Overcoming limitations of current antiplatelet drugs: A concerted effort for more profitable strategies of intervention

Figures & data

Table I. Platelet activation: agonists and signal transduction.

Agonist	Receptor(s)	Effect(s)	Comments
ADP	Gaq-coupled P2Y1; Gai-coupled P2Y12	P2Y1: shape change; P2Y12: aggregation	P2Y12 amplifies aggregation induced by 5-HT, TxA2, and thrombin
TxA2	TPa; TPb (secondary)	Shape change; platelet recruitment; platelet aggregation	In endothelial cells, COX-1-derived PGH2 is converted into PGI2, a strong antiaggregating and vasodilating agent
Thrombin	PAR-1; PAR-4 (secondary); GpIbα	Shape change; ADP and TxA2 secretion; P-selectin expression; αIIbβ3 integrin receptor; platelet activation	PAR-1 and P2Y12, cross-reaction (via Gαq and Gαi-coupled receptors)
Serotonin	5HT-2A receptors	Shape change; platelet recruitment; retention of fibrinogen and thrombospondin on the platelet surface	Implicated in shear-induced platelet aggregation and thrombus propagation

Figure 1. Platelet activation pathways and drug molecular targets. Thrombin binds to PAR-1 receptor, which leads to shape change, phospholipase C (PLC) activation, thromboxane A2 (TXA2) generation, and activation of the glycoprotein (GP) IIb/IIIa receptor, resulting in sustained platelet aggregation. Cyclooxygenase (COX)-1 catalyzes the production of TXA2, a potent platelet aggregator, generated by platelets activated by thrombin and other agonists. Adenosine 5′-diphosphate (ADP) binds to its 7-transmembrane domain receptors, P2Y1 and P2Y12, to activate platelets. P2Y1 is coupled to Gaq and G12. Gaq is linked to a signaling pathway involving PLC activation, resulting in a rise in the intracellular calcium concentration ([Ca+2]i) and protein kinase C (PKC) activation, leading to GP IIb/IIIa activation and transient platelet aggregation. G12 mediates platelet shape change. P2Y12 is linked to Gαi-coupled signaling cascades associated with adenylcyclase (Ac) down-regulation and decreased cyclic-3′,5′-monophosphate (cAMP) production, which mediates GP IIb/IIIa receptor activation, leading to sustained platelet aggregation.

Table II. Molecular targets of newer and emerging antiplatelet therapies.

Drug	Mechanism	Comment
Prasugrel	P2Y12 receptor inhibition	Irreversible inhibition; orally active
Cangrelor	Adenosine triphosphate analog with a high affinity for the P2Y12 receptor	Reversible inhibition; intravenous
Ticagrelor	P2Y12 and (partly) P2Y1 receptor inhibition	Reversible inhibition; orally active
Elinogrel	P2Y12 receptor inhibition	Reversible; oral and intravenous
Vorapaxar (E530348)	PAR-1 inhibitor	No effect on thrombin-induced fibrin production, orally active
Atopaxar (E5555)	Low-molecular-weight PAR-1 inhibitor	Inhibition of expression of the inflammatory markers (sCD40L and interleukin 6 and the expression of P-selectin), orally active
Sarpogrelate	Selective inhibitor of serotonin (5HT-2A) platelet receptors	Orally active
DZ-697b	Inhibits collagen and ristocetin-mediated platelet adhesion and aggregation	Orally active
Gas6 (growth arrest-specific gene 6)	Vitamin K-dependent protein; a polyclonal anti-Gas6 antibody lowers platelet thromboembolism induced by the intravenous injection of collagen plus epinephrine and aggregation by ADP	Stored in platelet α granules, released upon activation. Through its carboxy-terminal domains it interacts with the membrane receptor tyrosine kinases (RTKs) of the TAM family (Tyro3, Axl, MerTK); through its vitamin K-dependent Gla module it interacts with phosphatidylserine-containing membranes
Matrix metalloproteinases (MMPs)	By potentiating PI3K activation, MMP-2 amplifies platelet aggregation regardless of the presence of aspirin and of P2Y12 receptor antagonists	Involved in tissue remodeling and in the progression of atherosclerosis, MMP-2 is present in platelet cytosol and released upon aggregation
CD40 ligand (CD40L; CD154)	On activated platelets an exodomain (soluble CD40 ligand, sCD40L) is released and binds to αIIbβ3 integrin, thus promoting thrombus stabilization and blunting platelet reactivity	Transmembrane protein expressed on the surface of activated platelets. Shedding of sCD40L from the surface of activated platelets can be prevented by an anti-CD40L antibody (G28-5)

Table III. Efficacy and safety of newer antiplatelet drugs. Results from phase III studies.

Study (ref)
TRITON-TIMI 38 (48), 13,608 subjects:
Study design	Prasugrel (60-mg loading dose (LD) 10-mg maintenance dose (MD) versus Clopidogrel (300 mg LD→75 mg MD)
Efficacy end-point	9.9% versus 12.1%; P = 0.001
Safety end-point	2.4% versus 1.8%; P = 0.03
CHAMPION-PCI (52), 8,887 subjects:
Study design	Cangrelor (bolus 30 μg/kg + infusion 4 μg/kg/min) + Clopidogrel (600 mg LD) versus Placebo + Clopidogrel (600 mg LD)
Efficacy end-point	7.5% versus 7.9%; P = 0.59
Safety end-point	0.4% versus 0.3%; P = 0.39
CHAMPION-PLATFORM (53), 2,654 subjects:
Study design	Cangrelor (bolus 30 μg/kg or 4 μg/kg/min infusion for ≥ 2 h) + Clopidogrel (600 mg LD) versus Placebo + Clopidogrel (600 mg LD)
Efficacy end-point	7.0% versus 8.0%; P = 0.17
Safety end-point	3.5% versus 5.5%; P < 0.001
The PLATO trial (53), 18,624 subjects:
Study design	Ticagrelor (180 mg LD + 90 mg twice a day MD) or Clopidogrel (300–600 mg LD + 75 mg MD)
Efficacy end-point	9.8% versus 11.7%; P = 0.001
Safety end-point	11.6% versus 11.2%; P = 0.46

Efficacy end-point: CV death/non-fatal MI/non-fatal stroke. Safety end-point: major bleeding.

Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, . Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–15.

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