Polymorphisms of genes related to phase II metabolism and resistance to clopidogrel

Clopidogrel is an antiplatelet drug commonly used to prevent coagulation. This review aimed to investigate the effect of polymorphisms of G6PD, GCLC, GCLM, GSS, GST, GSR, HK and GLRX genes on clopidogrel during phase II metabolism through exploring previous studies. The results revealed that low glutathione plasma levels caused by several alleles related to these genes could affect the bioactivation process of the clopidogrel prodrug, making it unable to inhibit platelet aggregation perfectly and thus leading to severe consequences in patients with a high risk of blood coagulation. However, the study recommends platelet reactivity tests to predict clopidogrel efficacy rather than studying gene mutations, as most of these mutations are rare and other nongenetic factors could affect the drug’s efficacy.

Platelet binding to polymerizing fibrin is avidity driven and requires activated αIIbβ3 but not fibrin cross-linking

The molecular basis of platelet-fibrin interactions remains poorly understood despite the predominance of fibrin in thrombi. We have studied the interaction of platelets with polymerizing fibrin by adding thrombin to washed platelets in the presence of the peptide RGDW, which inhibits the initial platelet aggregation mediated by fibrinogen binding to αIIbβ3 but leaves intact a delayed increase in light transmission (delayed wave; DW) as platelets interact with the polymerizing fibrin. The DW was absent in platelets from a patient with Glanzmann thrombasthenia, indicating a requirement for αIIbβ3. The DW required αIIbb3 activation and it was inhibited by the αIIbβ3 antagonists eptifibatide and the monoclonal antibody (mAb) 7E3, but only at much higher concentrations than needed to inhibit platelet aggregation initiated by a thrombin receptor activating peptide (T6). Surface plasmon resonance and scanning electron microscopy studies both supported fibrin having greater avidity for αIIbβ3 than fibrinogen rather than greater affinity, consistent with fibrin’s multivalency. mAb 10E5, a potent inhibitor of T6-induced platelet aggregation, did not inhibit the DW, suggesting that fibrin differs from fibrinogen in its mechanism of binding. Inhibition of factor XIII–mediated fibrin cross-linking by >95% reduced the DW by only 32%. Clot retraction showed a pattern of inhibition similar to that of the DW. We conclude that activated αIIbβ3 is the primary mediator of platelet-fibrin interactions leading to clot retraction, and that the interaction is avidity driven, does not require fibrin cross-linking, and is mediated by a mechanism that differs subtly from that of the interaction of αIIbβ3 with fibrinogen.

Garlic inhibitory effect on platelet activity induced by different agonists

Platelets are essential elements of human blood. In addition to their normal role, platelets are involved in causing myocardial infarction, stroke and other thrombotic disorders. Platelet activation in vivo, probably involves a combination of agonists. Garlic has beneficial effects due to its ability to inhibit platelet aggregation and thromboxane formation. The aim of this work was to evaluate the ability of garlic extracts to inhibit platelet aggregation induced by different agonists and their mixtures in different donors. Significant differences were found in platelet aggregation in response to each agonist (P ≤ 0.05). The highest antiaggregatory effect was observed with arachidonic acid and the lowest effect with collagen-arachidonic acid mixture. Interaction effects between donor and agonist (or mixtures) were detected. The study showed the potential of aqueous garlic extracts to prevent platelet aggregation induced by different agonist. Highlights Platelets play a central role in the progression of atherosclerotic lesions. Blood from nine non-smoker healthy donors was used for in vitro platelet aggregation study. Significant differences were found in platelet aggregation in response to each agonist. Aqueous garlic extracts could prevent platelet aggregation induced by different agonist.

Antiplatelet activity and chemical analysis of leaf and fruit extracts from Aristotelia chilensis

Aristotelia chilensis (Mol.) Stuntz, also known as maqui, is a plant native to Chile without chemical characterization and quantification of the bioactive compounds present in it. HPLC-UV and HPLC-MS/MS studies have shown the presence, at different concentrations, of phenolic and anthocyanin compounds in fruit and leave extracts of the domesticated maqui clones Luna Nueva, Morena, and Perla Negra. The extracts from leaves and unripe fruits of Luna Nueva and Morena clones significantly inhibit platelet aggregation induced by several agonists; the extracts inhibit platelet granule secretion by decreasing the exposure of P-selectin and CD63 at the platelet membrane. Reactive oxygen species formation in platelets is lower in the presence of maqui extracts. Statistical Pearson analysis supports the levels of phenolic and anthocyanin compounds being responsible for the antiaggregant maqui effects. This work is the first evidence of antiplatelet activity from Aristotelia chilensis giving added value to the use of leaves and unripe fruits from this species.

Resveratrol inhibits Ca2+ signals and aggregation of platelets

Background Resveratrol has been shown to inhibit platelet aggregation. However, the mechanism for this action of resveratrol remains to be clarified. The purpose of this study was to elucidate the Ca2+-related mechanism for the inhibitory action of resveratrol on platelet aggregation. Methods Ca2+ entry and subsequent aggregation of human platelets induced by different stimulants including thrombin, thapsigargin, and 1-oleoyl-2-acetylglycerol (OAG) were measured by the fluorescence method and light transmittance method, respectively. Each stimulant was added to a nominally Ca2+-free medium containing platelets, and then CaCl2 was added to the medium to induce Ca2+ influx into platelets. Results Thapsigargin-induced Ca2+ entry into platelets and subsequent platelet aggregation were significantly inhibited in the presence of resveratrol at 6.25 μM or higher concentrations, while OAG-induced Ca2+ entry and subsequent platelet aggregation were not affected by resveratrol at concentrations up to 50 μM. In the nominally Ca2+-free medium, thrombin induced a small transient increase in intracellular Ca2+ concentrations, which was attenuated in the presence of resveratrol at 12.5 μM or higher concentrations. Thrombin-induced Ca2+ entry into platelets and subsequent platelet aggregation were significantly inhibited in the presence of resveratrol at 12.5 μM or higher concentrations. Conclusions The results suggest that resveratrol inhibits thrombin-induced platelet aggregation through decreasing Ca2+ release from its stores and inhibiting store-operated Ca2+ influx into platelets.

Stronger inhibitory effects of ticagrelor plus aspirin compared with clopidogrel plus aspirin on arachidonic acid induced platelet aggregation in patients with acute coronary syndrome with PCI

Antagonists of the adenosine diphosphate (ADP) receptor, P2Y12 may inhibit platelet aggregation resulting from stimulation with arachidonic acid (AA). The potent P2Y12 blocker, ticagrelor has greater anti-platelet effects than clopidogrel. We explored the effects of ticagrelor versus clopidogrel on mean maximum aggregation ratios (MAR%) in response to AA stimulation in patients receiving conventional aspirin dosages. A total of 613 acute coronary syndrome (ACS) patients were followed from October 2017 to October 2018. At the 1- and 6-month follow-up visit, mean AA-MAR% was lower in the ticagrelor group when compared with the clopidogrel group (28.9% vs. 31.7%, 28.4% vs. 31.0%, P<0.001 and P=0.001, respectively). BARC1-2 bleeding occurred with greater frequency with ticagrelor rather than clopidogrel treated patients (29.3% vs. 9.5%, P<0.001; 23.5% vs. 9.3%, P<0.001). Excessive platelet inhibition and decreased AA-MAR% were considered the main reasons for the severe subcutaneous/dermal bleeding in ticagrelor treated patients. Continuous...

A Review on the Effects of New Anti-Diabetic Drugs on Platelet Function

Background: Cardiovascular complications account for the majority of deaths caused by diabetes mellitus. Platelet hyperactivity has been shown to increase the risk of thrombotic events and is a therapeutic target for their prevention in diabetes. Modulation of platelet function by diabetes agents in addition to their hypoglycemic effects would contribute to cardiovascular protection. Newly introduced antidiabetic drugs of sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors may have anti-platelet effects, and in the case of SGLT2i and GLP-1RA may contribute to their proven cardiovascular benefit that has been shown clinically. Objective: Here, we reviewed the potential effects of these agents on platelet function in diabetes. Results and Conclusion: GLP-1RA and DPP-4i drugs have antiplatelet properties beyond their primary hypoglycemic effects. Whilst we have little direct evidence for the antiplatelet effects of SGLT2 inhibitors, some studies have shown that these agents may inhibit platelet aggregation and reduce the risk of thrombotic events in diabetes.

UPLC-Q-TOF/MS-Based Plasma Metabolomics to Evaluate the Effects of Aspirin Eugenol Ester on Blood Stasis in Rats

Aspirin eugenol ester (AEE) is a novel compound that is formed from the esterification of aspirin (acetylsalicylic acid (ASA)) and eugenol. This study aimed to investigate the effects of AEE on blood stasis in rats and to characterize the underlying mechanisms using a plasma metabolomic study. The results indicate that AEE and ASA could modulate whole blood viscosity (WBV), plasma viscosity (PV), blood coagulation parameters, platelet count, platelet aggregation, lactate dehydrogenase (LDH), creatinine (CR) and the levels of thromboxane A2 (TXA2) and 6-keto prostaglandin F1α (6-keto-PGF1α). The metabolic profiles of the plasma samples from all groups were clearly separated in the score plots. Nineteen potential metabolites were selected and identified, and disordered levels of these metabolites could be regulated by AEE and ASA. Pathway analysis showed that the mechanism of action of AEE on blood stasis might be principally related to the metabolism of amino acid, fatty acid, energy and glycerophospholipid. The above results indicate that AEE protected the rats against blood stasis, and that this effect might have been caused by the anticoagulation activity of AEE and its abilities to maintain a balance between TXA2 and PGI2, reduce blood viscosity, inhibit platelet aggregation and normalize the plasma metabolic profile.