Abstract
IntroductionPrevious study in mice using real-time intravital imaging revealed an acute deleterious effect of doxorubicin (DXR) on the gonadal vasculature, as a prototype of an end-organ, manifested by a reduction in blood flow and disintegration of the vessel wall. We hypothesized that this pattern may represent the formation of microthrombi. We aimed to further characterize the effect of DXR on platelets’ activity and interaction with endothelial cells (EC) and to examine potential protectants to reduce DXR acute effect on the blood flow.MethodsThe effect of DXR on platelet adhesion and aggregation were studied in vitro. For in vivo studies, mice were injected with either low molecular weight heparin (LMWH; Enoxaparin) or with eptifibatide (Integrilin©) prior to DXR treatment. Testicular arterial blood flow was examined in real-time by pulse wave Doppler ultrasound.ResultsPlatelet treatment with DXR did not affect platelet adhesion to a thrombogenic surface but significantly decreased ADP-induced platelet aggregation by up to 40% (p<0.001). However, there was a significant increase in GPIIbIIIa-mediated platelet adhesion to DXR-exposed endothelial cells (EC; 5.7-fold; p<0.001) reflecting the toxic effect of DXR on EC. The testicular arterial blood flow was preserved in mice pre-treated with LMWH or eptifibatide prior to DXR (P<0.01).ConclusionsDXR-induced acute vascular toxicity may involve increased platelet–EC adhesion leading to EC-bound microthrombi formation resulting in compromised blood flow. Anti-platelet/anti-coagulant agents are effective in reducing the detrimental effect of DXR on the vasculature and thus may serve as potential protectants to lessen this critical toxicity.
Highlights
Previous study in mice using real-time intravital imaging revealed an acute deleterious effect of doxorubicin (DXR) on the gonadal vasculature, as a prototype of an end-organ, manifested by a reduction in blood flow and disintegration of the vessel wall
Effect of DXR on platelet aggregation and adhesion Platelet rich plasma (PRP) was pre-incubated for 15 minutes with increasing concentrations of DXR, platelet aggregation was induced by ADP (5 μM) (Figure 1A)
Platelet adhesion Whole blood was pre-incubated for 15 minutes with increasing concentrations of DXR subjected to the ImpactR test (Figure 1B)
Summary
Previous study in mice using real-time intravital imaging revealed an acute deleterious effect of doxorubicin (DXR) on the gonadal vasculature, as a prototype of an end-organ, manifested by a reduction in blood flow and disintegration of the vessel wall. We hypothesized that this pattern may represent the formation of microthrombi. Based upon previous studies demonstrating DXR-induced apoptosis in EC resulting in hypercoagulable state [9,10], we hypothesized that the pattern of the immediate vessel disintegration following DXR treatment may represent the formation of microthrombi on a thrombogenic vessel wall. That led us to further investigate the role of platelets in this pathogenesis
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