To determine which venous malformations (VMs) are at risk for coagulopathy. Venous malformations are slow-flow vascular malformations present at birth, and localized intravascular coagulopathy (LIC) causes pain and thrombosis within a lesion and severe bleeding during surgical procedures.

We thank Drs Micheletti and Chevallier for their interest in our report. 1 First, we believe that odds ratios (ORs) and 95% confidence intervals (CIs) estimated from logistic regressions provide adequate information about significance and the size and direction of the effect of norpregnane derivatives. Because elevation in venous thromboembolism (VTE) risk is substantial (OR: 4) and significantly different from 1 (with the 95% CI not crossing 1), our results suggest a thrombogenic effect of norpregnanes, and the probability value (PϽ0.006) indicates that the probability of the result being due to chance is very small. Second, only the main effects of the route of estrogen administration and type of progestogens were estimated with a joint model ( Table 2 of the original article 1 ). Stratified analyses by route of estrogen administration and type of progestogens have also been performed. Among transdermal estrogen users, women received estrogen alone (10 cases and 35 controls; OR: 0.8, 95% CI: 0.4 to 1.8 after adjustment for obesity, family history of VTE, and varicose veins) or combined with either micronized progesterone (13 cases and 63 controls; OR: 0.6, 95% CI: 0.3 to 1.2), pregnane derivatives (16 cases and 51 controls; OR: 0.8, 95% CI: 0.4 to 1.6), or norpregnane derivatives (28 cases and 31 controls; OR: 3.1, 95% CI: 1.7 to 5.9). Among oral estrogen users, women received estrogen alone (4 cases and 5 controls) or combined with either micronized progesterone (6 cases and no controls), pregnane derivatives (23 cases and 28 controls), norpregnane derivatives (12 cases and 6 controls), or nortestosterone derivatives (12 cases and 7 controls). There was no significant difference in VTE risk between any of the progestogen subgroups among current users of oral estrogen (overall OR: 4.5, 95% CI: 2.6 to 7.5).Third, to allow for adequate numbers of subjects within subgroups, stratified analysis by time of exposure used the median of the distribution (5 years) as a cutoff point. Unlike oral estrogens, there was no significant interaction between the time of exposure to either transdermal estrogens or norpregnane derivatives and VTE risk. Therefore, differences in exposure time to hormone therapy cannot explain our results.Finally, although our results may be clinically relevant, we acknowledge that interpretation of data may have been biased by the inclusion of women with hyperestrogenic symptoms who were prescribed norpregnane derivatives. This prescription bias was emphasized in the Discussion section. Regarding the absence of thrombogenic mechanism underlying our results, Micheletti and Chevallier quote an inconclusive small trial 2 that failed to also show the well-known activation of blood coagulation among women using oral estrogens. In addition, relevant hemostatic tests such as plasmaactivated protein C sensitivity were not included as end points in this trial. Because relevant data are lacking, we are presently investigating the impact of norpregnanes on hemostasis among users of hormone therapy in the Stu...

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. (Circulation.