Open AccessDoxorubicin-Induced Vascular Toxicity – Targeting Potential Pathways May Reduce Procoagulant Activity
Author(s) -
Irit Ben Aharon,
Hadas Bar Joseph,
Moran Tzabari,
Борис Шенкман,
Nahid Farzam,
Mattan Levi,
Ruth Shalgi,
Salomon M. Stemmer,
Naphtali Savion
Publication year - 2013
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0075157
Subject(s) - platelet , pharmacology , doxorubicin , eptifibatide , platelet activation , chemistry , heparin , toxicity , endothelium , blood flow , medicine , immunology , biochemistry , chemotherapy , myocardial infarction , conventional pci
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. 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. Methods The 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. Results Platelet 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). Conclusions DXR-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.