Inhibitors of Platelet Aggregation A

Platelets can be activated by mechanical and diverse chemical stimuli, some of which, e.g., thromboxane A2, thrombin, serotonin, and PAF, act via receptors on the platelet membrane. These receptors are coupled to Gq proteins that mediate activation of phospholipase C and hence a rise in cytosolic Ca2+ concentration. Among other responses, this rise in Ca2+ triggers a conformational change in GPIIB/IIIA, which is thereby converted to its fbrinogen-binding form. In contrast, ADP activates platelets by inhibiting adenylyl cyclase, thus causing internal cAMP levels to decrease. High cAMP levels would stabilize the platelet in its inactive state. Formally, the two messenger substances, Ca2+ and cAMP, can be considered functional antagonists.

Platelet aggregation can be inhibited by acetylsalicylic acid (ASA), which blocks thromboxane synthase, or by recombinant hirudin (originally harvested from leech salivary gland), which binds and inactivates thrombin. As yet, no drugs are available for blocking aggregation induced by serotonin or PAF. ADP-induced aggregation can be prevented by ticlopidine and clopidogrel; these agents are not classic receptor antagonists. ADP-induced aggregation is inhibited only in vivo but not in vitro in stored blood; moreover, once induced, inhibition is irreversible. A possible explanation is that both agents already interfere with elements of ADP receptor signal transduction at the megakaryo-cytic stage. The ensuing functional defect would then be transmitted to newly formed platelets, which would be incapable of reversing it.

The intra-platelet levels of cAMP can be stabilized by prostacyclin or its analogues (e.g., iloprost) or by dipyrida-mole. The former activates adenyl cy-clase via a G-protein-coupled receptor; the latter inhibits a phosphodiesterase that breaks down cAMP.

The integrin (GPHB/fflA)-antago-nists prevent cross-linking of platelets. Their action is independent of the ag gregation-inducing stimulus. Abciximab is a chimeric human-murine monoclonal antibody directed against GPIIb/IIIa that blocks the fibrinogen-binding site and thus prevents attachment of fibrinogen. The peptide derivatives, epti-fibatide and tirofiban block GPIIB/IIIA competitively, more selectively and have a shorter effect than does abciximab.

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