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Nice paper. Thanks for putting that in your writeup:
Anti-platelet therapy: cyclo-oxygenase inhibition and the use of aspirin with particular regard to dual anti-platelet therapy
Aspirin and P2Y[12] antagonists are commonly used anti-platelet agents. Aspirin produces its effects through inhibition of thromboxane A[2] (TXA[2] ) production, while P2Y[12] antagonists attenuate the secondary responses to ADP released by activated ...
www.ncbi.nlm.nih.gov
Aspirin will give you an anti-clotting effect, and if you believe my results a reduction in Hct, but it's not all a free lunch.
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Aspirin's effects on the cardiovascular system other than the platelet
Because of its primary effect in platelets, it is often forgotten that aspirin is also inhibitory at other sites within the cardiovascular system. Recent concerns about the potential pro-thrombotic effects of the COX-2-selective drugs were initially prompted by studies showing that consumption of either celecoxib [39] or rofecoxib [38] reduced urinary PGI2 metabolites, an effect that was interpreted as being consistent with an increased risk of thrombosis because of a loss in anti-thrombotic PGI2. However, aspirin was shown more than 10 years earlier to reduce urinary PGI2 metabolites, although the reduction was less marked than the reduction in TXA2 metabolites [1]. These investigators used a wide dose range of aspirin, 20–2600 mg day−1, and found that lower doses of aspirin had greater inhibitory effects upon TXA2 than PGI2 metabolites. However, they found that inhibition of platelet function was not maximal at the lower aspirin dosage and notably that aspirin at doses greater than 80 mg day−1 caused substantial inhibition of endogenous PGI2 production. They concluded that it was ‘unlikely that any dose of aspirin can maximally inhibit thromboxane generation without also reducing endogenous prostacyclin biosynthesis’. In support of this idea, local infusion of aspirin to the human coronary bed has been shown to increase coronary vascular resistance and reduce coronary blood flow [69], as has i.v. infusion of indomethacin [70]. So if it is able to reduce the intravascular production of PGI2, aspirin could also release a brake upon atherosclerotic disease progression and platelet activation, as well as promoting vasoconstriction. Taken together these could increase the risk of adverse cardiovascular events, an idea supported by the report that individuals with dysfunctional IP receptors have accelerated cardiovascular disease [71]. Further support for this concept can be derived from studies using mouse models. For example, in a mouse model of atherosclerosis, deletion of the IP receptor was found to enhance disease progression, whereas deletion of the TP receptor or treatment with a TP receptor antagonist reduced atherogenesis [72, 73]. Similarly, platelet and vascular responses following experimental injury are enhanced in knockout mice lacking the IP receptor, and may be depressed in mice lacking the TP receptor [74, 75]. Finally, a gene/dose dependent relationship between blood pressure, platelet aggregation and thrombogenesis has been demonstrated using heterozygote and homozygote knock out mice for the IP receptor [76].The effects of aspirin at sites other than the platelet are informed by the recent understanding that inhibition of COX-2 isoforms by NSAIDs is associated with an increased risk of adverse cardiovascular events [4, 5, 8, 11, 18, 77]. While on the one hand these effects could be associated with inhibition of the vascular production of PGI2 leading directly to local increases in platelet reactivity, on the other hand it is also important to realize that aspirin and NSAIDs can increase blood pressure in normotensive subjects and in those with existing hypertension [4, 5, 9, 11, 14, 15, 18, 20, 23, 77] thereby increasing the risk of thrombotic events through exacerbation of the development of atherosclerotic disease [78]. Indeed, the use of these drugs is weakly associated with an increased risk of congestive heart failure [79] and an increased risk of hypertension [80]. As these effects are COX mechanism-driven and dose-related, it is clear that higher doses of aspirin and longer exposures have greater effects than lower doses and shorter exposures [80].
In addition to the PGI2 and TXA2 pathways, aspirin also affects the production of other prostanoids within the circulation, most notably PGE2. PGE2 has been identified as both an inhibitor and a potentiator of platelet aggregation via interaction with different isoforms of the EP receptor (see above). Interestingly, deletion of the F prostanoid receptor (FP) in mice reduces blood pressure and atherogenesis associated with disruption of renin release in the kidney [81], so it is important not to become too narrowly focused on aspirin and platelet endothelial cell interactions although this is very much where the weight of evidence lies.
Conclusion
In summary, in vitro, ex vivo and in vivo mechanistic studies link the anti-thrombotic effects of aspirin to irreversible inhibition of platelet COX-1 and formation of TXA2. However, aspirin also produces dose-dependent inhibition of COX at other sites within the body and some of these inhibitory effects, notably reduction in endothelial cell production of PGI2 and increase in blood pressure, are associated with an increase in overall cardiovascular risk. P2Y12-receptor antagonists have also been shown to be anti-thrombotic because of their blockade of ADP-dependent pathways of platelet activation, and dual therapy with aspirin has now become standard care for many patients at risk of thrombosis. While clinical trials using clopidogrel have investigated interactions with aspirin, large outcome studies of newer and more potent P2Y12-receptor antagonists, notably prasugrel and ticagrelor, have not randomized the dose of aspirin. As potent P2Y12-receptor antagonists can strongly inhibit TXA2-dependent pathways of platelet activation, i.e. those targeted by aspirin, and sensitize platelets to the anti-thrombotic effects of endogenously produced PGI2, there is the possibility that additional dosing with aspirin, in particular high-dose aspirin, will not confer any additional cardioprotective effect. On the contrary, there is a possibility that combining a high level of P2Y12 antagonism with high doses of aspirin could unmask an effect of aspirin on the production of anti-thrombotic prostanoids, notably PGI2, increase the risk of fluid retention and hypertension, and increase the risk of bleeds, particularly gastrointestinal bleeds. Clearly this currently is only a hypothesis. However, as these effects could impair the overall therapeutic benefit of the treatment, it will be important to evaluate further this concept in pre-clinical and clinical studies.====
