Increased risk of Venous Thrombosis in XXY/KS further exacerbated by testosterone therapy

This study demonstrates poor awareness of the known VTE risks in KS and the potential VTE risks of TT within this cohort. Patients not informed of the inherent risks associated with their condition may be less vigilant to complications, unaware of lifestyle decisions affecting risks, and not able to make informed decisions about medical care. Further studies are needed to understand the mechanisms leading to the increased VTE rate in KS. Moreover, an investigation into the relationship between TT and VTE is warranted to weigh the benefits of TT in VTE-prone patient groups like KS. Educational materials, such as a patient information pamphlet distributed in clinics and via associations like the UK’s KSA, are also needed to enhance awareness amongst KS patients of their VTE risk and potentially increased risk with TT.



Pulmonary Embolism in a Patient with Klinefelter’s Syndrome


Dyspnoea and syncope are common causes of admission to hospitals. Pulmonary embolism is often a differential diagnosis, and by examining the clinical history the clinician searches for known predisposing factors. This case report highlights the importance of Klinefelter’s syndrome as a predisposing factor for venous thromboembolism. The syndrome is caused by an extra X chromosome in men, among whom the prevalence is estimated to be 1:500−1:1000. Probably only 25 % of men with the syndrome are diagnosed.


A man in his forties was admitted to hospital due to dyspnoea and syncope. CT showed submassive pulmonary embolism. The course illustrates the challenges of pulmonary embolism and its association with Klinefelter’s syndrome.


Several studies have shown an increased incidence of venous thromboembolism in patients with Klinefelter’s syndrome. Klinefelter’s patients have a higher pre-test likelihood of venous thromboembolism than other patients, similar to patients with hereditary thrombophilia. Klinefelter’s syndrome is a persistent risk factor for recurrent thromboembolism. Thus, Klinefelter’s syndrome impacts both the diagnosis and treatment of thromboembolic disease.


No single factor has been identified that can explain why patients with Klinefelter’s syndrome are at increased risk of venous thromboembolism, but the genes for factor VIII and factor IX are located on the X chromosome, and increased levels of coagulation factors have been observed in Klinefelter’s syndrome. Testosterone-replacement therapy could potentially increase the risk of thromboembolism. Thrombosis risk should therefore be considered prior to the initiation of testosterone-replacement therapy in patients with Klinefelter’s syndrome.

Full Text

Association of Testosterone Therapy With Risk of Venous Thromboembolism Among Men With and Without Hypogonadism

Is clinical prescription of testosterone therapy associated with short-term risk of venous thromboembolism in men with and without hypogonadism?

In this case-crossover study comparing 6-month testosterone use for 39,622 men who had a venous thromboembolism with testosterone use 6 to 12 months before the venous thromboembolism, use of testosterone therapy in the 6-month case period was associated with an increased risk of venous thromboembolism among men with and without hypogonadism.

The findings suggest that testosterone therapy is associated with increased short-term risk of venous thrombo-embolism among all men prescribed the therapy

The clinical indication for testosterone therapy is primarily to treat hypogonadism, a condition in which serum testosterone levels in men decrease below a specific threshold, resulting in sexual dysfunction, altered bone metabolism and body composition, and potential emotional dysregulation. Although testosterone levels may decrease with age, external causes of clinical hypogonadism include genetic diseases or complications from surgery, infection, and medications. Testosterone prescriptions among men increased more than 300% from 2001 to 20135,6; the increase is thought to be caused by testosterone therapy being prescribed for common symptoms, such as low libido and fat redistribution, associated with ageing, obesity, and diabetes and not necessarily with clinical hypogonadism. This increase in prescription rate was more pronounced among men aged 18 to 45 years than among older men. In 2014, the US Food and Drug Administration released a warning about testosterone therapy and the potential risk of heart attack and stroke; since then, testosterone therapy prescriptions have decreased and eventually plateaued. Recent trends estimate that, in the United States, 2.3 million men older than 30 years (3.2%) were prescribed testosterone therapy in 2013 and that this trend decreased to approximately 1.15 million men (1.6%) in 2016. Evidence suggests that testosterone therapy is still being prescribed to men without hypogonadism.

Venous thromboembolism (VTE), consisting of deep vein thrombosis and pulmonary embolism, is a common condition in the United States, with more than 1 million individuals experiencing a VTE annually. Baseline testosterone levels are not associated with increase in VTE risk. However, exogenous testosterone therapy may increase endogenous hematocrit levels, which can increase blood viscosity, platelet accumulation, and thromboxane A2 concentrations for up to 6 months and could subsequently increase risk of blood clot formation and subsequent VTE events. Testosterone therapy is most commonly administered via transdermal gels, patches, or intramuscular routes, each having their own rate of absorption and prescription strengths that potentially affect cardiovascular pathophysiologic factors. Pathophysiologic research suggests that exogenous testosterone therapy could increase VTE risk, but the 2 largest observational studies evaluating this association reached conflicting conclusions. Furthermore, these studies were underpowered to examine testosterone therapy use within important clinical subgroups, such as by clinical hypogonadism status, age, route of testosterone therapy exposure, and duration of testosterone therapy use.

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47XXY and Deep Venous Thrombosis – Support

Klinefelter’s syndrome: Associations with increased blood clot (thrombosis)
events (deep venous thrombosis, pulmonary embolus, venous

Free consultation and evaluation.

The close association of Klinefelter’s syndrome (47XXY) with unexplained thrombosis has been known for at least 33 years. Venous thromboemboli (VTE) are ~20 fold more frequent in Klinefelter’s syndrome than in the general population. Previous single case studies of Klinefelters with VTE have found Protein C deficiency, Lupus anticoagulant and anticardiolipin antibodies, and protein S deficiency, homocysteinemeia, the lupus anticoagulant, Factor V Leiden Heterozygosity, Prothrombin gene 20210A heterozygosity, high Factor VIII and high Factor XI .

In our most recent publications, of 67 patients with VTE after taking testosterone, had Klinefelters treated with testosterone replacement therapy. The uniform normal practice to treat the testosterone deficiency of Klinefelters syndrome is with exogenous testosterone. Since exogenous testosterone can interact with previously undiagnosed thrombophilias to produce VTE, there is a reasonable likelihood that the VTE observed in Klinefelters cases does not represent some unique prothrombotic characteristic of Klinefelters itself, but reflects the thrombotic effects of uniform testosterone supplementation interacting with an inherited or acquired increased tendency to form blood clots (thrombophilia) in a group which may also be enriched with familial thrombophilia.

Take Action:

If you have a well-defined diagnosis of Klinefelters syndrome, and have had VTE while taking testosterone therapy, you may have a high likelihood of having an inherited or acquired thrombophilia. We would be glad to assist as follows:

  1. If you can get to Cincinnati for a FREE 1 hour outpatient consultation, we will obtain the appropriate blood tests for thrombophilia, as well as evaluate your case, and make recommendations for future therapy.
  2. If you cannot get to Cincinnati for the free 1 hour outpatient consultation, we will, FREE OF CHARGE, provide the necessary laboratory orders for the appropriate blood tests for thrombophilia, evaluate your case, and make recommendations for future therapy. However, your health insurance will have to cover the costs of the laboratory testing for thrombophilia, and unless your health policy covers these costs, they would be very very expensive for you to pay by yourself. If you already have laboratory results for thrombophilia, we will be glad, FREE OF CHARGE, to evaluate them and make recommendations.

Charles J. Glueck MD, Jewish Hospital of Cincinnati, 2135 Dana Avenue, Cincinnati OH, 45207. Email, Phone 513-924-8250; Fax 513-924-8273.

High Risk of Venous Thromboembolism in Klinefelter Syndrome