Pharmacological management of thrombotic complications is strongly influenced by antiplatelet treatment strategies. Recent clinical trials have clearly indicated that current antiplatelet strategies may not inhibit recurrent thrombotic events in selected patients and improvement is necessary. Recently, there has been a gradual modification in the guidelines for clopidogrel dosing. In addition, newly developed P2Y(12) receptor inhibitors and thrombin inhibitors are undergoing Phase II and III clinical trials. Moreover, research related to novel agents that interfere with other steps in coagulation and platelet adhesion, and platelet thromboxane and thrombin receptor blockers, show promise. An important future step will probably be the development of personalized therapy based on defining the individual patient's propensity for thrombosis through investigation of platelet-thrombin-fibrin interactions. Such an approach will enhance the targeting of specific therapy based on the pathophysiology of the individual patient.
"The multiple pathways of platelet activation limit the effect of specific receptor/pathway inhibitors, resulting in limited clinical efficacy  . Recent research has confirmed that combination therapy results in enhanced antithrombotic efficacy without increasing bleeding risk . "
[Show abstract][Hide abstract] ABSTRACT: Platelet activation is a critical component of atherothrombosis. The multiple pathways of platelet activation limit the effect of specific receptor/pathway inhibitors, resulting in limited clinical efficacy. Recent research has confirmed that combination therapy results in enhanced antithrombotic efficacy without increasing bleeding risk. In this way, the best-known inhibitor and turn off signaling in platelet activation is cAMP. In this article we discuss the mechanisms of regulation of intraplatelet cAMP levels, a) platelet-dependent pathway: Gi/Gs protein–coupled receptors, phosphodiesterase inhibition and activation of PPARs and b) platelet-independent pathway: inhibition of adenosine uptake by erythrocytes. With respect to the association between intraplatelet cAMP levels and bleeding risk it is possible to establish that compounds/drugs with pleitropic effect for increased intraplatelet cAMP level could have an antithrombotic activity with less risk of bleeding.
Thrombosis Research 08/2014; 134(2). DOI:10.1016/j.thromres.2014.04.027 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Controversy surrounds the optimal platelet aggregation measurement to assess clopidogrel non-responsiveness. The P2Y12 reactivity ratio (PRR) determined by vasodilator-stimulated phosphoprotein phosphorylation levels has been used to indicate the extent of P2Y(12) blockade.
We sought to compare the prevalence of non-responsiveness measured by maximum (MA) and 6 min aggregation (FA) and correlate these measurements with PRR in patients with non-responsiveness.
MA and FA were measured in stented patients (n=100) before and after clopidogrel treatment. The PRR was determined in 22 non-responsive patients. Responsiveness was defined as pre-treatment minus post-treatment aggregation; and non-responsiveness was defined as <10% change in platelet aggregation.
Responsiveness was greater as determined by FA, p=0.006 (5 microM ADP) and p=0.003 (20 microM ADP)). There was a strong correlation between MA and FA stimulated by 5 microM (r=0.84, p<0.0001) and 20 microM ADP (r=0.90, p<0.001). The prevalence of non-responsiveness rose with agonist concentration but did not differ significantly between methods: 5 microM ADP [22% (MA) vs. 17% (FA), p=0.186] and 20 microM ADP [33% (MA) vs. 29% (FA), p=0.270]. PRR correlated with both MA (r=0.66, p<0.001) and FA (r=0.74, p<0.001) in non-responsive patients indicating incomplete receptor blockade.
Clopidogrel responsiveness is higher when measured by FA as compared to MA. However, these measurements are equivalent in determining the prevalence of non-responsiveness: FA and MA are affected to the same degree in patients with non-responsiveness. These findings are relevant to ongoing studies assessing platelet inhibition by P2Y(12) inhibitors and support previous studies that employed MA to assess non-responsiveness.
Thrombosis Research 01/2007; 121(1):107-15. DOI:10.1016/j.thromres.2007.02.007 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The antiplatelet effect of aspirin is attributed to platelet cyclooxygenase-1 inhibition. Controversy exists on the prevalence of platelet resistance to aspirin in patients with coronary artery disease and effects of aspirin dose on inhibition. Our primary aim was to determine the degree of platelet aspirin responsiveness in patients, as measured by commonly used methods, and to study the relation of aspirin dose to platelet inhibition.
We prospectively studied the effect of aspirin dosing on platelet function in 125 stable outpatients with coronary artery disease randomized in a double-blind, double-crossover investigation (81, 162, and 325 mg/d for 4 weeks each over a 12-week period). At all doses of aspirin, platelet function was low as indicated by arachidonic acid (AA)-induced light transmittance aggregation, thrombelastography, and VerifyNow. At any 1 dose, resistance to aspirin was 0% to 6% in the overall group when AA was used as the agonist, whereas it was 1% to 27% by other methods [collagen and ADP-induced light transmittance aggregation, platelet function analyzer (PFA-100)]. Platelet response to aspirin as measured by collagen-induced light transmittance aggregation, ADP-induced light transmittance aggregation, PFA-100 (81 mg versus 162 mg, P < or = 0.05), and urinary 11-dehydrothromboxane B2 was dose-related (81 mg versus 325 mg, P = 0.003). No carryover effects were observed.
The assessment of aspirin resistance is highly assay-dependent; aspirin is an effective blocker of AA-induced platelet function at all doses, whereas higher estimates of resistance were observed with methods that do not use AA as the stimulus. The observation of dose-dependent effects despite nearly complete inhibition of AA-induced aggregation suggests that aspirin may exert antiplatelet properties through non-cyclooxygenase-1 pathways and deserves further investigation.
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