Semin Thromb Hemost 2014; 40(03): 325-331
DOI: 10.1055/s-0034-1370791
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Thrombosis in Brain Tumors

Jasmin T. Jo
1   Division of Neuro-Oncology, Dana Farber Cancer Institute, Massachusetts General Hospital, Boston, Massachusetts
,
David Schiff
2   Division of Neuro-Oncology, University of Virginia, Charlottesville, Virginia
,
James R. Perry
3   Division of Neurology, Sunnybrook Health Science and Odette Cancer Centre, University of Toronto, Toronto, Canada
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
05. März 2014 (online)

Abstract

Venous thromboembolism (VTE) is common in patients with brain tumors, occurring in up to 30% of patients with high-grade glioma and up to 20% of those with brain metastasis and primary central nervous system (CNS) lymphoma. The risk is correlated with higher grade malignancies and is directly associated with the production of the potent procoagulant, tissue factor (TF). Upregulation of TF influences both the coagulation pathway and oncogenic signaling mechanisms important for cancer progression. The risk of intracranial hemorrhage with the use of anticoagulants complicates the management of VTE in patients with brain tumor. We discuss the recommended anticoagulants used for initial and long-term treatment of established VTE, including unfractionated heparin, low-molecular-weight heparin (LMWH), and warfarin. Therapeutic anticoagulation, particularly LMWH followed by secondary prophylaxis, is generally safe and effective in the treatment of VTE, including patients on antiangiogenic agents. Anticoagulation also reduces the risk of VTE during the perioperative period. However, despite the high risk of VTE throughout the course of disease, present data do not support routine thromboprophylaxis in brain tumor patients. Further investigation regarding the mechanisms underlying the hypercoagulable state of patients with brain tumors and the potential role of the factors and products of thrombogenesis as biomarkers for risk stratification will be useful in identification and management of patients at risk of developing VTE. Novel oral anticoagulants that directly inhibit thrombin such as dabigatran or factor Xa, including rivaroxaban and apixaban have several potential advantages; however, due to limited data in the cancer population, the use of these newer oral anticoagulants is not currently recommended for patients with malignancy and VTE. Recent studies have explored the role of anticoagulants as anticancer agents, which may contribute to cancer treatment in the future.

 
  • References

  • 1 Sørensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 343 (25) 1846-1850
  • 2 Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006; 166 (4) 458-464
  • 3 Semrad TJ, O'Donnell R, Wun T , et al. Epidemiology of venous thromboembolism in 9489 patients with malignant glioma. J Neurosurg 2007; 106 (4) 601-608
  • 4 Drappatz J, Schiff D, Kesari S, Norden AD, Wen PY. Medical management of brain tumor patients. Neurol Clin 2007; 25 (4) 1035-1071 , ix
  • 5 Simanek R, Vormittag R, Hassler M , et al. Venous thromboembolism and survival in patients with high-grade glioma. Neuro-oncol 2007; 9 (2) 89-95
  • 6 Jenkins EO, Schiff D, Mackman N, Key NS. Venous thromboembolism in malignant gliomas. J Thromb Haemost 2010; 8 (2) 221-227
  • 7 Lacy J, Saadati H, Yu JB. Complications of brain tumors and their treatment. Hematol Oncol Clin North Am 2012; 26 (4) 779-796
  • 8 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 (9) 1959-1965
  • 9 Marras LC, Geerts WH, Perry JR. The risk of venous thromboembolism is increased throughout the course of malignant glioma: an evidence-based review. Cancer 2000; 89 (3) 640-646
  • 10 Gerber DE, Grossman SA, Streiff MB. Management of venous thromboembolism in patients with primary and metastatic brain tumors. J Clin Oncol 2006; 24 (8) 1310-1318
  • 11 Perry JR. Thromboembolic disease in patients with high-grade glioma. Neuro-oncol 2012; 14 (Suppl. 04) iv73-iv80
  • 12 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 (10) 1592-1596
  • 13 Streiff MB, Segal J, Grossman SA, Kickler TS, Weir EG. ABO blood group is a potent risk factor for venous thromboembolism in patients with malignant gliomas. Cancer 2004; 100 (8) 1717-1723
  • 14 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 (5) 2093-2098
  • 15 Rodas RA, Fenstermaker RA, McKeever PE , et al. Correlation of intraluminal thrombosis in brain tumor vessels with postoperative thrombotic complications: a preliminary report. J Neurosurg 1998; 89 (2) 200-205
  • 16 Dhami MS, Bona RD, Calogero JA, Hellman RM. Venous thromboembolism and high grade gliomas. Thromb Haemost 1993; 70 (3) 393-396
  • 17 Perry JR. Anticoagulation of malignant glioma patients in the era of novel antiangiogenic agents. Curr Opin Neurol 2010; 23 (6) 592-596
  • 18 Anand M, Brat DJ. Oncogenic regulation of tissue factor and thrombosis in cancer. Thromb Res 2012; 129 (Suppl. 01) S46-S49
  • 19 Kocatürk B, Versteeg HH. Tissue factor-integrin interactions in cancer and thrombosis: every Jack has his Jill. J Thromb Haemost 2013; 11 (Suppl. 01) 285-293
  • 20 Sciacca FL, Ciusani E, Silvani A , et al. Genetic and plasma markers of venous thromboembolism in patients with high grade glioma. Clin Cancer Res 2004; 10 (4) 1312-1317
  • 21 Hamada K, Kuratsu J, Saitoh Y, Takeshima H, Nishi T, Ushio Y. Expression of tissue factor correlates with grade of malignancy in human glioma. Cancer 1996; 77 (9) 1877-1883
  • 22 Thaler J, Preusser M, Ay C , et al. Intratumoral tissue factor expression and risk of venous thromboembolism in brain tumor patients. Thromb Res 2013; 131 (2) 162-165
  • 23 Rong Y, Post DE, Pieper RO, Durden DL, Van Meir EG, Brat DJ. PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. Cancer Res 2005; 65 (4) 1406-1413
  • 24 Rong Y, Durden DL, Van Meir EG, Brat DJ. 'Pseudopalisading' necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol 2006; 65 (6) 529-539
  • 25 Tehrani M, Friedman TM, Olson JJ, Brat DJ. Intravascular thrombosis in central nervous system malignancies: a potential role in astrocytoma progression to glioblastoma. Brain Pathol 2008; 18 (2) 164-171
  • 26 Rong Y, Belozerov VE, Tucker-Burden C , et al. Epidermal growth factor receptor and PTEN modulate tissue factor expression in glioblastoma through JunD/activator protein-1 transcriptional activity. Cancer Res 2009; 69 (6) 2540-2549
  • 27 Milsom CC, Yu JL, Mackman N , et al. Tissue factor regulation by epidermal growth factor receptor and epithelial-to-mesenchymal transitions: effect on tumor initiation and angiogenesis. Cancer Res 2008; 68 (24) 10068-10076
  • 28 Geddings JE, Mackman N. Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients. Blood 2013; 122 (11) 1873-1880
  • 29 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 (2) 378-385
  • 30 Gan HK, Kaye AH, Luwor RB. The EGFRvIII variant in glioblastoma multiforme. J Clin Neurosci 2009; 16 (6) 748-754
  • 31 Skog J, Würdinger T, van Rijn S , et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008; 10 (12) 1470-1476
  • 32 Carneiro-Lobo TC, Konig S, Machado DE , et al. Ixolaris, a tissue factor inhibitor, blocks primary tumor growth and angiogenesis in a glioblastoma model. J Thromb Haemost 2009; 7 (11) 1855-1864
  • 33 Ruff RL, Posner JB. Incidence and treatment of peripheral venous thrombosis in patients with glioma. Ann Neurol 1983; 13 (3) 334-336
  • 34 Choucair AK, Silver P, Levin VA. Risk of intracranial hemorrhage in glioma patients receiving anticoagulant therapy for venous thromboembolism. J Neurosurg 1987; 66 (3) 357-358
  • 35 Schiff D, DeAngelis LM. Therapy of venous thromboembolism in patients with brain metastases. Cancer 1994; 73 (2) 493-498
  • 36 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 (4) 310-315
  • 37 Uchino K. The balance of risk of bleeding and thrombosis in melanoma patients with brain metastases. Melanoma Res 2013; 23 (1) 82
  • 38 Lazio BE, Simard JM. Anticoagulation in neurosurgical patients. Neurosurgery 1999; 45 (4) 838-847 , discussion 847–848
  • 39 Khaldi A, Helo N, Schneck MJ, Origitano TC. Venous thromboembolism: deep venous thrombosis and pulmonary embolism in a neurosurgical population. J Neurosurg 2011; 114 (1) 40-46
  • 40 Goldhaber SZ, Dunn K, Gerhard-Herman M, Park JK, Black PM. Low rate of venous thromboembolism after craniotomy for brain tumor using multimodality prophylaxis. Chest 2002; 122 (6) 1933-1937
  • 41 Wen P, Lee EQ. Anticoagulant and antiplatelet therapy in patients with brain tumors [online]. Available at: http://www.uptodate.com/contents/anticoagulant-and-antiplatelet-therapy-in-patients-with-brain-tumors . Accessed October 28, 2013
  • 42 Levin JM, Schiff D, Loeffler JS, Fine HA, Black PM, Wen PY. Complications of therapy for venous thromboembolic disease in patients with brain tumors. Neurology 1993; 43 (6) 1111-1114
  • 43 Lyman GH, Khorana AA, Kuderer NM , et al; American Society of Clinical Oncology Clinical Practice. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 31 (17) 2189-2204
  • 44 Holbrook AM, Pereira JA, Labiris R , et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165 (10) 1095-1106
  • 45 Bates SM, Ginsberg JS. Clinical practice. Treatment of deep-vein thrombosis. N Engl J Med 2004; 351 (3) 268-277
  • 46 Monreal M, Zacharski L, Jiménez JA, Roncales J, Vilaseca B. 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 (8) 1311-1315
  • 47 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 (2) 80-85
  • 48 Lee AY, Levine MN, Baker RI , et al; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. 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) 146-153
  • 49 Levine MN, Gu C, Liebman HA , et al. A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J Thromb Haemost 2012; 10 (5) 807-814
  • 50 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 (2) 139-142
  • 51 Knovich MA, Lesser GJ. The management of thromboembolic disease in patients with central nervous system malignancies. Curr Treat Options Oncol 2004; 5 (6) 511-517
  • 52 Robins HI, O'Neill A, Gilbert M , et al. Effect of dalteparin and radiation on survival and thromboembolic events in glioblastoma multiforme: a phase II ECOG trial. Cancer Chemother Pharmacol 2008; 62 (2) 227-233
  • 53 Perry SL, Bohlin C, Reardon DA , et al. Tinzaparin prophylaxis against venous thromboembolic complications in brain tumor patients. J Neurooncol 2009; 95 (1) 129-134
  • 54 Kuderer NM, Ortel TL, Francis CW. Impact of venous thromboembolism and anticoagulation on cancer and cancer survival. J Clin Oncol 2009; 27 (29) 4902-4911
  • 55 Kuderer NM, Khorana AA, Lyman GH, Francis CW. A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment: impact on survival and bleeding complications. Cancer 2007; 110 (5) 1149-1161
  • 56 Armstrong TS, Wen PY, Gilbert MR, Schiff D. Management of treatment-associated toxicities of anti-angiogenic therapy in patients with brain tumors. Neuro-oncol 2012; 14 (10) 1203-1214
  • 57 Norden AD, Bartolomeo J, Tanaka S , et al. Safety of concurrent bevacizumab therapy and anticoagulation in glioma patients. J Neurooncol 2012; 106 (1) 121-125
  • 58 Avastin [package insert]. San Francisco, CA: Genentech USA, Inc.; 2011
  • 59 Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 2007; 96 (12) 1788-1795
  • 60 Meyer T, Robles-Carrillo L, Robson T , et al. Bevacizumab immune complexes activate platelets and induce thrombosis in FCGR2A transgenic mice. J Thromb Haemost 2009; 7 (1) 171-181
  • 61 Friedman HS, Prados MD, Wen PY , et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009; 27 (28) 4733-4740
  • 62 Nghiemphu PL, Green RM, Pope WB, Lai A, Cloughesy TF. Safety of anticoagulation use and bevacizumab in patients with glioma. Neuro-oncol 2008; 10 (3) 355-360