Figure 2.25 Time- and dose-dependent inhibition of arachidonic acid-induced formation ofTXB2 (a) and prostacyclin (6-keto-PGF1a) (b) in platelet-rich plasma in healthy volunteers ex vivo after i.v. or oral aspirin (note the different scaling at the ordinate forTXB2 and 6-keto-PGF1a) (modified after Hohlfeld and Nagelschmitz, in preparation).
conventional antiplatelet doses in vivo. Even pre-treatment with 1200 mg/day sodium salicylate for 3 days did not antagonize the inhibition of platelet function and thromboxane formation after 350 mg i.v. single-dose aspirin .
The inhibition of platelet COX-1 and platelet function by aspirin is functionally antagonized by the 10-15% fresh platelets that enterthe circulation every day from the bone marrow. Thus, some reduction of the antiplatelet activity after cessation of aspirin is seen at 1-2 days, but 4-5 days are required to fully restore normal platelet function in healthy volunteers .
Dose-Dependent Inhibition of Platelet Function by Aspirin No other issue in aspirin research has been discussed more intensively than the question of the optimal antithrombotic dose - frequently though not necessarily correctly put on a level with the antiplatelet dose. There is general agreement that daily doses of 75-100 mg aspirin are sufficient to inhibit platelet-dependent thromboxane formation. Somewhat higher doses may be required if enteric-coated preparations are used, possibly because of a lower bioavailability of aspirin . In terms of platelet-dependent thromboxane formation in serum - a surrogate estimate for the platelets' thromboxane-forming capacity - more than 95% have to be eliminated for a clinically relevant inhibition of platelet function [257-259]. However, this thromboxane-synthesizing capacity is an in vitro artifact useful to determine the pharmacological potency of aspirin to inhibit thrombox-ane formation but without any physiological correlate to circulating thromboxane levels in vivo, which are significantly lower (Section 3.1.2).
A direct comparison between single-dose and repeated-dose administration of aspirin to men shows two parallel dose-response curves differing in IC50 values by afactorof 8thatis equivalent to the platelet turnover rate and suggests that a daily maintenance dose that compensates for the entry of new platelets into the circulation is sufficient [255, 260] (Figure 2.26). However, this is also a pharmacological assay and most if not all doses of
Figure 2.26 Dose-dependent inhibition of thromboxane (B2) (TXB2) formation in serum after single (O) and repeated (5 days, •) oral administration of aspirin to healthy volunteers. Inhibition of thromboxane formation in serum by 50% (ID50) requires 26 mg aspirin as a single dose. Forthe same effect, only 3.2 mg is necessary at repeated administration. The about eightfold lower ID50 at repeated administration corresponds to the maintenance dose of aspirin necessary to acetylate fresh platelets that enter the circulation every day from the bone marrow. (modified after ).
aspirin used here inhibit thromboxane formation by less than 95%, that is, they do not inhibit platelet function and are, therefore, clinically ineffective.
The subcellular targets of thromboxane in platelets and their interactions are still not completely understood. At least theoretically, it is likely that thromboxane per se rather acts as a platelet-derived amplification factor for further platelet recruitment and activation than being a direct stimulus for platelet secretion . There is also evidence for thromboxane-dependent thrombin activation that then might connect platelet activation with the clotting process.
Platelet stimulation by thromboxane results in Gq-G12/13 coupled phospholipase C (PLC) activation and subsequent activation of protein kinase C (PKC). Similar activation pathways are used by thrombin. Since the receptor-G-protein-effector systems are complex networks, synergistic signaling between TXA2 and other platelet-activating agents, acting via the common G proteins (Gq), such as thrombin and thromboxane A2, occurs . In addition, thrombin transcriptionally upregulates thromboxane receptors in acute myocardial p 100
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