Thromboembolic complications in urogenital cancers: incidence, risk factors and prevention

Numerous studies indicate a decrease in overall survival among cancer patients who have developed thromboembolic complications. The article presents a review of literature on thromboembolic complications in patients with kidney, bladder, and prostate cancer. The analysis of publications indicates a variety of risk factors and heterogeneous frequency of thromboembolism in patients with malignant neoplasms of the genitourinary system. Prevention of thromboembolism is carried out at all stages of treatment: outpatient, after surgery, during chemotherapy, but is accompanied by a fairly high risk of hemorrhagic complications and recurrences. Direct oral anticoagulants are an alternative to low-molecular-weight heparin for prevention of cancer-associated thromboembolism due to their convenience, efficacy and safety for most patients. An important task is to select patients for primary thromboprophylaxis based on stratification of the risk of thromboembolic complications using prognostic scales.

1. Cornejo K.M., Rice-Stitt T., Wu C.L. Updates in staging and reporting of genitourinary malignancies. Arch Pathol Lab Med 2020;144(3):305–19. DOI: 10.5858/arpa.2019-0544-RA

2. Netto G.J., Amin M.B., Berney D.M. et al. The 2022 World Health Organization Classification of tumors of the urinary system and male genital organs – part B: prostate and urinary tract tumors. Eur Urol 2022;82(5):469–82. DOI: 10.1016/j.eururo.2022.07.002

3. Williams S.B., Ray-Zack M.D., Hudgins H.K. et al. Impact of centralizing care for genitourinary malignancies to high-volume providers: a systematic review. Eur Urol Oncol 2019;2(3):265–73. DOI: 10.1016/j.euo.2018.10.006

4. Somov A.N., Suslin S.A. Prostate cancer. Epidemiology, risk factors and early detection. Profilakticheskaya meditsina = The Russian Journal of Preventive Medicine 2020;23(3):149–55. (In Russ.). DOI: 10.17116/profmed202023031149

5. Sung H., Ferlay J., Siegel R.L. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71(3):209–49. DOI: 10.3322/caac.21660

6. Malignant tumors in Russia in 2021 (morbidity and mortality). Eds.: А.D. Kaprin, V.V. Starinskiy, A.O. Shakhzadova. Moscow: MNIOI im. P.A. Gertsena – filial FGBU “NMITS radiologii” Minzdrava Rossii, 2022. 252 p. (In Russ.).

7. Somonova O.V., Elizarova A.L., Borisenko N.N., Kornushenko U.A. Thrombosis in an oncological patient and cancer in a patient with thrombosis: What to do? Zlokachestvennye opukholi = Malignant Tumors 2018;(3s1):110–4. (In Russ.). DOI: 10.18027/2224-5057-2018-8-3s1-110-114

8. Shah S., Karathanasi A., Revythis A. et al. Cancer-associated thrombosis: a new light on an old story. Diseases 2021;9(2):34. DOI: 10.3390/diseases9020034

9. Mahajan A., Brunson A., Adesina O. et al. The incidence of cancer-associated thrombosis is increasing over time. Blood Adv 2022;6(1):307–20. DOI: 10.1182/bloodadvances.2021005590

10. Mukai M., Oka T. Mechanism and management of cancer-associated thrombosis. J Cardiol 2018;72(2):89–93. DOI: 10.1016/j.jjcc.2018.02.011

11. Mulder F.I., Horváth-Puhó E., van Es N. et al. Venous thromboembolism in cancer patients: a population-based cohort study. Blood 2021;137(14):1959–69. DOI: 10.1182/blood.2020007338

12. Rozenko D.A., Ushakova N.D., Tikhonova S.N. et al. Effective use of extracorporeal membrane oxygenation in surgical treatment of kidney cancer patient with tumor thrombosis. Yuzhno-Rossiyskiy onkologicheskiy zhurnal = South Russian Journal of Cancer 2022;3(3):32–40. (In Russ.). DOI: 10.37748/2686-9039-2022-3-3-4

13. Fernandes C.J., Morinaga L.T.K., Alves J.L. Jr et al. Cancer-associated thrombosis: the when, how and why. Eur Respir Rev 2019;28(151):180119. DOI: 10.1183/16000617.0119-2018

14. Navi B.B., Reiner A.S., Kamel H. et al. Arterial thromboembolic events preceding the diagnosis of cancer in older persons. Blood 2019;133(8):781–9. DOI: 10.1182/blood-2018-06-860874

15. Petrov V.I., Gorbatenko V.S., Shatalova O.V., Gerasimenko A.S. Venous thromboembolic complications in oncological patients: Etiopathogenesis and prevention. Lekarstvenniy vestnik = Drug Bulletin 2020;14(3):16–22. (In Russ.).

16. Suzuki-Inoue K. Platelets and cancer-associated thrombosis: focusing on the platelet activation receptor CLEC-2 and podoplanin. Blood 2019;134(22):1912–8. DOI: 10.1182/blood.2019001388

17. Kim A.S., Khorana A.A., McCrae K.R. Mechanisms and biomarkers of cancer-associated thrombosis. Transl Res 2020;225:33–53. DOI: 10.1016/j.trsl.2020.06.012

18. Costa J., Araújo A. Cancer-related venous thromboembolism: from pathogenesis to risk assessment. Semin Thromb Hemost 2021;47(6):669–76. DOI: 10.1055/s-0040-1718926

19. Khorana A.A., Mackman N., Falanga A. et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers 2022;8(1):11. DOI: 10.1038/s41572-022-00336-y

20. Chuang L.H., Gumbs P., van Hout B. et al. Health-related quality of life and mortality in patients with pulmonary embolism: a prospective cohort study in seven European countries. Qual Life Res 2019;28(8):2111–24. DOI: 10.1007/s11136-019-02175-z

21. Suzuki-Inoue K. Roles of the CLEC-2-podoplanin interaction in tumor progression. Platelets 2018:1–7. DOI: 10.1080/09537104.2018.1478401

22. Frere C., Benzidia I., Marjanovic Z., Farge D. Recent advances in the management of cancer-associated thrombosis: new hopes but new challenges. Cancers (Basel) 2019;11(1):71. DOI: 10.3390/cancers11010071

23. Raskob G.E., van Es N., Verhamme P. et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;378(7):615–24. DOI: 10.1056/NEJMoa1711948

24. Glise Sandblad K., Hansson P.O., Philipson J. et al. Prevalence of cancer in patients with venous thromboembolism: a retrospective nationwide case–control study in Sweden. Clin Appl Thromb Hemost 2023;29:10760296231158368. DOI: 10.1177/10760296231158368

25. Park H., Jeong C.W., Yuk H. et al. Influence of tumor thrombus on occurrence of distant venous thromboembolism and survival in patients with renal cell carcinoma after surgery. Clin Appl Thromb Hemost 2019;25:1076029618823288. DOI: 10.1177/1076029618823288

26. Streiff M.B., Holmstrom B., Angelini D. et al. NCCN Clinical Practice Guidelines in Oncology: cancer-associated venous thromboembolic disease, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021;19(10):1181–201. DOI: 10.6004/jnccn.2021.0047

27. Lyman G.H., Carrier M., Ay C. et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv 2021;5(4):927–74. DOI: 10.1182/bloodadvances.2020003442

28. Guman N.A.M., van Geffen R.J., Mulder F.I. et al. Evaluation of the Khorana, PROTECHT, and 5-SNP scores for prediction of venous thromboembolism in patients with cancer. J Thromb Haemost 2021;19(12):2974–83. DOI: 10.1111/jth.15503

29. Abdullah O., Parashar D., Mustafa I.J., Young A.M. Venous thromboembolism rate in patients with bladder cancer according to the type of treatment: a systematic review. Cureus 2022;14(3):e22945. DOI: 10.7759/cureus.22945

30. Ibragimova N.Sh., Usupova M.A. Risk factors of venous thromboembolic complications in oncological surgery. Avitsenna = Avicenna 2020;66:17–9. (In Russ.).

31. Slukhanchuk E.V., Bitsadze V.O., Tyan A.G. et al. Thrombosis risk factors in oncological patients. Vestnik RAMN = Annals of the Russian Academy of Medical Sciences 2021;76(5):465–75. (In Russ.). DOI: 10.15690/vramn1459

32. Pabinger I., van Es N., Heinze G. et al. A clinical prediction model for cancer-associated venous thromboembolism: a development and validation study in two independent prospective cohorts. Lancet Haematol 2018;5(7):e289–98. DOI: 10.1016/S2352-3026(18)30063-2

33. Sevestre M.A., Soudet S. Epidemiology and risk factors for cancer-associated thrombosis. J Med Vasc 2020;45(6S):6S3–7. DOI: 10.1016/S2542-4513(20)30513-7

34. Klaassen Z., Wallis C.J.D., Lavallée L.T., Violette P.D. Perioperative venous thromboembolism prophylaxis in prostate cancer surgery. World J Urol 2020;38(3):593–600. DOI: 10.1007/s00345-019-02705-x

35. Meguro S., Kataoka M., Endo Y.U. et al. Low risk of venous thromboembolism after robot-assisted radical prostatectomy through systemic image assessment: a prospective study. In Vivo 2022;36(5):2384–91. DOI: 10.21873/invivo.12971

36. Klaassen Z., Arora K., Goldberg H. et al. Extended venous thromboembolism prophylaxis after radical cystectomy: a call for adherence to current guidelines. J Urol 2018;199(4):906–14. DOI: 10.1016/j.juro.2017.08.130

37. Ottosson K., Pelander S., Johansson M. et al. The increased risk for thromboembolism pre-cystectomy in patients undergoing neoadjuvant chemotherapy for muscle-invasive urinary bladder cancer is mainly due to central venous access: a multicenter evaluation. Int Urol Nephrol 2020;52(4):661–9. DOI: 10.1007/s11255-019-02338-4.

38. Korotaeva A.A., Apanovich N.V., Braga E.A. et al. Current advances in kidney cancer immunotherapy. Onkourologiya = Cancer Urology 2019;15(4):30–8. (In Russ.). DOI: 10.17650/1726-9776-2019-15-4-30-38

39. Moiseenko F.V. Future of systemic therapy in oncourology: targeted and immunotherapy. Prakticheskaya onkologiya = Practical Oncology 2019;20(2):137–43. (In Russ.).

40. Moik F., Chan W.E., Wiedemann S. et al. Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy. Blood 2021;137(12):1669–78. DOI: 10.1182/blood.2020007878

41. Kacimi S.E.O., Moeinafshar A., Haghighi S.S. et al. Venous thromboembolism in cancer and cancer immunotherapy. Crit Rev Oncol Hematol 2022;178:103782. DOI: 10.1016/j.critrevonc.2022.103782

42. Kartolo A., Yeung C., Moffat G.T. et al. Venous thromboembolism events in patients with advanced cancer on immune checkpoint inhibitors. Immunotherapy 2022;14(1):23–30. DOI: 10.2217/imt-2021-0151

43. Sheng I.Y., Gupta S., Reddy C.A. et al. Thromboembolism in patients with metastatic renal cell carcinoma treated with immunotherapy. Target Oncol 2021;16(6):813–21. DOI: 10.1007/s11523-021-00852-z

44. Di Nisio M., van Es N., Rotunno L. et al. Long-term performance of risk scores for venous thromboembolism in ambulatory cancer patients. J Thromb Thrombolysis 2019;48(1):125–33. DOI: 10.1007/s11239-019-01845-6

45. Volkova M.I., Vashakmadze N.L., Klimov A.V. et al. Prognosis of patients operated on for renal cell carcinoma and tumor venous thrombosis: experience of the Urology Clinics, N.N. Blokhin National Medical Research Center of Oncology. Onkourologiya = Cancer Urology 2021;17(3):19–28. (In Russ.). DOI: 10.17650/1726-9776-2021-17-3-19-28

46. Garas S.N., McAlpine K., Ross J. et al. Venous thromboembolism risk in patients receiving neoadjuvant chemotherapy for bladder cancer. Urol Oncol 2022;40(8):381.e1–7. DOI: 10.1016/j.urolonc.2022.04.006

47. Van Es N., Ventresca M., Di Nisio M. et al. The Khorana score for prediction of venous thromboembolism in cancer patients: An individual patient data meta-analysis. J Thromb Haemost 2020;18(8):1940–51. DOI: 10.1111/jth.14824

48. Iqbal U., Elsayed A.S., Ozair S. et al. Validation of the Khorana score for prediction of venous thromboembolism after robot-assisted radical cystectomy. J Endourol 2021;35(6):821–7. DOI: 10.1089/end.2020.0800

49. Sushinskaya T.V., Stuklov N.I., Dobrokhotova Iu.E. Hemostasis and cancer-associated thrombosis: modern prevention and treatment. Onkologiya. Zhurnal im. P.A. Gertsena = P.A. Herzen Journal of Oncology 2018;7(4):64–72. (In Russ.). DOI: 10.17116/onkolog20187464

50. Elshoury A., Schaefer J.K., Lim M.Y. et al. Update on guidelines for the prevention of cancer-associated thrombosis. J Natl Compr Canc Netw 2022;20(13). DOI: 10.6004/jnccn.2021.7108

51. Kahale L.A., Hakoum M.B., Tsolakian I.G. et al. Anticoagulation for the long-term treatment of venous thromboembolism in people with cancer. Cochrane Database Syst Rev 2018;6(6):CD006650. DOI: 10.1002/14651858.CD006650.pub5

52. Rausa E., Kelly M.E., Asti E. et al. Extended versus conventional thromboprophylaxis after major abdominal and pelvic surgery: systematic review and meta-analysis of randomized clinical trials. Surgery 2018;164(6):1234–40. DOI: 10.1016/j.surg.2018.05.028

53. Bredikhin R.A., Akhmetzyanov R.V., Khayrullin N. Expanding the possibilities of treatment and prevention of venous thromboembolic complications in cancer patients. The role of oral anticoagulants. Klinitsist = The Clinician 2022;16(2):17–26. (In Russ.). DOI: 10.17650/1818-8338-2022-16-2-К667

54. Mosarla R.C., Vaduganathan M., Qamar A. et al. Anticoagulation strategies in patients with cancer: JACC review topic of the week. J Am Coll Cardiol 2019;73(11):1336–49. DOI: 10.1016/j.jacc.2019.01.017

55. Guntupalli S.R., Brennecke A., Behbakht K. et al. Safety and efficacy of apixaban vs enoxaparin for preventing postoperative venous thromboembolism in women undergoing surgery for gynecologic malignant neoplasm: a randomized clinical trial. JAMA Netw Open 2020;3(6):e207410. DOI: 10.1001/jamanetworkopen.2020.7410

56. Young A.M., Marshall A., Thirlwall J. et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol 2018;36(20):2017–23. DOI: 10.1200/JCO.2018.78.8034

57. Planquette B., Bertoletti L., Charles-Nelson A. et al. Rivaroxaban vs dalteparin in cancer-associated thromboembolism: a randomized trial. Chest 2022;161(3):781–90. DOI: 10.1016/j.chest.2021.09.037

58. McBane R.D. 2nd, Wysokinski W.E., Le-Rademacher J.G. et al. Apixaban and dalteparin in active malignancy-associated venous thromboembolism: the ADAM VTE trial. J Thromb Haemost 2020;18(2):411–21. DOI: 10.1111/jth.14662

59. Agnelli G., Becattini C., Meyer G. et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020;382(17):1599–607. DOI: 10.1056/NEJMoa1915103

60. Mahé I., Agnelli G., Ay C. et al. Extended anticoagulant treatment with full- or reduced-dose apixaban in patients with cancer-associated venous thromboembolism: rationale and design of the API-CAT study. Thromb Haemost 2022;122(4):646–56. DOI: 10.1055/a-1647-9896

61. Dai J.C., Morgan T.N., Kusin S. et al. Use of Pre-operative pharmacologic venous thromboembolism prophylaxis for robotic partial nephrectomy. Urology 2021;154:177–83. DOI: 10.1016/j.urology.2021.03.043

62. Lapébie F.X., Bura-Rivière A., Espitia O. et al. Predictors of recurrence of cancer–associated venous thromboembolism after discontinuation of anticoagulant therapy: a multicenter cohort study. J Thromb Haemost 2023:21(8):2189–201. DOI: 10.1016/j.jtha.2023.04.010

63. Key N.S., Khorana A.A., Kuderer N.M. et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol 2020;38(5):496–520. DOI: 10.1200/JCO.19.01461

64. Carrier M., Abou-Nassar K., Mallick R. et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med 2019;380(8):711–9. DOI: 10.1056/NEJMoa1814468

65. Khorana A.A., McNamara M.G., Kakkar A.K. et al. Assessing full benefit of rivaroxaban prophylaxis in high-risk ambulatory patients with cancer: thromboembolic events in the randomized CASSINI trial. TH Open 2020;4(2):e107–12. DOI: 10.1055/s-0040-1712143

66. Agnelli G. Direct oral anticoagulants for thromboprophylaxis in ambulatory patients with cancer. N Engl J Med 2019;380(8):781–3. DOI: 10.1056/NEJMe1816060

67. Xin Z., Liu F., Du Y. et al. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients: a systematic review and network meta-analysis. Ann Palliat Med 2020;9(5):2970–81. DOI: 10.21037/apm-20-47

68. Balabanova Y., Farahmand B., Stattin P. et al. Population-based study of long-term anticoagulation for treatment and secondary prophylaxis of venous thromboembolism in men with prostate cancer in Sweden. BMC Urol 2022;22(1):15. DOI: 10.1186/s12894-022-00967-z

69. Dall C.P., Shaw N., Egan J. et al. Practice patterns for extended venous thromboembolism chemoprophylaxis among urologic oncologists after radical cystectomy. Urol Oncol 2020;38(11):849.e19–23. DOI: 10.1016/j.urolonc.2020.05.030

70. Prisco D., Tufano A., Cenci C. et al. Position paper of the Italian Society of Internal Medicine (SIMI) on prophylaxis and treatment of venous thromboembolism in patients with cancer. Intern Emerg Med 2019;14(1):21–38. DOI: 10.1007/s11739-018-1956-1

71. Fedotkina Yu.A., Panchenko E.P. Modern approaches to the prevention of venous thromboembolic complications in patients with active cancer. Aterotromboz = Atherothrombosis 2022;12(2):44–62. (In Russ.) DOI: 10.21518/2307-1109-2022-12-2-44-62