mailing members of the International Society on Thrombosis and Haemostasis. Physicians were sent a clinical questionnaire. Confirmatory copies of the genetic results were obtained. One hundred individuals were enrolled; 58% were female. Seventy-one individuals had a venous thrombosis (includes superficial and deep vein thrombosis, and pulmonary embolism), 4 had an arterial thrombosis and 6 had both. Nineteen individuals had never had a thrombotic event. Thrombosis-free survival curves demonstrated that 50% of individuals had experienced a thrombotic event by 35 yrs of age, while 50% had a first venous thromboembolic event (VTE; includes all venous thrombosis except superficial thrombosis) by 41 yrs of age; 38.2% of first VTEs were unprovoked. 37% of patients had at least one VTE recurrence. Seventy percent of first pregnancies carried to term and not treated with anticoagulation were thrombosis-free. In conclusion, patients with these rare compound thrombophilias are not exceedingly thrombogenic, even though they have a substantial risk for VTE.

Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study.

BACKGROUND: Oral estrogen therapy increases the risk of venous thromboembolism (VTE) in postmenopausal women. Transdermal estrogen may be safer. However, currently available data have limited the ability to investigate the wide variety of types of progestogen. METHODS AND RESULTS: We performed a multicenter case-control study of VTE among postmenopausal women 45 to 70 years of age between 1999 and 2005 in France. We recruited 271 consecutive cases with a first documented episode of idiopathic VTE (208 hospital cases, 63 outpatient cases) and 610 controls (426 hospital controls, 184 community controls) matched for center, age, and admission date. After adjustment for potential confounding factors, odds ratios (ORs) for VTE in current users of oral and transdermal estrogen compared with nonusers were 4.2 (95% CI, 1.5 to 11.6) and 0.9 (95% CI, 0.4 to 2.1), respectively. There was no significant association of VTE with micronized progesterone and pregnane derivatives (OR, 0.7; 95% CI, 0.3 to 1.9 and OR, 0.9; 95% CI, 0.4 to 2.3, respectively). In contrast, norpregnane derivatives were associated with a 4-fold-increased VTE risk (OR, 3.9; 95% CI, 1.5 to 10.0). CONCLUSIONS: Oral but not transdermal estrogen is associated with an increased VTE risk. In addition, our data suggest that norpregnane derivatives may be thrombogenic, whereas micronized progesterone and pregnane derivatives appear safe with respect to thrombotic risk. If confirmed, these findings could benefit women in the management of their menopausal symptoms with respect to the VTE risk associated with oral estrogen and use of progestogens.

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.

Epidemiological studies have shown that hormone therapy (HT) increases the risk of venous thromboembolism in post menopausal women. The mechanism of this increased risk is unknown; however, activation of the haemostatic system is known to contribute to the pathogenesis of venous thromboembolism. In post-menopausal women the estrogen/progestogen composition of the HT can influence the level of haemostatic activation. It was the objective of this study to compare changes in inhibitors and activation markers of the haemostatic system in healthy post-menopausal women taking estradiol (2 mg) combined with dydrogesterone or a new progestin, trimegestone. A multicentre study of 186 women randomised to six months therapy with either estradiol (2 mg) +trimegestone (0.5 mg) or estradiol (2 mg) +dydrogesterone (10 mg) was performed. Antithrombin and protein S activity was decreased and activated protein C (APC) resistance, D-dimer and prothrombin fragment 1.2, were increased in both groups on treatment. Protein C activity was decreased and plasmin-antiplasmin complex was increased in the trimegestone group only. The increase in plasmin-antiplasmin complex and D-dimer was greater after six cycles of treatment in the trimegestone group compared with the dydrogesterone group. In conclusion, decreased levels of inhibitors of blood coagulation and increased thrombin production were found in both groups however a greater increase in the levels of plasmin-antiplasmin complex and D-dimer was found in the trimegestone group. This suggests an enhanced fibrinolytic response in this group. Further studies are required to determine the significance of this finding with respect to venous thrombosis risk.

Antithrombin alfa in hereditary antithrombin deficient patients: A phase 3 study of prophylactic intravenous administration in high risk situations.

During surgery and childbirth, patients with hereditary antithrombin (AT) deficiency are at high risk for thrombosis, and heparin prophylaxis may not be sufficiently efficacious. In these patients, exogenous AT may be used in association with heparin. A recombinant human AT (generic name: antithrombin alfa) has been developed. This multi-center study assessed the efficacy and safety of prophylactic intravenous administration of antithrombin alfa to hereditary AT deficient patients in high risk situations, including elective surgery, childbirth, or cesarean section. Antithrombin alfa was administered prior to and during the high risk period for restoration and maintenance of AT activity at 100% of normal. Heparin, low-molecular-weight heparin, and/or vitamin K antagonists were used according to standard of care. The primary efficacy endpoint was the incidence of acute deep vein thrombosis (DVT) from baseline up to day 30 post dosing as assessed by independent central review of duplex ultrasonograms and/or venograms. Safety was assessed based on adverse events (AEs) and laboratory evaluations. Five surgical and nine obstetrical hereditary AT deficiency patients received antithrombin alfa for a mean period of seven days. No clinically overt DVT occurred. Central review of ultrasonograms identified signs of acute DVT in two out of 13 evaluable patients. No antithrombin alfa-related AEs were reported. No patient developed anti-antithrombin alfa antibodies. In conclusion, this study suggests that antithrombin alfa is a safe and effective alternative to human plasma-derived AT for treating hereditary AT deficiency patients at high risk for thromboembolic events.

Type of Combined Contraceptives, Factor V Leiden Mutation and Risk of Venous Thromboembolism.

OBJECTIVE: This article estimates the interaction between types of combined hormonal contraception (CHC) and factor V Leiden (FVL) mutation on the risk of venous thrombosis event (VTE). SUBJECTS AND METHODS: All premenopausal women with first incident VTE who were referred to our unit (Paris, France) between 2000 and 2009 were included in this case-only study. Differences in interactions by progestin type were assessed on a multiplicative scale, assuming the independence of genotype and prescription of type of CHC. RESULTS: Among 2,613 women with VTE, 15.9% had a FVL and 69% used CHC. The interaction between CHC use and presence of FVL on VTE risk was statistically significant (1.37, 1.06-1.77 95% confidence interval [CI]). This interaction appeared higher for drospirenone 1.99 (1.18-3.38 95% CI) (n = 98) or cyproterone acetate users 1.71 (1.20-2.45 95% CI) (n = 326), but not significant for 1st or 2nd or norgestimate CHC users. The results were similar when excluding women with a family history of VTE or with provoked VTE. In this sub-group of women, these interactions appeared higher for third generation, cyproterone acetate and drospirenone CHC users as compared with 1st or 2nd or norgestimate CHC users (odds ratio [OR], 1.68 [1.04-2.70; 95% CI], 2.91 [1.71-4.95 95% CI], 3.22 [1.54-6.73 95% CI], respectively). CONCLUSION: Our results show that the interaction between FVL and CHC use differ by progestin type, which is higher in CHC containing third-generation progestin, drospirenone or cyproterone acetate, compared with second generation. Further studies are needed to assess the cost-effectiveness of biological thrombophilia screening (FVL) when such prescription of CHC is planned.

Effects of oral and transvaginal ethinyl estradiol on hemostatic factors and hepatic proteins in a randomized, crossover study.

CONTEXT: The use of combined hormonal contraceptives with ethinyl estradiol (EE) and a progestin results in alterations in potential biomarkers of venous thromboembolism risk. Evaluation of the impact of delivery route on these changes is difficult due to an interaction between EE and the progestin component. OBJECTIVE: The aim of the study was to compare the impact of oral and vaginal administration of EE alone on hemostatic variables and estrogen-sensitive liver proteins. DESIGN: This was a single-center, randomized, crossover study with two treatment cycles separated by a washout cycle. SETTING: The study was conducted in an academic outpatient center. PARTICIPANTS: Fourteen healthy postmenopausal women were enrolled; 13 completed the study and were included in the analyses. INTERVENTION: Participants were randomized to receive EE (15 microg/d) delivered by oral tablet or vaginal ring for 21 d in one of two treatment sequences. MAIN OUTCOME MEASURES: Changes in plasma concentration or activity of 10 hemostatic variables and six estrogen-sensitive liver proteins between baseline and d 21 of treatment were the primary outcomes. RESULTS: Prothrombin fragment 1 + 2 plasma level was unaffected by treatment or delivery route. Angiotensinogen (expressed as plasma level of angiotensin I) increased similarly with oral and vaginal delivery; mean (sd) increases were 2757 (1033) and 2864 (893) ng /ml, respectively (P = 0.0002). Alterations in other study variables, except total cholesterol, were similar with oral and vaginal administration. CONCLUSION: Our results provide evidence that the customary effects of combined hormonal contraceptives on hemostatic variables and estrogen-sensitive liver proteins are largely related to EE and independent of delivery route during short-term treatment.

Characterization of seven novel mutations causing factor XI deficiency.

BACKGROUND AND OBJECTIVES: Factor XI (FXI) deficiency is a rare autosomal recessive disorder, the main manifestation of which is injury-related bleeding. The disorder is rare in most populations, but common among Jews in whom two mutations, E117X and F283L, account for 98% of cases. Other mutations, C38R and C128X, are prevalent in French Basques and Britons, respectively. Additional sporadic mutations have been described in most parts of the world. The objective of this study was to identify the mutations in 15 unrelated FXI-deficient patients and characterize missense mutations by expression in baby hamster kidney (BHK) cells. DESIGN AND METHODS: Clinical and laboratory information and DNA samples were obtained from the patients and mutations were identified by sequencing. Missense mutations were expressed in BHK cells and their effect on FXI secretion and dimerization was assessed using enzyme-linked immunosorbent assay and immunoblotting. RESULTS: Of 16 mutations detected, seven are novel including two deletions, one splice site and four missense mutations. Expression of the four novel missense mutations (C58Y, Y427C, C527Y and V20A) in cells revealed no secretion of FXI-C58Y, Y427C and C527Y and secretion of only 22% of normal in the medium for FXI-V20A. Secretion of FXI from BHK cells harboring a previously reported E297K substitution cells was also impaired (4.5% of wild-type). Homodimerization was normal for all five mutants. INTERPRETATION AND CONCLUSIONS: Defective homodimerization of FXI was previously recognized as a major mechanism for defective secretion of FXI from producing cells. In this study, five FXI missense mutations (four novel) were associated with impaired secretion albeit normal dimerization, underscoring the existence of other mechanisms for defective secretion.

Severe prekallikrein deficiencies due to homozygous C529Y mutations.

Two consecutive severe prekallikrein deficiencies were investigated. The first was identified in a 63-year-old patient admitted for ischemic stroke. The second deficiency was identified in a 38-year-old patient admitted for a second-trimester pregnancy loss. A homozygous C529Y mutation was identified for both cases, whereas they are unrelated and no consanguineous marriage is known from the patients. These data point to a possible high frequency of this mutation as a cause of prekallikrein deficiency.

[Pregnancy, contraception and HRT and venous thromboembolism]. / Grossesse, contraception, THS et maladie thrombo-embolique veineuse.

Endogeneous and exogeneous hormonal factors may favor venous thromboembolism (VTE) in the woman. Pregnancy and post-partum, combined contraception and hormonal replacement therapy (HRT) of menopause are associated with an increased risk of VTE. Even when the relative risk is statistically significant, the absolute risk remains generally low unless additional factors are present. The occurrence of a thrombosis depends on the conditions associated to these risk factors: multiparity, caesarean section, type of contraception or HRT, and also on risk factors associated to the woman such as age, obesity, personal history of VTE, hereditary or acquired thrombophilia. The detection of high-risk women because of personal history of VTE, associated risk factors and/or thrombophilia should improve the clinical management and thrombosis prophylaxis, especially when hormonal treatments are prescribed.

Combined Hormonal Contraceptives and First Venous Thrombosis in Young French Women: Impact of Thrombotic Family History.

CONTEXT: In UK and French, but not World Health Organization (WHO), guidelines for combined hormonal contraception (CHC), family history of a venous thromboembolism (VTE) is a condition for which the theoretical risks usually outweigh the advantages of using CHC. OBJECTIVE: We estimated the prevalence of inappropriate prescriptions of CHC according to several international guidelines and their impact on VTE. DESIGN: A single-center observational study. SETTING: Hemostasis unit outpatient clinic (Paris, France). POPULATION: A total of 2088 French CHC users of childbearing age with a first documented VTE who were referred to our unit between 2000 and 2009. METHODS: Data were collected by a standardized questionnaire during a medical consultation. Family history of VTE was analyzed according to definitions from international recommendations (VTE before age 45 years, United Kingdom; before age 50 years, France). A CHC prescription was considered inappropriate for women with vascular contraindications and/or a family history of VTE. Cross-sectional analysis of the clinical and biological characteristics was performed. MAIN OUTCOME MEASURES: Prevalence of inappropriate prescription of CHC and potentially preventable events were estimated. RESULTS: According to the WHO, UK, or French guidelines, 8.8%, 18.9%, and 25.9%, respectively, of CHC prescriptions were considered inappropriate. Compliance with these guidelines could reduce the corresponding number of VTEs by 6.3%, 13.5%, and 18.5%, respectively. Characteristics of the women were similar. CONCLUSION: Our results suggest inappropriate CHC prescriptions are prevalent among CHC users with first VTE. The appropriate way to take family history of VTE into account should be further clarified.

First venous thromboembolism and hormonal contraceptives in young French women.

Information on the clinical and biological characteristics of combined hormonal contraceptives (CHC) users experiencing a venous thromboembolism (VTE) event is scarce. Better knowledge of factors determining the VTE risk in CHC users could help identify women at high risk.Data were obtained from a large cohort of consecutive women with the first documented VTE event. Cross-sectional analysis of clinical and biological characteristics of the women was performed.Of the 3009 women with the first VTE included, 31% were nonusers and 69% CHC users at time of VTE. CHC users were significantly younger (29.0 ±â€Š7.2) than nonusers (31.6 ±â€Š7.1) (P < .001). No difference in VTE familial history was observed between the 2 groups. Compared with nonusers, the CHC users experienced more frequently pulmonary embolism: odds ratio (OR) = 1.28 (1.06-1.55; 95% confidence interval [CI]), factor V Leiden mutations were more frequent in this group (OR = 1.41 [1.11-1.80; 95% CI]). Venous sclerotherapy and travel were associated with VTE in CHC users, whereas surgery and bed rest were significantly associated with VTE in nonusers. Finally, 2/3 of CHC users with VTE had additional VTE risk factors.CHC users experiencing the first VTE differ from nonusers with respect to clinical and genetic background. Better understanding of the characteristics of VTE and associated risk factors could allow more appropriate management of these women and contribute to more accurate benefit-risk assessment before prescribing a CHC.

Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration.

BACKGROUND: Oral estrogen increases the risk of venous thromboembolism (VTE) in postmenopausal women, particularly in those with a prothrombotic mutation. Transdermal estrogen may be safe with respect to VTE. We investigated the impact of the route of estrogen administration on the association between a prothrombotic mutation (factor V Leiden or prothrombin G20210A mutation) and VTE risk. METHODS AND RESULTS: We performed a multicenter case-control study of VTE among postmenopausal women who were enrolled in 1999 through 2004 at 7 clinical centers in France. We recruited 235 consecutive patients with a first documented episode of idiopathic VTE and 554 controls. Factor V Leiden was associated with a 3.4-fold-increased risk of VTE (95% confidence interval [CI], 2.0 to 5.8), and a prothrombin mutation was associated with a 4.8-fold-increased risk of VTE (95% CI, 2.5 to 9.4). Oral but not transdermal estrogen was associated with an increased risk of VTE (odds ratio [OR], 4.3; 95% CI, 2.6 to 7.2; and OR, 1.2; 95% CI, 0.8 to 1.7, respectively). After adjustment for potential confounding factors, the combination of either factor V Leiden or prothrombin G20210A mutation and oral estrogen gave a 25-fold-increased risk of VTE compared with nonusers without mutation (95% CI, 6.9 to 95.0). However, the risk for women with prothrombotic mutation using transdermal estrogen was similar to that of women with a mutation who were not using estrogen (OR, 4.4; 95% CI, 2.0 to 9.9; and OR, 4.1; 95% CI, 2.3 to 7.4, respectively). CONCLUSIONS: In contrast to oral estrogen, transdermal estrogen does not confer additional risk on women who carry a prothrombotic mutation. The safety of transdermal estrogen has to be confirmed in randomized trials.

Recurrence rate after a first venous thrombosis in patients with familial thrombophilia.

OBJECTIVE: Few comprehensive data are available on the recurrence rate of venous thrombosis in carriers of thrombophilic defects from thrombophilic families. We prospectively determined the recurrence rate after a first venous thrombotic event in patients with familial thrombophilia attributable to factor V Leiden or deficiencies of protein C, S, or antithrombin. METHODS AND RESULTS: Data were gathered during follow-up on the occurrence of risk situations, anticoagulation treatment, and events (eg, venous thrombosis, hemorrhage). Over a mean follow-up period of 5.6 years, 44 of the 180 patients with familial thrombophilia who did not use long-term anticoagulation experienced a recurrent venous thromboembolic event (5.0%/year; 95% CI 3.6 to 6.7) compared with 7 of the 124 patients on long-term anticoagulation (1.1%/year; 95% CI 0.4 to 2.2). Spontaneous events occurred less often in patients on long-term anticoagulation (57%) than in patients without long-term anticoagulation (75%). The highest recurrence rate was found among men with a deficiency in natural anticoagulants or multiple defects and women with antithrombin deficiency. Although long-term anticoagulation treatment decreased the incidence of recurrent events by 80%, it also resulted in a risk of major hemorrhage of 0.8% per year. CONCLUSIONS: Extra care after a first event is required for men with a deficiency in natural anticoagulants or multiple defects and women with antithrombin deficiency.

Antithrombin 'DREUX' (Lys 114Glu): a variant with complete loss of heparin affinity.

Here we report the finding of a new natural antithrombin mutation that confirms the critical contribution of lysine 114 to the binding of the core heparin pentasaccharide, with the replacement of lysine 114 by glutamate causing a complete loss in affinity. The variant was identified in a father and son, the father having been investigated for an episode of cerebral ischaemia associated with hypercholesterolaemia. The variant forms SDS-stable complexes with activated factor X (fXa) and its thermal stability and rate of factor Xa inhibition in the absence of heparin are identical to those of normal antithrombin. Normal antithrombin binds to the high affinity heparin pentasaccharide with a Kd of 1nM, as detected by a 45% change in intrinsic fluorescence, resulting in a 230-fold increase in rate of factor Xa inhibition. However, no change in fluorescence was detected for the variant when titrated with heparin or the heparin pentasaccharide, nor was there detectable activation towards factor Xa, indicating a complete loss of heparin binding.

Progestogen-only contraception in women at high risk of venous thromboembolism.

The objective of the study was to evaluate the venous impact of a progestogen-only contraception on women at high risk of venous thromboembolism (VTE). In this retrospective cohort study, 204 consecutive women at high risk of VTE were recruited between January 1992 and June 1997 and were prospectively followed. Women using chlormadinone acetate (CMA) at antigonadotropic doses (n=102) were matched by age and date of referral and history of venous thrombosis with women who had no hormonal contraception (n=102). During follow-up (mean of 33 months), nine episodes of VTE were observed: three in women receiving CMA and six in nontreated women. Using the Cox model to adjust for confounding variables such as age, thrombophilia and body mass index, the relative risk of VTE associated with the use of CMA was not significant [relative risk: 0.8 (0.2-3.9)]. These reassuring results need to be confirmed in other prospective studies.

[Pregnancy-associated venous thrombosis in women with hereditary heterozygous factor V Leiden and/or factor II gene mutations]. / Risque de thrombose lié à la grossesse chez les femmes porteuses d'une mutation hétérozygote du facteur V Leiden, du facteur II ou de leur association.

The risk of venous thromboembolism (VTE) in pregnant women with heterozygous factor V Leiden and/or heterozygous factor II 20210A gene mutations is poorly documented, and the need for prophylaxis is therefore controversial. We retrospectively studied 208 women with hereditary thrombophilia (heterozygous FV Leiden and/or factor II gene mutations), who had a total of 406 full-term pregnancies, including 10 with thromboprophylaxis. The ante- and post-partum incidence of VTE was significantly higher in women with both mutations (17.8 %) than in women with FII gene mutation alone (6.2%) p = 0.003. In contrast, there was no significant difference between women with FV+FII mutation and those with FV mutations alone (10%). Thus, the two most common hereditary risk factors for thrombophilia seem to have an additive rather than a synergistic effect on the antepartum/post-partum risk of VTE. In contrast, a previous history of VTE before pregnancy in women with both the FV and the FII gene mutations was associated with a very high risk of VTE (50%). The incidence of VTE was higher during the post-partum period than the ante-partum period. There was no significant difference in the incidence of fetal loss in the three groups, but this was not a primary endpoint. These results, obtained in a single center, have implications for VTE prophylaxis. Routine use of LMWH is not indicated during pregnancy in asymptomatic women with a single mutation. In contrast, it is justified throughout pregnancy in women with both mutations and a history of venous thrombosis. Regarding asymptomatic women with both mutations, the need for prophylaxis during part or all of the pregnancy should be weighed up on an individual basis. In the post-partum period, there is a consensus on the use of LMWH for 6 weeks in women with single or dual mutations associated with thrombophilia.

Hormonal contraception in women at risk of vascular and metabolic disorders: guidelines of the French Society of Endocrinology.

Hormonal contraceptive methods are widely used in France, including not only oral estrogen-progestin combinations but also non-oral estrogen-progestin delivery methods (patches, vaginal rings), as well as oral forms, implants and intra-uterine devices that deliver only a progestin. Hormonal contraception has only a modest impact on lipid and carbohydrate metabolism, but estrogen-progestin contraceptives have been linked to a variety of vascular risks. Overall, the risk of venous thrombosis is multiplied by a factor of about 4, depending on age, the compounds used, and other risk factors (including biological thrombophilia and a personal history of thrombosis), whereas the risk of arterial events is only increased in women with risk factors. Available data suggest there is no excess risk with progestin-based contraceptives, but far fewer studies have been conducted. At the initiative of the French Society of Endocrinology, an expert group met in 2010 in order to reach a consensus on the use of hormonal contraceptive methods in women with vascular or metabolic risk factors, based on available data and international guidelines published by WHO in 2009 and subsequently adapted to the United States context. The following text, intentionally limited to hormonal contraception, is intended to serve as a guide when prescribing in specific clinical situations, such as a family or personal history of arterial or venous thromboembolism, or the existence of cardiovascular risk factors (hypertension, smoking, diabetes, dyslipidemia, obesity).

Hormone therapy and recurrence of venous thromboembolism among postmenopausal women.

OBJECTIVES: The route of estrogen administration is an important determinant of the risk of the first venous thromboembolism (VTE) event in postmenopausal women using hormone therapy (HT). However, the impact of transdermal estrogens on VTE recurrence risk has not been investigated. The aim of our study was to assess the impact of HT by route of estrogen administration on the risk of recurrent VTE. METHODS: A total of 1,023 consecutive postmenopausal women aged 45 to 70 years with a confirmed first VTE were recruited from an outpatient clinic of a hemostasis hospital unit between January 2000 and December 2008 and were followed for an average of 79 months after discontinuation of anticoagulation therapy. RESULTS: Recurrent VTE occurred in 77 women (1.1% per year). During the follow-up, 130 women used HT (12.7%), including 103 transdermal estrogen users (10.0%) and 10 oral estrogen users (1.0%). After adjustment for potential confounders, there was no significant association between recurrent VTE and use of transdermal estrogens (hazard ratio, 1.0; 95% CI, 0.4-2.4), with the nonusers as a reference group. In contrast, women using oral estrogens had an increased risk of recurrent VTE (hazard ratio, 6.4; 95% CI, 1.5-27.3). Consistently, no subgroup of women had evidence of a risk of recurrent VTE with transdermal HT that significantly differed from that observed for all women. CONCLUSIONS: Oral but not transdermal estrogens are associated with a higher risk of recurrent VTE among postmenopausal women. This result provides further epidemiological evidence that transdermal estrogens may be safe with respect to VTE risk.