Exercise, Medicine and Icing (EMI) for the Knee: Small Instalments, Big Gains in Early Osteoarthritis.

Adenine di-Phosphate (ADP) is an important physiological agonist that plays a vital role in normal hemostasis and thrombosis. The importance of ADP in normal hemostasis is clearly demonstrated in patients suffering from storage pool disease who show excessive bleeding tendencies. It is well established that ADP activates platelets through 3 purinergic receptors, namely P2Y1, P2Y12 and P2X1. The P2Y1 receptor is a Galpha q coupled G-protein receptor that is important for platelet shape change, aggregation, thromboxane A2 generation, procoagulant activity, adhesion to immobilized fibrinogen and thrombus formation under shear conditions. The availability of P2Y1 antagonists and knockout mice have aided in demonstrating the multiple functions of this receptor in platelet function and normal hemostasis. The second ADP receptor, the P2Y12 signals through a Galpha i coupled G-protein receptor and has been shown to be important for platelet functions very similar to the P2Y1 receptor. In addition, the P2Y12 receptor is also important for potentiation of platelet activation mediated by other physiological agonists including collagen, von Willebrand and thromboxane A2. Advances in understanding the importance of the P2Y12 receptor has resulted in the development of drugs like clopidogrel and ticlopidine that is being successfully used clinically in the treatment of thrombotic disorders. The understanding of the function of this receptor has been possible due to the availability of multiple P2Y12 antagonists and the development of the P2Y12 null mice. The third and the final P2X1 receptor is an ion channel that upon activation causes an influx of calcium. Even though the activation of this receptor by itself doesn't lead to aggregation, it causes shape change and aids in the activation process of other agonists. Studies have also shown that it is important for thrombus formation under shear conditions in small arteries. Signaling by this receptor leads to significant ERK activation, which has been shown, to be important for collagen mediated platelet activation. The importance of ADP in hemostasis and thrombosis greatly underscores the significance of understanding the function of these receptors that would enable development of potent and safe anti-thrombotic drugs.