Coagulation Results & VTE In Transgender Population

by Donna Castellone, MS, MT (ASCP) SH • September 01, 2022



The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.


Introduction:

Gender is no longer binary. There are approximately 25 million people who identify as transgender. Medical care requires a team of providers, in particular coagulation specialists need to be familiar with endocrine therapy and the VTE risks associated with hormone regimens.1 It is important to understand baseline results as well as expected results in this population. The initial step in gender-affirmation treatment is hormones to promote development of the identified gender. Surgery is only performed after patients meet qualifying criteria and can include years of hormone use. This can cause decreased bone density, increased long term risk for malignancy, and altered lipid profile the risk of VTE is important and immediate.1 Risk was observed in a large Dutch study of 2517 transgender women who were followed for a median of 6 years. There was a 2 fold increase in transgender women when compared to cisgender women in ischemic stroke and myocardial infarction. Additionally, a 5-fold increase was seen in VTE in transgender women when compared to both cisgender women and men.2 The risks of prothrombic factors are the same in the general population but the risk over time may be different in this cohort. Not understanding these effects can complicate the management of other health problems.1



Coagulation Results:

When comparing PT, aPTT, factor VIII and von Willebrand antigen there were no differences in the transgender population. Increased d-dimer and fibrinogen were statistically significantly elevated when compared with cisgender male controls, however they did remain in the normal reference range.2 Transgender women had slightly prolonged PT than cisgender female controls, while FVIII levels were higher in the controls.

Generally, it is known that hormones use in women are important VTE risk factors with increases seen in factors II, FVII, FVIII, FIX, FX, FXI and protein C and fibrinogen and decreased levels of AT and PS. The impact of hormone use, testosterone in men has shown an increased risk of VTE in the first 6 months.3 All of the changes result in a prothrombotic state and an increase in VTE.1 Gender-affirming hormone therapy (GAHT) effects of the transgender cohort are largely unknown. Transmen receive testosterone and transwomen receive estrogens.3

The effect of GAHT on coagulation parameters associated with venous thromboembolism (VTE) risk was determined after 12 months. A study measured factors II, IX, XI, protein C, free protein S, fibrinogen and activated protein C ratio in 98 transwomen and 100 trans men pre and post 12 months of GAHT. Results showed that transwomen had a more procoagulant profile. There was a mean increase in FIX: 9.6 IU/dL and FXI: 13.5 IU/dL and a decrease in pC: −7.7 IU/d and increase in free protein S of 2.5 IU/dL. There was no change in FII levels. The route of administration impacted the changes in coagulation parameters (oral vs transdermal). Age was also a factor. Having a higher sex hormone binding globulin level after 12 months resulted in a lower APCR. This data supports the contribution of GAHT and the increased risk seen in transwomen.3

Transitioning from female to male relies on the use of testosterone. It can be administered via gels, patches, intramuscular or parenterally. The long acting parenteral form has been associated with pulmonary microemboli and is used infrequently. The risk for VTI for transmen is considered low. A study of transmen cohort comparing testosterone use in cismen and ciswomen were low at 1.6 vs 1.1. In the U.S. database study of transmen, results for ischemic stroke with versus without testosterone use were 1.1 and 1.3 and 0.7 and 1.3 for myocardial infarction.1



Global Coagulation Assays:

Routine coagulation tests such as the aPTT and the PT only measure the time to start of clot formation which only represents about <5% of thrombin generation. This makes these tests poor indicators of a hypercoagulable state. Looking at global coagulation assays can provide a more comprehensive assessment and may help in predicting venous and arterial thrombotic risks.2

Global coagulation assays can be used to measure hemostatic function of estradiol therapy. Comparing the profiles of transgender women to cisgender controls were tested using whole blood thromboelastography (TEG 5000), platelet poor thrombin generation; thrombogram and hemostatic potential assay by testing platelet poor plasma fibrin generation. In the study the results showed no differences in serum estradiol concentration and duration of therapy. Transgender women showed hypercoagulable parameters on thromboelastography and thrombin generation. They also have increased overall fibrinolytic potential when compared to cisgender men but there were no significant changed when compared to cisgender women.2



Conclusions:

It is important to understand the impact of hormone treatment and the risk of thrombosis as well as the coagulation profile of transgender patients. Studies are ongoing to address the long term health effects with transgender treatments. Absolute risks using hormone therapy are not so high that is shouldn't be used in transgender patients. Current preparations of estrogen for transwomen have a lower risk of VTE and the use of testosterone in transmen appears to be associated with a very limited VTE risk. Understanding how coagulation testing is affected in transgender patients will help in the evaluation of VTE risk.




References:

  1. Jean M. Connors,Saskia Middeldorp ,Transgender patients and the role of the coagulation clinician, Journal of Thrombosis and Hemostasis, 29 August 2019
  2. Hui Yin Lim, Shalem Y Leemaqz, Niloufar Torkamani, Mathis Grossmann, Jeffrey D Zajac, Harshal Nandurkar, Prahlad Ho, Ada S Cheung
  3. Global Coagulation Assays in Transgender Women on Oral and Transdermal Estradiol Therapy The Journal of Clinical Endocrinology and Metabolism 105(7), May 2020
  4. Luuk J.J. Scheres,Nienke L.D. Selier,Nienke M. Nota,Jeske J.K. van Diemen,Suzanne C. Cannegieter,Martin den Heijer, Effect of gender-affirming hormone use on coagulation profiles in transmen and transwomen Journal of Thrombosis and Hemostasis. 01 February 2021.