Androgen Deprivation Therapy for Prostate Cancer and the Risk of Venous Thromboembolism

Klil-Drori, Adi J.; Yin, Hui; Tagalakis, Vicky; Aprikian, Armen; Azoulay, Laurent

doi:10.1016/j.eururo.2015.06.022

Cited by 41 publications

(36 citation statements)

References 26 publications

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“…Overall, we believe, that our findings are especially important in the context of ADT, as it was previously shown that the VTE rate is increased in androgen‐deprived prostate cancer patients . It is thus likely that, in prostate cancer patients, castration leads to upregulation of NF‐κB, EGR1 and TF expression in prostate epithelial cells.…”

Section: Discussionsupporting

confidence: 59%

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Androgen receptor dampens tissue factor expression via nuclear factor‐κB and early growth response protein 1

Hoesel

Mußbacher

Dikorman

et al. 2018

Journal of Thrombosis and Haemostasis

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Background Prostate cancer is one of the leading causes of cancer death in men. Advanced prostate cancer is usually treated by androgen deprivation therapy (ADT), which is aimed at reducing circulating testosterone levels to reduce cancer growth. There is growing evidence that ADT can increase the rate of venous thromboembolism (VTE) in prostate cancer patients. The tissue factor (TF) gene is one of the most important mediators of coagulation and VTE, but, so far, there are limited data on androgen receptor (AR)-mediated TF gene expression. Objectives To characterize AR-mediated TF regulation in vitro and in vivo. Methods We used the androgen-dependent prostate cancer cell lines LNCaP and MyC-CaP to test whether TF expression is regulated by AR. Furthermore, we cloned the TF gene promoter into a luciferase reporter vector to identify the transcription factor-binding sites that mediate TF regulation downstream of AR. Finally, we used castration experiments in mice to characterize AR-mediated TF regulation in vivo. Results TF is directly regulated by AR. In LNCaP cells, nuclear factor-κB signaling and EGR1 mediate TF expression. By using castration experiments in mice, we could detect upregulation of TF and early growth response protein 1 mRNA and protein expression in prostate epithelial cells. Conclusion AR is crucial for dampening TF expression, which could be important for increased TF expression and TF-positive microvesicle release in androgen-deprived prostate cancer patients.

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Section: Discussionsupporting

confidence: 59%

“…Prostate cancer is a known risk factor for venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism . There is growing evidence that ADT increases the rate of VTE in prostate cancer patients, suggesting that low levels of testosterone can induce a hypercoagulable state .…”

Section: Introductionmentioning

confidence: 99%

Androgen receptor dampens tissue factor expression via nuclear factor‐κB and early growth response protein 1

Hoesel

Mußbacher

Dikorman

et al. 2018

Journal of Thrombosis and Haemostasis

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“…27 However, several previous clinical studies have demonstrated that androgen deprivation therapy may lead to a hypercoagulable state, with a subsequent link to thromboembolism events. 21,28,29 Moreover, Klil-Drori et al 30 also have shown that patients with prostate cancer on current androgen deprivation therapy use displayed the association with the increased risk of venous thromboembolism, but no association was observed in past use of androgen deprivation therapy. Significantly, Kaur et al 31 have implicated that androgen deprivation therapy do not appear to exacerbate hypercoagulability over time as a whole.…”

Section: Discussionmentioning

confidence: 99%

Comparison Between Thromboelastography and Conventional Coagulation Tests in Surgical Patients With Localized Prostate Cancer

Wang

Li²,

Cao

et al. 2017

Clin Appl Thromb Hemost

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We aimed to examine hypercoagulable and hypocoagulable conditions in patients with prostate cancer using thromboelastography (TEG) and correlate TEG parameters with conventional coagulation test. The t test was used for comparing TEG parameters and routine coagulation results. Spearman rank-order correlation was used to describe the relationship of TEG and conventional tests. Sensitivity, specificity, positive predictive values, and negative predictive values were determined for bleeding and thrombosis. Totally, 20 patients had active bleeding postoperatively, 16 of whom showed hypocoagulation on TEG test and 9 of whom showed hypocoagulation by routine coagulation test (P ¼ .024). Overall, 60 patients did not have active bleeding postoperatively, 51 of whom showed hypercoagulation detected by TEG test and 42 of whom showed hypercoagulation found by routine coagulation test (P ¼ .040). Remarkably, patients had a little higher fibrinogen (FIB) compared to controls. There was no statistical difference in any of the conventional coagulation indexes between the groups. Correlation analysis showed that reaction time (R) and coagulation time (K) were positively correlated with the prothrombin time-international normalized ratio (PT-INR) and negatively correlated with FIB (P < .001). Contrarily, a-angle and maximum amplitude (MA) were negatively correlated with PT-INR but positively correlated with FIB. Significantly, MA showed the strongest correlation with FIB and R exhibited the strongest correlation with PT-INR. Sensitivity and specificity for bleeding and thrombosis in TEG were higher than those in conventional coagulation test. Accordingly, TEG might be superior in evaluating hypercoagulation and detecting the risk of bleeding in patients with prostate cancer.

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“…28 Previous studies have documented a potential association between ADT and increased venous and arterial TE risk in PCa patients. 20,22,29 These studies, however, failed to explore the direct impact of ADT on coagulation and the independent role of disease burden. In this current study, we provide evidence that advanced cancer alone may contribute to increased coagulability, as the majority of our cohort demonstrated hyercoagulable TEG findings before initiation of ADT and this did not appear to increase over time.…”

Section: Discussionmentioning

confidence: 99%

Effects of androgen-deprivation therapy on hypercoagulability in prostate cancer patients: A prospective, longitudinal study

Kaur¹,

Black

Robb

et al. 2017

CUAJ

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Introduction: Androgen-deprivation therapy (ADT) is the mainstay of systemic therapy for advanced prostate cancer (PCa), but has significant adverse effects, including increasing concern for cardiovascular (CV) and thromboembolic (TE) complications. This study carefully investigates any relationship between ADT use and hypercoagulability as a possible mechanism of these adverse effects. Methods: We performed a prospective, longitudinal study in a cohort of patients with advanced PCa initiating ADT (n=18). Controls included men with biochemical failure after local therapy on watchful waiting (n=10), as well as healthy controls (n=8). Global hemostasis was evaluated using the sensitive global hemostasis assay, thromboelastography (TEG). Patients were evaluated at baseline and every three months for a minimum of 12 months. Results: The results of the TEG studies demonstrated 14/18 (78%) of advanced PCa patients had evidence of a hypercoagulable state before initiating therapy. Significant baseline hypercoagulability was documented in this cohort compared to the two control groups. ADT did not appear to exacerbate hypercoagulability over time as a whole: only 10/18 (56%) patients had TEG findings consistent with hypercoagulability at the end of study. However, 3/18 (17%) PCa patients initiating ADT had significantly new hypercoagulable TEG changes on treatment compared to baseline. Conclusions: This prospective pilot study demonstrates a complex interaction between ADT and hypercoagulable state in men with advanced PCa. TEG abnormalities were mostly associated with volume of cancer as compared to ADT use; however, it is possible that ADT may lead to hypercoagulability in a subset of men, suggesting that sensitive monitoring of coagulation of men on ADT could help identify those at risk of developing CV/TE complications. Study limitations include the relatively small cohort of men followed after initiating ADT and these results require confirmation in a larger trial to rule out subtle effects on hypercoagulability.

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Androgen Deprivation Therapy for Prostate Cancer and the Risk of Venous Thromboembolism

Cited by 41 publications

References 26 publications

Androgen receptor dampens tissue factor expression via nuclear factor‐κB and early growth response protein 1

Androgen receptor dampens tissue factor expression via nuclear factor‐κB and early growth response protein 1

Comparison Between Thromboelastography and Conventional Coagulation Tests in Surgical Patients With Localized Prostate Cancer

Effects of androgen-deprivation therapy on hypercoagulability in prostate cancer patients: A prospective, longitudinal study

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