Antithrombotic treatment in protection against thrombogenic effects of 5-fluorouracil on vascular endothelium: A scanning microscopy evaluation

Cardiotoxicity is a serious side effect of treatment of malignant diseases with 5‐fluorouracil (5‐FU). The underlying pathophysiologic mechanism remains unclear but clinical data suggest that the endothelium of coronary arteries may be involved. Experimental studies indicate that the endothelium is especially susceptible to 5‐FU and support the hypothesis that a thrombogenic effect of 5‐FU, secondary to its direct toxic effect on the endothelium, is one of the pathophysiologic mechanisms behind 5‐FU‐induced cardiotoxicity. In the present study we evaluate the role of antithrombotic treatment with dalteparin as protection against the thrombogenic effect of 5‐FU on the vascular endothelium in a rabbit model. The effects on the vascular endothelium of 5‐FU, dalteparin, and the combination of these two substances were evaluated with scanning electron microscopy 1, 3, 7, 14, and 30 days after treatment and compared with a control group. Very severe damage to the endothelium was seen in 5‐FU‐treated animals, often leading to intima disruption and denudation of underlying structures, with accompanying platelet accumulation and fibrin formation. The most extensive damage was observed on Day 3 after treatment. The cytotoxic effect of 5‐FU was partly reversible. The combination of 5‐FU and dalteparin gave lower scores on Day 3 because of less evidence of thrombotic events. However, the reversibility of the endothelial damage was poorer in this group, as well as in the group that received dalteparin alone. The findings support the hypothesis that antithrombotic treatment with dalteparin can protect against the thrombogenic effect of 5‐FU, secondary to its direct toxic effect on the vascular endothelium. However, the study indicates that dalteparin per se has a toxic effect on the endothelium that is different from that of 5‐FU.