Treatment and prevention of venous thromboembolism in patients with brain tumors
- Eudocia Quant Lee, MD, MPH
Eudocia Quant Lee, MD, MPH
- Assistant Professor of Neurology
- Harvard Medical School
- Patrick Y Wen, MD
Patrick Y Wen, MD
- Section Editor — Neurooncology
- Professor of Neurology
- Harvard Medical School
Treatment and prevention of venous thromboembolism (VTE) in patients with primary and metastatic brain tumors is complicated by two conflicting issues. Patients with brain tumors have a substantial risk for developing VTE due to a hypercoagulable state, neurosurgical procedures, and often leg paresis. However, there is concern that antithrombotic agents can precipitate hemorrhage into the tumor with neurological worsening.
The balance between these issues is discussed here. The overall risk, diagnosis, and treatment of VTE in patients with malignancy, as well as risk and treatment of anticoagulant-associated intracerebral hemorrhage, are reviewed separately. (See "Treatment of venous thromboembolism in patients with malignancy" and "Risk of intracerebral bleeding in patients treated with anticoagulants" and "Reversal of anticoagulation in warfarin-associated intracerebral hemorrhage".)
PREVALENCE AND RISK FACTORS
Patients with primary or metastatic brain tumors, as well as malignancies at other sites, have a latent hypercoagulable state that predisposes to thromboembolism, particularly in the postoperative period [1-3]. (See "Risk and prevention of venous thromboembolism in adults with cancer" and "Pathogenesis of the hypercoagulable state associated with malignancy".)
Estimates of the incidence of venous thromboembolism (VTE) consistently show increased relative risk among patients with cancer compared with the general population, particularly in patients with glioblastoma . In prospective studies of patients with malignant glioma, the observed incidence of symptomatic VTE ranges from 17 to 26 percent [5-8].
Although there is clustering of venous thromboembolic events in the postoperative period following craniotomy and during intensive chemotherapy, the risk persists throughout the clinical course . Risk factors for venous thromboembolism in brain tumor patients may include age ≥60 years, obesity, glioblastoma histology, large tumor size, subtotal resection, use of steroids, chemotherapy, neurosurgery within the past two months, the presence of leg paresis, and A or AB blood type [2,3,9-12].To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Gerber DE, Grossman SA, Streiff MB. Management of venous thromboembolism in patients with primary and metastatic brain tumors. J Clin Oncol 2006; 24:1310.
- Semrad TJ, O'Donnell R, Wun T, et al. Epidemiology of venous thromboembolism in 9489 patients with malignant glioma. J Neurosurg 2007; 106:601.
- Jenkins EO, Schiff D, Mackman N, Key NS. Venous thromboembolism in malignant gliomas. J Thromb Haemost 2010; 8:221.
- Perry JR. Thromboembolic disease in patients with high-grade glioma. Neuro Oncol 2012; 14 Suppl 4:iv73.
- Ay C, Vormittag R, Dunkler D, et al. D-dimer and prothrombin fragment 1 + 2 predict venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2009; 27:4124.
- Brandes AA, Scelzi E, Salmistraro G, et al. Incidence of risk of thromboembolism during treatment high-grade gliomas: a prospective study. Eur J Cancer 1997; 33:1592.
- Perry JR, Julian JA, Laperriere NJ, et al. PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. J Thromb Haemost 2010; 8:1959.
- Streiff MB, Ye X, Kickler TS, et al. A prospective multicenter study of venous thromboembolism in patients with newly-diagnosed high-grade glioma: hazard rate and risk factors. J Neurooncol 2015; 124:299.
- Ruff RL, Posner JB. Incidence and treatment of peripheral venous thrombosis in patients with glioma. Ann Neurol 1983; 13:334.
- Streiff MB, Segal J, Grossman SA, et al. ABO blood group is a potent risk factor for venous thromboembolism in patients with malignant gliomas. Cancer 2004; 100:1717.
- Misch M, Czabanka M, Dengler J, et al. D-dimer elevation and paresis predict thromboembolic events during bevacizumab therapy for recurrent malignant glioma. Anticancer Res 2013; 33:2093.
- Yust-Katz S, Mandel JJ, Wu J, et al. Venous thromboembolism (VTE) and glioblastoma. J Neurooncol 2015; 124:87.
- Wakai S, Yamakawa K, Manaka S, Takakura K. Spontaneous intracranial hemorrhage caused by brain tumor: its incidence and clinical significance. Neurosurgery 1982; 10:437.
- Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 2014; 370:709.
- Mandybur TI. Intracranial hemorrhage caused by metastatic tumors. Neurology 1977; 27:650.
- Donato J, Campigotto F, Uhlmann EJ, et al. Intracranial hemorrhage in patients with brain metastases treated with therapeutic enoxaparin: a matched cohort study. Blood 2015; 126:494.
- Nghiemphu PL, Green RM, Pope WB, et al. Safety of anticoagulation use and bevacizumab in patients with glioma. Neuro Oncol 2008; 10:355.
- Norden AD, Bartolomeo J, Tanaka S, et al. Safety of concurrent bevacizumab therapy and anticoagulation in glioma patients. J Neurooncol 2012; 106:121.
- Levin JM, Schiff D, Loeffler JS, et al. Complications of therapy for venous thromboembolic disease in patients with brain tumors. Neurology 1993; 43:1111.
- Olin JW, Young JR, Graor RA, et al. Treatment of deep vein thrombosis and pulmonary emboli in patients with primary and metastatic brain tumors. Anticoagulants or inferior vena cava filter? Arch Intern Med 1987; 147:2177.
- Wen PY, Marks PW. Medical management of patients with brain tumors. Curr Opin Oncol 2002; 14:299.
- Norris LK, Grossman SA. Treatment of thromboembolic complications in patients with brain tumors. J Neurooncol 1994; 22:127.
- Goldschmidt N, Linetsky E, Shalom E, et al. High incidence of thromboembolism in patients with central nervous system lymphoma. Cancer 2003; 98:1239.
- Schmidt F, Faul C, Dichgans J, Weller M. Low molecular weight heparin for deep vein thrombosis in glioma patients. J Neurol 2002; 249:1409.
- Dickinson LD, Miller LD, Patel CP, Gupta SK. Enoxaparin increases the incidence of postoperative intracranial hemorrhage when initiated preoperatively for deep venous thrombosis prophylaxis in patients with brain tumors. Neurosurgery 1998; 43:1074.
- Monreal M, Zacharski L, Jiménez JA, et al. Fixed-dose low-molecular-weight heparin for secondary prevention of venous thromboembolism in patients with disseminated cancer: a prospective cohort study. J Thromb Haemost 2004; 2:1311.
- Lee AY, 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.
- 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; :CD006649.
- Akl EA, Kahale LA, Ballout RA, et al. Parenteral anticoagulation in ambulatory patients with cancer. Cochrane Database Syst Rev 2014; :CD006652.
- Chai-Adisaksopha C, Linkins LA, ALKindi SY, et al. Outcomes of low-molecular-weight heparin treatment for venous thromboembolism in patients with primary and metastatic brain tumours. Thromb Haemost 2017; 117:589.
- Mantia C, Uhlmann EJ, Puligandla M, et al. Predicting the higher rate of intracranial hemorrhage in glioma patients receiving therapeutic enoxaparin. Blood 2017; 129:3379.
- Schiff D, DeAngelis LM. Therapy of venous thromboembolism in patients with brain metastases. Cancer 1994; 73:493.
- Choucair AK, Silver P, Levin VA. Risk of intracranial hemorrhage in glioma patients receiving anticoagulant therapy for venous thromboembolism. J Neurosurg 1987; 66:357.
- Altschuler E, Moosa H, Selker RG, Vertosick FT Jr. The risk and efficacy of anticoagulant therapy in the treatment of thromboembolic complications in patients with primary malignant brain tumors. Neurosurgery 1990; 27:74.
- Quevedo JF, Buckner JC, Schmidt JL, et al. Thromboembolism in patients with high-grade glioma. Mayo Clin Proc 1994; 69:329.
- Alvarado G, Noor R, Bassett R, et al. Risk of intracranial hemorrhage with anticoagulation therapy in melanoma patients with brain metastases. Melanoma Res 2012; 22:310.
- Edwin NC, Khoury MN, Sohal D, et al. Recurrent venous thromboembolism in glioblastoma. Thromb Res 2016; 137:184.
- Chan AT, Atiemo A, Diran LK, et al. Venous thromboembolism occurs frequently in patients undergoing brain tumor surgery despite prophylaxis. J Thromb Thrombolysis 1999; 8:139.
- Smith TR, Lall RR, Graham RB, et al. Venous thromboembolism in high grade glioma among surgical patients: results from a single center over a 10 year period. J Neurooncol 2014; 120:347.
- Agnelli G, Piovella F, Buoncristiani P, et al. Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery. N Engl J Med 1998; 339:80.
- Iorio A, Agnelli G. Low-molecular-weight and unfractionated heparin for prevention of venous thromboembolism in neurosurgery: a meta-analysis. Arch Intern Med 2000; 160:2327.
- Turpie AG, Gallus A, Beattie WS, Hirsh J. Prevention of venous thrombosis in patients with intracranial disease by intermittent pneumatic compression of the calf. Neurology 1977; 27:435.
- Constantini S, Kanner A, Friedman A, et al. Safety of perioperative minidose heparin in patients undergoing brain tumor surgery: a prospective, randomized, double-blind study. J Neurosurg 2001; 94:918.
- Gerber DE, Segal JB, Salhotra A, et al. Venous thromboembolism occurs infrequently in meningioma patients receiving combined modality prophylaxis. Cancer 2007; 109:300.
- Alshehri N, Cote DJ, Hulou MM, et al. Venous thromboembolism prophylaxis in brain tumor patients undergoing craniotomy: a meta-analysis. J Neurooncol 2016; 130:561.
- Perry SL, Bohlin C, Reardon DA, et al. Tinzaparin prophylaxis against venous thromboembolic complications in brain tumor patients. J Neurooncol 2009; 95:129.
- Hovens MM, Snoep JD, Tamsma JT, Huisman MV. Aspirin in the prevention and treatment of venous thromboembolism. J Thromb Haemost 2006; 4:1470.
- Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 31:2189.
- PREVALENCE AND RISK FACTORS
- RISK OF INTRACEREBRAL HEMORRHAGE
- Patients with primary brain tumors
- Patients with brain metastases
- Systemic malignancy without known brain metastases
- Treatment with antiangiogenic therapy
- TREATMENT OF VENOUS THROMBOEMBOLISM
- Patients at average risk for bleeding
- - Agent selection
- - Safety
- - Duration of therapy
- Patients at increased risk for bleeding
- - Inferior vena cava filter
- PREVENTION OF VENOUS THROMBOEMBOLISM
- Role of anticoagulation for primary prevention
- Role of daily aspirin
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS