Targets for Platelet Inhibition

Currently antiplatelet agents are used to prevent and treat arterial thromboses. The available agents, however, have significant limitations. Acetylsalicylic acid (Aspirin) has only a modest effect, preventing cardiovascular events in approximately 25% of patients with atherosclerosis. The thienopyridines (clopidogrel, ticlopidine) are only slightly more effective. For this reason, dual antiplatelet therapy with Aspirin and a thienopyridine is often recommended for high-risk patients. The modest efficacy of these drugs may be related to the fact that there are multiple alternate pathways for platelet activation.^{108, 135}

Several potential targets for antiplatelet action, including receptors involved in platelet adhesion and aggregation, are under investigation. Medications directed against these targets are in various stages of development.^{135, 136}

Platelet adhesion to the injured endothelium depends on the interaction between subendothelial proteins and glycoprotein receptors on the platelet surface. This preliminary step in coagulation theoretically could be inhibited by blocking the platelet receptors for collagen and von Willebrand factor (VWF). Blocking the attachment of VWF to collagen or directly binding VWF are other potential strategies.^{107, 135}

Like hirudin, an anticoagulant first isolated from leech saliva, a different type of anticoagulant protein has been isolated from mosquito saliva. This protein inhibits thrombosis by blocking platelet adhesion. Anopheline antiplatelet protein interferes with the link between collagen and the platelet glycoprotein VI receptor. The therapeutic potential of this compound is under study.¹³⁷

Platelet activation is stimulated by many routes, through many different receptors. One activator, thromboxane A₂ (TXA₂), is synthesised within platelets and then released to further stimulate platelet activity. Inhibiting thromboxane synthetase or blocking the TXA₂ platelet receptor may be a more potent approach to platelet inhibition than the effect of Aspirin, which works “upstream” in the prostanoid pathway by inhibiting the COX-1 enzyme. (Blocking COX-1 also blocks the synthesis of prostacyclin, with the effect of promoting thrombogenesis.)¹³⁵

The P2 receptors are another potential target of platelet inhibition. When bound to adenosine diphosphate (ADP) and adenosine triphosphate (ATP), these receptors lead to platelet activation and aggregation. One subtype of the P2 receptor class, P2X₁, binds to ATP; its effect is seen mainly under high-shear blood flow conditions seen in stenotic coronary arteries.¹³⁸

ADP is the ligand for both P2Y₁ and P2Y₁₂ receptors. Stimulation of P2Y₁ receptors initiates platelet activation and aggregation. Activation of P2Y₁₂ amplifies the process. The P2Y₁₂ receptor is the target for the thienopyridines in current use, clopidogrel and ticlopidine, whose metabolites irreversibly bind to the receptor. Prasugrel, a new thienopyridine nearing completion of its clinical development program, binds P2Y₁₂ more avidly than clopidogrel. Reversible receptor site antagonism is an alternative approach under study. Blockade of the P2Y₁ receptor, either alone or in combination with P2Y₁₂, is also being explored.¹³⁸

A different approach to platelet inhibition involves the hydrolysis of ADP into inactive AMP, thereby removing this potent stimulant from the platelet’s microenvironment. CD39, found on epithelial surfaces, has a hydrolytic function that confers both anti-inflammatory and antithrombotic properties. Recombinant human CD39 has been shown to inhibit platelet aggregation in vivo.¹³⁵

Thrombin exerts its platelet-stimulatory effects at the protease-activated receptors PAR1 and PAR4. These receptors play different roles in platelet aggregation, producing two sequential waves of intracellular calcium increase. The action of PAR1 is fast and terminates quickly; the action of PAR4 is more prolonged. Blocking these receptors theoretically would inhibit thrombin-induced platelet aggregation without interfering with the other roles of thrombin in clot formation.¹³⁹