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Semin Thromb Hemost 2021; 47(08): 914-919
DOI: 10.1055/s-0040-1718927
Review Article

Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy: Risk Factors and Prevention

Paolo Prandoni
1   Arianna Foundation on Anticoagulation, Bologna, Italy
,
Elena Campello
2   Department of Medicine, University Hospital of Padova, Padova, Italy
› Author Affiliations Funding None.
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Abstract

Ambulatory cancer patients undergoing chemotherapy are at a substantial risk for venous thromboembolism (VTE) over the course of therapy and beyond it. Factors accounting for this risk include the activation of extrinsic and intrinsic coagulation pathways, platelet activation, impaired fibrinolysis, use of catheters, infusion of blood products, and thrombogenic potential of several chemotherapeutic drugs. A few stratification models can help identify patients at a higher risk of chemotherapy-associated VTE, who may benefit from preventive strategies. Although low-molecular-weight heparins (LMWHs) effectively reduce the risk of VTE, current guidelines recommend against their routine use. Based on the results of recent randomized controlled clinical trials, the administration of prophylactic doses of the novel direct oral anticoagulants (DOACs) to ambulatory cancer patients undergoing chemotherapy has the potential to offer an effective and safe protection against VTE, obviating the inconveniences of heparins. Except for patients in whom the novel drugs are unsuitable or are contraindicated, in all other patients LMWHs should be replaced by low-dose DOACs.

Keywords

cancer - venous thromboembolism - chemotherapy - anticoagulation - direct oral anticoagulants - low-molecular-weight heparin

Note

This was a spontaneous, unfunded, unsponsored study. The corresponding author had full access to all the data in the study and takes the final responsibility for the decision to submit the manuscript for publication.




Publication History

Article published online:
22 January 2021

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  • References

  • 1 Cohen AT, Katholing A, Rietbrock S, Bamber L, Martinez C. Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study. Thromb Haemost 2017; 117 (01) 57-65
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 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 2007; 5 (03) 632-634
    CrossrefPubMedGoogle Scholar
  • 3 Lloyd AJ, Dewilde S, Noble S, Reimer E, Lee AYY. What impact does venous thromboembolism and bleeding have on cancer patients' quality of life?. Value Health 2018; 21 (04) 449-455
    CrossrefPubMedGoogle Scholar
  • 4 Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol 2005; 6 (06) 401-410
    CrossrefPubMedGoogle Scholar
  • 5 Connors JM. Prophylaxis against venous thromboembolism in ambulatory patients with cancer. N Engl J Med 2014; 370 (26) 2515-2519
    CrossrefPubMedGoogle Scholar
  • 6 Decousus H, Bourmaud A, Fournel P. et al. ONCOCIP Investigators. Cancer-associated thrombosis in patients with implanted ports: a prospective multicenter French cohort study (ONCOCIP). Blood 2018; 132 (07) 707-716
    CrossrefPubMedGoogle Scholar
  • 7 Lyman GH, Eckert L, Wang Y, Wang H, Cohen A. Venous thromboembolism risk in patients with cancer receiving chemotherapy: a real-world analysis. Oncologist 2013; 18 (12) 1321-1329
    CrossrefPubMedGoogle Scholar
  • 8 Hisada Y, Mackman N. Update from the laboratory: mechanistic studies of pathways of cancer-associated venous thrombosis using mouse models. Hematology (Am Soc Hematol Educ Program) 2019; 2019 (01) 182-186
    CrossrefPubMedGoogle Scholar
  • 9 Campello E, Ilich A, Simioni P, Key NS. The relationship between pancreatic cancer and hypercoagulability: a comprehensive review on epidemiological and biological issues. Br J Cancer 2019; 121 (05) 359-371
    CrossrefPubMedGoogle Scholar
  • 10 Zarà M, Canobbio I, Visconte C, Canino J, Torti M, Guidetti GF. Molecular mechanisms of platelet activation and aggregation induced by breast cancer cells. Cell Signal 2018; 48: 45-53
    CrossrefPubMedGoogle Scholar
  • 11 Hisada Y, Mackman N. Cancer-associated pathways and biomarkers of venous thrombosis. Blood 2017; 130 (13) 1499-1506
    CrossrefPubMedGoogle Scholar
  • 12 Reitter EM, Kaider A, Ay C. et al. Longitudinal analysis of hemostasis biomarkers in cancer patients during antitumor treatment. J Thromb Haemost 2016; 14 (02) 294-305
    CrossrefPubMedGoogle Scholar
  • 13 Sartori MT, Della Puppa A, Ballin A. et al. Circulating microparticles of glial origin and tissue factor bearing in high-grade glioma: a potential prothrombotic role. Thromb Haemost 2013; 110 (02) 378-385
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Rajasekhar A, Streiff MB. How I treat central venous access device-related upper extremity deep vein thrombosis. Blood 2017; 129 (20) 2727-2736
    CrossrefPubMedGoogle Scholar
  • 15 Campello E, Henderson MW, Noubouossie DF, Simioni P, Key NS. Contact system activation and cancer: new insights in the pathophysiology of cancer-associated thrombosis. Thromb Haemost 2018; 118 (02) 251-265
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Zarbin MA. Anti-VEGF agents and the risk of arteriothrombotic events. Asia Pac J Ophthalmol (Phila) 2018; 7 (01) 63-67
    PubMedGoogle Scholar
  • 17 Campello E, Spiezia L, Adamo A, Simioni P. Thrombophilia, risk factors and prevention. Expert Rev Hematol 2019; 12 (03) 147-158
    CrossrefPubMedGoogle Scholar
  • 18 Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111 (10) 4902-4907
    CrossrefPubMedGoogle Scholar
  • 19 Lyman GH, Bohlke K, Khorana AA. et al. American Society of Clinical Oncology. Venous thromboembolism prophylaxis and treatment in patients with cancer: american society of clinical oncology clinical practice guideline update 2014. J Clin Oncol 2015; 33 (06) 654-656
    CrossrefPubMedGoogle Scholar
  • 20 Streiff MB, Holmstrom B, Ashrani A. et al. Cancer-associated venous thromboembolic disease, version 1.2015: Featured updates to the NCCN Guidelines. J Natl Compr Cancer Netw 2015; 13 (09) 1079-1095
    CrossrefPubMedGoogle Scholar
  • 21 Mulder FI, Candeloro M, Kamphuisen PW. et al. CAT-prediction collaborators. The Khorana score for prediction of venous thromboembolism in cancer patients: a systematic review and meta-analysis. Haematologica 2019; 104 (06) 1277-1287
    CrossrefPubMedGoogle Scholar
  • 22 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 (07) e289-e298
    CrossrefPubMedGoogle Scholar
  • 23 Gerotziafas GT, Taher A, Abdel-Razeq H. et al. COMPASS–CAT Working Group. A predictive score for thrombosis associated with breast, colorectal, lung, or ovarian cancer: the prospective COMPASS-Cancer-Associated Thrombosis Study. Oncologist 2017; 22 (10) 1222-1231
    CrossrefPubMedGoogle Scholar
  • 24 Spyropoulos AC, Eldredge JB, Anand LN. et al. External validation of a venous thromboembolic risk score for cancer outpatients with solid tumors: the COMPASS-CAT venous thromboembolism risk assessment model. Oncologist 2020; 25 (07) e1083-e1090
    CrossrefPubMedGoogle Scholar
  • 25 Agnelli G, Gussoni G, Bianchini C. et al. PROTECHT Investigators. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 2009; 10 (10) 943-949
    CrossrefPubMedGoogle Scholar
  • 26 Agnelli G, George DJ, Kakkar AK. et al. SAVE-ONCO Investigators. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 2012; 366 (07) 601-609
    CrossrefPubMedGoogle Scholar
  • 27 Maraveyas A, Waters J, Roy R. et al. Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer 2012; 48 (09) 1283-1292
    CrossrefPubMedGoogle Scholar
  • 28 Pelzer U, Opitz B, Deutschinoff G. et al. Efficacy of prophylactic low-molecular weight heparin for ambulatory patients with advanced pancreatic cancer: outcomes from the CONKO-004 trial. J Clin Oncol 2015; 33 (18) 2028-2034
    CrossrefPubMedGoogle Scholar
  • 29 Macbeth F, Noble S, Evans J. et al. Randomized phase III trial of standard therapy plus low molecular weight heparin in patients with lung cancer: FRAGMATIC trial. J Clin Oncol 2016; 34 (05) 488-494
    CrossrefPubMedGoogle Scholar
  • 30 Di Nisio M, Porreca E, Ferrante N, Otten HM, Cuccurullo F, Rutjes AW. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev 2012; 2 (02) CD008500
    PubMedGoogle Scholar
  • 31 Carrier M, Abou-Nassar K, Mallick R. et al. AVERT Investigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med 2019; 380 (08) 711-719
    CrossrefPubMedGoogle Scholar
  • 32 Khorana AA, Soff GA, Kakkar AK. et al. Rivaroxaban thromboprophylaxis in high-risk ambulatory cancer patients receiving systemic therapy: results of a randomized clinical trial. N Engl J Med 2019; 380 (08) 720-728
    CrossrefPubMedGoogle Scholar
  • 33 Riess H, Prandoni P, Harder S, Kreher S, Bauersachs R. Direct oral anticoagulants for the treatment of venous thromboembolism in cancer patients: Potential for drug-drug interactions. Crit Rev Oncol Hematol 2018; 132: 169-179
    CrossrefPubMedGoogle Scholar
  • 34 Becattini C, Verso M, Muňoz A, Agnelli G. Updated meta-analysis on prevention of venous thromboembolism in ambulatory cancer patients. Haematologica 2020; 105 (03) 838-848
    CrossrefPubMedGoogle Scholar
  • 35 Haddad TC, Greeno EW. Chemotherapy-induced thrombosis. Thromb Res 2006; 118 (05) 555-568
    CrossrefPubMedGoogle Scholar
  • 36 Walsh J, Wheeler HR, Geczy CL. Modulation of tissue factor on human monocytes by cisplatin and adriamycin. Br J Haematol 1992; 81 (04) 480-488
    CrossrefPubMedGoogle Scholar
  • 37 Rohatgi S, Jagannathan JP, Rosenthal MH, Kim KW, Ramaiya NH, Krajewski KM. Vascular toxicity associated with chemotherapy and molecular targeted therapy: what should a radiologist know?. AJR Am J Roentgenol 2014; 203 (06) 1353-1362
    CrossrefPubMedGoogle Scholar
  • 38 Truelove E, Fielding AK, Hunt BJ. The coagulopathy and thrombotic risk associated with L-asparaginase treatment in adults with acute lymphoblastic leukaemia. Leukemia 2013; 27 (03) 553-559
    CrossrefPubMedGoogle Scholar
  • 39 van Kleef E, Verheij M, te Poele H, Oussoren Y, Dewit L, Stewart F. In vitro and in vivo expression of endothelial von Willebrand factor and leukocyte accumulation after fractionated irradiation. Radiat Res 2000; 154 (04) 375-381
    CrossrefPubMedGoogle Scholar
  • 40 Erman M, Abali H, Oran B. et al. Tamoxifen-induced tissue factor pathway inhibitor reduction: a clue for an acquired thrombophilic state?. Ann Oncol 2004; 15 (11) 1622-1626
    CrossrefPubMedGoogle Scholar
  • 41 Smith KJ, Bleyer AJ, Little WC, Sane DC. The cardiovascular effects of erythropoietin. Cardiovasc Res 2003; 59 (03) 538-548
    CrossrefPubMedGoogle Scholar
  • 42 Ramsey G, Lindholm PF. Thrombosis risk in cancer patients receiving red blood cell transfusions. Semin Thromb Hemost 2019; 45 (06) 648-656
    Article in Thieme ConnectPubMedGoogle Scholar