Medical Hypotheses 84 (2015) 341–343
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Testosterone therapy, thrombophilia, and hospitalization for deep venous thrombosis–pulmonary embolus, an exploratory, hypothesisgenerating study Charles J. Glueck a,⇑, Joel Friedman b, Ahsan Hafeez b, Atif Hassan b, Ping Wang a a b
Jewish Hospital Cholesterol Center, Jewish Hospital of Cincinnati, United States Internal Medicine Residency Program, Jewish Hospital of Cincinnati, United States
a r t i c l e
i n f o
Article history: Received 10 December 2013 Accepted 15 January 2015
a b s t r a c t Our hypothesis was that testosterone therapy (TT) interacts with previously undiagnosed thrombophilia– hypofibrinolysis, leading to hospitalization for deep venous thrombosis (DVT)–pulmonary emboli (PE). We determined the prevalence of DVT–PE associated with TT 147 men hospitalized in the last 12 months for DVT–PE. Of the 147 men, 2 (1.4%) had TT before and at the time of their DVT–PE. Neither had risk factors for thrombosis. Neither smoked. Case #1 (intramuscular T 50 mg/week) had 2 PE, 6 and 24 months after starting TT. DVT–PE in case #2 (T gel 100 mg/day) occurred 24 months after starting T. Both men were found to have previously undiagnosed familial thrombophilia (protein S deficiency, homocysteinemia, high Factor VIII). In case #2, on 100 mg T gel/day, serum estradiol was high, 51 pg/ ml (upper normal limit 42.6 pg/ml). At least 1.4% of men hospitalized for DVT–PE were on TT and had previously undiagnosed thrombophilia, suggesting a thrombotic interaction between exogenous T and thrombophilia–hypofibrinolysis. Given the increasing use of TT, our preliminary findings should facilitate design of a much-needed, multi-center, prospective study of pro-thrombotic interactions between T therapy and thrombophilia for subsequent thrombotic events including DVT–PE. Ó 2015 Elsevier Ltd. All rights reserved.
Introduction/background Pulmonary embolism (PE) is expensive to diagnose and treat ($8764/case) with a high case fatality rate (18%) [1], and approaches to reduce and/or prevent PE [2–5] are important, both medically and economically. In 596 men hospitalized over a 3 year period for deep venous thrombosis–PE (DVT–PE), we previously reported that 7 (1.2%) had taken testosterone (T) before and at the time of their admission [2]. Five of 7 DVT–PE events occurred within 3 months of initiation of T, with median and mean intervals between T initiation and DVT–PE 2 and 6.7 months [2]. Of the 7 men treated with T, all 5 men who had evaluation of thrombophilia–hypofibrinolysis were found to have previously undiagnosed thrombophilia–hypofibrinolysis, suggesting a thrombotic interaction between exogenous T and thrombophilia–hypofibrinolysis [2–5].
⇑ Corresponding author at: Cholesterol and Metabolism Center, Jewish Hospital, Suite 430, 2135 Dana Avenue, Cincinnati, OH 45207, United States. Tel.: +1 513 924 8250; fax: +1 513 924 8274. E-mail address: [email protected] (C.J. Glueck). http://dx.doi.org/10.1016/j.mehy.2015.01.020 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
Altogether in our 4 recent studies [2–5], we have described 26 men and 4 women with thrombotic events, 18 with DVT–PE, 10 with osteonecrosis, 1 with central retinal vein thrombosis, 1 with amaurosis fugax, 3 months (median) after starting T. Of these 30 cases, 28 had measures of thrombophilia–hypofibrinolysis; 27 of the 28 were found to have previously undiagnosed thrombophilia–hypofibrinolysis. Osteonecrosis may be caused, in part, by thrombophilia–hypofibrinolysis induced thrombus of the efferent veins of the head of the femur leading to increased intracortical pressure and reduced arterial inflow, subsequent bone hypoxia, and bone death [6]. We have suggested that men or women sustaining thrombotic events on T therapy should be screened for thrombophilia–hypofibrinolysis. To prevent thrombotic events, measures of thrombophilia should be made before starting T, particularly the Factor V Leiden mutation and plasminogen activator inhibitor 4G4G mutations, Factors VIII and XI, and homocysteine [2–5]. Since the major source of estradiol (E2) in men comes from the aromatization of T to E2 [7], we speculated [5] that when exogenous T is aromatized to E2 [7,8] and E2-induced thrombophilia is superimposed on underlying familial thrombophilia, thrombosis
342
C.J. Glueck et al. / Medical Hypotheses 84 (2015) 341–343
occurs. [5] In 60 men on T, we had previously reported that 20 (33%) had high estradiol (E2 > 42.6 pg/ml) [5]. The hypothesis Our hypothesis was that testosterone therapy interacts with previously undiagnosed thrombophilia–hypofibrinolysis, leading to hospitalization for deep venous thrombosis (DVT) and pulmonary emboli (PE). Evaluation of the hypothesis In the current, preliminary, hypothesis-generating study of 147 men hospitalized for DVT–PE in the past year, our specific aim was to determine the prevalence of T therapy interacting with previously undiagnosed thrombophilia leading to hospitalization for DVT–PE. Empirical data Patients, diagnosis of deep venous thrombosis and pulmonary emboli Electronic medical records were reviewed for all 147 men admitted to the Mercy Hospital System in the past year for DVT– PE, following a protocol approved by the Jewish Hospital Institutional Review Board. The diagnosis of DVT was confirmed by venous ultrasound, and the diagnosis of PE by spiral CT scan. Men who developed DVT–PE during hospitalization for other diseases were not included in this cohort. Signed informed consent was obtained for evaluation of men who took T before hospitalization for DVT–PE. Direct interviews of the patients were carried out to identify the type of T, the dose, and whether the T had been used at the time of the thrombotic event. The patients’ history was then confirmed by our review of electronic medical records.
Results Of the 147 men hospitalized in the last 12 months for DVT–PE, 34 (23%) were deceased or in hospice care, 6 (4%) had cancer thought to be a cause of DVT–PE, Fig. 1. Of the remaining 107 men, 63 could not be contacted, leaving 44 men, of whom 2 were taking T, 1.4% of the total cohort, Fig. 1. Neither of these 2 Caucasian previously healthy men had DVT, PE, or any other thrombotic events before taking T. Neither had risk factors for thrombosis including hip–knee or superficial leg vein surgery, leg fracture or dislocation, immobilization, or trauma. Neither smoked. Case #1, a 56 years old, sustained two DVT–PE, the first occurred 6 months after starting intramuscular T, 50 mg/week. There had been no recent trauma, surgery, inflammation, or immobility. There was no polycythemia; screening for occult cancer was negative. With T continued, warfarin was given for 6 months, and then discontinued. Twelve months later, he had a second DVT– PE. While on warfarin therapy after his second DVT–PE, he was found to have high homocysteine (18 umol/L, laboratory upper normal limit [11] 16) and low antigenic protein S (39%, lower normal limit [LNL] 70%). To determine whether the low antigenic protein S was inherited or a result of warfarin, his antigenic protein S/ antigenic factor VII ratio was determined, and found to be 0.5, LNL > 0.5. Before T therapy, total serum T was low (164 ng/dl, normal range 280–800 ng/dl), and E2 was normal (12.5 pg/ml, normal 642.6 pg/ml). While on T, his total serum T rose to 370 ng/dl, within the normal range, and E2 more than doubled to 27 pg/ml. Case #2, 62 years old, developed DVT–PE 24 months after starting T gel (100 mg/day). There had been no recent trauma, surgery, inflammation, or immobility. There was no polycythemia; screening for occult cancer was negative. He was found had high Factor VIII activity (190%, UNL 150%). Before taking T, serum T was low, (94 ng/dl, normal range 280–800 ng/dl) and E2 15.7 pg/ml (UNL 42.6 ng/dl). On T, serum T rose to 739 ng/dl, and serum estradiol became high (51 pg/ml, UNL 42.6 pg/ml).
Laboratory assessment of thrombophilia and hypofibrinolysis In all subjects, after an overnight fast, blood was drawn in the seated position for assessment of thrombophilia and hypofibrinolysis [9]. PCR assays PCR measures of thrombophilia–hypofibrinolysis (G1691A Factor V Leiden, G20210A prothrombin, MTHFR C677T-A1298C, and 4G5G plasminogen activator inhibitor activity gene mutations) were performed using previously published methods by laboratory staff blinded to the subjects’ status (diagnosis, severity of disease) [9,10]. Serologic measures of thrombophilia Measures of thrombophilia included anticardiolipin antibodies (IgG and IgM), lupus anticoagulant, antigenic protein C, total and free protein S, antithrombin III, resistance to activated protein C (RAPC), activated partial thromboplastin time (APTT), Factors VIII and XI, and homocysteine. Established, previously published methods were used [9,10]. In patients concurrently receiving Warfarin, the ratio of antigenic protein C to antigenic factor VII, and the ratio of total protein S to antigenic factor VII were measured. Serologic measures of hypofibrinolysis Measures of LP (a) were done using established, previously published methods. [9,10].
Fig. 1. Prevalence of testosterone use before and at the time of deep venous thrombosis–pulmonary embolism requiring hospitalization in 147 men.
C.J. Glueck et al. / Medical Hypotheses 84 (2015) 341–343
343
Discussion
Conflict of interest statement
To the best of our knowledge, this is only the second report of T therapy associated with hospitalization for DVT–PE in men without previous thrombotic episodes, subsequently found to have thrombophilia. Two of 147 men (1.4%) in the current report and 7/596 (1.2%) in our previous report [2] took T before and at the time of hospitalization for DVT–PE, and were later found to have previously undiagnosed thrombophilia. As recently reported by Baillargeon et al. [12] ‘‘. . .androgen use among men 40 years or older increased more than 3-fold, from 0.81% in 2001 to 2.91% in 2011.’’ Given an estimated population prevalence of thrombophilias of 18% to 28%, [13,14] and use of T by 2.91% of men age P40 [12], we estimate that 0.81% of men age P40 are both given T and have familial and acquired thrombophilias, thus facing high risk for DVT–PE or ON [2–5]. This estimate is consistent with our current and previous finding [2] of 1.4% and 1.2% [2] of men who took T, were hospitalized for DVT–PE, and had thrombophilia. In the current study, DVT–PE occurred 6 and 24 months after starting T, while in the 7 men whose DVT–PE necessitated hospitalization in our previous report [2], the mean interval between initiation of T and hospitalization with DVT–PE was 6.7 months, range of 3 weeks to 27 months. In the current report, both men who sustained DVT–PE while on T were found to have previously undiagnosed thrombophilia previously documented to be associated with DVT–PE (protein S deficiency [15], homocysteinemia [16,17], high Factor VIII [17]), congruent with our previous reports [2–5]. One of our two cases developed thrombophilic high serum E2 on T therapy, thought to interact with the underlying thrombophilia, leading to DVT–PE [5]. The increasingly widespread use of T, particularly in aging men [12], may be accompanied by adverse thrombotic [2–5] and cardiovascular [18] effects. We recommend that the FDA Medwatch [19] process should be followed in the future for adverse thrombotic and cardiovascular events associated with exogenous T, to document its impact. Our exploratory, hypothesis-generating study has several serious limitations. There is potential for selection bias because after deleting men who were deceased or in hospice care (23%) or had cancer (4%), we were able to obtain data on testosterone use in only 30% of the total cohort. However, this would have biased our results toward the null, rather than overstating the true prevalence. Although screening for thrombophilia (Factor V Leiden, Factors VIII and XI, homocysteine) before T therapy to prevent T-mediated DVT–PE is expensive ($500), pulmonary embolism has a high case fatality rate (18%) and is expensive to diagnose and treat ($8,764/patient) [1]. Given the increasing use of T therapy [12], our current and initial [2] reports of T-treated patients hospitalized for DVT–PE could be used to design a much larger, definitive, multi-center prospective study to determine the likelihood of developing DVT–PE when T is given, and to assess pro-thrombotic interactions between T therapy and thrombophilia for subsequent thrombotic events including DVT–PE.
None of the authors have any financial or personal relationships, which would inappropriately influence (bias) their work. The study was funded in part by the Lipoprotein Research Fund, an endowment fund of the Jewish Hospital of Cincinnati, under Dr. CJ Glueck’s direction. References [1] Fanikos J, Rao A, Seger AC, Carter D, Piazza G, Goldhaber SZ. Hospital costs of acute pulmonary embolism. Am J Med 2013;126(2):127–32. [2] Glueck CJ, Richardson-Royer C, Schultz R, et al. Testosterone therapy, thrombophilia–hypofibrinolysis, and hospitalization for deep venous thrombosis–pulmonary embolus: an exploratory, hypothesis-generating study. Clin Appl Thromb Hemost 2014;20:244–9. [3] Glueck CJ, Richardson-Royer C, Schultz R, et al. Testosterone, thrombophilia, and thrombosis. Clin Appl Thromb Hemost 2014;20:22–30. [4] Glueck CJ, Bowe D, Valdez A, Wang P. Thrombosis in three postmenopausal women receiving testosterone therapy for low libido. Womens Health (Lond Engl) 2013;9(4):405–10. [5] Glueck CJ, Goldenberg N, Budhani S, et al. Thrombotic events after starting exogenous testosterone in men with previously undiagnosed familial thrombophilia. Transl Res 2011;158(4):225–34. [6] Glueck CJ, Freiberg RA, Boriel G, et al. The role of the Factor V Leiden mutation in osteonecrosis of the hip. Clin Appl Thromb Hemost 2013;19:499–503. [7] Vermeulen A, Kaufman JM, Goemaere S, van Pottelberg I. Estradiol in elderly men. Aging Male 2002;5(2):98–102. [8] Cherrier MM, Matsumoto AM, Amory JK, et al. The role of aromatization in testosterone supplementation: effects on cognition in older men. Neurology 2005;64(2):290–6. [9] Glueck CJ, Freiberg RA, Wang P. Heritable thrombophilia–hypofibrinolysis and osteonecrosis of the femoral head. Clin Orthop Relat Res 2008;466(5):1034–40. [10] Glueck CJ, Wang P, Bell H, Rangaraj V, Goldenberg N. Associations of thrombophilia, hypofibrinolysis, and retinal vein occlusion. Clin Appl Thromb Hemost 2005;11(4):375–89. [11] Montella BJ, Nunley JA, Urbaniak JR. Osteonecrosis of the femoral head associated with pregnancy. A preliminary report. J Bone Joint Surg Am 1999;81(6):790–8. [12] Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med 2013;173(15):1465–6. [13] Middeldorp S. Is thrombophilia testing useful? Hematology Am Soc Hematol Educ Program 2011;2011:150–5. [14] Roldan V, Lecumberri R, Munoz-Torrero JF, et al. Thrombophilia testing in patients with venous thromboembolism. Findings from the RIETE registry. Thromb Res 2009;124(2):174–7. [15] Signorelli SS, Fiore V, Puccia G, Mastrosimone G, Anzaldi M. Thrombophilia in patients with lower limbs deep veins thrombosis (LDVT) results of a monocentric survey on 103 consecutive outpatients. Clin Appl Thromb Hemost 2013;20:589–93. [16] Herrmann M, Whiting MJ, Veillard AS, Ehnholm C, Sullivan DR, Keech AC. Plasma homocysteine and the risk of venous thromboembolism: insights from the FIELD study. Clin Chem Lab Med 2012;50(12):2213–9. [17] Grifoni E, Marcucci R, Ciuti G, et al. The thrombophilic pattern of different clinical manifestations of venous thromboembolism: a survey of 443 cases of venous thromboembolism. Semin Thromb Hemost 2012;38(2):230–4. [18] Vigen R, OD C, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310:1829–36. [19] Shane R. Risk evaluation and mitigation strategies: impact on patients, health care providers, and health systems. Am J Health Syst Pharm 2009;66(24 Suppl. 7):S6–S12.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Testosterone therapy, thrombophilia, and hospitalization for deep venous thrombosis–pulmonary embolus, an exploratory, hypothesisgenerating study Charles J. Glueck a,⇑, Joel Friedman b, Ahsan Hafeez b, Atif Hassan b, Ping Wang a a b
Jewish Hospital Cholesterol Center, Jewish Hospital of Cincinnati, United States Internal Medicine Residency Program, Jewish Hospital of Cincinnati, United States
a r t i c l e
i n f o
Article history: Received 10 December 2013 Accepted 15 January 2015
a b s t r a c t Our hypothesis was that testosterone therapy (TT) interacts with previously undiagnosed thrombophilia– hypofibrinolysis, leading to hospitalization for deep venous thrombosis (DVT)–pulmonary emboli (PE). We determined the prevalence of DVT–PE associated with TT 147 men hospitalized in the last 12 months for DVT–PE. Of the 147 men, 2 (1.4%) had TT before and at the time of their DVT–PE. Neither had risk factors for thrombosis. Neither smoked. Case #1 (intramuscular T 50 mg/week) had 2 PE, 6 and 24 months after starting TT. DVT–PE in case #2 (T gel 100 mg/day) occurred 24 months after starting T. Both men were found to have previously undiagnosed familial thrombophilia (protein S deficiency, homocysteinemia, high Factor VIII). In case #2, on 100 mg T gel/day, serum estradiol was high, 51 pg/ ml (upper normal limit 42.6 pg/ml). At least 1.4% of men hospitalized for DVT–PE were on TT and had previously undiagnosed thrombophilia, suggesting a thrombotic interaction between exogenous T and thrombophilia–hypofibrinolysis. Given the increasing use of TT, our preliminary findings should facilitate design of a much-needed, multi-center, prospective study of pro-thrombotic interactions between T therapy and thrombophilia for subsequent thrombotic events including DVT–PE. Ó 2015 Elsevier Ltd. All rights reserved.
Introduction/background Pulmonary embolism (PE) is expensive to diagnose and treat ($8764/case) with a high case fatality rate (18%) [1], and approaches to reduce and/or prevent PE [2–5] are important, both medically and economically. In 596 men hospitalized over a 3 year period for deep venous thrombosis–PE (DVT–PE), we previously reported that 7 (1.2%) had taken testosterone (T) before and at the time of their admission [2]. Five of 7 DVT–PE events occurred within 3 months of initiation of T, with median and mean intervals between T initiation and DVT–PE 2 and 6.7 months [2]. Of the 7 men treated with T, all 5 men who had evaluation of thrombophilia–hypofibrinolysis were found to have previously undiagnosed thrombophilia–hypofibrinolysis, suggesting a thrombotic interaction between exogenous T and thrombophilia–hypofibrinolysis [2–5].
⇑ Corresponding author at: Cholesterol and Metabolism Center, Jewish Hospital, Suite 430, 2135 Dana Avenue, Cincinnati, OH 45207, United States. Tel.: +1 513 924 8250; fax: +1 513 924 8274. E-mail address: [email protected] (C.J. Glueck). http://dx.doi.org/10.1016/j.mehy.2015.01.020 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
Altogether in our 4 recent studies [2–5], we have described 26 men and 4 women with thrombotic events, 18 with DVT–PE, 10 with osteonecrosis, 1 with central retinal vein thrombosis, 1 with amaurosis fugax, 3 months (median) after starting T. Of these 30 cases, 28 had measures of thrombophilia–hypofibrinolysis; 27 of the 28 were found to have previously undiagnosed thrombophilia–hypofibrinolysis. Osteonecrosis may be caused, in part, by thrombophilia–hypofibrinolysis induced thrombus of the efferent veins of the head of the femur leading to increased intracortical pressure and reduced arterial inflow, subsequent bone hypoxia, and bone death [6]. We have suggested that men or women sustaining thrombotic events on T therapy should be screened for thrombophilia–hypofibrinolysis. To prevent thrombotic events, measures of thrombophilia should be made before starting T, particularly the Factor V Leiden mutation and plasminogen activator inhibitor 4G4G mutations, Factors VIII and XI, and homocysteine [2–5]. Since the major source of estradiol (E2) in men comes from the aromatization of T to E2 [7], we speculated [5] that when exogenous T is aromatized to E2 [7,8] and E2-induced thrombophilia is superimposed on underlying familial thrombophilia, thrombosis
342
C.J. Glueck et al. / Medical Hypotheses 84 (2015) 341–343
occurs. [5] In 60 men on T, we had previously reported that 20 (33%) had high estradiol (E2 > 42.6 pg/ml) [5]. The hypothesis Our hypothesis was that testosterone therapy interacts with previously undiagnosed thrombophilia–hypofibrinolysis, leading to hospitalization for deep venous thrombosis (DVT) and pulmonary emboli (PE). Evaluation of the hypothesis In the current, preliminary, hypothesis-generating study of 147 men hospitalized for DVT–PE in the past year, our specific aim was to determine the prevalence of T therapy interacting with previously undiagnosed thrombophilia leading to hospitalization for DVT–PE. Empirical data Patients, diagnosis of deep venous thrombosis and pulmonary emboli Electronic medical records were reviewed for all 147 men admitted to the Mercy Hospital System in the past year for DVT– PE, following a protocol approved by the Jewish Hospital Institutional Review Board. The diagnosis of DVT was confirmed by venous ultrasound, and the diagnosis of PE by spiral CT scan. Men who developed DVT–PE during hospitalization for other diseases were not included in this cohort. Signed informed consent was obtained for evaluation of men who took T before hospitalization for DVT–PE. Direct interviews of the patients were carried out to identify the type of T, the dose, and whether the T had been used at the time of the thrombotic event. The patients’ history was then confirmed by our review of electronic medical records.
Results Of the 147 men hospitalized in the last 12 months for DVT–PE, 34 (23%) were deceased or in hospice care, 6 (4%) had cancer thought to be a cause of DVT–PE, Fig. 1. Of the remaining 107 men, 63 could not be contacted, leaving 44 men, of whom 2 were taking T, 1.4% of the total cohort, Fig. 1. Neither of these 2 Caucasian previously healthy men had DVT, PE, or any other thrombotic events before taking T. Neither had risk factors for thrombosis including hip–knee or superficial leg vein surgery, leg fracture or dislocation, immobilization, or trauma. Neither smoked. Case #1, a 56 years old, sustained two DVT–PE, the first occurred 6 months after starting intramuscular T, 50 mg/week. There had been no recent trauma, surgery, inflammation, or immobility. There was no polycythemia; screening for occult cancer was negative. With T continued, warfarin was given for 6 months, and then discontinued. Twelve months later, he had a second DVT– PE. While on warfarin therapy after his second DVT–PE, he was found to have high homocysteine (18 umol/L, laboratory upper normal limit [11] 16) and low antigenic protein S (39%, lower normal limit [LNL] 70%). To determine whether the low antigenic protein S was inherited or a result of warfarin, his antigenic protein S/ antigenic factor VII ratio was determined, and found to be 0.5, LNL > 0.5. Before T therapy, total serum T was low (164 ng/dl, normal range 280–800 ng/dl), and E2 was normal (12.5 pg/ml, normal 642.6 pg/ml). While on T, his total serum T rose to 370 ng/dl, within the normal range, and E2 more than doubled to 27 pg/ml. Case #2, 62 years old, developed DVT–PE 24 months after starting T gel (100 mg/day). There had been no recent trauma, surgery, inflammation, or immobility. There was no polycythemia; screening for occult cancer was negative. He was found had high Factor VIII activity (190%, UNL 150%). Before taking T, serum T was low, (94 ng/dl, normal range 280–800 ng/dl) and E2 15.7 pg/ml (UNL 42.6 ng/dl). On T, serum T rose to 739 ng/dl, and serum estradiol became high (51 pg/ml, UNL 42.6 pg/ml).
Laboratory assessment of thrombophilia and hypofibrinolysis In all subjects, after an overnight fast, blood was drawn in the seated position for assessment of thrombophilia and hypofibrinolysis [9]. PCR assays PCR measures of thrombophilia–hypofibrinolysis (G1691A Factor V Leiden, G20210A prothrombin, MTHFR C677T-A1298C, and 4G5G plasminogen activator inhibitor activity gene mutations) were performed using previously published methods by laboratory staff blinded to the subjects’ status (diagnosis, severity of disease) [9,10]. Serologic measures of thrombophilia Measures of thrombophilia included anticardiolipin antibodies (IgG and IgM), lupus anticoagulant, antigenic protein C, total and free protein S, antithrombin III, resistance to activated protein C (RAPC), activated partial thromboplastin time (APTT), Factors VIII and XI, and homocysteine. Established, previously published methods were used [9,10]. In patients concurrently receiving Warfarin, the ratio of antigenic protein C to antigenic factor VII, and the ratio of total protein S to antigenic factor VII were measured. Serologic measures of hypofibrinolysis Measures of LP (a) were done using established, previously published methods. [9,10].
Fig. 1. Prevalence of testosterone use before and at the time of deep venous thrombosis–pulmonary embolism requiring hospitalization in 147 men.
C.J. Glueck et al. / Medical Hypotheses 84 (2015) 341–343
343
Discussion
Conflict of interest statement
To the best of our knowledge, this is only the second report of T therapy associated with hospitalization for DVT–PE in men without previous thrombotic episodes, subsequently found to have thrombophilia. Two of 147 men (1.4%) in the current report and 7/596 (1.2%) in our previous report [2] took T before and at the time of hospitalization for DVT–PE, and were later found to have previously undiagnosed thrombophilia. As recently reported by Baillargeon et al. [12] ‘‘. . .androgen use among men 40 years or older increased more than 3-fold, from 0.81% in 2001 to 2.91% in 2011.’’ Given an estimated population prevalence of thrombophilias of 18% to 28%, [13,14] and use of T by 2.91% of men age P40 [12], we estimate that 0.81% of men age P40 are both given T and have familial and acquired thrombophilias, thus facing high risk for DVT–PE or ON [2–5]. This estimate is consistent with our current and previous finding [2] of 1.4% and 1.2% [2] of men who took T, were hospitalized for DVT–PE, and had thrombophilia. In the current study, DVT–PE occurred 6 and 24 months after starting T, while in the 7 men whose DVT–PE necessitated hospitalization in our previous report [2], the mean interval between initiation of T and hospitalization with DVT–PE was 6.7 months, range of 3 weeks to 27 months. In the current report, both men who sustained DVT–PE while on T were found to have previously undiagnosed thrombophilia previously documented to be associated with DVT–PE (protein S deficiency [15], homocysteinemia [16,17], high Factor VIII [17]), congruent with our previous reports [2–5]. One of our two cases developed thrombophilic high serum E2 on T therapy, thought to interact with the underlying thrombophilia, leading to DVT–PE [5]. The increasingly widespread use of T, particularly in aging men [12], may be accompanied by adverse thrombotic [2–5] and cardiovascular [18] effects. We recommend that the FDA Medwatch [19] process should be followed in the future for adverse thrombotic and cardiovascular events associated with exogenous T, to document its impact. Our exploratory, hypothesis-generating study has several serious limitations. There is potential for selection bias because after deleting men who were deceased or in hospice care (23%) or had cancer (4%), we were able to obtain data on testosterone use in only 30% of the total cohort. However, this would have biased our results toward the null, rather than overstating the true prevalence. Although screening for thrombophilia (Factor V Leiden, Factors VIII and XI, homocysteine) before T therapy to prevent T-mediated DVT–PE is expensive ($500), pulmonary embolism has a high case fatality rate (18%) and is expensive to diagnose and treat ($8,764/patient) [1]. Given the increasing use of T therapy [12], our current and initial [2] reports of T-treated patients hospitalized for DVT–PE could be used to design a much larger, definitive, multi-center prospective study to determine the likelihood of developing DVT–PE when T is given, and to assess pro-thrombotic interactions between T therapy and thrombophilia for subsequent thrombotic events including DVT–PE.
None of the authors have any financial or personal relationships, which would inappropriately influence (bias) their work. The study was funded in part by the Lipoprotein Research Fund, an endowment fund of the Jewish Hospital of Cincinnati, under Dr. CJ Glueck’s direction. References [1] Fanikos J, Rao A, Seger AC, Carter D, Piazza G, Goldhaber SZ. Hospital costs of acute pulmonary embolism. Am J Med 2013;126(2):127–32. [2] Glueck CJ, Richardson-Royer C, Schultz R, et al. Testosterone therapy, thrombophilia–hypofibrinolysis, and hospitalization for deep venous thrombosis–pulmonary embolus: an exploratory, hypothesis-generating study. Clin Appl Thromb Hemost 2014;20:244–9. [3] Glueck CJ, Richardson-Royer C, Schultz R, et al. Testosterone, thrombophilia, and thrombosis. Clin Appl Thromb Hemost 2014;20:22–30. [4] Glueck CJ, Bowe D, Valdez A, Wang P. Thrombosis in three postmenopausal women receiving testosterone therapy for low libido. Womens Health (Lond Engl) 2013;9(4):405–10. [5] Glueck CJ, Goldenberg N, Budhani S, et al. Thrombotic events after starting exogenous testosterone in men with previously undiagnosed familial thrombophilia. Transl Res 2011;158(4):225–34. [6] Glueck CJ, Freiberg RA, Boriel G, et al. The role of the Factor V Leiden mutation in osteonecrosis of the hip. Clin Appl Thromb Hemost 2013;19:499–503. [7] Vermeulen A, Kaufman JM, Goemaere S, van Pottelberg I. Estradiol in elderly men. Aging Male 2002;5(2):98–102. [8] Cherrier MM, Matsumoto AM, Amory JK, et al. The role of aromatization in testosterone supplementation: effects on cognition in older men. Neurology 2005;64(2):290–6. [9] Glueck CJ, Freiberg RA, Wang P. Heritable thrombophilia–hypofibrinolysis and osteonecrosis of the femoral head. Clin Orthop Relat Res 2008;466(5):1034–40. [10] Glueck CJ, Wang P, Bell H, Rangaraj V, Goldenberg N. Associations of thrombophilia, hypofibrinolysis, and retinal vein occlusion. Clin Appl Thromb Hemost 2005;11(4):375–89. [11] Montella BJ, Nunley JA, Urbaniak JR. Osteonecrosis of the femoral head associated with pregnancy. A preliminary report. J Bone Joint Surg Am 1999;81(6):790–8. [12] Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med 2013;173(15):1465–6. [13] Middeldorp S. Is thrombophilia testing useful? Hematology Am Soc Hematol Educ Program 2011;2011:150–5. [14] Roldan V, Lecumberri R, Munoz-Torrero JF, et al. Thrombophilia testing in patients with venous thromboembolism. Findings from the RIETE registry. Thromb Res 2009;124(2):174–7. [15] Signorelli SS, Fiore V, Puccia G, Mastrosimone G, Anzaldi M. Thrombophilia in patients with lower limbs deep veins thrombosis (LDVT) results of a monocentric survey on 103 consecutive outpatients. Clin Appl Thromb Hemost 2013;20:589–93. [16] Herrmann M, Whiting MJ, Veillard AS, Ehnholm C, Sullivan DR, Keech AC. Plasma homocysteine and the risk of venous thromboembolism: insights from the FIELD study. Clin Chem Lab Med 2012;50(12):2213–9. [17] Grifoni E, Marcucci R, Ciuti G, et al. The thrombophilic pattern of different clinical manifestations of venous thromboembolism: a survey of 443 cases of venous thromboembolism. Semin Thromb Hemost 2012;38(2):230–4. [18] Vigen R, OD C, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310:1829–36. [19] Shane R. Risk evaluation and mitigation strategies: impact on patients, health care providers, and health systems. Am J Health Syst Pharm 2009;66(24 Suppl. 7):S6–S12.
