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CC BY 4.0 · TH Open 2025; 09: a25134381
DOI: 10.1055/a-2513-4381
Original Article

Vascular Endothelial Growth Factor (VEGF) as a Biomarker for Cancer-Associated Venous Thrombosis: A Meta-analysis

Alison M. Brown
1   Department of Blood Sciences, The Newcastle upon Tyne Hospitals NHS Foundation Trust, United Kingdom
2   Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, United Kingdom
,
Sophie Nock
2   Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, United Kingdom
,
Kathryn Musgrave
3   Haematology Department, The Newcastle upon Tyne Hospitals NHS Foundation Trust, United Kingdom
,
Amanda J. Unsworth 
4   Thrombosis Collective, Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
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Abstract

Cancer-associated thrombosis affects between 1 and 20% of all patients diagnosed with cancer and is associated with significant morbidity and a poorer prognosis. Risk assessment scores exist which include the measurement of biomarkers, and which aim to identify patients at a higher risk of developing thrombotic events, but these are poor predictors and rarely used in routine clinical practice.

VEGF is a potent angiogenic factor, produced by tumour cells, and released by platelets and is essential for tumour growth and progression. It also plays a role in the promotion of thrombosis through platelet activation and adhesion, and by inducing the expression of tissue factor. Therefore, the potential of VEGF to be used as a biomarker to predict cancer-associated thrombosis requires further investigation.

This study reviewed the published literature to determine whether circulating VEGF levels are associated with increased risk of venous thromboembolism in patients with cancer.

PubMed and OVID databases were systematically searched according to PRISMA guidelines for relevant papers using the keywords “cancer” AND “thrombosis” AND “VEGF” up to July 2023. Inclusion and exclusion criteria were applied.

Seven papers (1,528 participants) were identified and included in the meta-analysis, three of which (922 participants) measured VEGF before a thrombotic event, and the remaining four (606 participants) measured VEGF at the time of the thrombosis. Our results showed that although plasma and serum VEGF tended to be higher in those who subsequently developed thrombosis than those who did not (mean difference 70.2 pg/mL for serum, and 11.44 pg/mL for plasma VEGF, 95% CI −2.39–25.73, p = 0.10), this was not found to be statistically significant. However, analysis of VEGF following blood sampling at the time of thrombosis showed a stronger statistically significant association between increased VEGF levels and presence of thrombosis (mean difference 117.02 pg/mL for serum, and 116.6 pg/mL for plasma VEGF, 95% CI 55.42–190.82, p = 0.0004).

Based on current studies, whilst it is increased at the time of thrombosis, VEGF is not effective as a predictive biomarker of CAT.

Keywords

VEGF - cancer - thrombosis - biomarker

Authors' Contributions

A.M.B., K.M., and A.J.U. were responsible for the conceptualization of the study, while resources were provided by A.M.B. The original draft was prepared by A.M.B. and A.J.U., with review and editing contributions from A.M.B., S.N., K.M., and A.J.U. Visualization was carried out by A.M.B., and the project was supervised by K.M. and A.J.U. Project administration and funding acquisition were managed by A.M.B. All authors have reviewed, read, and approved the final version of the manuscript. Furthermore, none of the authors have any competing interests to declare.




Publication History

Received: 25 May 2024

Accepted: 06 January 2025

Accepted Manuscript online:
10 January 2025

Article published online:
10 February 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

Bibliographical Record
Alison M. Brown, Sophie Nock, Kathryn Musgrave, Amanda J. Unsworth. Vascular Endothelial Growth Factor (VEGF) as a Biomarker for Cancer-Associated Venous Thrombosis: A Meta-analysis. TH Open 2025; 09: a25134381.
DOI: 10.1055/a-2513-4381
 

  • References

  • 1 Dogan M, Demirkazik A. Venous thromboembolism in patients with cancer and its relationship to the coagulation cascade and vascular endothelial growth factor. Support Cancer Ther 2005; 3 (01) 28-34
    Search in Google Scholar
  • 2 Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006; 166 (04) 458-464
    Search in Google Scholar
  • 3 van Es N, Di Nisio M, Cesarman G. et al. Comparison of risk prediction scores for venous thromboembolism in cancer patients: a prospective cohort study. Haematologica 2017; 102 (09) 1494-1501
    Search in Google Scholar
  • 4 Lyman GH, Carrier M, Ay C. et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv 2021; 5 (04) 927-974
    Search in Google Scholar
  • 5 Watson HG, Keeling DM, Laffan M, Tait RC, Makris M. British Committee for Standards in Haematology. Guideline on aspects of cancer-related venous thrombosis. Br J Haematol 2015; 170 (05) 640-648
    Search in Google Scholar
  • 6 Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111 (10) 4902-4907
    Search in Google Scholar
  • 7 Ay C, Dunkler D, Marosi C. et al. Prediction of venous thromboembolism in cancer patients. Blood 2010; 116 (24) 5377-5382
    Search in Google Scholar
  • 8 Moik F, Ay C, Pabinger I. Risk prediction for cancer-associated thrombosis in ambulatory patients with cancer: past, present and future. Thromb Res 2020; 191 (Suppl. 01) S3-S11
    Search in Google Scholar
  • 9 Li X, Feng G-S, Zheng C-S, Zhuo C-K, Liu X. Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol 2004; 10 (19) 2878-2882
    Search in Google Scholar
  • 10 Dogan M, Demirkazik A, Konuk N. et al. The effect of venous thromboembolism on survival of cancer patients and its relationship with serum levels of factor VIII and vascular endothelial growth factor: a prospective matched-paired study. Int J Biol Markers 2006; 21 (04) 206-210
    Search in Google Scholar
  • 11 Posch F, Thaler J, Zlabinger GJ. et al. Soluble vascular endothelial growth factor (sVEGF) and the risk of venous thromboembolism in patients with cancer: result from the Vienna cancer and thrombosis study. Clin Cancer Res 2016; 22 (01) 200-206
    Search in Google Scholar
  • 12 Salven P, Orpana A, Joensuu H. Leukocytes and platelets of patients with cancer contain high levels of vascular endothelial growth factor. Clin Cancer Res 1999; 5 (03) 487-491
    Search in Google Scholar
  • 13 Wang Y, Zhang Z, Tao P, Reyila M, Qi X, Yang J. The abnormal expression of miR-205-5p, miR-195-5p, and VEGF-A in human cervical cancer is related to the treatment of venous thromboembolism. BioMed Res Int 2020; 2020: 3929435
    Search in Google Scholar
  • 14 Page MJ, McKenzie JE, Bossuyt PM. et al. Updating guidance for reporting systematic reviews: development of the PRISMA 2020 statement. J Clin Epidemiol 2021; 134: 103-112
    Search in Google Scholar
  • 15 Kirwan CC, McDowell G, McCollum CN, Kumar S, Byrne GJ. Early changes in the haemostatic and procoagulant systems after chemotherapy for breast cancer. Br J Cancer 2008; 99 (07) 1000-1006
    Search in Google Scholar
  • 16 Kirwan CC, Byrne GJ, Kumar S, McDowell G. Platelet release of vascular endothelial growth factor (VEGF) in patients undergoing chemotherapy for breast cancer. J Angiogenes Res 2009; 1 (01) 7
    Search in Google Scholar
  • 17 Wells GA, Shea B, O'Connell D. et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2021 . Assessed November 18, 2023 at: https://ohri.ca/programs/clinical_epidemiology/oxford.asp
    Search in Google Scholar
  • 18 Page MJ, Sterne JAC, Boutron I. et al. ROB-ME: a tool for assessing risk of bias due to missing evidence in systematic reviews with meta-analysis. BMJ 2023; 383: e076754
    Search in Google Scholar
  • 19 Cacciola RR, Di Francesco E, Giustolisi R, Cacciola E. Elevated serum vascular endothelial growth factor levels in patients with polycythemia vera and thrombotic complications. Haematologica 2002; 87 (07) 774-775
    Search in Google Scholar
  • 20 Nazari PMS, Marosi C, Moik F. et al. Low systemic levels of chemokine C–C motif ligand 2 (CCL3) are associated with a high risk of venous thromboembolism in patients with glioma. Cancers (Basel) 2019; 11 (12) 2020
    Search in Google Scholar
  • 21 Musolino C, Calabro' L, Bellomo G. et al. Soluble angiogenic factors: implications for chronic myeloproliferative disorders. Am J Hematol 2002; 69 (03) 159-163
    Search in Google Scholar
  • 22 Kim SJ, Choi IK, Park KH. et al. Serum vascular endothelial growth factor per platelet count in hepatocellular carcinoma: correlations with clinical parameters and survival. Jpn J Clin Oncol 2004; 34 (04) 184-190
    Search in Google Scholar
  • 23 Ramadan HK, Meghezel EM, Abdel-Malek MO. et al. Correlation between vascular endothelial growth factor and long-term occurrence of HCV-related hepatocellular carcinoma after treatment with direct-acting antivirals. Cancer Invest 2021; 39 (08) 653-660
    Search in Google Scholar
  • 24 Malaponte G, Signorelli SS, Bevelacqua V. et al. Increased levels of NF-kB-dependent markers in cancer-associated deep venous thrombosis. PLoS One 2015; 10 (07) e0132496
    Search in Google Scholar
  • 25 Khorana AA, Ahrendt SA, Ryan CK. et al. Tissue factor expression, angiogenesis, and thrombosis in pancreatic cancer. Clin Cancer Res 2007; 13 (10) 2870-2875
    Search in Google Scholar
  • 26 Zhang Y, Deng Y, Luther T. et al. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. J Clin Invest 1994; 94 (03) 1320-1327
    Search in Google Scholar
  • 27 Echrish H, Madden LA, Greenman J, Maraveyas A. The hemostasis apparatus in pancreatic cancer and its importance beyond thrombosis. Cancers (Basel) 2011; 3 (01) 267-284
    Search in Google Scholar
  • 28 Verheul HM, Hoekman K, Luykx-de Bakker S. et al. Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 1997; 3 (12 Pt 1): 2187-2190
    Search in Google Scholar
  • 29 D'Souza A, Hayman SR, Buadi F. et al. The utility of plasma vascular endothelial growth factor levels in the diagnosis and follow-up of patients with POEMS syndrome. Blood 2011; 118 (17) 4663-4665
    Search in Google Scholar
  • 30 Kraft A, Weindel K, Ochs A. et al. Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer 1999; 85 (01) 178-187
    Search in Google Scholar
  • 31 Cohen AT, Spiro TE, Spyropoulos AC. et al; MAGELLAN Study Group. D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled MAGELLAN trial. J Thromb Haemost 2014; 12 (04) 479-487
    Search in Google Scholar
  • 32 Tan X, Chen G, Liu Y. et al. Serum D-dimer is a potential predictor for thromboembolism complications in patients with renal biopsy. Sci Rep 2017; 7 (01) 4836
    Search in Google Scholar
  • 33 Hansen E-S, Rinde FB, Edvardsen MS. et al. Elevated plasma D-dimer levels are associated with risk of future incident venous thromboembolism. Thromb Res 2021; 208: 121-126
    Search in Google Scholar
  • 34 Linkins L-A, Takach Lapner S. Review of D-dimer testing: good, bad, and ugly. Int J Lab Hematol 2017; 39 (Suppl. 01) 98-103
    Search in Google Scholar
  • 35 Verso M, Agnelli G, Barni S, Gasparini G, LaBianca R. A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: the Protecht score. Intern Emerg Med 2012; 7 (03) 291-292
    Search in Google Scholar
  • 36 Swamy S, Ueland T, Hansen J-B, Snir O, Brækkan SK. Plasma levels of P-selectin and future risk of incident venous thromboembolism. J Thromb Haemost 2023; 21 (09) 2451-2460
    Search in Google Scholar