BACKGROUND AND AIMS: It is well known that elevated cholesterol is associated with enhanced platelet aggregation and patients suffering from familial hypercholesterolemia (FH) have a high risk of thrombotic cardiovascular events. Although decreasing cholesterol level is associated with attenuation of platelet hyperactivity, there are currently no data on the effect of convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9ab) on platelet reactivity in FH. The aim of the study was to analyse the impact of different therapies including PCSK9ab on platelet aggregation in FH. METHODS: This study enrolled all 15 patients treated in the University Hospital Hradec Králové for FH. PCSK9ab have been administered in 12 of 15 patients while 8 patients were also undergoing lipid apheresis. Blood samples from all patients including pre- and post-apheresis period were tested for platelet aggregation triggered by 7 inducers, and the effect of 3 clinically used drugs (acetylsalicylic acid, ticagrelor and vorapaxar) was compared as well. RESULTS: Although apheresis decreased the reactivity of platelets in general, platelet responses were not different between non-apheresis patients treated with PCSK9ab and apheresis patients (post-apheresis values) with the exception of ristocetin. However, when compared to age-matched healthy population, FH patients had significantly lower platelet aggregation responses to 4 out of 7 used inducers and higher profit from 2 out of 3 used antiplatelet drugs even after exclusion of FH patients regularly receiving conventional antiplatelet treatment. CONCLUSION: This study showed for the first time the suitability of PCSK9ab treatment for reduction of platelet reactivity in FH patients.
- MeSH
- agregace trombocytů * účinky léků MeSH
- dospělí MeSH
- hyperlipoproteinemie typ II * krev terapie farmakoterapie MeSH
- inhibitory agregace trombocytů * terapeutické užití farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- monoklonální protilátky terapeutické užití farmakologie MeSH
- PCSK9 inhibitory * MeSH
- proproteinkonvertasa subtilisin/kexin typu 9 * imunologie MeSH
- senioři MeSH
- separace krevních složek * MeSH
- trombocyty účinky léků metabolismus imunologie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Platelet aggregation is a complicated process mediated by different signaling pathways. As the process is highly complex and apparently redundant, the relationships between these pathways are not yet fully known. The aim of this project was to study the interconnections among seven different aggregation pathways in a group of 53 generally healthy volunteers aged 20 to 66 years. Platelet aggregation was induced with thrombin receptor activating peptide 6 (TRAP), arachidonic acid (AA), platelet activating factor 16 (PAF), ADP, collagen, thromboxane A2 analogue U46619 or ristocetin (platelet agglutination) ex vivo in fasting blood samples according to standardized timetable protocol. Additionally, some samples were pre-treated with known clinically used antiplatelet drugs (vorapaxar, ticagrelor or acetylsalicylic acid (ASA)). Significant correlations among all used inducers were detected (Pearson correlation coefficients (rP): 0.3 to 0.85). Of all the triggers, AA showed to be the best predictor of the response to other inducers with rP ranging from 0.66 to 0.85. Interestingly, the antiplatelet response to ticagrelor strongly predicted the response to unrelated drug vorapaxar (rP = 0.71). Our results indicate that a response to one inducer can predict the response for other triggers or even to an antiplatelet drug. These data are useful for future testing but should be also confirmed in patients.
Rozmarýn lékařský (Rosmarinus officinalis L.) je využíván již od starověku k léčebným, kultovním i magickým účelům. S přibývajícím stresem a chorobami je dnes stále více v oblibě pro mnoho způsobů použití jak ve farmacii, tak aromaterapii a také jako koření v kuchyni nebo konzervant. Tato rostlina má mnoho zajímavých obsahových látek (např. kyselina rozmarýnová a karnosová, karnosol), jež vykazují značné množství pozitivních farmakologických účinků
Rosemary (Rosmarinus officinalis L.) has been used since ancient times for medicinal, cultic, and magic purposes. With the stress and diseases, it is increasingly popular today for many uses in both pharmacy and aromatherapy, as a spice in the kitchen and as a preservative. This plant has many interesting compounds (e.g. rosmarinic and carnosic acid, carnosol), which show a considerable amount of positive pharmacological effects.
- MeSH
- léčivé rostliny MeSH
- lidé MeSH
- rostlinné extrakty farmakologie terapeutické užití MeSH
- rozmarýn * chemie MeSH
- Check Tag
- lidé MeSH
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.
- MeSH
- adenosindifosfát farmakologie MeSH
- agregace trombocytů * MeSH
- Aspirin terapeutické užití MeSH
- inhibitory agregace trombocytů * terapeutické užití MeSH
- kyselina 15-hydroxy-11 alfa,9 alfa-(epoxymethano)prosta-5,13-dienová farmakologie MeSH
- kyselina arachidonová farmakologie MeSH
- laktony farmakologie MeSH
- lidé MeSH
- trombocyty MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Elevated low-density lipoprotein (LDL) cholesterol levels lead to atherosclerosis and platelet hyperaggregability, both of which are known culprits of arterial thrombosis. Normalization of LDL cholesterol in familial hypercholesterolemia (FH) is not an easy task and frequently requires specific treatment, such as regularly performed lipid apheresis and/or novel drugs such as proprotein convertase subtilisin kexin 9 monoclonal antibodies (PCSK9Ab). Moreover, a high resistance rate to the first-line antiplatelet drug acetylsalicylic acid (ASA) stimulated research of novel antiplatelet drugs. 4-methylcatechol (4-MC), a known metabolite of several dietary flavonoids, may be a suitable candidate. The aim of this study was to analyse the antiplatelet effect of 4-MC in FH patients and to compare its impact on two FH treatment modalities via whole-blood impedance aggregometry. When compared to age-matched, generally healthy controls, the antiplatelet effect of 4-MC against collagen-induced aggregation was higher in FH patients. Apheresis itself improved the effect of 4-MC on platelet aggregation and blood from patients treated with this procedure and pretreated with 4-MC had lower platelet aggregability when compared to those solely treated with PCKS9Ab. Although this study had some inherent limitations, e.g., a low number of patients and possible impact of administered drugs, it confirmed the suitability of 4-MC as a promising antiplatelet agent and also demonstrated the effect of 4-MC in patients with a genetic metabolic disease for the first time.
- MeSH
- hyperlipoproteinemie typ II * farmakoterapie MeSH
- LDL-cholesterol MeSH
- lidé MeSH
- monoklonální protilátky farmakologie terapeutické užití MeSH
- proproteinkonvertasa subtilisin/kexin typu 9 MeSH
- proproteinkonvertasy terapeutické užití MeSH
- separace krevních složek * metody MeSH
- subtilisin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
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. 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.
- MeSH
- fenoly MeSH
- imunologické testy * MeSH
- katecholy * farmakologie MeSH
- lidé MeSH
- polyfenoly MeSH
- vyšetření funkce trombocytů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
