infarction [263-265]. Interruption of this positive feedback loop by aspirin prevents thromboxane formation and its synergism with thrombin. This synergism is highly desirable and effective, for example, in treatment of myocardial infarction. Similar considerations may apply to other situations with an overproduction ofthromboxane or enhanced thromboxane receptor numbers, such as preeclampsia (Section 4.1.5), erythromelalgia, exposition to testosterone, or cigarette smoking .
The high sensitivity of platelet COX-1 against aspirin, the fact that platelet-dependent thrombox-ane formation occurs largely (>99%) via COX-1, and the functional irreversibility of this effect for the platelet were the main pharmacological reasons to search for the lowest dose of aspirin, in particular, for long-term use in cardiovascular prevention. However, prophylactic treatment of arterial thrombosis is frequently performed in patients at enhanced vascular risk, that is, patients at more or less advanced stages of atherosclerosis. In these (inflammatory) conditions, nonplatelet sources of prostaglandin endoperoxides, the immediate precursors of thromboxane A2, become increasingly important, for example, an upregulated COX-2 in endothelial cells or in monocytes/macrophages. This allows for transcellular precursor exchange and for platelet COX-1-independent thromboxane formation that is less sensitive to aspirin . Alternatively, endothelial cells may use platelet-derived prostaglandin endoperoxides to increase prostacyclin production . Moreover, studies in knockout mice have shown that prostacyclin inhibits thromboxane formation and intimal thickening via the prostacyclin receptor , pointing to the significance of (COX-2)-derived prostacyclin production for control of thrombox-ane formation. Thus, aspirin dosage recommendations, which are based solely on clotting blood assays or platelet-rich plasma of healthy volunteers ex vivo, may not apply directly to patients with atherosclerotic diseases and hyperreactive platelets in vivo.
Red Cells and Platelet "Recruitment" Red cells can markedly enhance platelet reactivity in vivo and in vitro. This becomes evident by increased platelet thromboxane formation, release of intracellular platelet granule components, and recruitment of additional platelets from the microenvironment into the developing thrombus . In consequence, antiplatelet effects of aspirin may also be modulated by red cells, in particular, at low aspirin doses. In one study, collagen-induced platelet activation in the presence of red cells was only partially inhibited by 50 mg aspirin/day in healthy volunteers and 200 or 300 mg aspirin/day in patients with ischemic heart disease, despite a nearly complete (>94%) inhibition of serum thromboxane formation. It was concluded that inhibition of platelet function in vitro in platelet-rich plasma might not reflect sufficiently the therapeutic efficacy of aspirin in vivo because of the absence of red cells . Interestingly, a loading dose of 500 mg aspirin was found to be sufficient to inhibit the proaggregatory activity of red cells on platelets . This agrees with the clinical experience on aspirin "loading" doses mentioned above.
Aspirin Versus Other Antiplatelet Drugs Aspirin is the only antiplatelet agent in clinical use that acts by blocking thromboxane formation. Therefore, aspirin will act synergistically with other antiplatelet compounds, such as ADP-receptor antagonists or antithrombins, that separately interact with other pathways of platelet activation. All currently used platelet antagonists eventually inhibit clustering and activation of the platelet GPIIb/IIIa receptor, that is, prevent binding of fibrinogen and von Willebrand factor and aggregation by interplatelet bridging (Table 2.11). The clinical potency of aspirin as an antiplatelet drug depends entirely on the significance of the thromboxane pathway for platelet activation and secretion. This explains why aspirin is more effective in some clinical situations of platelet hyperreactivity than in others. An overview on the mode of antiplatelet action of aspirin as compared with other antiplatelet agents is shown in Figure 2.27.
Aspirin also differs from other antiplatelet agents with respect to target selectivity. Aspirin
Table 2.11 Some pharmacological properties of antiplatelet drugs.
Mechanism of antiplatelet action
Action platelet specific
Oral administration possible
Additional effects within the circulation
Inhibition of TX generation
No No Yes
Blockade ofP2Y12-ADP receptor
Blockade of GPIIb/IIIa receptors
Yes Yes No
No aClopidogrel might indirectly modify cell function via inhibition of release of platelet-derived products (CD40, PDGF, and serotonin, etc.).
bAspirin at doses >300 mg not only has additional endothelial protective and anti-inflammatory properties but also largely prevents vascular prostacyclin production.
exhibits a broad spectrum of biological activities that are not restricted to or even specific for the platelet, whereas both thienopyridines and GPIIb/ Ilia antagonists are largely platelet specific. This is because ofthe fact that their molecular targets, the P2Y12 and GPIIb/IIIa receptors, are specifically expressed on platelets. This does not exclude pleio-tropic actions of aspirin and thienopyridines via the modification of generation and release of platelet-derived mediators and their action on nonplatelet targets, for example, P-selectin receptors (PSGL) or CD40L.
Thromboxane-Independent Pathways of Platelet Activation The antiplatelet potency of aspirin depends on the stimulus. At antiplateletdoses, aspirin will not inhibit platelet stimulation by thrombin, the most potent platelet-activating agent. Aspirin will also not antagonize platelet aggregation  or secretion  induced by ADP, shear stress [273, 275, 276], or high-dose collagen. Aspirin does only partially , if at all , antagonize the platelet activation by norepinephrine. Aspirin will also not antagonize the platelet stimulatory actions of isoprostanes and nonenzymatic products of lipid
(Collagen, thrombin, adrenaline, shear stress)
(Collagen, thrombin, adrenaline, shear stress)
Figure 2.27 Sites of action of antiplatelet drugs.
Fibrinogen binding aggregate formation
peroxidation that bind to the platelet thromboxane receptor  and might act synergistically with enzymatically generated TXA2 (Figure 2.27). Iso-prostane formation is, therefore, considered as one explanation for aspirin "resistance" (Section 4.1.6). Finally, aspirin will also not inhibit platelet activation induced by psychical stress [280, 281].
These variable actions of aspirin on platelet function in dependency of the activation mode explain its variable antiplatelet activity in clinical use. In vivo, not one but several different stimuli act together simultaneously and determine platelet reactivity and aggregation. This offers a simple explanation for the variable treatment efficacy or even treatment failure with the drug in vivo. Thus, treatment failures are not necessarily related to a pharmacological inability of aspirin to work, that is, to prevent platelet-/COX-1-derived thromboxane biosynthesis.
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