From the Guidelines
ADP activates clotting by binding to platelet receptors, primarily P2Y1 and P2Y12, triggering platelet activation and aggregation, as evidenced by the mechanism of action of antiplatelet agents such as clopidogrel and ticagrelor, which inhibit the P2Y12 receptor 1. The process of ADP-mediated clotting activation is complex and involves multiple pathways. When blood vessels are damaged, ADP is released from injured cells and activated platelets, serving as a critical secondary messenger in the clotting cascade.
- Key steps in this process include:
- ADP binding to platelet receptors, causing a shape change in platelets
- Increase in calcium mobilization inside the cells
- Promotion of the expression of glycoprotein IIb/IIIa receptors on the platelet surface
- Binding of these receptors to fibrinogen, creating bridges between platelets that form the initial platelet plug
- Enhancement of the release of additional clotting factors from platelets, amplifying the coagulation process As noted in the study by the French working group on perioperative haemostasis (GIHP) in collaboration with the French Society of Anaesthesia and Intensive Care Medicine (SFAR) 1, the inhibition of the P2Y12 receptor by thienopyridines, such as clopidogrel, is partial, and platelet activation by ADP also goes through another receptor, P2Y1.
- This highlights the importance of considering the multiple pathways involved in ADP-mediated clotting activation when developing strategies for preventing or treating thrombotic disorders. The careful regulation of ADP-mediated platelet activation is crucial for maintaining the balance between preventing excessive bleeding and avoiding inappropriate clot formation, and is a key consideration in the management of patients with bleeding complications or those undergoing non-elective invasive procedures 1.
From the Research
ADP and Clotting Activation
- ADP plays a major role in the development and extension of arterial thrombosis through blood platelet aggregation 2
- ADP induces the characteristic functional responses of platelets, including shape change, induction and exposure of the fibrinogen binding sites on the GP IIb-IIIa complex, fibrinogen binding to its receptor, and platelet aggregation 2
- ADP is an important agonist for platelet aggregation, causing primary and secondary aggregation of platelets, as well as inducing platelet shape change, secretion from storage granules, and influx and intracellular mobilization of Ca2+ 3
ADP Receptors and Clotting
- Blood platelets express two types of P2Y ADP receptors: P2Y(1) and P2Y(12), which play a crucial role in ADP-dependent platelet aggregation 4
- The P2Y(1) receptor initiates ADP-dependent platelet aggregation, while the P2Y(12) receptor augments the activating signal and promotes platelet release reaction 4
- Stimulation of P2Y(12) is essential for ADP-mediated complete activation of GPIIb-IIIa and GPIa-IIa, and further stabilization of platelet aggregates 4
Clinical Implications
- Anti-platelet therapy, including ADP receptor antagonists, has become a cornerstone in the treatment of patients with ischemic cardiovascular disease 5
- The use of dual anti-platelet therapy, including aspirin and an ADP receptor antagonist, has been shown to reduce the risk of arterial thrombotic events 5
- Different ADP receptor antagonists, such as clopidogrel, prasugrel, and ticagrelor, have varying pharmacokinetics and pharmacodynamics, and their use should be guided by individual patient characteristics and clinical presentation 5, 6