A polyphenol-rich diet has beneficial effects on cardiovascular health. However, dietary polyphenols generally have low bioavailability and reach low plasma concentrations. Small phenolic metabolites of these compounds formed by human microbiota are much more easily absorbable and could be responsible for this effect. One of these metabolites, 4-methylcatechol (4-MC), was suggested to be a potent anti-platelet compound. The effect of 4-MC was tested ex vivo in a group of 53 generally healthy donors using impedance blood aggregometry. The mechanism of action of this compound was also investigated by employing various aggregation inducers/inhibitors and a combination of aggregometry and enzyme linked immunosorbent assay (ELISA) methods. The 4-MC was confirmed to be more potent than acetylsalicylic acid on both arachidonic acid and collagen-triggered platelet aggregation. Its clinically relevant effect was found even at a concentration of 10 μM. Mechanistic studies showed that 4-MC is able to block platelet aggregation caused by the stimulation of different pathways (receptors for the von Willebrand factor and platelet-activating factor, glycoprotein IIb/IIIa, protein kinase C, intracellular calcium elevation). The major mechanism was defined as interference with cyclooxygenase-thromboxane synthase coupling. This study confirmed the strong antiplatelet potential of 4-MC in a group of healthy donors and defined its mechanism of action.

The process of platelet aggregation is often influenced by several factors including sex and age. A literature review confirmed the existence of sex-related differences in platelet aggregation. Although 68 out of 78 papers found such differences, there are still some controversies regarding these differences, which can be due to multiple factors (age, trigger, concomitant disease, sample handling, etc.). These outcomes are discussed in line with novel results obtained from a local study, in which blood samples from a total of 53 overall healthy women and men with ages ranging from 20 to 66 years were collected. Aggregation was induced with seven different triggers (ristocetin, thrombin receptor activating peptide 6 [TRAP-6], arachidonic acid [AA], platelet-activating factor 16 [PAF-16], ADP, collagen, or thromboxane A2 analog U-46619) ex vivo. In addition, three FDA-approved antiplatelet drugs (vorapaxar, ticagrelor, or acetylsalicylic acid [ASA]) were also tested. In general, women had higher aggregation responses to some agonists (ADP, TRAP), as well as lower benefit from inhibitors (ASA, vorapaxar). The aggregatory responses to AA and TRAP decreased with age in both sexes, while responses to ADP, U-46619, and PAF were affected by age only in women. In conclusion, more studies are needed to decipher the biological importance of sex-related differences in platelet aggregation in part to enable personalized antiplatelet treatment.