Chemotherapy-induced hypercoagulability and biomarkers for prediction of thromboembolic events in patients with metastatic testicular cancer

S. Lubberts, H. Boer, R. Altena, C. Meijer, J.D. Lefrandt, J. Nuver, A.B. Mulder, T. Lisman, P.W. Kamphuisen, J.A. Gietema



The majority of patients with disseminated testicular cancer can be cured with combination chemotherapy consisting of bleomycin, etoposide and cisplatin (BEP). Because of this success, focus shifts to adverse effects of this treatment. The incidences of venous and arterial thromboembolism (VTE and ATE) during and after chemotherapy are up to 15%. Low molecular weight heparin (LMWH) reduces VTE in cancer patients, but the incidence is too low to justify prophylaxis in most patients starting with chemotherapy. To investigate the influence of BEP-chemotherapy administered to testicular cancer patients on coagulation and to estimate the predictive value of plasma levels of hemostatic proteins and activation markers in prediction of VTE and ATE within 2 years after treatment. Patients with newly diagnosed metastatic testicular were included in this prospective cohort study, which was approved by the local ethical committee. Informed consent was obtained from all participants. Patients received 3 or 4 BEP-courses during 9-12 weeks. Serial measurements were performed at baseline, at the last day of the third BEPcourse (day 56) and directly after chemotherapy. We assessed the Khorana-score and measured levels of the following hemostatic proteins: von Willebrand factor (VWF), fibrinogen, tissue-type plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), soluble P-selectin (sP-selectin), coagulation factor VIII (FVIII) and D-dimer. Outcome parameters were symptomatic VTE or ATE or asymptomatic VTE or ATE discovered on staging CT-scans. We included 74 patients with a median age of 31 years at start of chemotherapy. Eight patients (10.8%) developed thrombosis during or after chemotherapy, 4 had pulmonary embolisms (PE), of which 3 asymptomatic, and 4 had ATE (3 ischemic stroke, 1 asymptomatic splenal infarction), during a median follow-up of 3.2 years. Median duration from start of chemotherapy until development of VTE was 82 days (range: 32-278) and for ATE 85 days (range: 69-435). Median baseline biomarker levels were not elevated. VWF, fibrinogen, FVIII, D-dimer and PAI-1 levels clearly increased during chemotherapy. Levels normalized to baseline 1 month after treatment, except for FVIII and VWF levels, which remained increased. High FVIII levels (> 150%) at baseline had a positive predictive value (PPV) of 50% (95%CI: 14-86) and a negative predictive value (NPV) of 92.3% (95% CI: 82-97), with a hazard ratio (HR) for TE of 4.7 (95%CI: 1-22) adjusted for age at start of chemotherapy. The Khorana-score had a low predictive value. Furthermore, a large increase between baseline and day 56 in both VWF (Δ > 86.5%) and D-dimer (Δ > 935 ng/mL) had a PPV of 44.4% (95%CI: 15-77), a NPV of 95.2% (95%CI: 86-99) and a HR of 7.0 (95% CI: 2-33) for TE occurring after day 56. Hemostatic markers correlated with tumor markers. BEP-chemotherapy in metastatic testicular cancer patients is associated with a hypercoagulable state. Elevated FVIII before start of chemotherapy and large increases in D-dimer and VWF levels during chemotherapy are associated with an increased risk of developing ATE or VTE. This study suggests that baseline FVIII is a predictor for future TE in testicular cancer patients.
Originele taal-2English
Pagina's (van-tot)94-95
Aantal pagina's2
StatusPublished - jul-2013

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