Abstract
Acute ischaemic stroke, myocardial infarction and pulmonary embolism are the main
causes of mortality and morbidity worldwide. Thrombolysis by intravenous injection
of recombinant tissue plasminogen activator (rtPA) remains the most common non-interventional
treatment to recanalize occluded vessels. However, this procedure is limited by significant
drawbacks, including high doses and bleeding complications. Recent studies showed
that fucoidan targets the intraluminal thrombus in vivo. We have developed a chimaera
covalently linking fucoidan, able to target platelets within the thrombus, to dilysine,
able to non-covalently bind rtPA. We hypothesize that this construct should vectorize
rtPA to the thrombus, thus increasing its fibrinolytic efficacy and avoiding its deleterious
effects. In vitro, rtPA mixed to dilysine fucoidan (DLF) shows a greater fibrinolytic
effect than rtPA alone, both on platelet-rich thrombus and in whole blood. In vivo,
occluded mesenteric vessels, carotid artery and vena cava were more efficiently recanalized
by DLF complexed to rtPA than by rtPA alone. This study thus provides evidence that
DLF may be a promising therapeutic tool to fight against acute thrombosis by enhancing
rtPA fibrinolytic efficiency.
Keywords
chimaera - clot - fucoidan - lysine - P-selectin - arterial thrombosis - venous thrombosis
