What is the risk of thrombosis (blood clot) with elevated Protein S (133, reference range 56-124) and Protein S free (146, reference range 56-124), particularly in a 40-year-old transgender woman on estrogen (hormone replacement therapy)?

From the Guidelines

Transgender women age 40 on estrogen therapy have a moderately increased risk of venous thromboembolism, and to minimize this risk, they should consider using transdermal estrogen patches or gels rather than oral estrogen when possible. Given the provided protein S levels (total protein S 133 and free protein S 146, both within the normal reference range of 56-124), there does not appear to be an increased risk of blood clots related to protein S deficiency. However, the risk of venous thromboembolism is increased in transgender women on estrogen therapy, as estrogen increases the production of certain clotting factors in the liver and decreases fibrinolysis, creating a more hypercoagulable state 1. The risk is highest in the first 1-2 years of hormone therapy and with oral estrogen formulations. Some key points to consider include:

• Typical estrogen regimens include estradiol patches (0.05-0.1 mg/day) or estradiol gel (2-4 mg/day) 1.
• Regular monitoring of hormone levels and periodic assessment of cardiovascular risk factors is recommended.
• The use of transdermal estrogen patches or gels may help minimize the risk of venous thromboembolism compared to oral estrogen formulations 1.
• Other risk factors for clotting, such as smoking, obesity, or family history of clots, should also be taken into consideration when assessing the overall risk of venous thromboembolism in transgender women on estrogen therapy. It's also worth noting that some studies suggest that the risk of thrombosis associated with thrombophilia is higher in women using oral estrogen preparations, and that selective screening based on prior history of venous thromboembolism may be more cost-effective than universal screening 1. Additionally, the 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases recommends prophylactic anticoagulation therapy with heparin or low molecular weight heparin in asymptomatic aPL-positive patients during ART procedures, and therapeutic anticoagulation in women with thrombotic APS 1. Overall, the management of transgender women on estrogen therapy should involve a comprehensive assessment of their individual risk factors for venous thromboembolism, as well as regular monitoring and adjustment of their hormone regimen as needed to minimize this risk.

From the FDA Drug Label

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. The relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older and in nonsmokers over the age of 40 among women who use oral contraceptives.

The risk of blood clot is increased with estrogen use, especially in women over 40 years old.

• Key factors that increase the risk of blood clots include:
  • Age over 40
  • Smoking
  • Predisposing conditions for venous thromboembolic disease
• Transgender women on estrogen may have an increased risk of blood clots due to the use of estrogen, especially if they are over 40 years old.
• Protein S and free protein S levels are not directly addressed in the provided drug labels as a factor that increases the risk of blood clots with estrogen use. 2 2

From the Research

Risk of Blood Clot with Protein S 133 (56-124) and Protein S Free 146 (56-124)

• The risk of blood clot with protein S 133 (56-124) and protein S free 146 (56-124) is not directly addressed in the provided studies.
• However, study 3 investigated the effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis, including protein S, in postmenopausal women.
• The study found that oral estrogen therapy decreased total protein S and free protein S levels, which may contribute to an increased risk of venous thrombosis.

Risk of Blood Clot in Transgender Women Age 40 on Estrogen

• Study 4 mentions that estrogen increases the risk of both arterial and venous thrombosis, and that transgender women are a unique population that requires careful evaluation and counseling for estrogen-related conditions or treatments.
• Study 5 highlights the importance of individualized clinical decision making in the acute care setting for patients on systemic estrogen therapies, including transgender women, to minimize the risk of venous thromboembolism (VTE).
• Study 6 notes that thrombosis risk with estrogen-containing compounds increases with increasing systemic dose of estrogen, and that patient-specific factors, such as age and medical history, may influence the choice of hormonal preparation.
• Overall, the risk of blood clot in transgender women age 40 on estrogen is likely increased due to the prothrombotic effects of estrogen, but the exact risk depends on various factors, including the dose and route of estrogen administration, as well as individual patient characteristics 4, 5, 6.