Antiplatelet drugs in cardiological practice: established strategies and new developments

Abstract

A common pathophysiological course in vascular diseases is an overwhelming activation and aggregation of blood platelets, which results in atherothrombosis. By causing the last decisive step of cerebral, coronary, or peripheral arterial ischemia thrombotic complications of atherosclerotic disease represent a major player in death cause statistics of most western countries. The development of novel therapies against platelet-dependent thrombosis and the concurrent improvement of existing therapeutic strategies thus is a paramount focus of pharmaceutical research. Currently, efficiency, dosing and indications of established antiplatelet substances are being re-evaluated, whilst new, so far unrecognized molecular targets for inhibition of platelet activity come up front. This not only allows for interesting new therapeutical options, but also widens our insight into the role platelets play in atherosclerosis in general. This article summarizes the relevant pathophysiology of platelet activation, presents current concepts in antiplatelet drug therapy, and highlights the role of platelets in vascular diseases apart from atherothrombosis.

Keywords: antiplatelet drug therapy; atherothrombosis; pathophysiology; platelet activation.

Figure 1

Signaling pathways that activate platelets intraarterially. Platelets possess different receptors that are specific for physiological stimuli such as collagen, ADP, TxA₂, thrombin, or vWF. Receptors for ADP are the purinergic P2Y₁ and P2Y₁₂ receptors, Collagen binds a GPIa/IIa integrin-receptor and activates platelets through the GPVI receptor. Thrombin activates via protease-activated receptors (PAR), of which 4 isotypes have been described. It also binds GPIb/V/IX, which is equally a receptor for vWF. TxA₂ activates through the TP-receptor, a prostanoid-receptor (not shown are epinephrine and serotonin, which may also activate platelets in vivo). Following receptor mediated platelet activation the platelet GPIIb/IIIa integrin receptor is activated and secreted from platelet granules, which ultimately mediates platelet-platelet binding through fibrinogen and thus is indispensable for aggregation. Other sequele of platelet activation include activation of platelet cyclooxygenase-1 (COX) which induces formation and release of auto-activating TxA₂. Abbreviations: ADP, adenosine diphosphate; TxA₂, thromboxane A₂; vWF, von-Willebrandt Factor.

Figure 2

Established antiplatelet substances. Thienopyridines such as ticlopidine or clopidogrel need to be hepatically converted into an unknown active metabolite in order to exert antagonistic action at the P2Y₁₂ ADP receptor. Aspirin acts as an irreversible inhibitor of cyclooxygenase (COX), which leads to a decreased production of platelet TxA₂. GPIIb/IIIa Inhibitors in contrast prevent a mechanic event in platelet activation, which is the binding of fibrinogen, the most important prerequisite for platelet-platelet binding and thus aggregation. GPIIb/IIIa inhibitors are either monoclonal antibodies (Abciximab) or peptides of low molecular weight (Eptifibatide, Tirofiban). (Not shown are the antiplatelet drugs dipyridamol, which is contained in Aggrenox™, or cilostazol, both inhibitors of phosphodiesterases). Abbreviation: ADP, adenosine diphosphate.

Figure 3

Potential new targets of antiplatelet substances. Aside from the development of further P2Y₁₂ ADP receptor antagonists, which are either thienopyridines or non-thienopyridine structured and may have improved efficacy and advantageous pharmacokinetics, there are receptors for important physiological platelet agonists that clinically have not been targeted yet, but represent structures with potential for pharmacological development, due to insights from experimental studies. Amongst these are the platelet collagen receptor GPVI, the GPIb receptor and thrombin binding protease activated receptors (PAR). Substances against the latter are already in preclinical testing.