Bleeding associated with current therapies for acute coronary syndrome: what are the mechanisms?

Coronary artery plaque rupture results in platelet adhesion and activation, the release of adenosine diphosphate (ADP), thromboxane A(2), and the generation of thrombin. These factors propagate further platelet activation through a positive feedback mechanism, resulting in the formation of a platelet plug. The treatment of patients with ACS is centered upon the prompt initiation of both antiplatelet and anticoagulant agents. The widespread use of antiplatelet and anticoagulant agents has resulted in a significant reduction in morbidity and mortality but has also increased the risk for bleeding complications. Female gender, advanced age, low body mass index (BMI), low creatinine clearance, and the use of percutaneous coronary intervention have been consistently shown to be risk factors for bleeding. While bleeding was thought to be a necessary side effect and of little clinical significance in the past, it is now clear that bleeding is an independent predictor of adverse ischemic events and mortality. The mechanisms underlying this relationship are not yet fully elucidated and are likely multifactorial (direct effects of bleeding, increased incidence of blood transfusions, less use of antiplatelet agents in both the short and long term). Current treatment guidelines for the use of antithrombotic therapy recommend utilization of evidence-based therapies using clinical strategies shown to minimize the risk of bleeding should when possible. Novel therapies that minimize bleeding risk while providing protection against thrombotic events are needed and may improve outcomes among patients with ACS. Multiple platelet activation pathways and the coagulation cascade regulate hemostasis and thrombosis. Current antiplatelet and anticoagulant therapies for acute coronary syndromes (ACS) act on distinct sites in the pathways for platelet activation and coagulation. While these therapies are effective in reducing the morbidity and mortality associated with ACS, they are associated with a clinically significant increase in the risk of bleeding events. Novel therapies that minimize bleeding risk while providing protection against thrombotic events may improve outcomes in patients with ACS.