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2.
Adv Biol Regul ; 77: 100735, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773098

RESUMO

The novel Corona virus infection (Covid-19) first identified in China in December 2019 has rapidly progressed in pandemic leading to significant mortality and unprecedented challenge for healthcare systems. Although the clinical spectrum of Covid-19 is variable, acute respiratory failure and systemic coagulopathy are common in severe Covid-19 patients. Lung is an important target of the SARS-CoV-2 virus causing eventually acute respiratory distress syndrome associated to a thromboinflammatory state. The cytokinic storm, thromboinflammation and pulmonary tropism are the bedrock of tissue lesions responsible for acute respiratory failure and for prolonged infection that may lead to multiple organ failure and death. The thrombogenicity of this infectious disease is illustrated by the high frequency of thromboembolic events observed even in Covid-19 patients treated with anticoagulation. Increased D-Dimers, a biomarker reflecting activation of hemostasis and fibrinolysis, and low platelet count (thrombocytopenia) are associated with higher mortality in Covid-19 patients. In this review, we will summarize our current knowledge on the thromboembolic manifestations, the disturbed hemostatic parameters, and the thromboinflammatory conditions associated to Covid-19 and we will discuss the modalities of anticoagulant treatment or other potential antithrombotic options.


Assuntos
Anticoagulantes/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/complicações , Coagulação Intravascular Disseminada/complicações , Pneumonia Viral/complicações , Embolia Pulmonar/complicações , Insuficiência Respiratória/complicações , Doença Aguda , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Plaquetas/virologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/virologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Heparina/uso terapêutico , Interações Hospedeiro-Patógeno , Humanos , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/virologia , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/virologia , Análise de Sobrevida
3.
Food Chem ; 332: 127384, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32615384

RESUMO

Dairy polar lipids (PL) seem to exhibit antiplatelet effects. However, it is not known what molecular species may be responsible. In this study, we confirmed using C30 reversed-phase (C30RP) ultra-high-performance liquid chromatography (UHPLC) coupled to high resolution accurate mass tandem mass spectrometry (HRAM-MS/MS) that fermentation of yoghurts from ovine milk using specific starter cultures altered the PL composition. These lipid alterations occurred concomitant with increased antithrombotic properties of the yoghurts PL fractions against platelet-activating factor (PAF) and thrombin-induced platelet aggregation. Specifically, elevation in phosphatidylethanolamine (PE), sphingomyelin (SM), phosphatidylcholine (PC) and their molecular species were observed following yoghurt fermentation. Furthermore, PC(18:0/18:1), PE(18:1/18:2), SM(d18:0/22:0) and several other molecular species were significantly inversely correlated with the inhibition of PAF and thrombin. These molecular species were abundant in the most bioactive yoghurts fermented by S. thermophilus and L. acidophilus, which suggest that fermentation by these microorganisms increases the antithrombotic properties of ovine milk PL.


Assuntos
Lipídeos/análise , Leite/metabolismo , Inibidores da Agregação de Plaquetas/análise , Iogurte/análise , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Cromatografia Líquida de Alta Pressão , Fermentação , Lipídeos/farmacologia , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Ovinos , Esfingomielinas/metabolismo , Espectrometria de Massas em Tandem , Trombina/farmacologia
4.
Arterioscler Thromb Vasc Biol ; 40(9): 2127-2142, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32698684

RESUMO

OBJECTIVE: Atherothrombosis occurs upon rupture of an atherosclerotic plaque and leads to the formation of a mural thrombus. Computational fluid dynamics and numerical models indicated that the mechanical stress applied to a thrombus increases dramatically as a thrombus grows, and that strong inter-platelet interactions are essential to maintain its stability. We investigated whether GPVI (glycoprotein VI)-mediated platelet activation helps to maintain thrombus stability by using real-time video-microscopy. Approach and Results: We showed that GPVI blockade with 2 distinct Fab fragments promoted efficient disaggregation of human thrombi preformed on collagen or on human atherosclerotic plaque material in the absence of thrombin. ACT017-induced disaggregation was achieved under arterial blood flow conditions, and its effect increased with wall shear rate. GPVI regulated platelet activation within a growing thrombus as evidenced by the loss in thrombus contraction when GPVI was blocked, and the absence of the disaggregating effect of an anti-GPVI agent when the thrombi were fully activated with soluble agonists. The GPVI-dependent thrombus stabilizing effect was further supported by the fact that inhibition of any of the 4 key immunoreceptor tyrosine-based motif signalling molecules, src-kinases, Syk, PI3Kß, or phospholipase C, resulted in kinetics of thrombus disaggregation similar to ACT017. The absence of ACT017-induced disaggregation of thrombi from 2 afibrinogenemic patients suggests that the role of GPVI requires interaction with fibrinogen. Finally, platelet disaggregation of fibrin-rich thrombi was also promoted by ACT017 in combination with r-tPA (recombinant tissue plasminogen activator). CONCLUSIONS: This work identifies an unrecognized role for GPVI in maintaining thrombus stability and suggests that targeting GPVI could dissolve platelet aggregates with a poor fibrin content.


Assuntos
Afibrinogenemia/sangue , Plaquetas/efeitos dos fármacos , Fibrinogênio/metabolismo , Fragmentos Fab das Imunoglobulinas/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Trombose/tratamento farmacológico , Afibrinogenemia/diagnóstico , Afibrinogenemia/genética , Plaquetas/metabolismo , Simulação por Computador , Fibrinogênio/genética , Fibrinolíticos/farmacologia , Humanos , Cinética , Microscopia de Vídeo , Modelos Biológicos , Glicoproteínas da Membrana de Plaquetas/metabolismo , Transdução de Sinais , Estresse Mecânico , Trombina/metabolismo , Trombose/sangue , Trombose/diagnóstico , Trombose/genética
5.
J Mol Cell Cardiol ; 146: 32-40, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32681845

RESUMO

SARS-CoV-2 causes a phenotype of pneumonia with diverse manifestation, which is termed as coronavirus disease 2019 (COVID-19). An impressive high transmission rate allows COVID-19 conferring enormous challenge for clinicians worldwide, and developing to a pandemic level. Combined with a series of complications, a part of COVID-19 patients progress into severe cases, which critically contributes to the risk of fatality. To date, coagulopathy has been found as a prominent feature of COVID-19 and severe coagulation dysfunction may be associated with poor prognosis. Coagulopathy in COVID-19 may predispose patients to hypercoagulability-related disorders including thrombosis and even fatal vascular events. Inflammatory storm, uncontrolled inflammation-mediated endothelial injury and renin angiotensin system (RAS) dysregulation are the potential mechanisms. Ongoing efforts made to develop promising therapies provide several potential strategies for hypercoagulability in COVID-19. In this review, we introduce the clinical features of coagulation and the increased vascular thrombotic risk conferred by coagulopathy according to present reports about COVID-19. The potential underlying mechanisms and emerging therapeutic avenues are discussed, emphasizing an urgent need for effective interventions.


Assuntos
Anticoagulantes/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/complicações , Coagulação Intravascular Disseminada/complicações , Pneumonia Viral/complicações , Embolia Pulmonar/complicações , Insuficiência Respiratória/complicações , Doença Aguda , Betacoronavirus/imunologia , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Plaquetas/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/mortalidade , Coagulação Intravascular Disseminada/virologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Heparina/uso terapêutico , Interações Hospedeiro-Patógeno/imunologia , Humanos , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pandemias , Tempo de Tromboplastina Parcial , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/mortalidade , Embolia Pulmonar/virologia , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/mortalidade , Insuficiência Respiratória/virologia , Análise de Sobrevida
6.
Cardiovasc Ther ; 2020: 2342837, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547635

RESUMO

Cardiovascular diseases (CVD) represent one of the biggest causes of death globally, and their prevalence, aetiology, and outcome are related to genetic, metabolic, and environmental factors, among which sex- and age-dependent differences may play a key role. Among CVD risk factors, platelet hyperactivity deserves particular mention, as it is involved in the pathophysiology of main cardiovascular events (including stroke, myocardial infarction, and peripheral vascular injury) and is closely related to sex/age differences. Several determinants (e.g., hormonal status and traditional cardiovascular risk factors), together with platelet-related factors (e.g., plasma membrane composition, receptor signaling, and platelet-derived microparticles) can elucidate sex-related disparity in platelet functionality and CVD onset and outcome, especially in relation to efficacy of current primary and secondary interventional strategies. Here, we examined the state of the art concerning sex differences in platelet biology and their relationship with specific cardiovascular events and responses to common antiplatelet therapies. Moreover, as healthy nutrition is widely recognized to play a key role in CVD, we also focused our attention on specific dietary components (especially polyunsaturated fatty acids and flavonoids) and patterns (such as Mediterranean diet), which also emerged to impact platelet functions in a sex-dependent manner. These results highlight that full understanding of gender-related differences will be useful for designing personalized strategies, in order to prevent and/or treat platelet-mediated vascular damage.


Assuntos
Plaquetas/efeitos dos fármacos , Doenças Cardiovasculares/dietoterapia , Doenças Cardiovasculares/tratamento farmacológico , Dieta Saudável , Dieta Mediterrânea , Disparidades nos Níveis de Saúde , Inibidores da Agregação de Plaquetas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Plaquetas/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Valor Nutritivo , Prevenção Primária , Fatores de Risco , Comportamento de Redução do Risco , Prevenção Secundária , Fatores Sexuais , Resultado do Tratamento , Adulto Jovem
7.
Life Sci ; 256: 117840, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32450173

RESUMO

AIMS: Platelet production improvement can resolve concerns about the limitations of external platelet supply and platelet transfusion in thrombocytopenia patients. To this end, scientists encourage to induce the generation of megakaryocyte and platelet. Curcumin is a safe ingredient of turmeric that affects various cellular pathways. The effect of this component on platelet production has not been yet reported. MAIN METHODS: Our in vitro experiments include the investigation of the effects of nanocurcumin on megakaryocytes production from K562 cells and hematopoietic stem cells via megakaryocyte markers expression, DNA content, ROS, and morphologic analysis, and CFC assay. The regulatory functions of MAPKs pathways were also determined. In the in vivo study tissue distribution of nanocurcumin was determined and two treatment schedules were used to evaluate the capability of nanocurcumin to prevent the occurrence of Busulfan-induced thrombocytopenia in the mouse model. KEY FINDING: In vitro evidences demonstrated that nanocurcumin can induce MK production from K562 cells and hematopoietic stem cells. Inhibition of ERK1/2 and JNK pathways arrested this activity. In vivo experiments showed the uptake of nanocurcumin by tissues in mice. Administration of nanocurcumin could preserve bone marrow integrity and increase of the number of circulating platelets in the Busulfan-treated mice models. SIGNIFICANCE: Our results have demonstrated that nanocurcumin administration can be useful for the improvement of megakaryocytes and platelet generation in vitro. This component may be exerting these beneficial effects on megakaryopoiesis by modulating ERK1/2 and JNK pathways. As well as nanocurcumin has the potential to prevent thrombocytopenia in chemotherapy threated mice.


Assuntos
Plaquetas/efeitos dos fármacos , Curcumina/farmacologia , Megacariócitos/efeitos dos fármacos , Nanoestruturas , Trombocitopenia/prevenção & controle , Animais , Antineoplásicos Alquilantes/toxicidade , Plaquetas/metabolismo , Bussulfano/toxicidade , Curcumina/administração & dosagem , Curcumina/farmacocinética , Feminino , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Células K562 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Megacariócitos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Trombocitopenia/induzido quimicamente , Distribuição Tecidual
8.
Clin Chim Acta ; 508: 98-102, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32405079

RESUMO

BACKGROUND: Novel coronavirus infectious disease (COVID-19) has been spreading worldwide, and tracking laboratory indexes during the diagnosis and treatment of patients with severe COVID-19 can provide a reference for patients in other countries and regions. METHODS: We closely tracked the epidemiological history, diagnosis and treatment process, as well as dynamic changes in routine blood indicators, of a severe COVID-19 patient who was hospitalized for 26 days. RESULTS: Our study found that the patient's condition worsened in the first week after admission, white blood cells (WBCs), neutrophils, lymphocytes, monocytes, eosinophils, red blood cells (RBCs), hemoglobin, neutrophil lymphocyte ratio (NLR), platelets (PLT) and platelet lymphocyte ratio (PLR) decreased. On the 7th day of admission, the levels of these cells decreased to their lowest values, though the red blood cell distribution width (RDW) and C-reactive protein (CRP) level remained at high values. From 8 to 14 days of admission, the patient's condition improved, hypoxemia was corrected, and mechanical ventilation was discontinued. The number of WBCs, neutrophils, monocytes, eosinophils and lymphocytes increased gradually, and the erythrocyte parameters stopped declining and stabilized in a certain range; CRP decreased rapidly. On the 20th day of admission, the nucleic acid test was negative, WBC, neutrophil, CRP, NLR and PLR decreased gradually, and monocyte, lymphocyte, and eosinophil counts increased. Although RBCs and hemoglobin (Hb) levels continued to decrease, RDW gradually increased, indicating the recovery of hematopoiesis. In addition, it should be noted that monocytes and eosinophils were at extremely low levels within 10 days after admission; the recovery time of eosinophils was approximately 12 days after admission, which was earlier than other parameters, which might be of great value in judging the progress of the disease. CONCLUSIONS: Dynamic changes in routine blood parameters might be helpful for the prognosis of COVID-19 patients and evaluation of the treatment effect.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Antibacterianos/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Plaquetas/virologia , Proteína C-Reativa/metabolismo , Contagem de Células , Convalescença , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Eritrócitos/efeitos dos fármacos , Eritrócitos/patologia , Eritrócitos/virologia , Feminino , Humanos , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/patologia , Monócitos/virologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Neutrófilos/virologia , Oseltamivir/uso terapêutico , Pandemias , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Prognóstico , Respiração Artificial , Índice de Gravidade de Doença
9.
PLoS One ; 15(5): e0227932, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469873

RESUMO

BACKGROUND AND OBJECTIVE: For many pathological states, microparticles are supposed to be one of the causes of hypercoagulation. Although there are some indirect data about microparticles participation in coagulation activation and propagation, the integral hemostasis test Thrombodynamics allows to measure micropaticles participation in these two coagulation phases directly. Demonstrates microparticles participation in coagulation activation by influence on the appearance of coagulation centres in the plasma volume and the rate of clot growth from the surface with immobilized tissue factor.Methods: Microparticles were obtained from platelets and erythrocytes by stimulation with thrombin receptor-activating peptide (SFLLRN) and calcium ionophore (A23187), respectively, from monocytes, endothelial HUVEC culture and monocytic THP cell culture by stimulation with lipopolysaccharides. Microparticles were counted by flow cytometry and titrated in microparticle-depleted normal plasma in the Thrombodynamics test. RESULTS: Monocyte microparticles induced the appearance of clotting centres through the TF pathway at concentrations approximately 100-fold lower than platelet and erythrocyte microparticles, which activated plasma by the contact pathway. For endothelial microparticles, both activation pathways were essential, and their activity was intermediate. Monocyte microparticles induced plasma clotting by the appearance of hundreds of clots with an extremely slow growth rate, while erythrocyte microparticles induced the appearance of a few clots with a growth rate similar to that from surface covered with high-density tissue factor. Patterns of clotting induced by platelet and endothelial microparticles were intermediate. Platelet, erythrocyte and endothelial microparticles impacts on the rate of clot growth from the surface with tissue factor did not differ significantly within the 0-200·103/ul range of microparticles concentrations. However, at concentrations greater than 500·103/ul, erythrocyte microparticles increased the stationary clot growth rate to significantly higher levels than do platelet microparticles or artificial phospholipid vesicles consisting of phosphatidylcholine and phosphatidylserine. CONCLUSION: Microparticles of different origins demonstrated qualitatively different characteristics related to coagulation activation and propagation.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Micropartículas Derivadas de Células/efeitos dos fármacos , Trombina/metabolismo , Trombose/sangue , Plaquetas/efeitos dos fármacos , Calcimicina/farmacologia , Cálcio/metabolismo , Micropartículas Derivadas de Células/metabolismo , Células Endoteliais/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Citometria de Fluxo , Células Endoteliais da Veia Umbilical Humana , Humanos , Monócitos/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Trombose/tratamento farmacológico , Trombose/patologia
10.
Thromb Haemost ; 120(5): 776-792, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32369849

RESUMO

BACKGROUND: Implantable cardiovascular therapeutic devices, while hemodynamically effective, remain limited by thrombosis. A driver of device-associated thrombosis is shear-mediated platelet activation (SMPA). Underlying mechanisms of SMPA, as well as useful biomarkers able to detect and discriminate mechanical versus biochemical platelet activation, are poorly defined. We hypothesized that SMPA induces a differing pattern of biomarkers compared with biochemical agonists. METHODS: Gel-filtered human platelets were subjected to mechanical activation via either uniform constant or dynamic shear; or to biochemical activation by adenosine diphosphate (ADP), thrombin receptor-activating peptide 6 (TRAP-6), thrombin, collagen, epinephrine, or arachidonic acid. Markers of platelet activation (P-selectin, integrin αIIbß3 activation) and apoptosis (mitochondrial membrane potential, caspase 3 activation, and phosphatidylserine externalization [PSE]) were examined using flow cytometry. Platelet procoagulant activity was detected by chromogenic assay measuring thrombin generation. Contribution of platelet calcium flux in SMPA was tested employing calcium chelators, ethylenediaminetetraacetic acid (EDTA), and BAPTA-AM. RESULTS: Platelet exposure to continuous shear stress, but not biochemical agonists, resulted in a dramatic increase of PSE and procoagulant activity, while no integrin αIIbß3 activation occurred, and P-selectin levels remained barely elevated. SMPA was associated with dissipation of mitochondrial membrane potential, but no caspase 3 activation was observed. Shear-mediated PSE was significantly decreased by chelation of extracellular calcium with EDTA, while intracellular calcium depletion with BAPTA-AM had no significant effect. In contrast, biochemical agonists ADP, TRAP-6, arachidonic acid, and thrombin were potent inducers of αIIbß3 activation and/or P-selectin exposure. This differing pattern of biomarkers seen for SMPA for continuous uniform shear was replicated in platelets exposed to dynamic shear stress via circulation through a ventricular assist device-propelled circulatory loop. CONCLUSION: Elevated shear stress, but not biochemical agonists, induces a differing pattern of platelet biomarkers-with enhanced PSE and thrombin generation on the platelet surface. This differential biomarker phenotype of SMPA offers the potential for early detection and discrimination from that mediated by biochemical agonists.


Assuntos
Plaquetas/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Mecanotransdução Celular , Ativação Plaquetária/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Biomarcadores/sangue , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/metabolismo , Plaquetas/patologia , Caspase 3/sangue , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Selectina-P/sangue , Fosfatidilserinas/sangue , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Estresse Mecânico
11.
J Stroke Cerebrovasc Dis ; 29(7): 104877, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32414579

RESUMO

OBJECTIVES: To assess the prevalence of high on-clopidogrel platelet reactivity (HCPR) in patients with ischaemic stroke or transient ischaemic attack (IS/TIA), their outcome and genetic basis of on-treatment response variability in IS/TIA patients. METHODS: We conducted a comprehensive search of PubMed and EMBASE from their inceptions to March 9, 2019. Studies that reported absolute numbers/percentages of HCRP at any time point after IS/TIA onset evaluated with any type of platelet function tests, clinical outcomes and genotyping data were included. RESULTS: Among 21 studies of 4312 IS/TIA patients treated with clopidogrel, the pooled prevalence of HCPR was 28% (95%CI: 24-32%; high heterogeneity: I2 = 88.2%, p < 0.001). Heterogeneity degree diminished across groups defined by the HCPR testing method. Clopidogrel non-responder IS/TIA patients had poorer outcome compared to responders (RR = 2.09, 95%CI: 1.61-2.70; p = 0.036; low heterogeneity across studies: I2 = 27.4%, p = 0.210). IS/TIA carriers of CYP2C19*2 or CYP2C19*3 loss of function alleles had a higher risk of HCPR compared to wild type (RR = 1.69, 95%CI: 1.47-1.95; p < 0.001; I2 = 0.01%, p = 0.475). CONCLUSIONS: This systematic review shows a high prevalence of clopidogrel resistance in IS/TIA and poor outcome in these patients. CYP2C19 polymorphisms may potentially influence clopidogrel resistance.


Assuntos
Plaquetas/efeitos dos fármacos , Clopidogrel/uso terapêutico , Resistência a Medicamentos , Ataque Isquêmico Transitório/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Plaquetas/metabolismo , Clopidogrel/efeitos adversos , Clopidogrel/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Resistência a Medicamentos/genética , Humanos , Ataque Isquêmico Transitório/sangue , Ataque Isquêmico Transitório/diagnóstico , Variantes Farmacogenômicos , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Polimorfismo Genético , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Resultado do Tratamento
12.
Am J Physiol Heart Circ Physiol ; 319(1): H133-H143, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32469636

RESUMO

In clinical studies, platelet aggregation and risk of thrombosis are increased in patients after doxorubicin treatment. However, the exact role of doxorubicin in platelet functions and thrombus formation in vivo remain unclear. The present study is to investigate the role of doxorubicin in platelet function in relation to thrombus formation and vascular toxicity, as well as the efficacy of antiplatelet therapy. Mice were treated with doxorubicin or vehicle (5 mg/kg iv, 4 wk), and the following parameters were determined: platelet count and size, platelet surface adhesive receptors by flow cytometry, density of granules by electron microscopy, platelet aggregation and degranulation at resting or agonist-stimulated state, platelet adhesion on fibrinogen or endothelial cells, and thrombus formation on collagen matrix. The efficacy of clopidogrel (15 mg·kg-1·day-1, followed by 5 mg·kg-1·day-1) on doxorubicin-induced changes in the aforementioned parameters as well as vascular injury were also determined. Whereas platelet count and size were similar between doxorubicin-treated and vehicle-treated mice, doxorubicin promoted thrombus formation evidenced by greater platelet aggregation, degranulation, and adhesion to endothelial cells evoked by agonists. Clopidogrel treatment attenuated the enhanced platelet activity and thrombus formation by doxorubicin, as well as vascular platelet infiltration and reactive oxygen species generation. Collectively, this study demonstrates that platelet functions are enhanced after long-term doxorubicin administration, which leads to thrombus formation and vascular toxicity, and that doxorubicin-induced changes in the functionality of platelets can be effectively inhibited by antiplatelet drugs.NEW & NOTEWORTHY Doxorubicin therapy in mice (antitumor dosage) markedly enhanced platelet functions measured as agonist-induced platelet aggregation, degranulation, and adhesion to endothelial cells, actions leading to thrombus formation and thrombosis-independent vascular injury. Clopidogrel treatment ameliorated thrombus formation and vascular toxicity induced by doxorubicin via inhibiting platelet activity.


Assuntos
Antineoplásicos/toxicidade , Plaquetas/efeitos dos fármacos , Doxorrubicina/toxicidade , Endotélio Vascular/efeitos dos fármacos , Trombose/etiologia , Animais , Antineoplásicos/farmacologia , Plaquetas/fisiologia , Células Cultivadas , Doxorrubicina/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Agregação Plaquetária
13.
Med Sci (Paris) ; 36(4): 348-357, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32356711

RESUMO

Cardiovascular diseases are the leading cause of deaths in the world. Platelets play a major role in the occurrence of these diseases and the development of antiplatelet drugs is a priority in the fight against cardiovascular diseases-associated mortality. Aspirin and thienopyridine-based P2Y12 inhibitors are the main drugs currently used. These molecules target the initiation of platelets activation and are responsible for a moderate inhibitory action. Other antiplatelet agents, as glycoprotein (GP) IIb/IIIa antagonists, inhibit platelet aggregation independently of initial activation-associated pathways, but are responsible for increased hemorrhagic events. Regarding each antiplatelet agent's specific characteristics, the prescription of these drugs must take into account the type of cardiovascular event, the age of the patient, the past medical history, and the potential hemorrhagic adverse events. Thus, there is a need for the development of new molecules with a more targeted effect, maintaining optimal efficiency but with a reduction of the hemorrhagic risk, which is the principal limitation of these treatments.


Assuntos
Terapia de Alvo Molecular/tendências , Inibidores da Agregação de Plaquetas/uso terapêutico , Terapias em Estudo/tendências , Aspirina/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/fisiologia , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/mortalidade , Hemorragia/induzido quimicamente , Humanos , Terapia de Alvo Molecular/métodos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Fatores de Risco , Terapias em Estudo/métodos
14.
Medicine (Baltimore) ; 99(20): e20307, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443379

RESUMO

INTRODUCTION: Uncertainty remains regarding the impact of enteric-coated (EC) aspirin as it relates to the reduction of cardiovascular risk. We hypothesize that EC formulation based on a previous report may blunt aspirin response as evidenced by reduced Thromboxane A2 (TXA 2) levels in diabetic patients. Thus, it was imperative to ascertain and validate the effect of the EC formulation of Aspirin on the Thromboxane B2 (TXB2) level. METHODS/DESIGN: An open-label consecutive randomized interventional controlled trial. Patients with newly diagnosed ischemic stroke who are just about to start Aspirin were assessed for eligibility and inclusion in our trial. Consecutive patients (admitted to the stroke unit of Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar) will be randomized to receive either EC aspirin or plain Aspirin. They will be required to continue taking them throughout the study (3 days). Demographics and laboratory records of the study participants will be abstracted from online records. Further study variables will be obtained manually in designated case record forms (CRF). The primary outcomes are the incidence of aspirin non-responders (level of residual serum TXB2 associated with elevated thrombotic risk (<99.0% inhibition or TXB2 >3.1 ng/mL) within 72 h after three daily aspirin doses). Whereas secondary outcomes are the incidence of GIT bleeding of various preparations of Aspirin. The study was approved by MRC and IRB of Hamad Medical Corporation (MRC number: 01-18-156). DISCUSSION: This trial will determine potential differences in the efficacy of EC Aspirin and plain Aspirin on the Thromboxane B2 level. Additionally, it will ascertain the tolerability and safety of both formulations of Aspirin in patients with newly diagnosed ischemic stroke. These results will either support the current notion of no difference between the two formulations. However, if a difference is found, this will invite for future trials exploring clinical outcomes occurrence between various formulations. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT04330872 registered on April 2, 2020.


Assuntos
Aspirina/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Adolescente , Adulto , Idoso , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Plaquetas/efeitos dos fármacos , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/efeitos adversos , Método Simples-Cego , Fatores Socioeconômicos , Comprimidos com Revestimento Entérico , Tromboxano B2/sangue , Adulto Jovem
15.
Platelets ; 31(6): 825-826, 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32367749

RESUMO

EDTA dependent pseudothrombocytopenia (EDTA-PCTP) is a phenomenon that characterized by a spurious decrease of platelets in vitro due to the aggregation of platelets in EDTA anticoagulant blood samples. We report the first case of a transient appearance of EDTA-PCTP in a patient with 2019 novel coronavirus pneumonia (COVID-19). A 59-year-old woman was admitted to the isolated ward for severe type of 2019 novel coronavirus pneumonia. At the time of admission, her platelet count was in a normal range. Two days later, her platelet count decreased gradually without any signs or symptoms of bleeding. Since the peripheral blood smear showed a platelet aggregation, a blood sample anticoagulanted with citrate was tested and the number of platelet was normal. The phenomenon disappeared after 17 days when the patient was cured. This case emphasized the importance of peripheral blood smear and clinical manifestation, especially in the differential diagnosis of thrombocytopenia.


Assuntos
Betacoronavirus , Plaquetas/efeitos dos fármacos , Infecções por Coronavirus/sangue , Erros de Diagnóstico , Ácido Edético/farmacologia , Pandemias , Agregação Plaquetária/efeitos dos fármacos , Contagem de Plaquetas , Pneumonia Viral/sangue , Trombocitopenia/diagnóstico , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Reações Falso-Positivas , Feminino , Humanos , Pessoa de Meia-Idade , Transfusão de Plaquetas , Pneumonia Viral/complicações , Procedimentos Desnecessários
16.
Nat Commun ; 11(1): 1996, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332723

RESUMO

Small molecules that selectively kill senescent cells (SCs), termed senolytics, have the potential to prevent and treat various age-related diseases and extend healthspan. The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity. Here, we report the use of proteolysis-targeting chimera (PROTAC) technology to reduce the platelet toxicity of navitoclax (also known as ABT263), a Bcl-2 and Bcl-xl dual inhibitor, by converting it into PZ15227 (PZ), a Bcl-xl PROTAC, which targets Bcl-xl to the cereblon (CRBN) E3 ligase for degradation. Compared to ABT263, PZ is less toxic to platelets, but equally or slightly more potent against SCs because CRBN is poorly expressed in platelets. PZ effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia. With further improvement, Bcl-xl PROTACs have the potential to become safer and more potent senolytic agents than Bcl-xl inhibitors.


Assuntos
Envelhecimento/efeitos dos fármacos , Compostos de Anilina/farmacologia , Plaquetas/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Sulfonamidas/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Compostos de Anilina/química , Animais , Linhagem Celular , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Cultura Primária de Células , Proteólise/efeitos dos fármacos , Sulfonamidas/química , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/metabolismo
17.
Cardiovasc Diabetol ; 19(1): 46, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32264868

RESUMO

BACKGROUND: The clear evidence of cardiovascular benefits in cardiovascular outcome trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes might suggest an effect on atherosclerotic plaque vulnerability and/or thrombosis, in which myeloid angiogenic cells (MAC) and platelets (PLT) are implicated. We tested the effects of SGLT2i on inflammation and oxidant stress in a model of stearic acid (SA)-induced lipotoxicity in MAC and on PLT activation. The possible involvement of the Na+/H+ exchanger (NHE) was also explored. METHOD: MAC and PLT were isolated from peripheral blood of healthy subjects and incubated with/without SGLT2i [empagliflozin (EMPA) and dapagliflozin (DAPA) 1-100 µM] to assess their effects on SA (100 µM)-induced readouts of inflammation, oxidant stress and apoptosis in MAC and on expression of PLT activation markers by flow-cytometry after ADP-stimulation. Potential NHE involvement was tested with amiloride (aspecific NHE inhibitor) or cariporide (NHE1 inhibitor). Differences among culture conditions were identified using one-way ANOVA or Friedman test. RESULTS: NHE isoforms (1,5-9), but not SGLT2 expression, were expressed in MAC and PLT. EMPA and DAPA (100 µM) significantly reduced SA-induced inflammation (IL1ß, TNFα, MCP1), oxidant stress (SOD2, TXN, HO1), but not apoptosis in MAC. EMPA and DAPA (both 1 µM) reduced PLT activation (CD62p and PAC1 expression). SGLT2i effects were mimicked by amiloride, and only partially by cariporide, in MAC, and by both inhibitors in PLT. CONCLUSIONS: EMPA and DAPA ameliorated lipotoxic damage in stearate-treated MAC, and reduced ADP-stimulated PLT activation, potentially via NHE-inhibition, thereby pointing to plaque stabilization and/or thrombosis inhibition as potential mechanism(s) involved in SGLT2i-mediated cardiovascular protection.


Assuntos
Difosfato de Adenosina/farmacologia , Compostos Benzidrílicos/farmacologia , Plaquetas/efeitos dos fármacos , Células Progenitoras Endoteliais/efeitos dos fármacos , Glucosídeos/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Ácidos Esteáricos/toxicidade , Apoptose/efeitos dos fármacos , Plaquetas/metabolismo , Plaquetas/patologia , Células Cultivadas , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/patologia , Humanos , Mediadores da Inflamação/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Trocadores de Sódio-Hidrogênio/metabolismo
19.
PLoS One ; 15(4): e0220163, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294080

RESUMO

BACKGROUND: Clinical application of mesenchymal stromal cells (MSCs) usually requires an in vitro expansion step to reach clinically relevant numbers. In vitro cell expansion necessitates supplementation of basal mammalian cell culture medium with growth factors. To avoid using supplements containing animal substances, human platelet lysates (hPL) produced from expired and pathogen inactivated platelet concentrates can be used in place of fetal bovine serum. However, globally, most transfusion units are currently not pathogen inactivated. As blood banks are the sole source of platelet concentrates for hPL production, it is important to ensure product safety and standardized production methods. In this proof-of-concept study we assessed the feasibility of producing hPL from expired platelet concentrates with pathogen inactivation applied after platelet lysis by evaluating the retention of growth factors, cytokines, and the ability to support MSC proliferation and tri-lineage differentiation. METHODOLOGY/PRINCIPAL FINDINGS: Bone marrow-derived MSCs (BM-MSCs) were expanded and differentiated using hPL derived from pathogen inactivated platelet lysates (hPL-PIPL), with pathogen inactivation by amotosalen/ultraviolet A treatment applied after lysis of expired platelets. Results were compared to those using hPL produced from conventional expired pathogen inactivated platelet concentrates (hPL-PIPC), with pathogen inactivation applied after blood donation. hPL-PIPL treatment had lower concentrations of soluble growth factors and cytokines than hPL-PIPC treatment. When used as supplementation in cell culture, BM-MSCs proliferated at a reduced rate, but more consistently, in hPL-PIPL than in hPL-PIPC. The ability to support tri-lineage differentiation was comparable between lysates. CONCLUSION/SIGNIFICANCE: These results suggest that functional hPL can be produced from expired and untreated platelet lysates by applying pathogen inactivation after platelet lysis. When carried out post-expiration, pathogen inactivation may provide a valuable solution for further standardizing global hPL production methods, increasing the pool of starting material, and meeting future demand for animal-free supplements in human cell culturing.


Assuntos
Plaquetas/química , Extratos Celulares/farmacologia , Meios de Cultura/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Plaquetas/efeitos da radiação , Segurança do Sangue/métodos , Técnicas de Cultura de Células/métodos , Diferenciação Celular/efeitos dos fármacos , Extratos Celulares/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Meios de Cultura/química , Furocumarinas/farmacologia , Humanos , Células-Tronco Mesenquimais/citologia
20.
Cardiovasc Ther ; 2020: 8703627, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32284734

RESUMO

Antiplatelet therapy is the mainstay of treatment and secondary prevention of cardiovascular disease (CVD), including acute coronary syndrome (ACS), transient ischemic attack (TIA) or minor stroke, and peripheral artery disease (PAD). The P2Y12 inhibitors, of which clopidogrel was the first, play an integral role in antiplatelet therapy and therefore in the treatment and secondary prevention of CVD. This review discusses the available evidence concerning antiplatelet therapy in patients with CVD, with a focus on the role of clopidogrel. In combination with aspirin, clopidogrel is often used as part of dual antiplatelet therapy (DAPT) for the secondary prevention of ACS. Although newer, more potent P2Y12 inhibitors (prasugrel and ticagrelor) show a greater reduction in ischemic risk compared with clopidogrel in randomized trials of ACS patients, these newer P2Y12 inhibitors are often associated with an increased risk of bleeding. Deescalation of DAPT by switching from prasugrel or ticagrelor to clopidogrel may be required in some patients with ACS. Furthermore, real-world studies of ACS patients have not confirmed the benefits of the newer P2Y12 inhibitors over clopidogrel. In patients with very high-risk TIA or stroke, short-term DAPT with clopidogrel plus aspirin for 21-28 days, followed by clopidogrel monotherapy for up to 90 days, is recommended. Clopidogrel monotherapy may also be used in patients with symptomatic PAD. In conclusion, there is strong evidence supporting the use of clopidogrel antiplatelet therapy in several clinical settings, which emphasizes the importance of this medication in clinical practice.


Assuntos
Plaquetas/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Clopidogrel/uso terapêutico , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/uso terapêutico , Plaquetas/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Clopidogrel/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Inibidores da Agregação de Plaquetas/efeitos adversos , Medição de Risco , Fatores de Risco , Prevenção Secundária , Resultado do Tratamento
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