Effect of intravitreal injection of aflibercept on blood coagulation parameters in patients with age-related macular degeneration

Constantinos D Georgakopoulos, Olga E Makri, Athina Pallikari, Konstantinos Kagkelaris, Panagiotis Plotas, Vasiliki Grammenou, Andreas Emmanuil, Constantinos D Georgakopoulos, Olga E Makri, Athina Pallikari, Konstantinos Kagkelaris, Panagiotis Plotas, Vasiliki Grammenou, Andreas Emmanuil

Abstract

Purpose: Treatment with intravitreal injections of anti-vascular endothelial growth factor agents has been associated with an increased risk of arterial thromboembolic events. The aim of the present pilot study was to assess the effect of a single intravitreal injection of aflibercept on coagulation.

Methods: Treatment-naïve patients with age-related macular degeneration (n = 47), who were scheduled to undergo treatment with intravitreal injections of aflibercept, were enrolled. None of the included patients received any anticoagulation therapy or had a history of a recent arterial thromboembolic event. Blood samples were collected before the first intravitreal injection, and at 7 and 30 days after aflibercept administration. We evaluated coagulation parameters, such as platelet count and plasma fibrinogen and D-dimer levels; functional clotting parameters, such as prothrombin time, international normalized ratio, and activated partial thromboplastin time; and anticoagulant parameters, such as the levels of Proteins S and C.

Results: The levels of all of the evaluated biomarkers were within the normal range at baseline and at both the time points throughout the study. No statistically significant changes were observed in any of the measured parameters at 1 week and 1 month after aflibercept administration.

Conclusion: A single intravitreal injection of aflibercept in treatment-naïve patients with exudative age-related macular degeneration has no statistically significant effect on blood coagulation parameters for up to 1 month after aflibercept administration. Our results also provide an explorative statistical data, and further studies are required to evaluate any significant clinical effects of aflibercept on blood coagulation parameters.

Clinicaltrialsgov id: NCT03509623.

Keywords: Protein C; Protein S; activated partial thromboplastin time; aflibercept; age-related macular degeneration; arterial thromboembolic events; fibrinogen; international normalized ratio; plasma D-dimer; prothrombin time.

Conflict of interest statement

Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

© The Author(s), 2020.

References

    1. Eylea summary of product characteristics, (accessed 19 February 2018).
    1. Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J Ophthalmol 2014; 98: 1636–1641.
    1. Zarbin MA. Anti-VEGF agents and the risk of arteriothrombotic events. Asia Pac J Ophthalmol 2018; 7: 63–67.
    1. Ferroni P, Formica V, Roselli M, et al. Thromboembolic events in patients treated with anti-angiogenic drugs. Curr Vasc Pharmacol 2010; 8: 102–113.
    1. Blann AD, Lip GY. Virchow’s triad revisited: the importance of soluble coagulation factors, the endothelium, and platelets. Thromb Res 2001; 101: 321–327.
    1. Alexander M, Burbury K. A systematic review of biomarkers for the prediction of thromboembolism in lung cancer – results, practical issues and proposed strategies for future risk prediction models. Thromb Res 2016; 148: 63–69.
    1. Pabinger I, Thaler J, Ay C. Biomarkers for prediction of venous thromboembolism in cancer. Blood 2013; 122: 2011–2018.
    1. Yi Z, Chen C, Su Y, et al. Changes in clotting time, plasma fibrinogen levels, and blood viscosity after administration of ranibizumab for treatment of choroidal neovascularization. Curr Eye Res 2015; 40: 1166–1171.
    1. Jee D, Zako M, La TY. Serum D-dimer levels to evaluate the risk for arterial thromboembolism after intravitreal injection of bevacizumab and ranibizumab. J Ocul Pharmacol Ther 2015; 31: 32–36.
    1. Sobolewska B, Grimmel C, Gatsiou A, et al. Different effects of ranibizumab and bevacizumab on platelet activation profile. Ophthalmologica 2015; 234: 195–210.
    1. Tabernero J, Van Cutsem E, Lakomý R, et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer 2014; 50: 320–331.
    1. Semeraro F, Morescalchi F, Duse S, et al. Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an overview. Expert Opin Drug Saf 2014; 13: 785–802.
    1. Virgili G, Parravano M, Menchini F, et al. Anti-vascular endothelial growth factor for diabetic macular oedema. Cochrane Database Syst Rev 2014; 10: CD007419.
    1. Dedania VS, Bakri SJ. Systemic safety of intravitreal anti-vascular endothelial growth factor agents in age-related macular degeneration. Curr Opin Ophthalmol 2016; 27: 224–243.
    1. Lucentis summary of product characteristics, (accessed 19 February 2018).
    1. Periayah MH, Halim AS, Mat Saad AZ. Mechanism action of platelets and crucial blood coagulation pathways in hemostasis. Int J Hematol Oncol Stem Cell Res 2017; 11: 319–327.
    1. Simanek R, Vormittag R, Ay C, et al. High platelet count associated with venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). J Thromb Haemost 2010; 8: 114–120.
    1. Nomura Y, Kaneko M, Miyata K, et al. Bevacizumab and aflibercept activate platelets via FcγRIIa. Investig Ophthalmol Vis Sci 2015; 56: 8075–8082.
    1. Walton BL, Byrnes JR, Wolberg AS. Fibrinogen, red blood cells, and factor XIII in venous thrombosis. J Thromb Haemost 2015; 13(Suppl. 1): S208–S215.
    1. Kleinegris M-CF, ten Cate H, ten Cate-Hoek AJ. D-dimer as a marker for cardiovascular and arterial thrombotic events in patients with peripheral arterial disease. Thromb Haemost 2013; 110: 233–243.
    1. Douxfils J, Ageno W, Samama C-M, et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost 2018; 16: 209–219.
    1. Li E, Greenberg PB, Tseng V, et al. In vitro coagulation effects of ophthalmic doses of bevacizumab. J Ocul Pharmacol Ther 2012; 28: 219–221.
    1. Griffin JH, Mosnier LO, Zlokovic BV, et al. Protein C anticoagulant and cytoprotective pathways. Int J Hematol 2012; 95: 333–345.
    1. Wypasek E, Undas A. Protein C and protein S deficiency – practical diagnostic issues. Adv Clin Exp Med 2013; 22: 459–467.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner