Doxorubicin-Induced Vascular Toxicity – Targeting Potential Pathways May Reduce Procoagulant Activity

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.

Anti-cancer drugs-induced arterial injury: risk stratification, prevention, and treatment

“…Caspase-3-mediated apoptosis has also been observed in endothelial cells, in vitro. Small animal models have demonstrated microthrombus formation in coronary arterioles after doxorubicin treatment [13].…”

Chemotherapy-induced Vascular Toxicity - Real-time <em>In vivo</em> Imaging of Vessel Impairment

“…Several chemotherapies have been implied as vasculo-toxicants as observed in clinical studies using serum biomarkers. Among these are alkylating agents (such as cyclophosphamide), platinum compounds (such as cisplatin) and anthracyclines 1,2,[5][6][7] .…”

Arterial stiffness in hematologic malignancies

“…The acute vascular effect of doxorubicin begins shortly after administration, with no recovery during the next 8 minutes of real-time imaging, and depends on the size of blood vessels (more prominent in smaller vessels) 34. Doxorubicin-induced acute vascular toxicity may also involve increased platelet–endothelial cell adhesion, mediated by glycoprotein IIb/IIIa; enhanced procoagulant activity of macrophages and endothelial cells; impaired membrane fluidity and protein C anticoagulant pathway and facilitated activation of tissue factor, resulting in microthrombi formation and compromised blood flow 47. Antiplatelet and anti-coagulant agents may protect the vessels against the detrimental effects of doxorubicin, but there is no clinical evidence for massive acute thrombotic events in the population treated with doxorubicin 47.…”

“…Doxorubicin-induced acute vascular toxicity may also involve increased platelet–endothelial cell adhesion, mediated by glycoprotein IIb/IIIa; enhanced procoagulant activity of macrophages and endothelial cells; impaired membrane fluidity and protein C anticoagulant pathway and facilitated activation of tissue factor, resulting in microthrombi formation and compromised blood flow 47. Antiplatelet and anti-coagulant agents may protect the vessels against the detrimental effects of doxorubicin, but there is no clinical evidence for massive acute thrombotic events in the population treated with doxorubicin 47. The explanation is a platelet paradox effect of doxorubicin, enhancing platelet adhesion to endothelial cells on one hand and inhibiting platelet aggregation on the other hand, resulting in unstable endothelium-bound surface platelet aggregates that could reduce blood flow but not cause complete vessel occlusion 47.…”