In Vitro Coagulation Effects of Ophthalmic Doses of Bevacizumab

Abstract

In vitro coagulation effects of bevacizumab, a drug with potential risks for severe hemorrhagic and arterial thromboembolic events (ATEs), are unknown. The aim of this study was to evaluate the effects of bevacizumab, including the common ophthalmic dose of 1.25 mg, on the coagulation cascade. Bevacizumab doses of 0.25, 0.5, 1.0, 1.25, 2.0, 2.5, and 4.0 mg were incubated at 37 °C in the presence of pooled normal plasma (PNP) to determine its biological activity via activated partial thromboplastin time (aPTT) and prothrombin time (PT) at 30 min, 1 h, and 2 h. The control consisted of 40% normal saline and 60% PNP. All evaluations were conducted in triplet. Coagulation at each time point was compared with the control group by analysis of variance with Tukey's post hoc test. A P value of ≤ 0.05 was considered significant. Mean bevacizumab aPTT ranged from 38.4 to 43.9 s, 37.4 to 43.1 s, and 39.0 to 43.2 s at 30 min, 1 h, and 2 h, respectively. Mean bevacizumab PT ranged from 15.7 to 16.8 s at 30 min, 14.6 to 16.2 s at 1 h, and 14.0 to 15.8 s at 2 h. For the control, aPTT was similar over time (40.1, 40.0, and 40.5 s), while PT decreased from 16.5 at 30 min to 15.4 s at 2 h. Bevacizumab decreased PT significantly at 2 h, compared with the PNP control, for the following doses: 0.25 mg [difference between means 1.04 s, 95% confidence interval (CI) 0.12-1.96], 1.25 mg (1.16 s, 95% CI 0.16-2.15), 2.5 mg (0.94 s, 95% CI 0.02-1.86), and 4 mg (1.41 s, 95% CI 0.41-2.40). Significant differences were not observed in PT at 30 min and 1 h as compared with controls. For all doses of bevacizumab, aPTT did not vary from controls at the 3 measured times. A common ophthalmic dose of bevacizumab 1.25 mg significantly increased in vitro coagulation. Further examination of the impact of ophthalmic bevacizumab on coagulation is warranted to provide insight into any putative link between ophthalmic bevacizumab and the risk for severe ATEs.