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

New P2Y₁₂ antagonists

In February 2009, the thienopyridine prasugrel was granted marketing approval by the European Commission for the prevention of atherothrombotic events in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI).²⁶⁵ Prasugrel binds P2Y₁₂ more avidly than clopidogrel, and a Phase III study found that prasugrel was 19% more effective than clopidogrel in preventing cardiovascular death, nonfatal heart attacks and strokes.^{240, 243} The same study, however, showed that prasugrel was 32% more likely to cause serious bleeding.²⁴³ Based on these data, the UK National Institute for Health and Clinical Excellence (NICE) published provisional guidance that limited use of prasugrel in combination with aspirin to patients with ACS undergoing PCI under very specific circumstances. These include when immediate intervention is necessary due to ST-segment-elevation myocardial infarction (MI), when stent-thrombosis has occurred during clopidogrel treatment, or when the patient has diabetes mellitus.²⁴⁵

Other novel P2Y₁₂ antagonists in development include ticagrelor, elinogrel and cangrelor. Like prasugrel, these compounds achieve more rapid, less variable and more complete platelet inhibition than clopidogrel.¹⁹⁶ Compared with clopidogrel, these P2Y₁₂ antagonists could potentially facilitate management of patients undergoing coronary stent insertion.¹⁹⁶ A Phase III trial demonstrated that ticagrelor had a greater efficacy in reducing cardiovascular events (cardiovascular death, MI, stroke) than did clopidogrel, without an increase in major bleeding in this population.²⁷⁹ However, intracranial bleeding was more common with ticagrelor treatment.²⁷⁹

In recent years, there has been an increasing interest in the concept of “platelet resistance” ― decreased platelet responsiveness ― to medications such as aspirin and clopidogrel.¹⁹⁸ This phenotype is described as “high platelet reactivity” (HPR), and certain patients with HPR have been shown to have a higher risk of subsequent thrombotic events.²⁵² In one clinical trial, the direct-acting oral P2Y₁₂ antagonist elinogrel overcame HPR in the majority of patients on clopidogrel and aspirin therapy within 4 hours.²⁰⁰ This effect abated completely within 24 hours of dosing.²⁰⁰ Elinogrel is the first P2Y₁₂ antagonist that can be administered both intravenously and orally, which could facilitate the transition from short-term to long-term treatment.²⁰⁰

You can find information on current clinical trials of these newer agents at www.clinicaltrials.gov .

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Article references

108 - Roth GJ. Antiplatelet therapy. In: Colman RW, Marder VJ, Clowes AW, George JN, Goldhaber SZ, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2006:1725-1737.
135 - Bates SM, Weitz JI. New antithrombotic drugs. In: Colman RW, Marder VJ, Clowes AW, George JN, Goldhaber SZ, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2006:1763-1783.
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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.
265 - Summary of product characteristics for Effient. London, England: European Medicines Agency; 2010.
240 - Michelson AD. New P2Y12 antagonists. Curr Opin Hematol. 2009;16(5):371-377.
243 - Montalescot G, Wiviott SD, Braunwald E, et al; TRITON-TIMI 38 investigators. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised, controlled trial. Lancet. 2009;373(9665):723-731.
245 - National Institute for Health and Clinical Excellence. Final appraisal determination: Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention. London, England: National Clinical Guideline Centre; 2009.
196 - Gaglia MA Jr, Manoukian SV, Waksman R. Novel antiplatelet therapy. Am Heart J. 2010;160(4):595-604.
279 - Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. New Engl J Med. 2009;361(11):1045-1057.
198 - Gasparyan AY. Aspirin and clopidogrel resistance: methodological challenges and opportunities. Vasc Health Risk Manag. 2010;6:109-112.
252 - Price MJ, Endemann S, Gollapudi RR, et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J. 2008;29(8):992-1000.
200 - Gurbel PA, Bliden KP, Antonino MJ, et al. The effect of elinogrel on high platelet reactivity during dual antiplatelet therapy and the relation to CYP2C19*2 genotype: first experience in patients. J Thromb Haemost. 2010;8(1):43-53.

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.
Myocardial infarction: Destruction of heart tissue due to reduced blood flow to the heart. Also known as a heart attack. It usually results from coronary artery disease and is more severe than angina.