**2.5.2 Angiogenic Inhibitors and immunomodulatory agents**

a. Angiogenesis Inhibitors Associated with VTE:

Angiogenesis is a process involving the proliferation of new blood vessels and plays a central role in the growth and metastasis of cancer (85). The angiogenesis is driven mainly by the vascular endothelial growth factor (VEGF). The signaling pathway of VEGF has been a target of many angiogenesis inhibitors including bevacizumab, sorafenib and others (86- 87). Bevacizumab (Avastin, Genentech Inc., South San Francisco California) is a recombinant humanized monoclonal neutralizing antibody against VEGF has shown efficacy in treatment of many solid tumors including colorectal cancer, non-small cell lung cancer and renal cell carcinoma.

Shobha R Nalluri et al (88) in their metanalysis of 15 randomized controlled trials (RCTs) demonstrated that bevacizumab is associated with significantly higher risk of VTE (RR, 1.33[95% CI 1.13-1.56]; P<0.001) in patients with a variety of metastatic solid tumors and this risk is observed for all grades of VTE.

The thrombogenic effect of bevacizumab may be related to (a) its exposure of the subendothelial procoagulant layer and inhibition of the VEGF induced endothelial cell regeneration (89), (b) reduction of production of nitric oxide and prostacyclin by bevacizumab (90), (c) release of procoagulant molecules from the tumor cells into the circulation (91) and (d) increasing the haematocrit and blood viscosity via over production of erythropoietin (92).

b. Thalidomide and its derivative Lenalidomide are immunomodulatory agents with antiangiogenic properties through blockade of basic fibroblastic growth factor and VEGF and are associated with increased risk of VTE in cancer patients. This topic has been well covered in chapter 5 of this book by Drs Gonzalez-Porras and Mateos.
