Cisplatin chemotherapy has been reported to cause PE, DVT, myocardial infarction, and peripheral arterial thrombosis[11,15,16]. Several pathogenic mechanisms have been identified between cisplatin and thrombosis, including endothelial cell damage marked by increased plasma levels of Von Willebrand factor during chemotherapy, platelet activation, and up-regulation of prothrombotic factors. Lauritsen et al[17] investigated cardiovascular risk factors and disease following BEP treatment for male germ cell cancer[17]. These authors reported that patients had a more than 20-fold increased hazard ratio of venous TEE compared with the normal population which decreased to a hazard ratio of 1.4 after 10 years.

In our literature review the percentage of patients who experienced a TEE with testicular cancer ranged between 5.2% and 19%[6,9,16,18,19]. Most of the TEE occurred during chemotherapy[9,16,18,19]. Various risk factors for a TEE were confirmed, including retroperitoneal and supraclavicular lymph node metastases, elevated serum lactic acid dehydrogenase, higher clinical stage, CVC, high body surface area, and febrile neutropenia. Paffenholz et al[16] reported a significantly reduced overall survival in patients with a TEE during a median follow-up of 8 mo[16]. The present study concurs with this finding, as the TEE occurred during the cisplatin-based chemotherapy in 13 (68%) patients.

The Khorana score is a predictive model for chemotherapy-associated TEE and is based on the following: (1) Site of cancer; (2) Prechemotherapy platelet count 350 × 10⁹/L or more; (3) Hemoglobin level less than 100 g/L or use of red cell growth factors; (4) Prechemotherapy leukocyte count more than 11 × 10⁹/L; and (5) BMI 35 kg/m² or more[2,20,21]. The risk of TEE is 4-6-fold higher in patients with cancer than in those without, and the TEE incidence is 3%-15% annually in cancer patients[14,18]. The use of thromboprophylaxis to reduce the recurrence of cancer-associated TEE have been examined primarily in cancers such as breast, colorectal, lung, pancreatic, and multiple myeloma that usually affect older individuals[14,21-24].

Carrier et al[22] determined that apixaban resulted in a significantly lower rate of venous thromboembolism (VTE) than placebo among intermediate-to-high-risk ambulatory patients with cancer who started chemotherapy[22]. In the intention-to-treat analysis, major bleeding occurred in 10 (3.5%) patients in the apixaban group and in 5 (1.8%) patients in the placebo group (P = 0.046). Khorana et al[25] concluded that high-risk ambulatory patients with metastatic cancer who were receiving chemotherapy and were treated with rivaroxaban did not have a significantly lower incidence of VTE or death due to VTE in a 180-d trial period[25]. Despite these two large randomized phase III trials, routine prophylaxis for TEE has not been embraced by clinicians in the outpatient setting as the absolute risk reduction is small and thromboprophylaxis is associated with a heightened risk of major bleeding and high cost[14,18,22].

Of the 574 patients in Carrier and colleagues’ placebo-controlled study, only 3 patients were diagnosed with testicular cancer. Khorana et al[25]’s study of 1080 patients did not specify the number of patients with testicular cancer, however, mentioned that there were 32 cases of “genitourinary” cancers that included renal, bladder, ureteral, and testicular cancers but not prostate cancer. Young men with TGCT are generally without co-morbidities. This patient population was not represented in large trials investigating thromboprophylaxis in metastatic cancer during chemotherapy. This is largely due to inclusion and exclusion criteria based on the Khorana scoring system used in these trials.

The cisplatin-based chemotherapy used to treat TGCT often does not cause severe thrombocytopenia. A relatively short course of chemotherapy in metastatic testicular cancer often leads to a cure despite the need for ongoing systemic therapy in most other metastatic solid tumors. Additionally, the cisplatin dose in the BEP regimen is higher compared to most regimens used for non-testicular cancer. This important difference may lead to better outcomes with the use of thromboprophylaxis. TGCT possesses numerous risk factors that increase the risk for clotting including bulky retroperitoneal disease, cisplatin-based chemotherapy, cigarette smoking, and possibly marijuana use. Furthermore, the risk of bleeding in TGCT is likely to be lower compared to other types of cancers due to the shorter duration of chemotherapy in TGCT and younger patient population with better bone marrow function. These factors support further investigation into the use of thromboprophylaxis as patients receive chemotherapy for TGCT.

We propose conducting a multicenter randomized double blind placebo control trial examining the efficacy and safety of thromboprophylaxis in patients undergoing systemic treatment for metastatic TGCT. Such a trial will use a novel inclusion scoring system specific for TGCT that incorporates risk factors often encountered with this cancer. Carrier et al[22]’s as well as Khorana et al[25]’s studies only included patients who had 2 risk factors on the Khorana scale[22,25]. Most of the patients who experienced a TEE in the present study would not have fulfilled the criteria for inclusion for thromboprophylaxis in these 2 trials. The new TGCT scoring system should incorporate the following risk factors: Higher pathologic stage and greater number of chemotherapy cycles as confirmed by the current study as well as elevated serum lactate dehydrogenase, CVC, large RPLN, and seminoma[6,9,16,18,19].

Several studies have reported the limited use of thromboprophylaxis in TGCT with cisplatin-based chemotherapy (Table 4). Paffenholz et al[16] reported that 93% of all of their TCGT received prophylactic anticoagulation which is customary in Germany[16]. Thromboprophylaxis during chemotherapy for TGCT is not customary in the United States.

Kentucky has both the highest incidence and death rates for lung cancer in the United States[26,27]. In 2017, a total of 24.6% of adults in Kentucky smoked while the national average was 14.0%[26,28]. Cigarette smoking is a well-recognized risk factor for both atherosclerotic disease and TEE[29]. Half of the patients in our study were either current or previous cigarette smokers, and 42% of these patients experienced a TEE while undergoing cisplatin-based chemotherapy. Cannabis is the most commonly used recreation drug in the United States and has been suggested to cause myocardial infarction and ischemic stroke[30]. Only a single case of PE in a young male following heavy cannabis use has been reported[30]. It has been suggested that cannabinoids, the active component of cannabis, cause endothelial cell disruption leading to vascular thrombosis. A total of 23.5% of the patients in our study were current cannabis users, and 16% of the cannabis users suffered a TEE while undergoing chemotherapy.

Our study of TCGT offers several unique aspects that shed light on the risk factors for a TEE and educational opportunities for preventing a TEE. Our study, consisting of a single Institution in a metropolitan community in Kentucky, has a large number of patients with TCGT over a 6-year period. The high percentage (28%) of patients who experienced a TEE compared to the literature may be attributed to numerous cumulative factors leading to a hypercoagulable state that may provoke a TEE, including bulky retroperitoneal disease, higher pathologic stage, greater number of chemotherapy cycles, metastatic disease, the remarkably large number of patients who smoke cigarettes and use cannabis, high number of patients with CVC, and lack of patients who were treated with thromboprophylaxis. The limitation of the present study is its retrospective nature and limited number of patients.

Several risk factors have been identified as increasing the risk of developing VTE, including the patient’s age (> 60 years), obesity, and history of anterior VTE[31]. The tumor’s site, histological type, and stage also elevate the risk of VTE. Pancreatic cancer is the solid tumor with the highest likelihood of VTE, while lymphoma, acute leukemia, and multiple myeloma represent hematologic malignancies that pose a strong risk of VTE. Adenocarcinomas have a higher risk of VTE compared to squamous cell carcinomas, and an advanced tumor stage increases the prospect of developing a VTE[31]. Advanced tumor stage and use of subclavian catheters are the main risk factors for CVC-associated thrombosis[32]. Our Institution generally does not use CVC for delivering chemotherapy in patients with TCGT. However, CVC placement may be unavoidable for patients with poor venous access or patient preference. Educating patients and providers about the thromboembolic risk of CVC may discourage them from selecting CVC as the desired route of chemotherapy infusion. Further educational opportunities with patients that may decrease the likelihood of TEE and enhance overall medical health include an emphasis on discontinuing cigarette smoking and cannabis use as well as promoting weight loss.