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A journal club style critical review of current publications in evidence-based transgender medical care.

Tuesday, October 18, 2011

Incidence of Thrombophilia and Venous Thrombosis in Transsexuals Under Cross-Sex Hormone Therapy

     Retrospective cohort study of 162 MTF patients on transdermal estradiol + cyproterone acetate with an 8% prevalence of baseline thrombophilic conditions showed no incidents of venous thromboembolism over an average 49.6 months. (1)

     Venous thromboembolism (VTE) is a common concern for providers providing cross gender hormone therapy (cHRT) for male-to-female (MTF) transgender persons.  Additional concern may exist for patients with pre-existing prothrombotic mutations, and the question arises as to weather or not it is important to pre-screen MTF persons for hypercoagulability prior to initiation of cHRT.

     Researchers conducted a retrospective review of outcomes in a cohort of 162 MTF women who had a baseline prevalence of 8% (13/162) prothrombotic mutations, which is consistant with the baseline prevalence in non-transgender caucasian persons.  All 13 patients exhibited activated protein C (aPC) resistance and four were smokers.  No cases of antithrombin III or protein C deficiency were found the study population.  Only one patient (a smoker) was on anticoagulation therapy.  161/162 patients received either transdermal estradiol monotherapy (if post-op) or transdermal estradiol + cyproterone acetate + finasteride (if pre-op).  One patient with multiple cardiovascular risk factors and aPC resistance (not on anticoagulation) was given cyproterone acetate monotherapy.  60/162 patients had reported prior self-directed cHRT use, all had been off cHRT for a minimum of 4 weeks prior to treatment at the study site.

     Over a mean duration of 49.6 months on cHRT (range 12-135 months), no incidents of VTE were observed in the study cohort.  The expected incidence of VTE in 0.43/18 patients with a prothrombotic mutation did not differ significantly from the observed incidence of 0/18.  The authors concluded that cHRT in transgender persons with a prothrombotic mutation is safe, and that routine pre-cHRT screening for prothrombotic mutations is not recommended if there is no family or personal history of VTE.


     Venous thromboembolism is a commonly feared outcome of cross gender hormone therapy, but a growing body of recent evidence has shown that the use of transdermal estradiol (or oral estradiol as opposed to conjugated equine or synthetic estrogens) minimizes this risk.  The authors chose to look at the risk of VTE in a cohort of MTF women who were pre-screened for the presence of a prothrombotic mutation.  None of the women, with or without a mutation had a VTE during the study period of an average 49.6 months.  Since most incidents of VTE occur in the first year of HRT in non-transgender contexts, their conclusions that cHRT with respect to thrombophilia is safe seems reasonable.  This study should help reassure the clinician that the use of safe cHRT such as transdermal estradiol minimizes VTE risk in the general population and in those with minor prothrombotic mutations such as aPC resistance / factor V Leiden.

     Shortcomings include the relatively small number of patients, retrospective nature and the lack of any patients in the cohort with more serious prothrombotic mutations such as antithrombin III or protein C deficiency.

     Of note, the study also looked at an FTM cohort and found similar results.  While the authors cite several basic science articles suggesting testosterone increase thrombotic risk in lab animals, this is not congruent with publications in trauma research which suggest that testosterone leads to a hypocoaguable state. (2)


1) Ott J, Kaufmann U, Bentz E-K, Huber JC, Tempfer CB; Incidence of Thrombophilia and Venous Thrombosis in Transsexuals Under Cross-Sex Hormone Therapy; Fertil Steril 2010;93:1267-72

2) Gee AC, Sawai RS, Differding J, Muller P, Underwood S, Schreiber MA; The Influence of Sex Hormones on Coagulation and Inflammation in the Trauma Patient; Shock 2008;29:334-41


  1. I track all VTE events in our practice. We have about 300 patient years of experience with injectable, topical, oral, and patch CHT. Less than 10% of which is oral route. There has NOT been 1 VTE event thus far in the Papillon CHT program. Of note, there have been 2 MTF and 1 FTM that had a history of VTE prior to CHT who were placed on CHT elsewhere following VTE and successfully had surgery and CHT post VTE without recurrence.

    I have, however, had 3 VTE discovered 1-2 weeks after vaginoplasty over the last 5 years. 1 had an obscure genetic disorder, 1 was a heavy smoker that quit 4 weeks prior to surgery and the other had no additional risk factors that we could find. Our protocol is to stop estradiol and progesterone 2 weeks prior to surgery and two weeks after, to ambulate within 24-48 hours of surgery, the use of thigh high sequential stockings and to give a one time dose of Lovenox 40mg SC just prior to incision. This exceeds the recommendation by the American Academy of Chest Surgeons. Even with these 3 vte we have a rate of less than 2%. The risk for vte in major gynaecologic, major open urologic, and neurologic surgery without propylaxis is 15-30% and with prophylaxis is 1-5% for major gyn/urology with prophylaxis and 3% for ortho. In speaking with other gender surgeons, most do not use any anticoagulation, but just early ambulation and sequential stockings. Some do not stop estradiol or progesterone stating that natal women have these hormone levels during surgery. We clearly do not have a standard of care for this type of surgery, but in speaking to the other surgeons, our VTE rates anecdotally seem to be wnl.

    Lastly, I have one patinet who had a severe VTE and PE who continues on warfarin 1.5 years post vte. She had been on Evamist 1 spray daily for the past year without incident. We will have to have a long discussion about what her options are if/when she comes off warfarin

  2. Dr. McGinn,

    Thank you for sharing your clinical experiences. Given that your rate of VTE is much less than that encountered in a general population of pelvic surgery patients, what would you think of allowing patients to provide informed consent with respect to the use of perioperative hormone therapy in concert with heparin prophylaxis? The perioperative period in vaginoplasty is a time of great emotional and physiologic stress and the concern arises of worsening both of these with the cessation of hormone therapy.

    Can you comment on any perceived or actual increase in postoperative hemorrhage or edema/hematoma using your unfractionated heparin protocol?