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Introduction:Targeting the human platelet for prevention of occlusive thrombotic events remains an active area of research due to the high incidence of myocardial infarction and stroke due to platelet-rich thrombotic clots. While, many patients taking FXa anticoagulant therapy require further inhibition of thrombosis, dual therapy including anticoagulant plus antiplatelet drugs result in an increased risk for bleeding. The current study sought to determine if a histone deacetylase (HDAC) inhibitor, either alone or in combination with the FXa inhibitor rivaroxaban, is able to effectively inhibit platelet and fibrin formation at the site of vascular injury without causing a significant increase in the bleeding risk in mice.

Anti-platelet therapeutics are common tools in the treatment of thrombotic diseases, decreasing morbidity and mortality resulting from cardiovascular complications. However, many patients remain at risk for a cardiovascular event while others experience bleeding due to hemostatic dysregulation. The need for target specificity and lasting stability presents a major challenge in the development of novel antithrombotic therapeutics. While increasing platelet cAMP levels through activation of the prostacyclin (IP) receptor is a viable therapeutic approach, the IP receptor is currently considered a challenging target due to the non-selectivity and instability of existing IP agonists. Our lab has developed a novel IV and orally available IP receptor agonist, CS585, with selectivity towards the IP receptor and sustained in vivoprotection from injury-induced thrombosis without observed bleeding. CS585 demonstrates IP receptor-dependent activity, leading to activation of protein kinase A (PKA), a key player in inhibitory signaling. While indications of current IP receptor agonists are limited to pulmonary arterial hypertension and temporary relief of peripheral artery disease, CS585 presents a new approach to selectively regulate platelet activation and thrombosis.