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New Targets for Platelet Inhibition

Novel approaches under investigation

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 novel 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

Inhibiting platelet adhesion

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

Inhibiting platelet activation, recruitment, and aggregation

Platelets 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. Medications targeting this receptor have potential application in treating acute coronary syndrome (ACS).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
 
  • 108 - Roth GJ. Antiplatelet therapy. In: Colman RW, Clowes AW, George JN, Goldhaber SZ, Marder VJ, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2006:1725-1738.
  • 135 - Bates SM, Weitz JI. New antithrombotic drugs. In: Colman RW, Clowes AW, George JN, Goldhaber SZ, Marder VJ, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2006:1763-1783.
  • 136 - Rich JD, Wiviott SD. New antiplatelet therapies for acute coronary syndromes. Curr Cardiol Rep. 2007;9(4):303-311.
  • 107 - Messmore HL Jr, Jeske WP, Wehrmacher W, et al. Antiplatelet agents: current drugs and future trends. Hematol Oncol Clin North Am. 2005;19(1):87-117, vi.
  • 137 - Yoshida S, Sudo T, Niimi M, et al. Inhibition of collagen-induced platelet aggregation by anopheline antiplatelet protein, a saliva protein from a malaria vector mosquito. Blood. 2008;111(4):2007-2014.
  • 138 - Gachet C. The platelet P2 receptors as molecular targets for old and new antiplatelet drugs. Pharmacol Ther. 2005;108(2):180-192.
  • 139 - Leger AJ, Jacques SL, Badar J, et al. Blocking the protease-activated receptor 1-4 heterodimer in platelet-mediated thrombosis. Circulation. 2006;113(9):1244-1254.
Aspirin
The brand name of acetylsalicylic acid (ASA), an antithrombotic medication that prevents thrombosis by inhibiting the activity of platelets – a component of blood that helps to prevent blood loss.
Platelet
(Thrombocyte) Cell circulating in the blood that is involved in the cellular mechanisms of primary haemostasis leading to the formation of blood clots. When a blood vessel is injured, platelets gather at the site of injury and stick together to form a plug, thereby preventing blood loss.
Acute coronary syndrome
This is an umbrella term used to cover any group of clinical symptoms compatible with acute myocardial ischaemia (chest pain due to insufficient blood supply to the heart muscle that results from coronary artery disease). Acute coronary syndrome covers the spectrum of clinical conditions ranging from unstable angina to STEMI and NSTEMI.
Clopidogrel
Oral antiplatelet agent used in the treatment of coronary artery disease, peripheral vascular disease and cerebrovascular disease.
Thrombin
Also called Factor IIa, thrombin performs two functions in the coagulation cascade: activating platelets, and catalysing the conversion of soluble fibrinogen into insoluble fibrin. It is formed from prothrombin by a reaction that is catalysed by Factor Xa.

From the Image Library

Positive duplex ultrasound showing a common femoral vein clot Positive duplex ultrasound showing the posterior tibial vein Vein image 1: venous thrombus formation in cusps of veins See all Venous Thrombosis

Did You Know?

Heart attack, a leading cause of death in the developed world, is most often triggered by acute thrombus formation within a coronary artery.95

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