Endothelial Dysfunction in Antiangiogenesis-Associated Thrombosis
Authors: Varsha Kaushal, Manish Kohli, Maurizio Zangari, Louis Fink, Paulette Mehta, Bart Kuenen, Giuseppe Giaccone
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.13.3042 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12089240 Endothelial Dysfunction in Antiangiogenesis-Associated Thrombosis Varsha KaushalxVarsha KaushalSearch for articles by this author , Manish KohlixManish KohliSearch for articles by this author , Maurizio ZangarixMaurizio ZangariSearch for articles by this author , Louis FinkxLouis FinkSearch for articles by this author , Paulette MehtaxPaulette MehtaSearch for articles by this author Bart KuenenxBart KuenenSearch for articles by this author , Giuseppe GiacconexGiuseppe GiacconeSearch for articles by this author Show More University of Arkansas for Medical Sciences, Central Arkansas Veterans Healthcare System, Little Rock, ARVrije Universiteit Medical Center, Amsterdam, the Netherlands https://doi.org/10.1200/JCO.2002.20.13.3042 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01072002In Reply:Mehta et al propose an interaction of the antiangiogenesis agent with subendothelium, which occurs after apoptosis of endothelium as a result of the cytostatic agents, in particular gemcitabine, as the common pathogenic pathway of thrombosis in patients receiving combination therapy. We have another hypothesis because gemcitabine alone does not induce apoptosis of endothelial cells.1 Only the tyrosine kinase inhibitor PKI166, which targets the epidermal growth factor receptor, alone and in combination with gemcitabine, does induce endothelial cell apoptosis.1 We hypothesize that endothelial cells become vulnerable during treatment with compounds that interfere with, for instance, vascular endothelial growth factor (VEGF) signaling, because VEGF, among other growth factors, induces the expression of antiapoptotic genes and proteins, such as bcl-2 and survivin.2 Subsequently, endothelial cells become probably procoagulant and in case of apoptosis, blood will be exposed to subendothelium and tissue factor, which is the trigger for activation of the coagulation cascade.It would be of great value to discriminate patients at risk for thrombotic and cardiovascular complications. There are several markers, such as von Willebrand's factor and vascular adhesion molecules (although there is a debate ongoing), that have predictive value in determining cardiovascular death, and which in our opinion provide information concerning the condition of the endothelium.3-8 We have determined von Willebrand's factor, soluble(s)-E-selectin, and soluble tissue factor in three of our study patients, two of whom developed a thromboembolic event.9 Normal levels of these parameters were found at the start of the treatment but increased significantly during the first and second cycle, indicating endothelial cell activation. We agree that it is necessary to screen and monitor endothelial cell parameters during antiangiogenesis therapy, especially when combined with cytotoxic agents.1. Bruns CJ, Solorzano CC, Harbison MT, et al: Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res 60:: 2926,2000-2935, Medline, Google Scholar2. Benjamin LE: The controls of microvascular survival. Cancer Metastasis Rev 19:: 75,2000-81, Crossref, Medline, Google Scholar3. Jager A, van Hinsbergh VW, Kostense PJ, et al: von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: The Hoorn Study. Arterioscler Thromb Vasc Biol 19:: 3071,1999-3078, Crossref, Medline, Google Scholar4. Blankenberg S, Rupprecht HJ, Bickel C, et al: Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation 104:: 1336,2001-1342, Crossref, Medline, Google Scholar5. Malik I, Danesh J, Whincup P, et al: Soluble adhesion molecules and prediction of coronary heart disease: A prospective study and meta-analysis. Lancet 358:: 971,2001-976, Crossref, Medline, Google Scholar6. Ballantyne CM: Soluble adhesion molecules and coronary heart disease. Lancet 359:525, discussion 526-527, 2002 Google Scholar7. Blann AD, Lip GY: Soluble adhesion molecules and cor-onary heart disease. Lancet 359:525-526, discussion 526-527, 2002 Google Scholar8. Cappuccio FP, Miller MA: Soluble adhesion molecules and coronary heart disease. Lancet 359:: 526,2002-527, Crossref, Medline, Google Scholar9. Kuenen BC, Rosen L, Smit EF, et al: Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. J Clin Oncol 20:: 1657,2002-1667, Link, Google Scholar