Future innovations in anti-platelet therapies

Abstract

Platelets have long been recognized to be of central importance in haemostasis, but their participation in pathological conditions such as thrombosis, atherosclerosis and inflammation is now also well established. The platelet has therefore become a key target in therapies to combat cardiovascular disease. Anti-platelet therapies are used widely, but current approaches lack efficacy in a proportion of patients, and are associated with side effects including problem bleeding. In the last decade, substantial progress has been made in understanding the regulation of platelet function, including the characterization of new ligands, platelet-specific receptors and cell signalling pathways. It is anticipated this progress will impact positively on the future innovations towards more effective and safer anti-platelet agents. In this review, the mechanisms of platelet regulation and current anti-platelet therapies are introduced, and strong, and some more speculative, potential candidate target molecules for future anti-platelet drug development are discussed.

Figure 1

Platelet thrombus formation. Initial interaction of platelets with exposed collagens in the blood vessel wall under arterial shear conditions (left to right) is mediated indirectly through von Willebrand factor (vWF), which binds both GPIb and collagen. This transient interaction results in rolling along the collagen, effectively slowing down the platelet and enabling interaction of collagen with integrin α₂β₁ and GPVI, supporting stable platelet adhesion and activation. Activation results in spreading, to cover the area of damage, the secretion of a range of pro-thrombotic factors from α-granules and dense granules, and the synthesis and release of thromboxane A₂. The binding of released factors to cognate G protein-coupled receptors (GPCRs) on the platelet surface leads to rapid thrombus propagation through positive feedback regulation. Platelet activation results in an increase in the affinity of integrin α_IIbβ₃ (GPIIbIIIa), which through interaction with bivalent plasma fibrinogen results in stable platelet thrombus formation.

Figure 2

The molecular targets of anti-platelet drugs. Current anti-platelet drugs target key elements of the platelet regulatory machinery. This includes cyclooxygenase (COX) inhibitors for the inhibition of thromboxane A₂ (TXA₂) production, ADP receptor antagonists, fibrinogen receptor (integrin α_IIbβ₃) blockers, prostacyclin receptor agonists, phosphodiesterase inhibitors and inhibitors of thrombin generation. Future potential targets for anti-platelet drug development include GPIb–V–IX, GPVI and integrin α₂β₁. Adapted with permission from Jackson and Schoenwaelder (2003).