The Platelet P2 Receptors

Platelets play an important role not only in hemostasis but also in the pathogenesis of arterial thrombosis. In both cases, platelets adhere to injured endothelium that is followed by platelet aggregation. During adhesion, several nucleotides are released, especially adenosine diphosphate (ADP) and adenosine triphosphate (ATP), which facilitate the aggregation response. ADP activates platelets via several P2 receptors, two different types of which have been identified: P2Y and P2X.

This issue of Seminars in Thrombosis and Hemostasis comprehensively examines the role of the P2 receptors in hemostasis and thrombosis, the various regulatory mechanisms that govern these responses and pharmaceutical compounds, already marketed or under development, that interfere in these events.

In the first contribution, Packham and Mustard provide a historical perspective on the role of ADP in platelet function, the discovery of receptors for ADP on the platelet surface, the signaling mechanisms involved and some the genetic abnormalities associated with these receptors. This excellent article provides the readers with a basis of understanding for the articles in this issue that follow.

Boeynaems and coworkers give an overview of the P2 receptors. Several mechanisms exist to release nucleotides into the extracellular fluids. Once released they act, in principle, with two receptor families, the P2Y and the P2X receptors; each of these present as structurally distinct subfamilies. The authors extensively summarize the present knowledge of these receptors, from gene expression to their physiological functions in many different organ systems. This article also provides a very useful basis for the following contributions.

The role of the P2 receptors in platelet function is discussed by Hechler and colleagues. The adenine nucleotides that play such a vital role in platelet aggregation act through three distinct P2 receptors, two G protein-complex ADP receptors (P2Y₁ and P2Y₁₂) and one P2X receptor ligand-gated cation channel that is activated by ATP. The two P2Y receptors mediate platelet aggregation by ADP and platelet shape change and potentiate the actions of other agonists, such as thrombin, collagen, or immune complexes. Each receptor plays a distinct role in facilitating hemostasis and importantly also thrombosis. These receptors thus represent a potential target for antithrombotic drugs.

The role of the P2 receptors in thrombosis is discussed by Gachet and Hechler. Because these receptors play a pivotal role in hemostasis, they are of equal importance in thrombogenesis. Of the two P2Y receptors, the P2Y₁₂ appears to play an important function in thrombus formation and stabilization. Antagonists to P2Y₁₂, such as clopidogrel, have shown to be effective antithrombotic drugs, especially in the prevention of arterial forms of thrombosis. The authors present evidence that antagonists to P2Y₁ and P2X₁ might also be useful antithrombotic agents.

Next, Cattaneo reviews the congenital defects associated with the P2 receptors on platelets. Although these bleeding disorders appear to be very rare, the author suggests that many defects presently labeled as “primary platelet defects” are likely due to dysfunctional P2 receptors. So far, most congenital defects have been identified with the P2Y₁₂ receptor and gene defects have been detected. Patients with these problems present with a mild bleeding tendency, and the diagnosis of these defects is reviewed.

Savi and Herbert report on the development of P2Y₁₂ receptor antagonists, especially ticlopidine and clopidogrel. Because this receptor plays a pivotal role in platelet activation, its blockade should be an ideal target for antithrombotic compounds that prevent arterial forms of thrombosis. The authors describe the pharmacology of these two antiplatelet agents and review extensively the clinical trials conducted so far in a variety of clinical settings.

Niitsu and coworkers report on a newly developed antiplatelet agent, CS-747. This compound is similar in structure to ticlopidine and clopidogrel and also blocks the P2Y₁₂ receptor. In contrast to ticlopidine and clopidogrel, however, CS-747 is more potent, is more quickly active, and has a longer-lasting effect. The authors review the pharmacology of this new compound and discuss the clinical trials so far conducted.

Van Giezen and Humphries describe two newly developed P2Y₁₂ receptor antagonists, cangrelor and AZD6140. Cangrelor can be administered intravenously, AZD6140 orally. In contrast to clopidogrel, both compounds block the receptor in a reversible and complete manner without markedly increasing the bleeding risk. The two drugs display certain advantages over the existing antiplatelet agents. The authors describe the pharmacology of the two compounds, reveal their in vitro effects, summarize their actions in animal models of arterial thrombosis, and discuss the clinical trials so far conducted, especially with cangrelor.

Jacobson and coworkers review the molecular recognition at adenine nucleotide (P2) receptors in platelets. They describe the structure of the P2Y and the P2X receptors and identify several distinct subgroups of these receptors. They then review agonists and antagonists of the two most important receptors P2Y₁ and P2Y_12, as well as agonists and antagonists of the P2X₁ receptor. These studies are fundamental to the development of more potent agonists and antagonists and raise the possibility that even more potent antiplatelet drugs may become available than the ones presently in clinical use.

Robson and colleagues discuss the role of ectonucleotidases of the CD39 family as regulators of nucleotide functions and how they have an impact on vascular inflammation and thrombosis during transplantation. CD39 plays a major role in the differential regulations of P2 receptors and thus a major role in the rejection of transplanted organs. The authors extensively review the complex mechanisms at play during organ transplantation and how these events might be modulated to improve organ survival. They suggest that CD39 modulation may lead to new treatment modalities to minimize allograft damage and acute and chronic rejections. These new potential avenues may even make xenotransplantation possible. The article contains a wealth of information on the important issue of organ transplantation and its future.

In the last article, Marcus and coworkers discuss the role of CD39 in the regulation of thrombosis, in cerebroprotection and in cardioprotection. After a brief review of the physiology of CD39 and its effect on nucleotide metabolism, the authors present evidence that CD39 plays a key role in the regulation of prothrombotic, platelet-related events. They also report on the development of a soluble form of CD39 that exerts major protection in animals with experimental strokes and in cardiovascular disease and the potential protective effects in this group of prevalent disorders. It appears that CD39 and its variants are a new class of platelet inhibitors that do not affect platelets directly (in contrast to the presently available compounds) but remove prothrombotic mediators and thus prevent occlusive arterial thrombi.

My great appreciation is expressed to all authors who contributed to this information and special thanks go to Drs. Gachet and Cattaneo for assembling this interesting issue. Readers will undoubtedly find the information expertly and comprehensively reviewed. They can find a wealth of information on the topic, some of it entirely new.