Bevacizumab, Bleeding, Thrombosis, and Warfarin

Kılıçkap, Saadettin; Abalı, Hüseyin; Çeli̇k, İsmai̇l

doi:10.1200/jco.2003.99.046

Cited by 158 publications

(98 citation statements)

References 4 publications

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“…19 The mechanism of developing VTEs may result from the anti-VEGF effect of VEGFR-TKIs: VEGF not only stimulates endothelial cell proliferation, but also promotes endothelial cell survival and helps maintain vascular integrity. Inhibition of VEGF could thereby impair vascular integrity by diminishing the regenerative capacity of endothelial cell, and exposure of pro-coagulant phospholipids on the luminal plasma membrane or underlying matrix, leading to thrombosis 45 ; in addition, VEGF increases production of nitric oxide (NO) and prostacylin (PGI 2 , prostaglandin I 2 ), suppresses pathways involved in endothelial cell activation, apoptosis, and pro-coagulant changes, and inhibits proliferation of vascular smooth muscle cells. 46 Reduction in NO and PGI 2 after inhibition of VEGF signaling may predispose to thrombosis.…”

Section: Discussionmentioning

confidence: 99%

Risk of venous thromboembolic events associated with VEGFR‐TKIs: A systematic review and meta‐analysis

Min

Shen

et al. 2012

Intl Journal of Cancer

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Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have been widely used in advanced cancers. Concerns have arisen regarding the risk of venous thromboembolism with the use of these drugs. Currently, the contribution of VEGFR-TKIs to venous thromboembolism is still unknown. We performed a meta-analysis to determine the incidence and relative risk (RR) of venous thromboembolism events (VTEs) associated with these agents. Eligible studies included phase II and III prospective trials evaluating US Food and Drug Administration approved VEGFR-TKIs (pazopanib, sunitinib, sorafenib and vandetanib), and data on VTEs were available. Overall incidence rates, RR and 95% confidence intervals (CI) were calculated employing fixed-or random-effects models depending on the heterogeneity of included trials. A total of 14 studies (4,430 patients) were selected for this meta-analysis. The incidence of VTEs related to VEGFR-TKIs was 3% (95%CI: 1.7-5.1%), and there was no statistically significant increase in the risk of VTEs for VEGFR-TKIs versus controls in overall population (RR0.912, 95%CI: 0.617-1.348, p 5 0.643). On subgroup analysis, no significant increase in the risk of VTEs was found among different VEGFR-TKIs or tumor types. No evidence of publication bias was observed. The use of VEGFRTKIs does not significantly increase the risk of VTEs, the risk of VTEs in patients with cancer is driven predominantly by tumor types, host factors and concomitant usage of anticancer agents. These results would provide important information for clinicians who use VEGFR-TKIs to treat patients with solid cancer.

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Section: Discussionmentioning

confidence: 99%

Risk of venous thromboembolic events associated with VEGFR‐TKIs: A systematic review and meta‐analysis

Min

Shen

et al. 2012

Intl Journal of Cancer

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“…Vascular endothelial growth factor not only stimulates endothelial cell proliferation, but also promotes endothelial cell survival and helps maintain vascular integrity. Inhibition of VEGF could thereby diminish the regenerative capacity of endothelial cells and cause defects that expose pro-coagulant phospholipids on the luminal plasma membrane or underlying matrix, leading to thrombosis or haemorrhage (Kilickap et al, 2003). Vascular endothelial growth factor increases production of NO and prostacyclin (PGI 2 , prostaglandin I 2 ), suppresses pathways involved in endothelial cell activation, apoptosis, and pro-coagulant changes, and inhibits proliferation of vascular smooth muscle cells (Zachary, 2001).…”

Section: Haemorrhage and Thrombosismentioning

confidence: 99%

Mechanisms of adverse effects of anti-VEGF therapy for cancer

2007

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Advances in understanding the role of vascular endothelial growth factor (VEGF) in normal physiology are giving insight into the basis of adverse effects attributed to the use of VEGF inhibitors in clinical oncology. These effects are typically downstream consequences of suppression of cellular signalling pathways important in the regulation and maintenance of the microvasculature. Downregulation of these pathways in normal organs can lead to vascular disturbances and even regression of blood vessels, which could be intensified by concurrent pathological conditions. These changes are generally manageable and pose less risk than the tumours being treated, but they highlight the properties shared by tumour vessels and the vasculature of normal organs.

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“…The impairment of endothelial regeneration induced by VEGF inhibition allows platelets and coagulation factors, in particular tissue factor and von Willebrand factor, to be exposed to the subendothelial procoagulant phospholipids in the basement membrane, resulting in activation the hemostatic system [53]. Other downstream effects of VEGF include involvement in the production of prostacyclin and NO by endothelial cells, both of which have antiplatelet actions and result in the promotion of thrombosis when inhibited [69].…”

Section: Pathogenesismentioning

confidence: 99%

“…VEGF has a maintenance role for normal endothelium [52]. The current hypothesis is that inhibition of VEGF decreases the renewal capacity of endothelial cells, making vessels weak and susceptible to further damage induced by trauma, inducing bleeding [53]. Inhibition of VEGF also induces nonphysiological apoptosis (rare in normostatic states) of endothelial cells, increasing susceptibility for hemorrhage [52].…”

Section: Pathogenesismentioning

confidence: 99%

Noncardiac Vascular Toxicities of Vascular Endothelial Growth Factor Inhibitors in Advanced Cancer: A Review

et al. 2011

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Summary. The introduction of molecularly targeted anticancer therapies has brought the promise of longer survival times for select patients with cancers previously considered untreatable. However, it has also brought new toxicities that require understanding and management, sometimes for long periods of time. Vascular endothelial growth factor inhibitors are associated with a broad range of adverse effects, with vascular toxicity being particularly serious. This review focuses on the current understanding of the pathophysiology and mechanisms of macrovascular toxicities (hypertension, hemorrhage, and thromboembolism), their incidence and severity, the current clinical management, and implications in the advanced cancer setting. Movement of these agents into the early disease setting will alter the impact of these toxicities.Search Strategy and Selection Criteria. Information for this review was collected by searching PubMed/ Medline and American Society of Clinical Oncology abstract databases. The medical subject heading terms used included toxicity, hypertension, thromboembolism, hemorrhage, intestinal perforation, risk factors, pharmacokinetics, and metabolism, combined with free text search terms including, but not limited to, VEGF inhibitor*, bevacizumab, sunitinib, and sorafenib. Articles published in English before March 2010 were included, in addition to information from case reports and pharmaceutical agent package inserts. The Oncologist 2011;16:432-444

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Bevacizumab, Bleeding, Thrombosis, and Warfarin

Cited by 158 publications

References 4 publications

Risk of venous thromboembolic events associated with VEGFR‐TKIs: A systematic review and meta‐analysis

Risk of venous thromboembolic events associated with VEGFR‐TKIs: A systematic review and meta‐analysis

Mechanisms of adverse effects of anti-VEGF therapy for cancer

Noncardiac Vascular Toxicities of Vascular Endothelial Growth Factor Inhibitors in Advanced Cancer: A Review

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