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Thromboembolic Disorders as a Consequence of Cancer

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Manual of Cardio-oncology
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Abstract

Cancer cells and coagulation system are strictly connected. General prothrombotic mechanisms are related both to the host response to cancer and to the procoagulant activity of cancer cells (Fig. 4.1). Host-related factors include the acute-phase reaction, paraprotein production, inflammation, necrosis, and hemodynamic disorders. Malignant cells can activate blood coagulation in several ways. They can produce: procoagulant factors as tissue factor (TF) and cancer procoagulant factor (CP), which are the most powerful procoagulant observed; microparticles (MP); inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1); pro-angiogenic factors as vascular endothelial growth factor (VEGF), which promote both endothelial prothrombotic alterations and angiogenesis. VEGF is an indirect procoagulant that increases microvascular permeability, reprograms gene expression, and promotes the survival of endothelial cells; the resulting increased vascular density plays a key role in the pathophysiology of many cancers. The same procoagulant factors contribute to tumor progression. Also platelets, endothelial cells, and neutrophils of host cells are stimulated to express procoagulant activity. Thus, thromboembolism frequently complicates the course of malignancy and can be the first symptom of cancer [1, 2].

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References

  1. Falanga A, Marchetti M, Russo L. The mechanisms of cancer-associated thrombosis. Thromb Res. 2015;135 Suppl 1:S8–11.

    Article  CAS  PubMed  Google Scholar 

  2. Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol. 2005;6:401–10.

    Article  PubMed  Google Scholar 

  3. Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5(3):632–4.

    Article  CAS  PubMed  Google Scholar 

  4. Sanon S, Lenihan DJ, Mouhayar E. Peripheral arterial ischemic events in cancer patients. Vasc Med. 2011;16:119–30.

    Article  PubMed  Google Scholar 

  5. Di Nisio M, Ferrante N, Feragalli B, et al. Arterial thrombosis in ambulatory cancer patients treated with chemotherapy. Thromb Res. 2011;127:382–3.

    Article  PubMed  Google Scholar 

  6. Khorana AA, Dalal M, Lin J, Connolly GC. Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States. Cancer. 2013;119:648–55.

    Article  CAS  PubMed  Google Scholar 

  7. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100:3484–8.

    Article  CAS  PubMed  Google Scholar 

  8. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood. 2013;122:1712.

    Article  CAS  PubMed  Google Scholar 

  9. Sproul EE. Carcinoma and venous thrombosis: the frequency of association of carcinoma in the body or tail of the pancreas with multiple venous thrombosis. Am J Cancer. 1938;34:566.

    Google Scholar 

  10. Khorana AA, Dalal MR, Lin J, Connolly GC. Health care costs associated with venous thromboembolism in selected high risk ambulatory patients with solid tumors undergoing chemotherapy in the United States. Clinicoecon Outcomes Res. 2013;5:101–8.

    Article  PubMed  PubMed Central  Google Scholar 

  11. White RH, Chew HK, Zhou H, et al. Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528,693 adults. Arch Intern Med. 2005;165:1782–7.

    Article  PubMed  Google Scholar 

  12. Carrier M, Lazo-Langner A, Shivakumar S, SOME Investigators, et al. Screening for occult cancer in unprovoked venous thromboembolism. N Engl J Med. 2015;373(8):697–70.

    Article  CAS  PubMed  Google Scholar 

  13. Khorana AA, Carrier M, Garcia DA, Lee AY. Guidance for the prevention and treatment of cancer-associated venous thromboembolism. J Thromb Thrombolysis. 2016;41(1):81–91. doi:10.1007/s11239-015-1313-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. ENOXACAN Study Group. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. Br J Surg. 1997;84:1099–103.

    Article  Google Scholar 

  15. Akl EA, Kahale L, Sperati F, et al. Low molecular weight heparin versus unfractionated heparin for perioperative thromboprophylaxis in patients with cancer. Cochrane Database Syst Rev. 2014;6:CD009447. doi:10.1002/14651858.CD009447.pub2.

    Google Scholar 

  16. Akl EA, Kahale LA, Schünemann HJ. Association between perioperative low-molecular-weight heparin vs unfractionated heparin and clinical outcomes in patients with cancer undergoing surgery. JAMA. 2015;313:1364–5.

    Article  CAS  PubMed  Google Scholar 

  17. Bergqvist D, Agnelli G, Cohen AT, ENOXACAN II Investigators, et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med. 2002;346:975.

    Article  CAS  PubMed  Google Scholar 

  18. Kakkar VV, Balibrea JL, Martínez-González J, Prandoni P, CANBESURE Study Group. Extended prophylaxis with bemiparin for the prevention of venous thromboembolism after abdominal or pelvic surgery for cancer: the CANBESURE randomized study. J Thromb Haemost. 2010;8:1223–9.

    Article  CAS  PubMed  Google Scholar 

  19. Rasmussen MS, Jorgensen LN, Wille-Jørgensen P, FAME Investigators, et al. Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter randomized open-label study. J Thromb Haemost. 2006;4:2384–90.

    Article  CAS  PubMed  Google Scholar 

  20. Cui G, Wang X, Yao W, Li H. Incidence of postoperative venous thromboembolism after laparoscopic versus open colorectal cancer surgery: a meta-analysis. Surg Laparosc Endosc Percutan Tech. 2013;23:128–34.

    Article  PubMed  Google Scholar 

  21. Horsted F, West J, Grainge MJ. Risk of venous thromboembolism in patients with cancer: a systematic review and meta-analysis. PLoS Med. 2012;9:e1001275.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lyman GH, Bohlke K, Khorana AA, American Society of Clinical Oncology, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American society of clinical oncology clinical practice guideline update 2014. J Clin Oncol. 2015;33(6):654–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Merkow RP, Bilimoria KY, McCarter MD, et al. Post-discharge venous thromboembolism after cancer surgery: extending the case for extended prophylaxis. Ann Surg. 2011;254:131.

    Article  PubMed  Google Scholar 

  24. Choueiri TK, Schutz FA, Je Y, Rosenberg JE, Bellmunt J. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol. 2010;28:2280–5.

    Article  CAS  PubMed  Google Scholar 

  25. Cavo M, Zamagni E, Cellini C, et al. Deep-vein thrombosis in patients with multiple myeloma receiving first-line thalidomide-dexamethasone therapy. Blood. 2002;100:2272–3.

    Article  CAS  PubMed  Google Scholar 

  26. Petrelli F, Cabiddu M, Borgonovo K, Barni S. Risk of venous and arterial thromboembolic events associated with anti-EGFR agents: a meta-analysis of randomized clinical trials. Ann Oncol. 2012;23:1672–9.

    Article  CAS  PubMed  Google Scholar 

  27. Palumbo A, Rajkumar SV, Dimopoulos MA, International Myeloma Working Group, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414.

    Article  CAS  PubMed  Google Scholar 

  28. Zangari M, Anaissie E, Barlogie B, et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood. 2001;98:1614.

    Article  CAS  PubMed  Google Scholar 

  29. Rajkumar SV, Blood E. Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med. 2006;354:2079.

    Article  PubMed  Google Scholar 

  30. Rajkumar SV, Jacobus S, Callender N, et al. Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group (abstract). Clin Oncol. 2007;25:968s.

    Google Scholar 

  31. Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler Thromb Vasc Biol. 2004;24:1015–22.

    Article  CAS  PubMed  Google Scholar 

  32. Khorana AA, Liebman HA, White RH, et al. The risk of venous thromboembolism in patients with cancer. Alexandria, VA: American Society of Clinical Oncology, ASCO Educational Book; 2008. p. 240–8.

    Google Scholar 

  33. Carrier M, Le Gal G, Wells PS, et al. Systematic review: the Trousseau syndrome revisited: should we screen extensively for cancer in patients with venous thromboembolism? Ann Intern Med. 2008;149:323–33.

    Article  PubMed  Google Scholar 

  34. Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111:4902–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ay C, Dunkler D, Marosi C, et al. Prediction of venous thromboembolism in cancer patients. Blood. 2010;116:5377.

    Article  CAS  PubMed  Google Scholar 

  36. Posch F, Thaler J, Zlabinger GJ, et al. Soluble vascular endothelial growth factor (sVEGF) and the risk of venous thromboembolism in patients with cancer: results from the Vienna cancer and thrombosis study (CATS). Clin Cancer Res. 2016;22:200–6.

    Article  CAS  PubMed  Google Scholar 

  37. Verso M, Agnelli G, Barni S, et al. A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: the Protecht score. Intern Emerg Med. 2012;7:291–2.

    Article  PubMed  Google Scholar 

  38. George D, Agnelli G, Fisher W, et al. Poster presentation: venous thromboembolism (VTE) prevention with semuloparin in cancer patients initiating chemotherapy: benefit risk assessment by VTE risk in SAVE-ONCO. https://ash.confex.com/ash/2011/webprogram/Paper39639.

  39. Carrier M, Khorana AA, Moretto P, et al. Lack of evidence to support thromboprophylaxis in hospitalized medical patients with cancer. Am J Med. 2014;127(1):82–6.

    Article  PubMed  Google Scholar 

  40. Palumbo A, Cavo M, Bringhen S, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized tri. J Clin Oncol. 2011;29:986–9381.

    Article  CAS  PubMed  Google Scholar 

  41. Larocca A, Cavallo F, Bringhen S, et al. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012;119:933–9.

    Article  CAS  PubMed  Google Scholar 

  42. Zangari M, Fink L, Zhan F, Tricot G. Low venous thromboembolic risk with bortezomib in multiple myeloma and potential protective effect with thalidomide/lenalidomide-based therapy: review of data from phase 3 trials and studies of novel combination regimens. Clin Lymphoma Myeloma Leuk. 2011;11:228–36.

    Article  CAS  PubMed  Google Scholar 

  43. Akl EA, Kahale L, Neumann I, et al. Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2014; 19;(6):CD006649.

    Google Scholar 

  44. Van Doormaal FF, Raskob GE, Davidson BL, et al. Treatment of venous thromboembolism in patients with cancer: subgroup analysis of the Matisse clinical trials. Thromb Haemost. 2009;101:762–9.

    PubMed  Google Scholar 

  45. Akl EA, Kahale L, Barba M, et al. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2014;7:CD006650.

    Google Scholar 

  46. Lee AYY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146–1539.

    Article  CAS  PubMed  Google Scholar 

  47. Lee AY, Kamphuisen PW, Meyer G, CATCH Investigators, et al. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA. 2015;314(7):677–8.

    Article  CAS  PubMed  Google Scholar 

  48. Pesavento R, Amitrano M, Trujillo-Santos J, et al. Fondaparinux in the initial and long-term treatment of venous thromboembolism. Thromb Res. 2015;135:311–7.

    Article  CAS  PubMed  Google Scholar 

  49. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499–510.

    Article  CAS  PubMed  Google Scholar 

  50. Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287–97.

    Article  PubMed  Google Scholar 

  51. Buller HR, Decousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406–15.

    Article  PubMed  Google Scholar 

  52. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799–808.

    Article  CAS  PubMed  Google Scholar 

  53. Vedovati MC, Germini F, Agnelli G, Becattini C. Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. Chest. 2015;147:475–83.

    Article  PubMed  Google Scholar 

  54. Franchini M, Bonfanti C, Lippi G. Cancer-associated thrombosis: investigating the role of new oral anticoagulants. Thromb Res. 2015;135:777–81.

    Article  CAS  PubMed  Google Scholar 

  55. Lee AY, Peterson EA. Treatment of cancer-associated thrombosis. Blood. 2013;122:2310–7.

    Article  CAS  PubMed  Google Scholar 

  56. Carrier M, Cameron C, Delluc A, et al. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta-analysis. Thromb Res. 2014;134:1214–9.

    Article  CAS  PubMed  Google Scholar 

  57. Lyman GH, Khorana AA, Kuderer NM, et al. American society of clinical oncology clinical practice. J Clin Oncol. 2013;31:2189–204.

    Article  CAS  PubMed  Google Scholar 

  58. Streiff MB, Holmstrom B, Ashrani A, et al. Cancer-associated venous thromboembolic disease, version 1.2015. J Natl Compr Canc Netw. 2015;13:1079–95.

    Article  PubMed  Google Scholar 

  59. Watson HG, Keeling DM, Laffan M, et al. British Committee for Standards in Haematology Guideline on aspects of cancer-related venous thrombosis Guideline on aspects of cancer-related venous thrombosis. Br J Haematol. 2015;170:640–8.

    Article  PubMed  Google Scholar 

  60. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315–52.

    Article  PubMed  Google Scholar 

  61. Debourdeau P, Farge D, Beckers M, et al. International clinical practice guidelines for the treatment and prophylaxis of thrombosis associated with central venous catheters in patients with cancer. J Thromb Haemost. 2013;11:71–80.

    Article  CAS  PubMed  Google Scholar 

  62. Schiffer CA, Mangu PB, Wade JC, et al. Central venous catheter care for the patient with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31:1357–70.

    Article  PubMed  Google Scholar 

  63. Abtahian F, Hawkins BM, Ryan DP, et al. Inferior vena cava filter usage, complications, and retrieval rate in cancer patients. Am J Med. 2014;127:1111–7.

    Article  PubMed  Google Scholar 

  64. Casanegra AI, Landrum LM, Tafur AJ. Retrievable inferior vena cava filters in patients with cancer: complications and retrieval success rate. Int J Vasc Med. 2016;2016:6413541.

    PubMed  PubMed Central  Google Scholar 

  65. Carrier M, Le Gal G, Cho R, et al. Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients. J Thromb Haemost. 2009;7:760–5.

    Article  CAS  PubMed  Google Scholar 

  66. Heit JA, Mohr DN, Silverstein MD, et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med. 2000;160:761–8.

    Article  CAS  PubMed  Google Scholar 

  67. Herishanu Y, Misgav M, Kirgner I, et al. Enoxaparin can be used safely in patients with severe thrombocytopenia due to intensive chemotherapy regimens. Leuk Lymphoma. 2004;45:1407–11. Review.

    Article  CAS  PubMed  Google Scholar 

Suggested Reading: Society Guidelines

  • Streiff MB, Holmstrom B, Ashrani A, et al. Cancer-associated venous thromboembolic disease, version 1.2015. J Natl Compr Canc Netw. 2015;13(9):1079–9554.

    Google Scholar 

  • Lyman GH, Khorana AA, Kuderer NM, et al. American society of clinical oncology clinical practice. J Clin Oncol. 2013;31(17):2189–20455.

    Google Scholar 

  • Lyman GH, Bohlke K1, Khorana AA, American Society of Clinical Oncology, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American society of clinical oncology clinical practice guideline update 2014. J Clin Oncol. 2015;33:654–6.

    Google Scholar 

  • Watson HG, Keeling DM, Laffan M, et al. British Committee for Standards in Haematology Guideline on aspects of cancer-related venous thrombosis. Guideline on aspects of cancer-related venous thrombosis. Br J Haematol. 2015;170:640–857.

    Google Scholar 

  • Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315–5258.

    Google Scholar 

  • Debourdeau P, Farge D, Beckers M, et al. International clinical practice guidelines for the treatment and prophylaxis of thrombosis associated with central venous catheters in patients with cancer. J Thromb Haemost. 2013;11:71–8059.

    Google Scholar 

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Bisceglia, I., Maurea, N. (2017). Thromboembolic Disorders as a Consequence of Cancer. In: Lestuzzi, C., Oliva, S., Ferraù, F. (eds) Manual of Cardio-oncology. Springer, Cham. https://doi.org/10.1007/978-3-319-40236-9_4

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