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Prostacyclin (prostaglandin I2 [PGI2]) is an eicosanoid lipid mediator produced by the endothelial cells. It plays pivotal roles in vascular homeostasis by virtue of its potent vasodilatory and antithrombotic effects. Stable pharmacological analogues of PGI2 are used for treatment of pulmonary hypertension and right ventricular failure. PGI2 dose dependently inhibits platelet activation induced by adenosine-5′-diphosphate, arachidonic acid, collagen, and low-dose thrombin. This property has led to its use as an alternative to direct thrombin inhibitors in patients with type II heparin-induced thrombocytopenia (HIT) undergoing cardiac surgery. The aims of this review are the following: (1) to review the pharmacology of PGI2 and its derivatives, (2) to present the evidence for their use in pulmonary hypertension and right heart failure, and (3) to discuss their utility in the management of HIT in cardiac surgery.