Advertisement

Thromboembolism and Bleeding

  • Simon NobleEmail author
Reference work entry

Abstract

While thromboembolism and bleeding appear, at first glance, to be hematological processes at opposite ends of the clinical spectrum, they share many commonalities of relevance to palliative care teams. Both are increased in the malignant state, particularly with metastatic disease, and consequently confer a significant symptom burden, resulting in high level of distress for patients and carers. Furthermore, they are often the cause, or contributory cause, of death and frequently complicate care at the end of life.

The evidence base for the management of cancer-associated thrombosis (CAT) has increased significantly over the past 15 years, yet few studies have included or considered patients with advanced cancer or those nearing the end of life. With respect to the management of bleeding at the end of life, particularly terminal hemorrhage, management is informed by little more than case reports and expert opinion.

This chapter will comprise of two sections. First, it will provide an overview of the management of bleeding in the palliative setting with particular focus on terminal hemorrhage. The second section will focus on the treatment and prevention of venous thromboembolism in the advanced cancer setting, including the management of patients with recurrent thrombosis, thrombocytopenia, and bleeding. It will also review the new oral anticoagulants and consider their place in CAT management.

References

  1. A Medical Research Council (MRC) randomised trial of palliative radiotherapy with two fractions or a single fraction in patients with inoperable non-small-cell lung cancer (NSCLC) and poor performance status. Medical Research Council Lung Cancer Working Party. Br J Cancer. 1992;65(6):934–41.CrossRefGoogle Scholar
  2. Abt D, Bywater M, Engeler DS, Schmid HP. Therapeutic options for intractable hematuria in advanced bladder cancer. Int J Urol. 2013;20(7):651–60.PubMedCrossRefGoogle Scholar
  3. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808.PubMedCrossRefGoogle Scholar
  4. Ambrus JL, Ambrus CM, Mink IB, Pickren JW. Causes of death in cancer patients. J Med. 1975;6(1):61–4.PubMedGoogle Scholar
  5. Bennett P, Patterson K, Noble S. Predicting post-traumatic stress and health anxiety following a venous thrombotic embolism. J Health Psychol. 2016;21(5):863–71.PubMedCrossRefGoogle Scholar
  6. Broadley KE, Kurowska A, Dick R, Platts A, Tookman A. The role of embolization in palliative care. Palliat Med. 1995;9(4):331–5.PubMedCrossRefGoogle Scholar
  7. Cameron MG, Kersten C, Vistad I, Fossa S, Guren MG. Palliative pelvic radiotherapy of symptomatic incurable rectal cancer – a systematic review. Acta Oncol. 2014;53(2):164–73.PubMedCrossRefGoogle Scholar
  8. Carrier M, Khorana AA, Zwicker JI, Noble S, Lee AY, Subcommittee on Haemostasis, et al. Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH: a reply to a rebuttal. J Thromb Haemost: JTH. 2014;12(1):116–7.PubMedCrossRefGoogle Scholar
  9. Carrier M, Lazo-Langner A, Shivakumar S, Tagalakis V, Zarychanski R, Solymoss S, et al. Screening for occult cancer in unprovoked venous thromboembolism. N Engl J Med. 2015;373(8):697–704.PubMedCrossRefGoogle Scholar
  10. Chee CE, Ashrani AA, Marks RS, Petterson TM, Bailey KR, Melton LJ 3rd, et al. Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a population-based cohort study. Blood. 2014;123(25):3972–8.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost. 2007;98(4):756–64.PubMedGoogle Scholar
  12. Dequanter D, Shahla M, Paulus P, Aubert C, Lothaire P.Transarterial endovascular treatment in the management of life-threatening carotid blowout syndrome in head and neck cancer patients: review of the literature. J Mal Vasc. 2013;38(6):341–4.PubMedCrossRefGoogle Scholar
  13. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499–510.CrossRefGoogle Scholar
  14. Eleje GU, Eke AC, Igberase GO, Igwegbe AO, Eleje LI. Palliative interventions for controlling vaginal bleeding in advanced cervical cancer. Cochrane Database Syst Rev. 2015;(5):CD011000.Google Scholar
  15. Eriksson LG, Ljungdahl M, Sundbom M, Nyman R. Transcatheter arterial embolization versus surgery in the treatment of upper gastrointestinal bleeding after therapeutic endoscopy failure. J Vasc Interv Radiol. 2008;19(10):1413–8.PubMedCrossRefGoogle Scholar
  16. Gando S. The utility of a diagnostic scoring system for disseminated intravascular coagulation. Crit Care Clin. 2012;28(3):373–88, viPubMedCrossRefGoogle Scholar
  17. Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail elderly. N Engl J Med. 2012;366(9):864–6.PubMedCrossRefGoogle Scholar
  18. Harrington DJ, Western H, Seton-Jones C, Rangarajan S, Beynon T, Shearer MJ. A study of the prevalence of vitamin K deficiency in patients with cancer referred to a hospital palliative care team and its association with abnormal haemostasis. J Clin Pathol. 2008;61(4): 537–40.PubMedCrossRefGoogle Scholar
  19. Harris DG, Finlay IG, Flowers S, Noble SI. The use of crisis medication in the management of terminal haemorrhage due to incurable cancer: a qualitative study. Palliat Med. 2011;25(7):691–700.PubMedCrossRefGoogle Scholar
  20. Havig O. Deep vein thrombosis and pulmonary embolism. An autopsy study with multiple regression analysis of possible risk factors. Acta Chir Scand Suppl. 1977;478:1–120.PubMedGoogle Scholar
  21. Hokusai VTEI, Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–15.CrossRefGoogle Scholar
  22. Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, et al. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006;119(12):1062–72.PubMedCrossRefGoogle Scholar
  23. Hunt BJ. The current place of tranexamic acid in the management of bleeding. Anaesthesia. 2015;70(Suppl 1):50–3, e18PubMedCrossRefGoogle Scholar
  24. Johnson MJ, Sherry K. How do palliative physicians manage venous thromboembolism? Palliat Med. 1997;11(6):462–8.PubMedCrossRefGoogle Scholar
  25. Johnson MJ, Sproule MW, Paul J. The prevalence and associated variables of deep venous thrombosis in patients with advanced cancer. Clin Oncol (R Coll Radiol). 1999;11(2):105–10.CrossRefGoogle Scholar
  26. Johnson MJ, Sheard L, Maraveyas A, Noble S, Prout H, Watt I, et al. Diagnosis and management of people with venous thromboembolism and advanced cancer: how do doctors decide? A qualitative study. BMC Med Inform Decis Mak. 2012;12:75.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Johnson MJ, McMillan B, Fairhurst C, Gabe R, Ward J, Wiseman J, et al. Primary thromboprophylaxis in hospices: the association between risk of venous thromboembolism and development of symptoms. J Pain Symptom Manag. 2014;48(1):56–64.CrossRefGoogle Scholar
  28. Kakkar VV, Howe CT, Flanc C, Clarke MB. Natural history of postoperative deep-vein thrombosis. Lancet. 1969;2(7614):230–2.PubMedCrossRefGoogle Scholar
  29. Kawaguchi T, Tanaka M, Itano S, Ono N, Shimauchi Y, Nagamatsu H, et al. Successful treatment for bronchial bleeding from invasive pulmonary metastasis of hepatocellular carcinoma: a case report. Hepato-Gastroenterology. 2001;48(39):851–3.PubMedGoogle Scholar
  30. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost: JTH. 2007a;5(3):632–4.PubMedCrossRefGoogle Scholar
  31. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer. 2007b;110(10):2339–46.PubMedCrossRefGoogle Scholar
  32. Kundu A, Sardar P, Chatterjee S, Aronow WS, Owan T, Ryan JJ. Minimizing the risk of bleeding with NOACs in the elderly. Drugs Aging. 2016;33:491–500.PubMedCrossRefGoogle Scholar
  33. Langendijk JA, ten Velde GP, Aaronson NK, de Jong JM, Muller MJ, Wouters EF. Quality of life after palliative radiotherapy in non-small cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys. 2000;47(1): 149–55.PubMedCrossRefGoogle Scholar
  34. Lee AY, Peterson EA. Treatment of cancer-associated thrombosis. Blood. 2013;122(14):2310–7.PubMedCrossRefGoogle Scholar
  35. Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, 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(2):146–53.PubMedCrossRefGoogle Scholar
  36. Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, et al. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA. 2015;314(7):677–86.PubMedCrossRefGoogle Scholar
  37. Louzada ML, Carrier M, Lazo-Langner A, Dao V, Kovacs MJ, Ramsay TO, et al. Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism. Circulation. 2012;126(4): 448–54.PubMedCrossRefGoogle Scholar
  38. Martins BC, Wodak S, Gusmon CC, Safatle-Ribeiro AV, Kawaguti FS, Baba ER, et al. Argon plasma coagulation for the endoscopic treatment of gastrointestinal tumor bleeding: a retrospective comparison with a non-treated historical cohort. United European Gastroenterol J. 2016;4(1):49–54.PubMedCrossRefGoogle Scholar
  39. Meignan M, Rosso J, Gauthier H, Brunengo F, Claudel S, Sagnard L, et al. Systematic lung scans reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis. Arch Intern Med. 2000;160(2):159–64.PubMedCrossRefGoogle Scholar
  40. Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002;162(15):1729–35.PubMedCrossRefGoogle Scholar
  41. Nabi G, Sheikh N, Greene D, Marsh R. Therapeutic transcatheter arterial embolization in the management of intractable haemorrhage from pelvic urological malignancies: preliminary experience and long-term follow-up. BJU Int. 2003;92(3):245–7.PubMedCrossRefGoogle Scholar
  42. National Institute for Health and Care Excellence (NICE). Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. NICE Guideline (NG89). NICE publishing, London; 2018.Google Scholar
  43. Noble SF, Finlay IG. Is long-term low-molecular-weight heparin acceptable to palliative care patients in the treatment of cancer related venous thromboembolism? A qualitative study. Palliat Med. 2005;19(3):197–201.PubMedCrossRefGoogle Scholar
  44. Noble SI, Finlay IG. Have palliative care teams’ attitudes toward venous thromboembolism changed? A survey of thromboprophylaxis practice across British specialist palliative care units in the years 2000 and 2005. J Pain Symptom Manag. 2006;32(1):38–43.CrossRefGoogle Scholar
  45. Noble S, Johnson M. Finding the evidence for thromboprophylaxis in palliative care: first let us agree on the question. Palliat Med. 2010;24(4):359–61.PubMedCrossRefGoogle Scholar
  46. Noble SI, Nelson A, Turner C, Finlay IG. Acceptability of low molecular weight heparin thromboprophylaxis for inpatients receiving palliative care: qualitative study. BMJ. 2006;332(7541):577–80.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Noble SI, Nelson A, Finlay IG. Factors influencing hospice thromboprophylaxis policy: a qualitative study. Palliat Med. 2008;22(7):808–13.PubMedCrossRefGoogle Scholar
  48. Noble S, Lewis R, Whithers J, Lewis S, Bennett P. Long-term psychological consequences of symptomatic pulmonary embolism: a qualitative study. BMJ Open. 2014;4(4):e004561.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Noble S, Matzdorff A, Maraveyas A, Holm MV, Pisa G. Assessing patients’ anticoagulation preferences for the treatment of cancer-associated thrombosis using conjoint methodology. Haematologica. 2015a;100(11): 1486–92.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Noble S, Prout H, Nelson A. Patients’ Experiences of LIving with CANcer-associated thrombosis: the PELICAN study. Patient Prefer Adherence. 2015b;9: 337–45.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Noble S, Pease N, Sui J, Davies J, Lewis S, Malik U, et al. Impact of a dedicated cancer-associated thrombosis service on clinical outcomes: a mixed-methods evaluation of a clinical improvement exercise. BMJ Open. 2016;6(11):e013321.PubMedPubMedCentralCrossRefGoogle Scholar
  52. O’Shaughnessy DF, Atterbury C, Bolton Maggs P, Murphy M, Thomas D, Yates S, et al. Guidelines for the use of fresh-frozen plasma cryoprecipitate and cryosupernatant. Br J Haematol. 2004;126(1):11–28.PubMedCrossRefGoogle Scholar
  53. Pace V, Hall E, Bailey C. Prophylactic heparin in palliative care: a cautious welcome. BMJ. 2006;332(7543): 728–9.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Pereira J, Phan T. Management of bleeding in patients with advanced cancer. Oncologist. 2004;9(5):561–70.PubMedCrossRefGoogle Scholar
  55. Preston NJ, Hurlow A, Brine J, Bennett MI. Blood transfusions for anaemia in patients with advanced cancer. Cochrane Database Syst Rev. 2012;(2):CD009007.Google Scholar
  56. Prins MLA, Brighton T, Lyons R, Rehm J, Trajanovic M, Davidson B, Beyer-Westendorf J, Pap A, Berkowitz S, Cohen A, Kovacs M, Wells P, Prandoni P. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematol. 2014;1(1):e37–e46A.PubMedCrossRefGoogle Scholar
  57. Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378(7):615–24.PubMedCrossRefGoogle Scholar
  58. Rickles FR, Falanga A. Activation of clotting factors in cancer. Cancer Treat Res. 2009;148:31–41.PubMedCrossRefGoogle Scholar
  59. Roberts I, Shakur H, Coats T, Hunt B, Balogun E, Barnetson L, et al. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess. 2013;17(10):1–79.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Rodrigues G, Videtic GM, Sur R, Bezjak A, Bradley J, Hahn CA, et al. Palliative thoracic radiotherapy in lung cancer: an American Society for Radiation Oncology evidence-based clinical practice guideline. Pract Radiat Oncol. 2011;1(2):60–71.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Sakr L, Dutau H. Massive hemoptysis: an update on the role of bronchoscopy in diagnosis and management. Respiration. 2010;80(1):38–58.PubMedCrossRefGoogle Scholar
  62. Schiffer CA, Anderson KC, Bennett CL, Bernstein S, Elting LS, Goldsmith M, et al. Platelet transfusion for patients with cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001;19(5):1519–38.PubMedCrossRefGoogle Scholar
  63. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–52.PubMedCrossRefGoogle Scholar
  64. Seaman S, Nelson A, Noble S. Cancer-associated thrombosis, low-molecular-weight heparin, and the patient experience: a qualitative study. Patient Prefer Adherence. 2014;8:453–61.PubMedPubMedCentralGoogle Scholar
  65. Sheard L, Prout H, Dowding D, Noble S, Watt I, Maraveyas A, et al. Barriers to the diagnosis and treatment of venous thromboembolism in advanced cancer patients: a qualitative study. Palliat Med. 2013;27(4): 339–48.PubMedCrossRefGoogle Scholar
  66. Tardy B, Picard S, Guirimand F, Chapelle C, Danel Delerue M, Celarier T, et al. Bleeding risk of terminally ill patients hospitalized in palliative care units: the RHESO study. J Thromb Haemost: JTH. 2017;15(3): 420–8.PubMedCrossRefGoogle Scholar
  67. Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galie N, Pruszczyk P, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008;29(18): 2276–315.PubMedCrossRefGoogle Scholar
  68. van der Hulle T, den Exter PL, Kooiman J, van der Hoeven JJ, Huisman MV, Klok FA. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J Thromb Haemost: JTH. 2014;12(7): 1116–20.PubMedCrossRefGoogle Scholar
  69. Wells PS, Forgie MA, Rodger MA. Treatment of venous thromboembolism. JAMA. 2014;311(7):717–28.PubMedCrossRefGoogle Scholar
  70. Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. 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.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Marie Curie Palliative Care Research Centre, Division of Population MedicineCardiff UniversityCardiffUK

Personalised recommendations