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1.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445660

RESUMO

Bortezomib (BTZ) has demonstrated its efficacy in several hematological disorders and has been associated with thrombocytopenia. There is controversy about the effect of BTZ on human platelets, so we set out to determine its effect on various types of platelet samples. Human platelets were investigated in platelet-rich plasma (PRP) and as gel-filtered platelets (GFPs). Mitochondrial inner membrane potential depolarization and phosphatidylserine (PS) and P-selectin expression levels were studied by flow cytometry, while thrombin generation was measured by a fluorescent method. In PRP, BTZ caused negligible PS expression after 60 min of treatment. However, in GFPs, PS expression was dose- and time-dependently increased in the BTZ-treated groups, as was P-selectin. The percentage of depolarized cells was also higher after BTZ pretreatment at both time points. Peak thrombin and velocity index increased significantly even with the lowest BTZ concentration (p = 0.0019; p = 0.0032) whereas time to peak and start tail parameters decreased (p = 0.0007; p = 0.0034). The difference between PRP and GFP results can be attributed to the presence of plasma proteins in PRP, as the PS-stimulating effect of BTZ could be attenuated by supplementing GFPs with purified human albumin. Overall, BTZ induces a procoagulant platelet phenotype in an experimental setting devoid of plasma proteins.


Assuntos
Apoptose , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/patologia , Bortezomib/farmacologia , Selectina-P/metabolismo , Ativação Plaquetária , Inibidores de Proteassoma/farmacologia , Antineoplásicos/farmacologia , Plaquetas/efeitos dos fármacos , Humanos , Selectina-P/genética
2.
Clin Pharmacol Ther ; 110(3): 702-713, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34255863

RESUMO

The African American (AA) population displays a 1.6 to 3-fold higher incidence of thrombosis and stroke mortality compared with European Americans (EAs). Current antiplatelet therapies target the ADP-mediated signaling pathway, which displays significant pharmacogenetic variation for platelet reactivity. The focus of this study was to define underlying population differences in platelet function in an effort to identify novel molecular targets for future antiplatelet therapy. We performed deep coverage RNA-Seq to compare gene expression levels in platelets derived from a cohort of healthy volunteers defined by ancestry determination. We identified > 13,000 expressed platelet genes of which 480 were significantly differentially expressed genes (DEGs) between AAs and EAs. DEGs encoding proteins known or predicted to modulate platelet aggregation, morphology, or platelet count were upregulated in AA platelets. Numerous G-protein coupled receptors, ion channels, and pro-inflammatory cytokines not previously associated with platelet function were likewise differentially expressed. Many of the signaling proteins represent potential pharmacologic targets of intervention. Notably, we confirmed the differential expression of cytokines IL32 and PROK2 in an independent cohort by quantitative real-time polymerase chain reaction, and provide functional validation of the opposing actions of these two cytokines on collagen-induced AA platelet aggregation. Using Genotype-Tissue Expression whole blood data, we identified 516 expression quantitative trait locuses with Fst values > 0.25, suggesting that population-differentiated alleles may contribute to differences in gene expression. This study identifies gene expression differences at the population level that may affect platelet function and serve as potential biomarkers to identify cardiovascular disease risk. Additionally, our analysis uncovers candidate novel druggable targets for future antiplatelet therapies.


Assuntos
Plaquetas/fisiologia , Grupos de Populações Continentais/genética , RNA Mensageiro/genética , Adolescente , Afro-Americanos/genética , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Citocinas/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Humanos , Masculino , Inibidores da Agregação Plaquetária/uso terapêutico , Testes de Função Plaquetária/métodos
3.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205175

RESUMO

The FcγRIIA/CD32A is mainly expressed on platelets, myeloid and several endothelial cells. Its affinity is considered insufficient for allowing significant binding of monomeric IgG, while its H131R polymorphism (histidine > arginine at position 131) influences affinity for multimeric IgG2. Platelet FcγRIIA has been reported to contribute to IgG-containing immune-complexe clearance. Given our finding that platelet FcγRIIA actually binds monomeric IgG, we investigated the role of platelets and FcγRIIA in IgG antibody elimination. We used pharmacokinetics analysis of infliximab (IgG1) in individuals with controlled Crohn's disease. The influence of platelet count and FcγRIIA polymorphism was quantified by multivariate linear modelling. The infliximab half-life increased with R allele number (13.2, 14.4 and 15.6 days for HH, HR and RR patients, respectively). It decreased with increasing platelet count in R carriers: from ≈20 days (RR) and ≈17 days (HR) at 150 × 109/L, respectively, to ≈13 days (both HR and RR) at 350 × 109/L. Moreover, a flow cytometry assay showed that infliximab and monomeric IgG1 bound efficiently to platelet FcγRIIA H and R allotypes, whereas panitumumab and IgG2 bound poorly to the latter. We propose that infliximab (and presumably any IgG1 antibody) elimination is partly due to an unappreciated mechanism dependent on binding to platelet FcγRIIA, which is probably tuned by its affinity for IgG2.


Assuntos
Doença de Crohn/tratamento farmacológico , Imunoglobulina G/genética , Infliximab/administração & dosagem , Receptores de IgG/genética , Adulto , Complexo Antígeno-Anticorpo/genética , Complexo Antígeno-Anticorpo/imunologia , Plaquetas/efeitos dos fármacos , Plaquetas/imunologia , Doença de Crohn/sangue , Doença de Crohn/genética , Doença de Crohn/imunologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina G/imunologia , Infliximab/farmacocinética , Masculino , Ativação Plaquetária/efeitos dos fármacos , Contagem de Plaquetas , Polimorfismo Genético/genética
4.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199303

RESUMO

The main purpose of new stent technologies is to overcome unfavorable material-related incompatibilities by producing bio- and hemo-compatible polymers with anti-inflammatory and anti-thrombogenic properties. In this context, wettability is an important surface property, which has a major impact on the biological response of blood cells. However, the influence of local hemodynamic changes also influences blood cell activation. Therefore, we investigated biodegradable polymers with different wettability to identify possible aspects for a better prediction of blood compatibility. We applied shear rates of 100 s-1 and 1500 s-1 and assessed platelet and monocyte activation as well as the formation of CD62P+ monocyte-bound platelets via flow cytometry. Aggregation of circulating platelets induced by collagen was assessed by light transmission aggregometry. Via live cell imaging, leukocytes were tracked on biomaterial surfaces to assess their average velocity. Monocyte adhesion on biomaterials was determined by fluorescence microscopy. In response to low shear rates of 100 s-1, activation of circulating platelets and monocytes as well as the formation of CD62P+ monocyte-bound platelets corresponded to the wettability of the underlying material with the most favorable conditions on more hydrophilic surfaces. Under high shear rates, however, blood compatibility cannot only be predicted by the concept of wettability. We assume that the mechanisms of blood cell-polymer interactions do not allow for a rule-of-thumb prediction of the blood compatibility of a material, which makes extensive in vitro testing mandatory.


Assuntos
Plaquetas/citologia , Comunicação Celular/efeitos dos fármacos , Monócitos/citologia , Monócitos/efeitos dos fármacos , Poliésteres/farmacologia , Plaquetas/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Agregação Plaquetária/efeitos dos fármacos , Água , Molhabilidade
5.
Blood Coagul Fibrinolysis ; 32(5): 305-311, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34231501

RESUMO

Treatment of venous thromboembolism with concomitant thrombocytopenia is challenging. The platelet threshold for safe administration of anticoagulants is under debate, with minimum platelet count of 50 × 109/l being recommended as the safe cutoff. However, some evidence suggests administration of anticoagulants may still be safe at platelet levels of 30 × 109/l. Therefore, we developed an in-vitro thromboelastography (TEG) study to examine the effect of therapeutic or prophylactic levels of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) on the clotting profile of platelet-reduced whole blood. Using magnetic bead-based antibody chromatography, platelets were removed to achieve platelet-depleted blood (<10 × 109/l of platelets). Platelet-depleted blood was then mixed with whole blood to produce blood samples with platelet counts of 30 × 109, 50 × 109 and 150 × 109/l. These blood samples were incubated with therapeutic or prophylactic levels of UFH or LMWH in disposable TEG cups. Clotting was initiated with 10 mmol/l calcium and optimized tissue factor levels for each anticoagulant used (2.25 pmol/l for UFH and 2.05 pmol/l for LMWH). Clotting was monitored by TEG at 37 °C for 180 min. The following TEG parameters were evaluated: R (time to clot), maximum amplitude (strength of clot) and area under the curve in 15 min (overall speed and strength of the clot at 15 min of clotting). No statistically significant differences were observed between platelet counts of 30 × 109 and 50 × 109/l for R, maximum amplitude or area under the curve in 15 min for most of the therapeutic and prophylactic doses of UFH and LMWH tested in this study. Use of anticoagulants compromised all of the TEG parameters relative to a normal platelet count of 150 × 109/l, in a dose dependent manner. The current study demonstrates that in-vitro clotting is impaired with use and increasing doses of anticoagulants. Despite this observation, we did not observe a significant difference in clotting between platelet levels of 30 × 109 and 50 × 109/l. Overall, this work provides further insight in the debated use of anticoagulants in patients with venous thromboembolism and concomitant thrombocytopenia, and provides support for possible use of anticoagulants at lower platelet thresholds.


Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas , Heparina de Baixo Peso Molecular/farmacologia , Heparina/farmacologia , Plaquetas/efeitos dos fármacos , Humanos , Contagem de Plaquetas , Tromboelastografia , Trombocitopenia/sangue , Tromboembolia Venosa/sangue
6.
Nutrients ; 13(7)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201950

RESUMO

Our understanding of platelet functionality has undergone a sea change in the last decade. No longer are platelets viewed simply as regulators of haemostasis; they are now acknowledged to be pivotal in coordinating the inflammatory and immune responses. This expanded role for platelets brings new opportunities for controlling a range of health conditions, targeting platelet activation and their interactions with other vascular cells. Antiplatelet drugs may be of wider utility than ever expected but often cause platelet suppression too strong to be used out of clinical settings. Dietary antiplatelets represent a nutritional approach that can be efficacious while safe for general use. In this review, we discuss potential new uses for dietary antiplatelets outside the field of cardiovascular health, with specific reference to the water-soluble tomato extract Fruitflow®. Its uses in different aspects of inflammation and immune function are discussed, highlighting exercise-induced inflammation, mediating the effects of air pollution, and controlling thrombotic aspects of the immune response. Potential future developments in women's health, erectile dysfunction, and the allergic response indicate how broad the utility of dietary antiplatelets can be.


Assuntos
Plaquetas/efeitos dos fármacos , Dieta/métodos , Lycopersicon esculentum , Extratos Vegetais/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Humanos , Imunidade/efeitos dos fármacos , Inflamação , Ativação Plaquetária/efeitos dos fármacos
7.
Hematology ; 26(1): 497-502, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34238136

RESUMO

OBJECTIVES: The objective of this analysis was to assess the effectiveness and safety of romiplostim in the real-world by duration of primary immune thrombocytopenia (ITP): <3 ('newly diagnosed'), 3-12 ('persistent'), and >12 ('chronic') months. METHODS: This was a post-hoc analysis of the PLATON single-arm, observational cohort study of adults from five Central and Eastern European countries receiving ≥1 romiplostim dose as second-line therapy, or where surgery was contraindicated. Durable (≥75% of measurements with ≥50 × 109 platelets/L during weeks 14-24) and overall platelet response (≥30 or ≥50 × 109 platelets/L at least once), rescue therapy, bleeding, discontinuation of other ITP medications, and adverse drug reactions (ADRs) were assessed. RESULTS: Of 100 participants, 22.0% had newly diagnosed, 17.0% had persistent, and 61.0% had chronic ITP. Prior splenectomy was most frequently reported in chronic ITP (32.8%), prior bleeding was predominant in newly diagnosed patients (68.2%). Durable platelet response was achieved in 50.0% (95% confidence interval [CI]: 28.2-71.8%) of newly diagnosed, 35.3% (95% CI: 14.2-61.7%) of persistent, and 31.1% (95% CI: 19.9-44.3%) of chronic ITP patients. Overall platelet response was achieved in >80% across all strata. Safety was comparable across groups, with a low incidence of thrombotic ADRs and no bone marrow ADRs. DISCUSSION: In this real-world study, platelet response to romiplostim was consistent across all strata of ITP duration. ADRs were infrequent and similar across ITP settings. CONCLUSION: These findings support the utilization of romiplostim in patients with newly diagnosed and persistent ITP in accordance with recent guidelines and the recent romiplostim label extension.


Assuntos
Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/uso terapêutico , Plaquetas/efeitos dos fármacos , Europa (Continente)/epidemiologia , Europa Oriental/epidemiologia , Humanos , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/epidemiologia , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/efeitos adversos , Trombopoetina/efeitos adversos , Resultado do Tratamento
8.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209789

RESUMO

Near-physiological in vitro thrombogenicity test systems for the evaluation of blood-contacting endothelialized biomaterials requires co-cultivation with platelets (PLT). However, the addition of PLT has led to unphysiological endothelial cell (EC) detachment in such in vitro systems. A possible cause for this phenomenon may be PLT activation triggered by the applied endothelial cell medium, which typically consists of basal medium (BM) and nine different supplements. To verify this hypothesis, the influence of BM and its supplements was systematically analyzed regarding PLT responses. For this, human platelet rich plasma (PRP) was mixed with BM, BM containing one of nine supplements, or with BM containing all supplements together. PLT adherence analysis was carried out in six-channel slides with plasma-treated cyclic olefin copolymer (COC) and poly(tetrafluoro ethylene) (PTFE, as a positive control) substrates as part of the six-channel slides in the absence of EC and under static conditions. PLT activation and aggregation were analyzed using light transmission aggregometry and flow cytometry (CD62P). Medium supplements had no effect on PLT activation and aggregation. In contrast, supplements differentially affected PLT adherence, however, in a polymer- and donor-dependent manner. Thus, the use of standard endothelial growth medium (BM + all supplements) maintains functionality of PLT under EC compatible conditions without masking the differences of PLT adherence on different polymeric substrates. These findings are important prerequisites for the establishment of a near-physiological in vitro thrombogenicity test system assessing polymer-based cardiovascular implant materials in contact with EC and PLT.


Assuntos
Materiais Biocompatíveis/farmacologia , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Meios de Cultura/farmacologia , Adulto , Materiais Biocompatíveis/química , Plaquetas/citologia , Meios de Cultura/química , Endotélio/citologia , Feminino , Humanos , Masculino , Teste de Materiais , Pessoa de Meia-Idade , Ativação Plaquetária/efeitos dos fármacos , Adesividade Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Polímeros/farmacologia , Tecidos Suporte/química
9.
Transfusion ; 61 Suppl 1: S101-S110, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34269459

RESUMO

BACKGROUND: There is a global increase in whole blood usage and at the same time, emerging pathogens give cause for pathogen reduction technology (PRT). The Mirasol PRT has shown promising results for plasma and platelet concentrate products. Treatment of whole blood with subsequent platelet survival and recovery analysis would be of global value. STUDY DESIGN AND METHODS: A two-arm, open-label laboratory study was performed with 40 whole blood collections in four groups: non-leukoreduced non-PRT-treated, non-leukoreduced PRT-treated, leukoreduced non-PRT-treated, and leukoreduced PRT-treated. Leukoreduction and/or PRT-treatment was performed on the day of collection, then all WB units were stored at room temperature for 24 h. Sampling was performed after hold-time and after 24-h storage in RT. If PRT-treatment or leukoreduction, samples were also taken subsequently after treatment. Thirteen healthy volunteer blood donors completed the in vivo study per protocol. All WB units were non-leukoreduced and PRT-treated. Radioactive labeling of platelets from RT-stored, PRT-treated whole blood, sampling of subjects, recovery, and survival calculations were performed according to the Biomedical Excellence for Safer Transfusion Collaborative protocol. RESULTS: In vitro characteristics show that PRT-treatment leads to increased levels of hemolysis, potassium, and lactate, while there are decreased levels of glucose, FVIII, and fibrinogen after 24 h of storage. All values are within requirements for WB. In vivo recovery and survival of platelets were 85.4% and 81.3% of untreated fresh control, respectively. CONCLUSIONS: PRT-treatment moderately reduces whole blood quality but is well within the limits of international guidelines. Recovery and survival of platelets are satisfactory after Mirasol treatment.


Assuntos
Plaquetas/efeitos dos fármacos , Plaquetas/efeitos da radiação , Segurança do Sangue , Fármacos Fotossensibilizantes/farmacologia , Riboflavina/farmacologia , Raios Ultravioleta , Plaquetas/citologia , Preservação de Sangue , Humanos , Testes de Função Plaquetária , Fatores de Tempo
10.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202163

RESUMO

Lusianthridin is a phenanthrene derivative isolated from Dendrobium venustum. Some phenanthrene compounds have antiplatelet aggregation activities via undefined pathways. This study aims to determine the inhibitory effects and potential mechanisms of lusianthridin on platelet aggregation. The results indicated that lusianthridin inhibited arachidonic acid, collagen, and adenosine diphosphate (ADP)-stimulated platelet aggregation (IC50 of 0.02 ± 0.001 mM, 0.14 ± 0.018 mM, and 0.22 ± 0.046 mM, respectively). Lusianthridin also increased the delaying time of arachidonic acid-stimulated and the lag time of collagen-stimulated and showed a more selective effect on the secondary wave of ADP-stimulated aggregations. Molecular docking studies revealed that lusianthridin bound to the entrance site of the cyclooxygenase-1 (COX-1) enzyme and probably the active region of the cyclooxygenase-2 (COX-2) enzyme. In addition, lusianthridin showed inhibitory effects on both COX-1 and COX-2 enzymatic activities (IC50 value of 10.81 ± 1.12 µM and 0.17 ± 1.62 µM, respectively). Furthermore, lusianthridin significantly inhibited ADP-induced suppression of cAMP formation in platelets at 0.4 mM concentration (p < 0.05). These findings suggested that possible mechanisms of lusianthridin on the antiplatelet effects might act via arachidonic acid-thromboxane and adenylate cyclase pathways.


Assuntos
Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Fenantrenos/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Difosfato de Adenosina/metabolismo , AMP Cíclico , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Humanos , Modelos Moleculares , Conformação Molecular , Fenantrenos/química , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Relação Estrutura-Atividade
11.
Front Immunol ; 12: 631696, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093524

RESUMO

In 2019 10 million people developed symptomatic tuberculosis (TB) disease and 1.2 million died. In active TB the inflammatory response causes tissue destruction, which leads to both acute morbidity and mortality. Tissue destruction in TB is driven by host innate immunity and mediated via enzymes, chiefly matrix metalloproteinases (MMPs) which are secreted by leukocytes and stromal cells and degrade the extracellular matrix. Here we review the growing evidence implicating platelets in TB immunopathology. TB patients typically have high platelet counts, which correlate with disease severity, and a hypercoagulable profile. Platelets are present in human TB granulomas and platelet-associated gene transcripts are increased in TB patients versus healthy controls. Platelets most likely drive TB immunopathology through their effect on other immune cells, particularly monocytes, to lead to upregulation of activation markers, increased MMP secretion, and enhanced phagocytosis. Finally, we consider current evidence supporting use of targeted anti-platelet agents in the treatment of TB due to growing interest in developing host-directed therapies to limit tissue damage and improve treatment outcomes. In summary, platelets are implicated in TB disease and contribute to MMP-mediated tissue damage via their cellular interactions with other leukocytes, and are potential targets for novel host-directed therapies.


Assuntos
Ativação Plaquetária/imunologia , Tuberculose/imunologia , Plaquetas/efeitos dos fármacos , Plaquetas/imunologia , Matriz Extracelular/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Tuberculose/tratamento farmacológico
12.
BMC Neurol ; 21(1): 247, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34182941

RESUMO

BACKGROUND: Dual antiplatelet therapy (DAPT) is necessary for stent assisted coiling. However, long term use of DAPT has a potential risk of hemorrhagic events. We aimed to examine the relationship between clopidogrel reactivity and complications. METHODS: Patients who underwent stent assisted coiling for unruptured aneurysms or previously treated aneurysms and received periprocedural DAPT in our institution between August 2011 to March 2020 were included. Platelet reactivity for clopidogrel was measured by VerifyNow assay system, and we defined the cut off value of P2Y12 Reaction Units (PRU) at 208 and classified patients as hypo-responders (PRU≧208) or responders (PRU<208). The rates of hemorrhagic and thrombotic events within 30 days (acute phase) and 30 days after the procedure (delayed phase) were compared between the two groups. Furthermore, changes in hemoglobin levels were measured before and after the procedure and at chronic stages (1 to 6 months thereafter). RESULTS: From 61 patients included in this study, 36 patients were hypo-responders and 25 patients were responders. Hemorrhagic events occurred 8.0% only in responders in the acute phase (p = 0.16), and 2.78% in hypo-responders and 20.0% in responders in the delayed phase (p = 0.037). Changes in hemoglobin levels before and after the procedure were 1.22 g/dl in hypo-responders and 1.74 g/dl in responders (p = 0.032) while before the procedure and chronic stages they were 0.39 g/dl in hypo-responders and 1.39 g/dl in responders (p <  0.01). Thrombotic events were not significantly different between the two groups. CONCLUSION: Long term use of DAPT after stent assisted coiling is related to hemorrhagic events in the delayed phase. Preventing for hemorrhagic events, the duration of DAPT should be carefully considered in clopidogrel responders.


Assuntos
Clopidogrel/efeitos adversos , Hemorragia , Inibidores da Agregação Plaquetária/efeitos adversos , Stents , Plaquetas/efeitos dos fármacos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Hemorragia/prevenção & controle , Humanos
13.
ACS Appl Mater Interfaces ; 13(24): 29021-29033, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34102844

RESUMO

Fabrication of a blood-repellent surface is essential for implantable or interventional medical devices to avoid thrombosis which can induce several serious complications. In this research, a novel micropatterned surface was fabricated via a facile and cost-effective method, and then, the in vitro and in vivo blood-repellent performances of the controllable superhydrophobic surface were systematically evaluated. First, a facile and cost-effective strategy was proposed to fabricate a controllable superhydrophobic surface on a medically pure titanium substrate using an ultraviolet laser process, ultrasonic acid treatment, and chemical modification. Second, the superhydrophobicity, durability, stability, and corrosion resistance of the superhydrophobic surface were confirmed with advanced testing techniques, which display a high contact angle, low adhesion to water and blood, and excellent resistant element precipitation. Third, the platelet-rich plasma and whole blood were applied to evaluate the hemocompatibility of the superhydrophobic surface by means of an in vitro experiment, and no blood cell activation or aggregation was observed on the superhydrophobic surface. Finally, hollow tubes with an inner superhydrophobic surface were implanted into the left carotid artery of rabbits for 2 weeks to verify the biocompatibility in vivo. The superhydrophobic surface could effectively eliminate blood cell adhesion and thrombosis. No obvious inflammation or inordinate proliferation was found by histological analysis. This research provides a facile and cost-effective strategy to prepare a blood-repellent surface, which may have promising applications in implanted biomedical devices.


Assuntos
Materiais Revestidos Biocompatíveis/química , Próteses e Implantes , Trombose/prevenção & controle , Animais , Plaquetas/efeitos dos fármacos , Artérias Carótidas/cirurgia , Adesão Celular/efeitos dos fármacos , Corrosão , Humanos , Interações Hidrofóbicas e Hidrofílicas , Coelhos , Titânio/química , Molhabilidade
14.
Molecules ; 26(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069658

RESUMO

Atherosclerotic cardiovascular disease is the leading cause of death in developed countries. Therefore, there is an increasing interest in developing new potent and safe antiplatelet agents. Coumarins are a family of polyphenolic compounds with several pharmacological activities, including platelet aggregation inhibition. However, their antiplatelet mechanism of action needs to be further elucidated. The aim of this study is to provide insight into the biochemical mechanisms involved in this activity, as well as to establish a structure-activity relationship for these compounds. With this purpose, the antiplatelet aggregation activities of coumarin, esculetin and esculin were determined in vitro in human whole blood and platelet-rich plasma, to set the potential interference with the arachidonic acid cascade. Here, the platelet COX activity was evaluated from 0.75 mM to 6.5 mM concentration by measuring the levels of metabolites derived from its activity (MDA and TXB2), together with colorimetric assays performed with the pure recombinant enzyme. Our results evidenced that the coumarin aglycones present the greatest antiplatelet activity at 5 mM and 6.5 mM on aggregometry experiments and inhibiting MDA levels.


Assuntos
Plaquetas/efeitos dos fármacos , Cumarínicos/farmacologia , Ciclo-Oxigenase 1/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Plaquetas/enzimologia , Plaquetas/metabolismo , Humanos , Técnicas In Vitro , Malondialdeído/metabolismo
16.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063076

RESUMO

Platelet function is developmentally regulated. Healthy neonates do not spontaneously bleed, but their platelets are hypo-reactive to several agonists. The mechanisms underlying immature platelet function in neonates are incompletely understood. This critical issue remains challenging for the establishment of age-specific reference ranges. In this study, we evaluated platelet reactivity of five pediatric age categories, ranging from healthy full-term neonates up to adolescents (11-18 years) in comparison to healthy adults (>18 years) by flow cytometry. We confirmed that platelet hypo-reactivity detected by fibrinogen binding, P-selectin, and CD63 surface expression was most pronounced in neonates compared to other pediatric age groups. However, maturation of platelet responsiveness varied with age, agonist, and activation marker. In contrast to TRAP and ADP, collagen-induced platelet activation was nearly absent in neonates. Granule secretion markedly remained impaired at least up to 10 years of age compared to adults. We show for the first time that neonatal platelets are deficient in thrombospondin-1, and exogenous platelet-derived thrombospondin-1 allows platelet responsiveness to collagen. Platelets from all pediatric age groups normally responded to the C-terminal thrombospondin-1 peptide RFYVVMWK. Thus, thrombospondin-1 deficiency of neonatal platelets might contribute to the relatively impaired response to collagen, and platelet-derived thrombospondin-1 may control distinct collagen-induced platelet responses.


Assuntos
Envelhecimento/fisiologia , Plaquetas/metabolismo , Colágeno/farmacologia , Trombospondina 1/farmacologia , Difosfato de Adenosina/farmacologia , Adolescente , Adulto , Plaquetas/efeitos dos fármacos , Criança , Venenos de Crotalídeos/farmacologia , Exocitose/efeitos dos fármacos , Humanos , Lactente , Recém-Nascido , Lectinas Tipo C , Peptídeos/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Receptores Ativados por Proteinase/metabolismo , Trombospondina 1/química
17.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065600

RESUMO

Curcumin is a natural bioactive component derived from the turmeric plant Curcuma longa, which exhibits a range of beneficial activities on human cells. Previously, an inhibitory effect of curcumin on platelets was demonstrated. However, it is unknown whether this inhibitory effect is due to platelet apoptosis or procoagulant platelet formation. In this study, curcumin did not activate caspase 3-dependent apoptosis of human platelets, but rather induced the formation of procoagulant platelets. Interestingly, curcumin at low concentration (5 µM) potentiated, and at high concentration (50 µM) inhibited ABT-737-induced platelet apoptosis, which was accompanied by inhibition of ABT-737-mediated thrombin generation. Platelet viability was not affected by curcumin at low concentration and was reduced by 17% at high concentration. Furthermore, curcumin-induced autophagy in human platelets via increased translocation of LC3I to LC3II, which was associated with activation of adenosine monophosphate (AMP) kinase and inhibition of protein kinase B activity. Because curcumin inhibits P-glycoprotein (P-gp) in cancer cells and contributes to overcoming multidrug resistance, we showed that curcumin similarly inhibited platelet P-gp activity. Our results revealed that the platelet inhibitory effect of curcumin is mediated by complex processes, including procoagulant platelet formation. Thus, curcumin may protect against or enhance caspase-dependent apoptosis in platelets under certain conditions.


Assuntos
Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Plaquetas/efeitos dos fármacos , Curcumina/farmacologia , Nitrofenóis/farmacologia , Sulfonamidas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Monofosfato de Adenosina/metabolismo , Plaquetas/metabolismo , Curcuma/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Piperazinas/farmacologia , Extratos Vegetais/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
18.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070931

RESUMO

It is now about 20 years since the first case of a gain-of-function mutation involving the as-yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and clinical value as a therapeutic strategy for dyslipidemia and atherosclerosis-associated cardiovascular disease (CVD) management. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, mainly produced by the liver, and essential for metabolism of LDL particles by inhibiting LDL receptor (LDLR) recirculation to the cell surface with the consequent upregulation of LDLR-dependent LDL-C levels. Beyond its effects on LDL metabolism, several studies revealed the existence of additional roles of PCSK9 in different stages of atherosclerosis, also for its ability to target other members of the LDLR family. PCSK9 from plasma and vascular cells can contribute to the development of atherosclerotic plaque and thrombosis by promoting platelet activation, leukocyte recruitment and clot formation, also through mechanisms not related to systemic lipid changes. These results further supported the value for the potential cardiovascular benefits of therapies based on PCSK9 inhibition. Actually, the passive immunization with anti-PCSK9 antibodies, evolocumab and alirocumab, is shown to be effective in dramatically reducing the LDL-C levels and attenuating CVD. While monoclonal antibodies sequester circulating PCSK9, inclisiran, a small interfering RNA, is a new drug that inhibits PCSK9 synthesis with the important advantage, compared with PCSK9 mAbs, to preserve its pharmacodynamic effects when administrated every 6 months. Here, we will focus on the major understandings related to PCSK9, from its discovery to its role in lipoprotein metabolism, involvement in atherothrombosis and a brief excursus on approved current therapies used to inhibit its action.


Assuntos
Aterosclerose/genética , LDL-Colesterol/metabolismo , Dislipidemias/genética , Placa Aterosclerótica/genética , Pró-Proteína Convertase 9/genética , Trombose/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/enzimologia , Aterosclerose/patologia , Plaquetas/efeitos dos fármacos , Plaquetas/enzimologia , Plaquetas/patologia , LDL-Colesterol/antagonistas & inibidores , Dislipidemias/tratamento farmacológico , Dislipidemias/enzimologia , Dislipidemias/patologia , Fibrinolíticos/uso terapêutico , Regulação da Expressão Gênica , Humanos , Hipolipemiantes/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/enzimologia , Placa Aterosclerótica/patologia , Ativação Plaquetária/efeitos dos fármacos , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/biossíntese , RNA Interferente Pequeno/uso terapêutico , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transdução de Sinais , Trombose/enzimologia , Trombose/patologia , Trombose/prevenção & controle
19.
Biomed Pharmacother ; 140: 111698, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34029954

RESUMO

Glycoprotein (GP) Ib is a platelet membrane receptor complex exposed to vascular injury, proposed as an effective target for stroke therapy. Previously, we have observed that the GPIb antagonist anfibatide (ANF) could mitigate blood-brain barrier (BBB) disruption following cerebral ischemia/reperfusion (CI/R) injury. The current study was designed to investigate whether the amelioration of the BBB by ANF is mediated via the Epac signaling pathway. A murine model of CI/R injury was induced following 90 min of transient middle cerebral artery occlusion (MCAO). ANF (4 µg/kg) was intravenously injected 1 h after reperfusion. Herein, ANF ameliorated BBB disruption, increased the expression of tight junction proteins, suppressed F-actin cytoskeleton rearrangement, decreased the permeability of the ischemic brain tissue, and relieved brain edema. ANF-treated mice had smaller infarct volumes and less severe neurological deficits than the MCAO mice. Moreover, the effects of ANF and Epac1 agonists were very similar in the MCAO mice. Epac activation with a cAMP analog, 8-CPT-2'-O-Me-cAMP, mitigated the breakdown of BBB function and CI/R injury. The Epac specific antagonist, ESI-09, worsened barrier damage and cerebral impairment, antagonizing the protective effects afforded by ANF. In addition, ANF upregulated the expression of Epac1 protein in the ischemic cerebral cortex. Collectively, our results indicate that the protective effect of ANF on the BBB after CI/R could be attributed to the activation of the Epac pathway.


Assuntos
Plaquetas/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Fatores de Troca do Nucleotídeo Guanina/metabolismo , AVC Isquêmico/tratamento farmacológico , Complexo Glicoproteico GPIb-IX de Plaquetas/antagonistas & inibidores , Animais , Plaquetas/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Edema Encefálico/tratamento farmacológico , Edema Encefálico/metabolismo , Isquemia Encefálica/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , AVC Isquêmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Carbohydr Res ; 505: 108326, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34015720

RESUMO

The viral infection caused by SARS-CoV-2 has increased the mortality rate and engaged several adverse effects on the affected individuals. Currently available antiviral drugs have found to be unsuccessful in the treatment of COVID-19 patients. The demand for efficient antiviral drugs has created a huge burden on physicians and health workers. Plasma therapy seems to be less accomplishable due to insufficient donors to donate plasma and low recovery rate from viral infection. Repurposing of antivirals has been evolved as a suitable strategy in the current treatment and preventive measures. The concept of drug repurposing represents new experimental approaches for effective therapeutic benefits. Besides, SARS-CoV-2 exhibits several complications such as lung damage, blood clot formation, respiratory illness and organ failures in most of the patients. Based on the accumulation of data, sulfated marine polysaccharides have exerted successful inhibition of virus entry, attachment and replication with known or unknown possible mechanisms against deadly animal and human viruses so far. Since the virus entry into the host cells is the key process, the prevention of such entry mechanism makes any antiviral strategy effective. Enveloped viruses are more sensitive to polyanions than non-enveloped viruses. Besides, the viral infection caused by RNA virus types embarks severe oxidative stress in the human body that leads to malfunction of tissues and organs. In this context, polysaccharides play a very significant role in providing shielding effect against the virus due to their polyanionic rich features and a molecular weight that hinders their reactive surface glycoproteins. Significantly the functional groups especially sulfate, sulfate pattern and addition, uronic acids, monosaccharides, glycosidic linkage and high molecular weight have greater influence in the antiviral activity. Moreover, they are very good antioxidants that can reduce the free radical generation and provokes intracellular antioxidant enzymes. Additionally, polysaccharides enable a host-virus immune response, activate phagocytosis and stimulate interferon systems. Therefore, polysaccharides can be used as candidate drugs, adjuvants in vaccines or combination with other antivirals, antioxidants and immune-activating nutritional supplements and antiviral materials in healthcare products to prevent SARS-CoV-2 infection.


Assuntos
Anticoagulantes/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Polissacarídeos/uso terapêutico , Embolia Pulmonar/tratamento farmacológico , Insuficiência Respiratória/tratamento farmacológico , Anticoagulantes/química , Anticoagulantes/isolamento & purificação , Antivirais/química , Antivirais/isolamento & purificação , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Plaquetas/virologia , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/virologia , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Feófitas/química , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Embolia Pulmonar/complicações , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/virologia , Insuficiência Respiratória/complicações , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/virologia , Rodófitas/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Ésteres do Ácido Sulfúrico/química , Ligação Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
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