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Thrombosis in Brain Tumors Jasmin T. Jo, MD1
David Schiff, MD2
James R. Perry, MD, FRCPC3
1 Division of Neuro-Oncology, Dana Farber Cancer Institute,
Massachusetts General Hospital, Boston, Massachusetts 2 Division of Neuro-Oncology, University of Virginia, Charlottesville, Virginia 3 Division of Neurology, Sunnybrook Health Science and Odette Cancer Centre, University of Toronto, Toronto, Canada
Address for correspondence James R. Perry, MD, FRCPC, Division of Neurology, Sunnybrook Health Sciences Centre, A402, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada (e-mail: [email protected]).
Abstract
Keywords
► ► ► ► ►
thromboembolism brain tumors glioma tissue factor bevacizumab
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.
Venous thromboembolism (VTE) in patients with cancer correlates with advanced disease, poor prognosis, greater tendency toward clinical deterioration, and in-hospital mortality.1,2 The association between VTE and brain tumors, both primary and secondary, is well recognized. VTE negatively
impacts the survival and quality of life of these patients. VTE in patients with malignant glioma was linked with a 30% increased risk of death within 2 years.3 Therefore, clinicians should have a high index of suspicion for prompt diagnosis and timely treatment.
published online March 5, 2014
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
Issue Theme Cancer and Thrombosis: An Update; Guest Editor, Hau C. Kwaan, MD, FRCP.
DOI http://dx.doi.org/ 10.1055/s-0034-1370791. ISSN 0094-6176.
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Semin Thromb Hemost 2014;40:325–331.
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Epidemiology and Risk Factors The incidence of VTE in patients with brain tumors ranges from 3 to 60%.3–5 VTE occurs in 20 to 30% of patients with high-grade glioma (HGG) and up to 20% in patients with brain metastases and primary central nervous system (CNS) lymphoma.5–8 The risk in patients with HGG is greatest in the first few months postsurgery and remains higher than other malignancies throughout the course of disease.9,10 Prolonged immobility and presence of an indwelling catheter are established risk factors for VTE.6 Patients who are older than 75 years, obese, with A and AB blood type, leg paresis, multiple medical comorbidities, and history of thrombosis or pulmonary embolism are at a greater risk for thromboembolic events.4,6,11–14 Disease-specific risk factors include glioblastoma (GBM) tumor subtype, presence of intraluminal thrombosis in the pathologic specimen, recurrent disease, glioma diameter greater than 5 cm, and subtotal resection.3,5,12,15 Risk factors related to treatment include chemotherapy administration, anti-vascular endothelial growth factor (VEGF) treatment, and hormonal therapy.11,16,17 Radiotherapy and corticosteroids increase the risk of VTE in other cancers, but their contribution with glioma is unclear.6 ►Table 1 summarizes the risk factors for VTE in patients with brain tumors.
Pathophysiology Patients with cancer, including brain tumors, have alterations in homeostatic mechanisms of coagulation and fibrinolysis, predisposing them to a hypercoagulable state. Tissue factor (TF) or thromboplastin is a potent procoagulant that is vital in both physiological and pathological coagulation. Upregulation of TF and its downstream effectors leads not only to activation of clotting factors but also stimulation of oncogenic signaling mechanisms important for cancer progression.18
Activation of the Coagulation Cascade TF is considered to be the main initiator of the extrinsic coagulation cascade. With endothelial damage, TF is exposed to the circulation, leading to binding and activation of factor VII, which then converts factor X into Xa, resulting in thrombin formation.19 TF is upregulated in cancer development,
causing dysregulation of the normally tightly controlled coagulation system. Tumor and tumor-associated endothelial cells are able to produce and release factors that influence activation of coagulation cascade, including VEGF, tissue-type plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1).14,20
TF and Its Oncogenic Influence in Glioma TF can be focally or widely expressed in glioma and is correlated with the histologic grade. It is overexpressed in more than 90% of HGG and 10 to 20% in low-grade glioma.21–23 Intravascular thrombosis may initiate the transition from anaplastic astrocytoma to GBM by triggering vaso-occlusion, causing tumor migration away from hypoxia, hypoxia-inducible factor–mediated VEGF secretion, adjacent angiogenesis (microvascular hyperplasia), and rapid peripheral tumor expansion. These cascades produce pseudopalisading necrosis and microvascular proliferation.23,24 TF expression is highest within the cells forming hypoxic pseudopalisades.23 Common genetic events in the progression of anaplastic astrocytoma to GBM, including phosphatase and tensin homolog (PTEN) loss (20–40% of GBM) and epidermal growth factor receptor (EGFR) amplification (40–50% of GBM), have been shown to increase TF expression.25 PTEN regulates the PI3-kinase/Akt/mTOR and Ras/MEK/ERK signaling pathways, capable of modulating TF expression under hypoxic conditions.23,25,26 EGFR-driven TF expression is associated with enhanced VEGF production and epithelialto-mesenchyme transition-like event, suggesting a role of TF in tumor initiation, tumor growth, angiogenesis, and metastasis.27
Biomarkers of Venous Thromboembolism Risk The factors and products of thrombogenesis are potential biomarkers for risk stratification of patients. In patients with HGG, plasma markers of activated coagulation and fibrinolytic pathways are elevated, including D-dimer, lipoprotein (a), homocysteine, tPA, and PAI-1.14,20 TF is typically bound to cell surface, as well as on the surface of submicron vesicles termed microparticles (MPs) that shed from the surface of intravascular cells, such as
Table 1 Risk factors for VTE in patients with brain tumor Generic factors
Patient factors Age > 75 y Obesity Blood types A and AB Leg paresis Multiple medical comorbidities • Prior thrombosis or pulmonary embolism
• Prolonged immobility • Presence of indwelling catheter
• • • • •
Disease-specific factors • Glioblastoma tumor subtype • Intraluminal thrombosis in pathologic specimen • Recurrent disease • Glioma size > 5 cm • Subtotal resection
Abbreviations: VEGF, vascular endothelial growth factor; VTE, venous thromboembolism. Seminars in Thrombosis & Hemostasis
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Treatment-related factors • Chemotherapy • Anti-VEGF therapy • Hormonal therapy
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platelets, endothelial cells, leukocytes, and tumor cells.19 MPTF concentration directly correlates with risk of VTE in variety of cancers, including GBM.6,19,28 Preliminary data suggest this may be true in GBM as well. Prospective evaluation of 61 patients with GBM who underwent gross total or subtotal resection followed by radiation and chemotherapy demonstrated higher glial-derived (glial fibrillary acidic protein [GFAP]) and/or TF-bearing MPs, compared with healthy controls, and the levels significantly increased after surgery especially in patients with subtotal resection. TF þ /GFAPMPs levels were significantly higher in GBM patients who developed VTE than in those who did not, and levels above 90th percentile were associated with higher risk of VTE.29 EGFRvIII is the most common EGFR mutation, with a prevalence of 20 to 30% in unselected GBM and 50 to 60% of patients with EGFR mutation.30 EGFRvIII mutation leads to upregulation of TF and VEGF production, inducing angiogenesis. MPs containing EGFRvIII messenger RNA can be detected in the serum.6,11,26,27,31 Serum levels of TF-bearing MPs can potentially serve as biomarker and therapeutic target.6,11 A potential agent that blocks TF-bearing MPs, Ixolaris, which is a tick anticoagulant has been investigated for this indication. This agent has been shown to effectively block in vitro TF-dependent procoagulant activity and tumorigenic potential in human GBM cell line, without observable bleeding. The antitumor activity is associated with downregulation of VEGF, preventing angiogenesis and merits further evaluation as an antitumor treatment in humans.32
Management: Treatment and Secondary Prophylaxis Concerns of increased risk of intracranial hemorrhage (ICH) with anticoagulation complicate the treatment of VTE in patients with brain tumors. Therefore, careful evaluation of the risk of bleeding and choice of treatment are essential.
Assessment of Risk of Bleeding and Initiation of Treatment About 2% of patients with HGG develop symptomatic intratumoral hemorrhage in the absence of antithrombotic treatment, which is similar to its incidence of HGG patients receiving anticoagulants (1.9%) in one study.33 In another study, all 22 HGG patients treated with intravenous heparin followed by either subcutaneous heparin or oral warfarin for late postoperative VTE did not develop bleeding complications.34 These studies suggest that antithrombotic treatment does not increase the risk of ICH in HGG patients.33,34 In patients with brain metastases, 2 out of 51 patients developed fatal ICH in the setting of supratherapeutic anticoagulation with warfarin.35 Brain metastases from melanoma, choriocarcinoma, thyroid carcinoma, and renal carcinoma have high propensity for spontaneous bleeding (up to 70%), thus the use of anticoagulation is generally not advisable.10 Challenging this dogma, a recent study utilizing anticoagulation in melanoma patients with brain metastases and VTE found no significant increase risk of ICH or decrease in overall survival.36 However, the subsequent VTE events, VTE hospi-
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talization, or PE were not reported in this retrospective study.37 Metastases from solid tumors, including breast and lung cancers, have a relatively low incidence of spontaneous hemorrhage and anticoagulation can be safely administered.10 The presence of blood products in the surgical cavity of postoperative brain tumor patients is a common finding and is not a contraindication for initiating antithrombotic treatment.10 A systematic review indicated increased risk of ICH when preoperative correction of coagulation abnormalities was inadequate, when anticoagulation is initiated as early as 24 to 48 hours, and when anticoagulation exceeds therapeutic levels.38 This review does not advocate reinstitution of anticoagulation in the first 24 to 48 hours after intracranial procedure. Moreover, intravenous heparin should be given by continuous infusion rather than bolus to prevent likelihood of supratherapeutic levels.38 In contrast, a recent study involving 555 high-risk neurosurgical patients (20% had brain tumors) showed subcutaneous prophylactic heparin given 5,000 U twice daily, initiated as early as either 24 or 48 hours postoperatively, and was associated with a 43% decreased of developing deep vein thrombosis, without increase of surgical site hemorrhage.39 A randomized, double-blind study demonstrated prophylactic dosing of subcutaneous heparin and enoxaparin initiated on first day postcraniotomy is safe and effective in preventing VTE in patients with brain tumors.40 Most data demonstrate safe use of prophylactic anticoagulation even as a bolus, given as early as 24 hours postsurgery. Anticoagulation is generally avoided in patients with history of previous ICH, bleeding diathesis, thrombocytopenia (< 50,000/µL), coagulopathy, or ongoing life-threatening extracranial bleeding.7,41 Thrombolytic agents for life-threatening pulmonary embolism are absolutely contraindicated in patients with brain tumors.6 Concerns regarding compliance, blood test monitoring, and fall risk should be taken into consideration before the decision to initiate treatment.10 Neuroimaging before anticoagulation is debated, although its use to screen the presence of hemorrhage is widely accepted. Noncontrast head computed tomography, which is readily available and easily performed, is generally recommended for patients whose brain tumors have high propensity for spontaneous bleeding, including melanoma, small cell lung carcinoma, choriocarcinoma, renal cell carcinoma, and thyroid carcinoma. In patients with these types of primary malignancy without known brain metastasis, cranial magnetic resonance imaging to search for occult metastases may be prudent before anticoagulation. The need for neuroimaging in patients with other types of malignancies without neurologic symptoms remains controversial.7,41
Inferior Vena Cava Filter Inferior vena cava (IVC) filters were historically favored over anticoagulation in the treatment of VTE for patients with brain tumors. However, recent studies suggest their use is associated with a high frequency of complications, including procedure-associated morbidity (pneumothorax, infection, bleeding, IVC wall damage), and thrombotic events (recurrent Seminars in Thrombosis & Hemostasis
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PE in 12%, IVC or filter thrombosis in 26%, postphlebitic syndrome in 10%), severely reducing the quality of life of these patients.42 Recurrent VTE is reported in 40% in patients with brain metastases treated with IVC filters.35 Due to these complications, IVC filter is best reserved for patients with an absolute contraindication to anticoagulation.10
Anticoagulation Anticoagulation, including unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or warfarin, is recommended in the initial and long-term treatment for established VTE in patients with primary brain tumors. In the recent American Society of Clinical Oncology guideline, recommendations for patients with primary CNS malignancies with established VTE are similar to other patients with cancer.43 ►Table 2 summarizes the options for treatment and prophylaxis of VTE in brain tumor patients. For initial treatment, LMWH is preferred over UFH for the initial 5 to 10 days in patients with newly diagnosed VTE without renal impairment.43 UFH is reserved for patients with symptomatic PE, those with renal insufficiency and for highrisk patients, because of its shorter half-life and more complete reversibility with protamine compared with LMWH.4,43 For long-term anticoagulation, Food and Drug Administration (FDA)-approved agents include LMWH and warfarin.43 Proper use of warfarin has been reported to be reasonably safe in patients with brain tumors.10,33,35 However, patients with brain tumors often take medications that commonly interact with warfarin, including cimetidine or omeprazole, trimethoprim-sulfamethoxazole, and antiepileptic drugs such as phenytoin.10,44 Due to warfarin’s significant drug– drug interactions and the need for frequent blood monitoring, LMWH has been increasingly used in this population for treatment and prevention of VTE. LMWH also has better bioavailability, longer half-life, and a more predictable dose response, but is more expensive than warfarin.4,41,45 Commonly used LMWHs for the treatment of VTE are enoxaparin, dalteparin, and tinzaparin.4,45 The use of LMWH is safe to use without associated increased risk of major bleeding, even when initiated within 24 hours after surgery.46,47 Randomized data directly comparing LMWH to heparin in a brain tumor population are still lacking. The CLOT trial randomized 673 patients with VTE (34 brain tumors and an unknown number of brain metastasis) to either LMWH or oral anticoagulation. LMWH was more effective in reducing recurrent
VTE without increasing the risk of bleeding. However, the study was not designed to assess the risk of intracranial hemorrhage.48 Fondaparinux, an indirect factor Xa, has been used for initial and maintenance treatment in small number of patients with cancer, and may be an alternative for patients with heparin-induced thrombocytopenia (HIT). However, it is currently not approved by FDA for this indication.43 The duration of anticoagulation treatment depends on the continued presence of factors predisposing patients to hypercoagulability. An indefinite duration of treatment is generally recommended for HGG patients, those who have residual brain tumor, or active systemic malignancy. In patients who are no longer considered at risk for increased hypercoagulability, such as those with grossly resected meningioma, primary CNS lymphoma with complete response, malignancies with durable response to chemotherapy, and metastatic germ cell tumors fully treated with chemotherapy, treatment duration ranges from 6 to 12 months.4,10 Novel oral anticoagulants that directly inhibit thrombin such as dabigatran or factor Xa, including rivaroxaban and apixaban have the advantage of being administered orally, not requiring laboratory monitoring, and infrequent dose adjustment. These agents can effectively prevent VTE following major orthopedic surgery or stroke from nonvalvular atrial fibrillation.11 Apixaban given for 12 weeks appeared to be well tolerated and acceptable for prevention of VTE in ambulatory patients with advanced metastatic cancer undergoing first- or second-line chemotherapy.49 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.43 The lack of antidote, absence of standard assays to measure its anticoagulant activity, and drug interaction with chemotherapeutic agents are additional concerns in using these agents in patients with cancer.43 These oral anticoagulants, nevertheless can be used in patients with HIT.4,10
Role of Primary Prevention The risk of perioperative VTE is high with a reported incidence of 7.5% after resection of primary brain tumor and 19% for metastatic cancer.50 A multimodality approach utilizing anticoagulation with either LMWH or UFH 5,000 units given twice a day, in combination with graduated compression
Table 2 Treatment and prophylaxis of VTE in patients with brain tumors4,43 Initial treatment
Secondary prophylaxis
• UFH: 80 U/kg IV bolus, then 18 U/kg per hour IV, dose adjusted based on aPTT • Dalteparin: 200 U/kg once daily or 100 U/kg, every 12 h (mo 1) • Enoxaparin: 1.5 mg/kg once daily or 1 mg/kg every 12 h • Tinzaparin: 175 U once daily
• Warfarin: Adjusted based on INR • Dalteparin: Decrease to 150 U/kg once daily (mo 2–6) • Enoxaparin: 40 mg, daily, 1.5 mg/kg once daily or 1 mg/kg every 12 h • Tinzaparin: 175 U once daily
Abbreviation: aPTT, activated partial thromboplastin time; mo, months; IV, intravenous; VTE, venous thromboembolism.
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stocking and intermittent pneumatic compression, is effective and safe to reduce VTE during perioperative period.40,51 Since the risk of VTE in patients with brain tumor persists throughout the disease course, the efficacy and safety of anticoagulation for primary prophylaxis in newly diagnosed HGG have been investigated. Two small prospective phase II studies demonstrated anticoagulation using LMWH in newly diagnosed GBM patients was safe, with no reported grade 3 or 4 bleeding and no thromboembolic events.52,53 The efficacy of primary prophylaxis in patients with malignant glioma was then evaluated in the phase III PRODIGE study. Patients were randomized to receive either dalteparin or placebo with the primary outcome of 6-month VTE survival. There was a trend toward reduced VTE in treatment group (11 vs. 7%); however, ICH was more common in patients who received anticoagulation than in the placebo cohort (5 vs. 1%). This trial was terminated prematurely due to expiration of study drug and therefore no definite conclusion can be made due to inadequate statistical power.8 With limited high-quality data, primary prophylaxis beyond the postoperative period in patients with brain tumors is currently not recommended.
Anticoagulation as Antineoplastic Therapy Certain components of the clotting cascade and the associated vascular factors have been postulated to play important roles in tumor progression, invasion, angiogenesis, and metastasis.54 It has been reported that anticoagulants exert antineoplastic effects through inhibition of primary tumor growth, reduction of tumor motility, inhibition of tumor cell migration, reduction of metastases potential, enhancement of antitumor effects of chemotherapy; they also prolong survival of laboratory animals after tumor cell inoculation.54 The precise mechanism remains elusive but evidence supports antiangiogenesis by inhibition of VEGF and basic fibroblast growth factor, antiproliferative effects and induction of differentiation and apoptosis, reduction of tumor invasiveness by inhibition of heparinases, and other extracellular matrix components, as well as blockage of adhesion molecules such as Pand L-selectins, and enhancement of natural killer cells through increased activity of tumor necrosis factor and interferon.6,54 A meta-analysis demonstrated that anticoagulants, particularly LMWH, significantly improve overall survival of cancer patients without venous thrombosis but with greater risk of bleeding complications.55 In the newly diagnosed GBM population, dalteparin given daily with and after traditional radiotherapy did not show a significant survival benefit between treatment and control groups.52 Given the data available, the use of anticoagulants as an anticancer agent is not currently recommended.
Thromboembolic Complications in the Era of Antiangiogenic Therapies Vascular events, including venous and arterial thrombosis, as well as hemorrhage are known complications of antiangiogenic treatments.56,57 Bevacizumab, a humanized monoclonal antibody that binds VEGF, is a FDA-approved therapy for
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recurrent GBM.58 Inhibition of VEGF may induce thrombosis by increasing endothelial cell apoptosis, which disturbs the endothelial lining and exposes underlying procoagulant factors.59 In addition, bevacizumab immune complexes activate platelets via Fc gamma RIIa receptor, leading to induction of platelet aggregation, degranulation, and thrombosis.60 In the BRAIN study, which included 163 recurrent GBM patients treated with either bevacizumab alone or in combination with CPT-11, grades 3 to 5 VTE occurred in 3 to 9% and arterial thrombotic events (ATE) in 3% of patients.61 The risk of bleeding further complicates the treatment of VTE in patients receiving anti-VEGF treatment. Grade 3 or 4 overall hemorrhage occurred in approximately 3% and ICH in 1.3% of patients in the BRAIN study.61 A large retrospective study involving 282 bevacizumab-treated glioma patients, 64 of whom received anticoagulation, demonstrated increased risk of hemorrhage in 20% of patients. Intracerebral hemorrhage accounts for 11%, for which 3% were grade 4 and most were asymptomatic. For patients who did not receive anticoagulation, 1% of patients suffered grade 4 intracranial bleeding.57 In another retrospective study involving 21 HGG patients who received bevacizumab and anticoagulation concurrently, 3 patients had small intraparenchymal hemorrhages, but only 1 was symptomatic.62 Taken together, current evidence suggests that although the risk of intracranial hemorrhage increases with anticoagulation during bevacizumab therapy in HGG patients, the majority of these events are asymptomatic, and the risk-to-benefit ratio favors treatment.41 For patients who develop ATE such as cerebrovascular disease, transient ischemic attack, angina, myocardial infarction, or peripheral vascular occlusion, antiangiogenic agents should be stopped and treatment is guided based on the specific disease process.56
Conclusion VTE commonly occurs in patients with brain tumor and contributes to morbidity and mortality. The risk is high in the perioperative period and remains elevated throughout the disease course. Certain disease factors such as GBM histology and treatment factors, including anti-VEGF treatment, increase the risk of VTE. TF is expressed in glioma, particularly in HGGs, and activates the coagulation pathways, as well as oncogenic mechanisms important in tumor progression. Management of VTE entails balanced evaluation of the risk of hemorrhage versus treatment efficacy. Anticoagulation, particularly LWMH, is generally safe and is recommended for secondary prophylaxis in patients with brain tumors. IVC filters are associated with higher complication rates and advisable only for patients who have absolute contraindications to anticoagulation. The risk of ICH may outweigh the benefit of primary thromboprophylaxis in patients with HGG and is currently not recommended. However, in the perioperative setting, anticoagulation in combination with mechanical compression or antiembolic stockings is safe and effective in reducing the incidence of VTE. Antiangiogenic agents such as bevacizumab increase the risk of venous and arterial thromboembolism. Despite the Seminars in Thrombosis & Hemostasis
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feared risk of hemorrhage, the risk-benefit ratio favors anticoagulation in patients who developed VTE while on anti-VEGF treatment. Serum biomarkers may play an important role in identifying patients at a greater risk of developing VTE and would benefit from preventive anticoagulation. Emerging data show a potential antineoplastic role of anticoagulants, which could become a novel anticancer treatment for HGG.
19 Kocatürk B, Versteeg HH. Tissue factor-integrin interactions in
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21
22
References 1 Sørensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of
2
3
4
5
6 7 8
9
10
11 12
13
14
15
16
17
18
cancers associated with venous thromboembolism. N Engl J Med 2000;343(25):1846–1850 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 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 Drappatz J, Schiff D, Kesari S, Norden AD, Wen PY. Medical management of brain tumor patients. Neurol Clin 2007;25(4): 1035–1071, ix 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 Jenkins EO, Schiff D, Mackman N, Key NS. Venous thromboembolism in malignant gliomas. J Thromb Haemost 2010;8(2):221–227 Lacy J, Saadati H, Yu JB. Complications of brain tumors and their treatment. Hematol Oncol Clin North Am 2012;26(4):779–796 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 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 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 Perry JR. Thromboembolic disease in patients with high-grade glioma. Neuro-oncol 2012;14(Suppl 4):iv73–iv80 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 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 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 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 Dhami MS, Bona RD, Calogero JA, Hellman RM. Venous thromboembolism and high grade gliomas. Thromb Haemost 1993;70(3): 393–396 Perry JR. Anticoagulation of malignant glioma patients in the era of novel antiangiogenic agents. Curr Opin Neurol 2010;23(6): 592–596 Anand M, Brat DJ. Oncogenic regulation of tissue factor and thrombosis in cancer. Thromb Res 2012;129(Suppl 1):S46–S49
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No. 3/2014
23
24
25
26
27
28
29
30 31
32
33
34
35 36
37
38 39
cancer and thrombosis: every Jack has his Jill. J Thromb Haemost 2013;11(Suppl 1):285–293 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 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 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 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 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 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 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 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 Geddings JE, Mackman N. Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients. Blood 2013;122(11):1873–1880 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 Gan HK, Kaye AH, Luwor RB. The EGFRvIII variant in glioblastoma multiforme. J Clin Neurosci 2009;16(6):748–754 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 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 Ruff RL, Posner JB. Incidence and treatment of peripheral venous thrombosis in patients with glioma. Ann Neurol 1983;13(3): 334–336 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 Schiff D, DeAngelis LM. Therapy of venous thromboembolism in patients with brain metastases. Cancer 1994;73(2):493–498 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 Uchino K. The balance of risk of bleeding and thrombosis in melanoma patients with brain metastases. Melanoma Res 2013; 23(1):82 Lazio BE, Simard JM. Anticoagulation in neurosurgical patients. Neurosurgery 1999;45(4):838–847, discussion 847–848 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
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
330
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40 Goldhaber SZ, Dunn K, Gerhard-Herman M, Park JK, Black PM. Low
50 Chan AT, Atiemo A, Diran LK, et al. Venous thromboembolism
rate of venous thromboembolism after craniotomy for brain tumor using multimodality prophylaxis. Chest 2002;122(6):1933–1937 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 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 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 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 Bates SM, Ginsberg JS. Clinical practice. Treatment of deep-vein thrombosis. N Engl J Med 2004;351(3):268–277 Monreal M, Zacharski L, Jiménez JA, Roncales J, Vilaseca B. Fixeddose 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 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 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 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
occurs frequently in patients undergoing brain tumor surgery despite prophylaxis. J Thromb Thrombolysis 1999;8(2): 139–142 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 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 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 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 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 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 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 Avastin [package insert]. San Francisco, CA: Genentech USA, Inc.; 2011 Kamba T, McDonald DM. Mechanisms of adverse effects of antiVEGF therapy for cancer. Br J Cancer 2007;96(12):1788–1795 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 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 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
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Thrombosis in Brain Tumors
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Thrombosis in Brain Tumors Jasmin T. Jo, MD1
David Schiff, MD2
James R. Perry, MD, FRCPC3
1 Division of Neuro-Oncology, Dana Farber Cancer Institute,
Massachusetts General Hospital, Boston, Massachusetts 2 Division of Neuro-Oncology, University of Virginia, Charlottesville, Virginia 3 Division of Neurology, Sunnybrook Health Science and Odette Cancer Centre, University of Toronto, Toronto, Canada
Address for correspondence James R. Perry, MD, FRCPC, Division of Neurology, Sunnybrook Health Sciences Centre, A402, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada (e-mail: [email protected]).
Abstract
Keywords
► ► ► ► ►
thromboembolism brain tumors glioma tissue factor bevacizumab
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.
Venous thromboembolism (VTE) in patients with cancer correlates with advanced disease, poor prognosis, greater tendency toward clinical deterioration, and in-hospital mortality.1,2 The association between VTE and brain tumors, both primary and secondary, is well recognized. VTE negatively
impacts the survival and quality of life of these patients. VTE in patients with malignant glioma was linked with a 30% increased risk of death within 2 years.3 Therefore, clinicians should have a high index of suspicion for prompt diagnosis and timely treatment.
published online March 5, 2014
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
Issue Theme Cancer and Thrombosis: An Update; Guest Editor, Hau C. Kwaan, MD, FRCP.
DOI http://dx.doi.org/ 10.1055/s-0034-1370791. ISSN 0094-6176.
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Semin Thromb Hemost 2014;40:325–331.
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Epidemiology and Risk Factors The incidence of VTE in patients with brain tumors ranges from 3 to 60%.3–5 VTE occurs in 20 to 30% of patients with high-grade glioma (HGG) and up to 20% in patients with brain metastases and primary central nervous system (CNS) lymphoma.5–8 The risk in patients with HGG is greatest in the first few months postsurgery and remains higher than other malignancies throughout the course of disease.9,10 Prolonged immobility and presence of an indwelling catheter are established risk factors for VTE.6 Patients who are older than 75 years, obese, with A and AB blood type, leg paresis, multiple medical comorbidities, and history of thrombosis or pulmonary embolism are at a greater risk for thromboembolic events.4,6,11–14 Disease-specific risk factors include glioblastoma (GBM) tumor subtype, presence of intraluminal thrombosis in the pathologic specimen, recurrent disease, glioma diameter greater than 5 cm, and subtotal resection.3,5,12,15 Risk factors related to treatment include chemotherapy administration, anti-vascular endothelial growth factor (VEGF) treatment, and hormonal therapy.11,16,17 Radiotherapy and corticosteroids increase the risk of VTE in other cancers, but their contribution with glioma is unclear.6 ►Table 1 summarizes the risk factors for VTE in patients with brain tumors.
Pathophysiology Patients with cancer, including brain tumors, have alterations in homeostatic mechanisms of coagulation and fibrinolysis, predisposing them to a hypercoagulable state. Tissue factor (TF) or thromboplastin is a potent procoagulant that is vital in both physiological and pathological coagulation. Upregulation of TF and its downstream effectors leads not only to activation of clotting factors but also stimulation of oncogenic signaling mechanisms important for cancer progression.18
Activation of the Coagulation Cascade TF is considered to be the main initiator of the extrinsic coagulation cascade. With endothelial damage, TF is exposed to the circulation, leading to binding and activation of factor VII, which then converts factor X into Xa, resulting in thrombin formation.19 TF is upregulated in cancer development,
causing dysregulation of the normally tightly controlled coagulation system. Tumor and tumor-associated endothelial cells are able to produce and release factors that influence activation of coagulation cascade, including VEGF, tissue-type plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1).14,20
TF and Its Oncogenic Influence in Glioma TF can be focally or widely expressed in glioma and is correlated with the histologic grade. It is overexpressed in more than 90% of HGG and 10 to 20% in low-grade glioma.21–23 Intravascular thrombosis may initiate the transition from anaplastic astrocytoma to GBM by triggering vaso-occlusion, causing tumor migration away from hypoxia, hypoxia-inducible factor–mediated VEGF secretion, adjacent angiogenesis (microvascular hyperplasia), and rapid peripheral tumor expansion. These cascades produce pseudopalisading necrosis and microvascular proliferation.23,24 TF expression is highest within the cells forming hypoxic pseudopalisades.23 Common genetic events in the progression of anaplastic astrocytoma to GBM, including phosphatase and tensin homolog (PTEN) loss (20–40% of GBM) and epidermal growth factor receptor (EGFR) amplification (40–50% of GBM), have been shown to increase TF expression.25 PTEN regulates the PI3-kinase/Akt/mTOR and Ras/MEK/ERK signaling pathways, capable of modulating TF expression under hypoxic conditions.23,25,26 EGFR-driven TF expression is associated with enhanced VEGF production and epithelialto-mesenchyme transition-like event, suggesting a role of TF in tumor initiation, tumor growth, angiogenesis, and metastasis.27
Biomarkers of Venous Thromboembolism Risk The factors and products of thrombogenesis are potential biomarkers for risk stratification of patients. In patients with HGG, plasma markers of activated coagulation and fibrinolytic pathways are elevated, including D-dimer, lipoprotein (a), homocysteine, tPA, and PAI-1.14,20 TF is typically bound to cell surface, as well as on the surface of submicron vesicles termed microparticles (MPs) that shed from the surface of intravascular cells, such as
Table 1 Risk factors for VTE in patients with brain tumor Generic factors
Patient factors Age > 75 y Obesity Blood types A and AB Leg paresis Multiple medical comorbidities • Prior thrombosis or pulmonary embolism
• Prolonged immobility • Presence of indwelling catheter
• • • • •
Disease-specific factors • Glioblastoma tumor subtype • Intraluminal thrombosis in pathologic specimen • Recurrent disease • Glioma size > 5 cm • Subtotal resection
Abbreviations: VEGF, vascular endothelial growth factor; VTE, venous thromboembolism. Seminars in Thrombosis & Hemostasis
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Treatment-related factors • Chemotherapy • Anti-VEGF therapy • Hormonal therapy
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platelets, endothelial cells, leukocytes, and tumor cells.19 MPTF concentration directly correlates with risk of VTE in variety of cancers, including GBM.6,19,28 Preliminary data suggest this may be true in GBM as well. Prospective evaluation of 61 patients with GBM who underwent gross total or subtotal resection followed by radiation and chemotherapy demonstrated higher glial-derived (glial fibrillary acidic protein [GFAP]) and/or TF-bearing MPs, compared with healthy controls, and the levels significantly increased after surgery especially in patients with subtotal resection. TF þ /GFAPMPs levels were significantly higher in GBM patients who developed VTE than in those who did not, and levels above 90th percentile were associated with higher risk of VTE.29 EGFRvIII is the most common EGFR mutation, with a prevalence of 20 to 30% in unselected GBM and 50 to 60% of patients with EGFR mutation.30 EGFRvIII mutation leads to upregulation of TF and VEGF production, inducing angiogenesis. MPs containing EGFRvIII messenger RNA can be detected in the serum.6,11,26,27,31 Serum levels of TF-bearing MPs can potentially serve as biomarker and therapeutic target.6,11 A potential agent that blocks TF-bearing MPs, Ixolaris, which is a tick anticoagulant has been investigated for this indication. This agent has been shown to effectively block in vitro TF-dependent procoagulant activity and tumorigenic potential in human GBM cell line, without observable bleeding. The antitumor activity is associated with downregulation of VEGF, preventing angiogenesis and merits further evaluation as an antitumor treatment in humans.32
Management: Treatment and Secondary Prophylaxis Concerns of increased risk of intracranial hemorrhage (ICH) with anticoagulation complicate the treatment of VTE in patients with brain tumors. Therefore, careful evaluation of the risk of bleeding and choice of treatment are essential.
Assessment of Risk of Bleeding and Initiation of Treatment About 2% of patients with HGG develop symptomatic intratumoral hemorrhage in the absence of antithrombotic treatment, which is similar to its incidence of HGG patients receiving anticoagulants (1.9%) in one study.33 In another study, all 22 HGG patients treated with intravenous heparin followed by either subcutaneous heparin or oral warfarin for late postoperative VTE did not develop bleeding complications.34 These studies suggest that antithrombotic treatment does not increase the risk of ICH in HGG patients.33,34 In patients with brain metastases, 2 out of 51 patients developed fatal ICH in the setting of supratherapeutic anticoagulation with warfarin.35 Brain metastases from melanoma, choriocarcinoma, thyroid carcinoma, and renal carcinoma have high propensity for spontaneous bleeding (up to 70%), thus the use of anticoagulation is generally not advisable.10 Challenging this dogma, a recent study utilizing anticoagulation in melanoma patients with brain metastases and VTE found no significant increase risk of ICH or decrease in overall survival.36 However, the subsequent VTE events, VTE hospi-
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talization, or PE were not reported in this retrospective study.37 Metastases from solid tumors, including breast and lung cancers, have a relatively low incidence of spontaneous hemorrhage and anticoagulation can be safely administered.10 The presence of blood products in the surgical cavity of postoperative brain tumor patients is a common finding and is not a contraindication for initiating antithrombotic treatment.10 A systematic review indicated increased risk of ICH when preoperative correction of coagulation abnormalities was inadequate, when anticoagulation is initiated as early as 24 to 48 hours, and when anticoagulation exceeds therapeutic levels.38 This review does not advocate reinstitution of anticoagulation in the first 24 to 48 hours after intracranial procedure. Moreover, intravenous heparin should be given by continuous infusion rather than bolus to prevent likelihood of supratherapeutic levels.38 In contrast, a recent study involving 555 high-risk neurosurgical patients (20% had brain tumors) showed subcutaneous prophylactic heparin given 5,000 U twice daily, initiated as early as either 24 or 48 hours postoperatively, and was associated with a 43% decreased of developing deep vein thrombosis, without increase of surgical site hemorrhage.39 A randomized, double-blind study demonstrated prophylactic dosing of subcutaneous heparin and enoxaparin initiated on first day postcraniotomy is safe and effective in preventing VTE in patients with brain tumors.40 Most data demonstrate safe use of prophylactic anticoagulation even as a bolus, given as early as 24 hours postsurgery. Anticoagulation is generally avoided in patients with history of previous ICH, bleeding diathesis, thrombocytopenia (< 50,000/µL), coagulopathy, or ongoing life-threatening extracranial bleeding.7,41 Thrombolytic agents for life-threatening pulmonary embolism are absolutely contraindicated in patients with brain tumors.6 Concerns regarding compliance, blood test monitoring, and fall risk should be taken into consideration before the decision to initiate treatment.10 Neuroimaging before anticoagulation is debated, although its use to screen the presence of hemorrhage is widely accepted. Noncontrast head computed tomography, which is readily available and easily performed, is generally recommended for patients whose brain tumors have high propensity for spontaneous bleeding, including melanoma, small cell lung carcinoma, choriocarcinoma, renal cell carcinoma, and thyroid carcinoma. In patients with these types of primary malignancy without known brain metastasis, cranial magnetic resonance imaging to search for occult metastases may be prudent before anticoagulation. The need for neuroimaging in patients with other types of malignancies without neurologic symptoms remains controversial.7,41
Inferior Vena Cava Filter Inferior vena cava (IVC) filters were historically favored over anticoagulation in the treatment of VTE for patients with brain tumors. However, recent studies suggest their use is associated with a high frequency of complications, including procedure-associated morbidity (pneumothorax, infection, bleeding, IVC wall damage), and thrombotic events (recurrent Seminars in Thrombosis & Hemostasis
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PE in 12%, IVC or filter thrombosis in 26%, postphlebitic syndrome in 10%), severely reducing the quality of life of these patients.42 Recurrent VTE is reported in 40% in patients with brain metastases treated with IVC filters.35 Due to these complications, IVC filter is best reserved for patients with an absolute contraindication to anticoagulation.10
Anticoagulation Anticoagulation, including unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or warfarin, is recommended in the initial and long-term treatment for established VTE in patients with primary brain tumors. In the recent American Society of Clinical Oncology guideline, recommendations for patients with primary CNS malignancies with established VTE are similar to other patients with cancer.43 ►Table 2 summarizes the options for treatment and prophylaxis of VTE in brain tumor patients. For initial treatment, LMWH is preferred over UFH for the initial 5 to 10 days in patients with newly diagnosed VTE without renal impairment.43 UFH is reserved for patients with symptomatic PE, those with renal insufficiency and for highrisk patients, because of its shorter half-life and more complete reversibility with protamine compared with LMWH.4,43 For long-term anticoagulation, Food and Drug Administration (FDA)-approved agents include LMWH and warfarin.43 Proper use of warfarin has been reported to be reasonably safe in patients with brain tumors.10,33,35 However, patients with brain tumors often take medications that commonly interact with warfarin, including cimetidine or omeprazole, trimethoprim-sulfamethoxazole, and antiepileptic drugs such as phenytoin.10,44 Due to warfarin’s significant drug– drug interactions and the need for frequent blood monitoring, LMWH has been increasingly used in this population for treatment and prevention of VTE. LMWH also has better bioavailability, longer half-life, and a more predictable dose response, but is more expensive than warfarin.4,41,45 Commonly used LMWHs for the treatment of VTE are enoxaparin, dalteparin, and tinzaparin.4,45 The use of LMWH is safe to use without associated increased risk of major bleeding, even when initiated within 24 hours after surgery.46,47 Randomized data directly comparing LMWH to heparin in a brain tumor population are still lacking. The CLOT trial randomized 673 patients with VTE (34 brain tumors and an unknown number of brain metastasis) to either LMWH or oral anticoagulation. LMWH was more effective in reducing recurrent
VTE without increasing the risk of bleeding. However, the study was not designed to assess the risk of intracranial hemorrhage.48 Fondaparinux, an indirect factor Xa, has been used for initial and maintenance treatment in small number of patients with cancer, and may be an alternative for patients with heparin-induced thrombocytopenia (HIT). However, it is currently not approved by FDA for this indication.43 The duration of anticoagulation treatment depends on the continued presence of factors predisposing patients to hypercoagulability. An indefinite duration of treatment is generally recommended for HGG patients, those who have residual brain tumor, or active systemic malignancy. In patients who are no longer considered at risk for increased hypercoagulability, such as those with grossly resected meningioma, primary CNS lymphoma with complete response, malignancies with durable response to chemotherapy, and metastatic germ cell tumors fully treated with chemotherapy, treatment duration ranges from 6 to 12 months.4,10 Novel oral anticoagulants that directly inhibit thrombin such as dabigatran or factor Xa, including rivaroxaban and apixaban have the advantage of being administered orally, not requiring laboratory monitoring, and infrequent dose adjustment. These agents can effectively prevent VTE following major orthopedic surgery or stroke from nonvalvular atrial fibrillation.11 Apixaban given for 12 weeks appeared to be well tolerated and acceptable for prevention of VTE in ambulatory patients with advanced metastatic cancer undergoing first- or second-line chemotherapy.49 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.43 The lack of antidote, absence of standard assays to measure its anticoagulant activity, and drug interaction with chemotherapeutic agents are additional concerns in using these agents in patients with cancer.43 These oral anticoagulants, nevertheless can be used in patients with HIT.4,10
Role of Primary Prevention The risk of perioperative VTE is high with a reported incidence of 7.5% after resection of primary brain tumor and 19% for metastatic cancer.50 A multimodality approach utilizing anticoagulation with either LMWH or UFH 5,000 units given twice a day, in combination with graduated compression
Table 2 Treatment and prophylaxis of VTE in patients with brain tumors4,43 Initial treatment
Secondary prophylaxis
• UFH: 80 U/kg IV bolus, then 18 U/kg per hour IV, dose adjusted based on aPTT • Dalteparin: 200 U/kg once daily or 100 U/kg, every 12 h (mo 1) • Enoxaparin: 1.5 mg/kg once daily or 1 mg/kg every 12 h • Tinzaparin: 175 U once daily
• Warfarin: Adjusted based on INR • Dalteparin: Decrease to 150 U/kg once daily (mo 2–6) • Enoxaparin: 40 mg, daily, 1.5 mg/kg once daily or 1 mg/kg every 12 h • Tinzaparin: 175 U once daily
Abbreviation: aPTT, activated partial thromboplastin time; mo, months; IV, intravenous; VTE, venous thromboembolism.
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stocking and intermittent pneumatic compression, is effective and safe to reduce VTE during perioperative period.40,51 Since the risk of VTE in patients with brain tumor persists throughout the disease course, the efficacy and safety of anticoagulation for primary prophylaxis in newly diagnosed HGG have been investigated. Two small prospective phase II studies demonstrated anticoagulation using LMWH in newly diagnosed GBM patients was safe, with no reported grade 3 or 4 bleeding and no thromboembolic events.52,53 The efficacy of primary prophylaxis in patients with malignant glioma was then evaluated in the phase III PRODIGE study. Patients were randomized to receive either dalteparin or placebo with the primary outcome of 6-month VTE survival. There was a trend toward reduced VTE in treatment group (11 vs. 7%); however, ICH was more common in patients who received anticoagulation than in the placebo cohort (5 vs. 1%). This trial was terminated prematurely due to expiration of study drug and therefore no definite conclusion can be made due to inadequate statistical power.8 With limited high-quality data, primary prophylaxis beyond the postoperative period in patients with brain tumors is currently not recommended.
Anticoagulation as Antineoplastic Therapy Certain components of the clotting cascade and the associated vascular factors have been postulated to play important roles in tumor progression, invasion, angiogenesis, and metastasis.54 It has been reported that anticoagulants exert antineoplastic effects through inhibition of primary tumor growth, reduction of tumor motility, inhibition of tumor cell migration, reduction of metastases potential, enhancement of antitumor effects of chemotherapy; they also prolong survival of laboratory animals after tumor cell inoculation.54 The precise mechanism remains elusive but evidence supports antiangiogenesis by inhibition of VEGF and basic fibroblast growth factor, antiproliferative effects and induction of differentiation and apoptosis, reduction of tumor invasiveness by inhibition of heparinases, and other extracellular matrix components, as well as blockage of adhesion molecules such as Pand L-selectins, and enhancement of natural killer cells through increased activity of tumor necrosis factor and interferon.6,54 A meta-analysis demonstrated that anticoagulants, particularly LMWH, significantly improve overall survival of cancer patients without venous thrombosis but with greater risk of bleeding complications.55 In the newly diagnosed GBM population, dalteparin given daily with and after traditional radiotherapy did not show a significant survival benefit between treatment and control groups.52 Given the data available, the use of anticoagulants as an anticancer agent is not currently recommended.
Thromboembolic Complications in the Era of Antiangiogenic Therapies Vascular events, including venous and arterial thrombosis, as well as hemorrhage are known complications of antiangiogenic treatments.56,57 Bevacizumab, a humanized monoclonal antibody that binds VEGF, is a FDA-approved therapy for
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recurrent GBM.58 Inhibition of VEGF may induce thrombosis by increasing endothelial cell apoptosis, which disturbs the endothelial lining and exposes underlying procoagulant factors.59 In addition, bevacizumab immune complexes activate platelets via Fc gamma RIIa receptor, leading to induction of platelet aggregation, degranulation, and thrombosis.60 In the BRAIN study, which included 163 recurrent GBM patients treated with either bevacizumab alone or in combination with CPT-11, grades 3 to 5 VTE occurred in 3 to 9% and arterial thrombotic events (ATE) in 3% of patients.61 The risk of bleeding further complicates the treatment of VTE in patients receiving anti-VEGF treatment. Grade 3 or 4 overall hemorrhage occurred in approximately 3% and ICH in 1.3% of patients in the BRAIN study.61 A large retrospective study involving 282 bevacizumab-treated glioma patients, 64 of whom received anticoagulation, demonstrated increased risk of hemorrhage in 20% of patients. Intracerebral hemorrhage accounts for 11%, for which 3% were grade 4 and most were asymptomatic. For patients who did not receive anticoagulation, 1% of patients suffered grade 4 intracranial bleeding.57 In another retrospective study involving 21 HGG patients who received bevacizumab and anticoagulation concurrently, 3 patients had small intraparenchymal hemorrhages, but only 1 was symptomatic.62 Taken together, current evidence suggests that although the risk of intracranial hemorrhage increases with anticoagulation during bevacizumab therapy in HGG patients, the majority of these events are asymptomatic, and the risk-to-benefit ratio favors treatment.41 For patients who develop ATE such as cerebrovascular disease, transient ischemic attack, angina, myocardial infarction, or peripheral vascular occlusion, antiangiogenic agents should be stopped and treatment is guided based on the specific disease process.56
Conclusion VTE commonly occurs in patients with brain tumor and contributes to morbidity and mortality. The risk is high in the perioperative period and remains elevated throughout the disease course. Certain disease factors such as GBM histology and treatment factors, including anti-VEGF treatment, increase the risk of VTE. TF is expressed in glioma, particularly in HGGs, and activates the coagulation pathways, as well as oncogenic mechanisms important in tumor progression. Management of VTE entails balanced evaluation of the risk of hemorrhage versus treatment efficacy. Anticoagulation, particularly LWMH, is generally safe and is recommended for secondary prophylaxis in patients with brain tumors. IVC filters are associated with higher complication rates and advisable only for patients who have absolute contraindications to anticoagulation. The risk of ICH may outweigh the benefit of primary thromboprophylaxis in patients with HGG and is currently not recommended. However, in the perioperative setting, anticoagulation in combination with mechanical compression or antiembolic stockings is safe and effective in reducing the incidence of VTE. Antiangiogenic agents such as bevacizumab increase the risk of venous and arterial thromboembolism. Despite the Seminars in Thrombosis & Hemostasis
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feared risk of hemorrhage, the risk-benefit ratio favors anticoagulation in patients who developed VTE while on anti-VEGF treatment. Serum biomarkers may play an important role in identifying patients at a greater risk of developing VTE and would benefit from preventive anticoagulation. Emerging data show a potential antineoplastic role of anticoagulants, which could become a novel anticancer treatment for HGG.
19 Kocatürk B, Versteeg HH. Tissue factor-integrin interactions in
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References 1 Sørensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of
2
3
4
5
6 7 8
9
10
11 12
13
14
15
16
17
18
cancers associated with venous thromboembolism. N Engl J Med 2000;343(25):1846–1850 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 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 Drappatz J, Schiff D, Kesari S, Norden AD, Wen PY. Medical management of brain tumor patients. Neurol Clin 2007;25(4): 1035–1071, ix 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 Jenkins EO, Schiff D, Mackman N, Key NS. Venous thromboembolism in malignant gliomas. J Thromb Haemost 2010;8(2):221–227 Lacy J, Saadati H, Yu JB. Complications of brain tumors and their treatment. Hematol Oncol Clin North Am 2012;26(4):779–796 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 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 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 Perry JR. Thromboembolic disease in patients with high-grade glioma. Neuro-oncol 2012;14(Suppl 4):iv73–iv80 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 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 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 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 Dhami MS, Bona RD, Calogero JA, Hellman RM. Venous thromboembolism and high grade gliomas. Thromb Haemost 1993;70(3): 393–396 Perry JR. Anticoagulation of malignant glioma patients in the era of novel antiangiogenic agents. Curr Opin Neurol 2010;23(6): 592–596 Anand M, Brat DJ. Oncogenic regulation of tissue factor and thrombosis in cancer. Thromb Res 2012;129(Suppl 1):S46–S49
Seminars in Thrombosis & Hemostasis
Vol. 40
No. 3/2014
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cancer and thrombosis: every Jack has his Jill. J Thromb Haemost 2013;11(Suppl 1):285–293 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 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 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 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 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 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 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 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 Geddings JE, Mackman N. Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients. Blood 2013;122(11):1873–1880 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 Gan HK, Kaye AH, Luwor RB. The EGFRvIII variant in glioblastoma multiforme. J Clin Neurosci 2009;16(6):748–754 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 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 Ruff RL, Posner JB. Incidence and treatment of peripheral venous thrombosis in patients with glioma. Ann Neurol 1983;13(3): 334–336 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 Schiff D, DeAngelis LM. Therapy of venous thromboembolism in patients with brain metastases. Cancer 1994;73(2):493–498 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 Uchino K. The balance of risk of bleeding and thrombosis in melanoma patients with brain metastases. Melanoma Res 2013; 23(1):82 Lazio BE, Simard JM. Anticoagulation in neurosurgical patients. Neurosurgery 1999;45(4):838–847, discussion 847–848 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
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
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Jo et al.
40 Goldhaber SZ, Dunn K, Gerhard-Herman M, Park JK, Black PM. Low
50 Chan AT, Atiemo A, Diran LK, et al. Venous thromboembolism
rate of venous thromboembolism after craniotomy for brain tumor using multimodality prophylaxis. Chest 2002;122(6):1933–1937 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 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 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 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 Bates SM, Ginsberg JS. Clinical practice. Treatment of deep-vein thrombosis. N Engl J Med 2004;351(3):268–277 Monreal M, Zacharski L, Jiménez JA, Roncales J, Vilaseca B. Fixeddose 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 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 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 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
occurs frequently in patients undergoing brain tumor surgery despite prophylaxis. J Thromb Thrombolysis 1999;8(2): 139–142 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 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 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 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 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 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 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 Avastin [package insert]. San Francisco, CA: Genentech USA, Inc.; 2011 Kamba T, McDonald DM. Mechanisms of adverse effects of antiVEGF therapy for cancer. Br J Cancer 2007;96(12):1788–1795 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 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 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
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Thrombosis in Brain Tumors
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