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 blood clots compared to cisgender men, though this risk is lower than that observed in cisgender women taking oral contraceptives. Based on the provided protein S levels (total protein S 133 and free protein S 146), there does not appear to be an increased risk of blood clots as these values fall within the normal reference range (56-124). The risk is primarily associated with oral estrogen, especially ethinyl estradiol, which should be avoided 1. Transdermal estrogen (patches, gels) carries a lower thrombotic risk and is preferred, particularly for those over 40 or with additional risk factors 1. The typical regimen includes estradiol 2-6 mg daily orally or 0.025-0.1 mg/day transdermally, often combined with anti-androgens. Regular monitoring of hormone levels and thrombotic risk factors is recommended. The increased clotting risk occurs because estrogen increases production of certain clotting factors and decreases natural anticoagulants like protein S in some individuals 1. Lifestyle modifications such as maintaining healthy weight, regular exercise, avoiding smoking, and staying hydrated can help minimize this risk. Some key risk factors for venous thromboembolism include antithrombin deficiency, protein C deficiency, factor V Leiden, and protein S deficiency 1, but the provided protein S levels do not indicate an increased risk. Overall, the management of transgender women on estrogen therapy should focus on minimizing the risk of blood clots while also considering the benefits of hormone therapy, and the most recent guidelines should be consulted for the best approach 1.

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

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

• The provided protein S levels are Protein S 133 (56-124) and Protein S free 146 (56-124), but there is no direct information on how these specific levels affect blood clot risk.
• However, according to 3 and 4, Protein S is an essential natural anticoagulant, and its deficiency is a major contributor to acquired hypercoagulability, which can lead to an increased risk of blood clots.

Increased Risk of Clots for Transgender Women Age 40 on Estrogen

• Studies 5, 6, and 7 suggest that estrogen therapy is associated with an increased risk of venous thromboembolism (VTE) in various populations, including postmenopausal women and transgender women.
• Specifically, 5 found that oral estrogen increases the risk of VTE in postmenopausal women, particularly in those with a prothrombotic mutation.
• 6 highlights the importance of individualized clinical decision-making when managing systemic estrogen therapy in patients at risk of thrombosis, including transgender women.
• 7 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.
• Therefore, it is likely that transgender women age 40 on estrogen may have an increased risk of blood clots, but the exact risk depends on various factors, including the type and dose of estrogen, individual medical history, and other prothrombotic risk factors.