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1.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802928

RESUMO

Blood platelets' adenosine receptors (AR) are considered to be a new target for the anti-platelet therapy. This idea is based on in vitro studies which show that signaling mediated by these receptors leads to a decreased platelet response to activating stimuli. In vivo evidence for the antithrombotic activity of AR agonists published to date were limited, however, to the usage of relatively high doses given in bolus. The present study was aimed at verifying if these substances used in lower doses in combination with inhibitors of P2Y12 could serve as components of dual anti-platelet therapy. We have found that a selective A2A agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine (HE-NECA) improved the anti-thrombotic properties of either cangrelor or prasugrel in the model of ferric chloride-induced experimental thrombosis in mice. Importantly, HE-NECA was effective not only when applied in bolus as other AR agonists in the up-to-date published studies, but also when given chronically. In vitro thrombus formation under flow conditions revealed that HE-NECA enhanced the ability of P2Y12 inhibitors to decrease fibrinogen content in thrombi, possibly resulting in their lower stability. Adenosine receptor agonists possess a certain hypotensive effect and an ability to increase the blood-brain barrier permeability. Therefore, the effects of anti-thrombotic doses of HE-NECA on blood pressure and the blood-brain barrier permeability in mice were tested. HE-NECA applied in bolus caused a significant hypotension in mice, but the effect was much lower when the substance was given in doses corresponding to that obtained by chronic administration. At the same time, no significant effect of HE-NECA was observed on the blood-brain barrier. We conclude that chronic administration of the A2A agonist can be considered a potential component of a dual antithrombotic therapy. However, due to the hypotensive effect of the substances, dosage and administration must be elaborated to minimize the side-effects. The total number of animals used in the experiments was 146.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Adenosina-5'-(N-etilcarboxamida)/análogos & derivados , Antitrombinas/farmacologia , Fibrinogênio/metabolismo , Cloridrato de Prasugrel/farmacologia , Agonistas do Receptor Purinérgico P1/farmacologia , Trombose/metabolismo , Monofosfato de Adenosina/farmacologia , Adenosina-5'-(N-etilcarboxamida)/farmacologia , Adulto , Animais , Pressão Sanguínea/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Cloretos , Diástole/efeitos dos fármacos , Feminino , Compostos Férricos , Humanos , Fluxometria por Laser-Doppler , Masculino , Camundongos Endogâmicos C57BL , Permeabilidade/efeitos dos fármacos , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Sístole/efeitos dos fármacos
2.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799528

RESUMO

Obstructive sleep apnoea (OSA) is a common disease which is characterised by repetitive collapse of the upper airways during sleep resulting in chronic intermittent hypoxaemia and frequent microarousals, consequently leading to sympathetic overflow, enhanced oxidative stress, systemic inflammation, and metabolic disturbances. OSA is associated with increased risk for cardiovascular morbidity and mortality, and accelerated coagulation, platelet activation, and impaired fibrinolysis serve the link between OSA and cardiovascular disease. In this article we briefly describe physiological coagulation and fibrinolysis focusing on processes which could be altered in OSA. Then, we discuss how OSA-associated disturbances, such as hypoxaemia, sympathetic system activation, and systemic inflammation, affect these processes. Finally, we critically review the literature on OSA-related changes in markers of coagulation and fibrinolysis, discuss potential reasons for discrepancies, and comment on the clinical implications and future research needs.


Assuntos
Síndrome Coronariana Aguda/metabolismo , Fibrinólise/genética , Hipóxia/metabolismo , Apneia Obstrutiva do Sono/metabolismo , Acidente Vascular Cerebral/metabolismo , Trombose Venosa/metabolismo , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/genética , Síndrome Coronariana Aguda/fisiopatologia , Fatores de Coagulação Sanguínea/genética , Fatores de Coagulação Sanguínea/metabolismo , Plaquetas/metabolismo , Plaquetas/patologia , Fibrinogênio/genética , Fibrinogênio/metabolismo , Regulação da Expressão Gênica , Humanos , Hipóxia/complicações , Hipóxia/genética , Hipóxia/fisiopatologia , Inflamação , Estresse Oxidativo , Ativação Plaquetária/genética , Agregação Plaquetária/genética , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/genética , Apneia Obstrutiva do Sono/fisiopatologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/fisiopatologia , Trombose Venosa/complicações , Trombose Venosa/genética , Trombose Venosa/fisiopatologia
3.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807403

RESUMO

Platelets play a crucial role in the physiology of primary hemostasis and pathological processes such as arterial thrombosis; thus, developing a therapeutic target that prevents platelet activation can reduce arterial thrombosis. Pterostilbene (PTE) has remarkable pharmacological activities, including anticancer and neuroprotection. Few studies have reported the effects of pterostilbene on platelet activation. Thus, we examined the inhibitory mechanisms of pterostilbene in human platelets and its role in vascular thrombosis prevention in mice. At low concentrations (2-8 µM), pterostilbene strongly inhibited collagen-induced platelet aggregation. Furthermore, pterostilbene markedly diminished Lyn, Fyn, and Syk phosphorylation and hydroxyl radical formation stimulated by collagen. Moreover, PTE directly hindered integrin αIIbß3 activation through interfering with PAC-1 binding stimulated by collagen. In addition, pterostilbene affected integrin αIIbß3-mediated outside-in signaling, such as integrin ß3, Src, and FAK phosphorylation, and reduced the number of adherent platelets and the single platelet spreading area on immobilized fibrinogen as well as thrombin-stimulated fibrin clot retraction. Furthermore, pterostilbene substantially prolonged the occlusion time of thrombotic platelet plug formation in mice. This study demonstrated that pterostilbene exhibits a strong activity against platelet activation through the inhibition of integrin αIIbß3-mediated inside-out and outside-in signaling, suggesting that pterostilbene can serve as a therapeutic agent for thromboembolic disorders.


Assuntos
Plaquetas/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/efeitos dos fármacos , Estilbenos/metabolismo , Animais , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Retração do Coágulo/efeitos dos fármacos , Colágeno , Fibrinogênio/metabolismo , Hemostasia/efeitos dos fármacos , Humanos , Integrina alfa2/efeitos dos fármacos , Integrina alfa2/metabolismo , Integrina beta3/efeitos dos fármacos , Integrina beta3/metabolismo , Integrinas/efeitos dos fármacos , Integrinas/metabolismo , Camundongos , Selectina-P/metabolismo , Fosforilação , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Trombose/metabolismo
4.
Bratisl Lek Listy ; 122(5): 320-324, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33848181

RESUMO

BACKGROUND: The aim of this study was to assess the effect of anticoagulation treatment on platelet aggregation. METHODS: The study group consisted of 24 patients on long-term warfarin therapy without any antiaggregation therapy. Platelet aggregation was measured using VerifyNow with arachidonic acid (AA) as an inducer in 23 patients and with light transmission aggregometry (LTA) in 19 patients using four different agonists. All patients had their international normalized ratio (INR) checked regularly. RESULTS: The mean INR value was 2.07 (SD 0.6). The average aggregation measured by VerifyNow was found to be 637.5 (SD 36.6) aspirin reaction units. The values of average aggregability in LTA were 73.3 % (SD 4.5 %), 73.2 % (SD 6 %) and 72.1 % (SD 4.8 %) in case of aggregation induced by AA, ADP, and collagen, respectively. Epinephrine­induced aggregability was 65.3 % (SD 14.7 %). Regression analysis between INR and values of collagen- or epinephrine­induced aggregability (r = 0.654 and 0.575) was found statistically significant (p = 0.004 and 0.016); every increase in INR by 0,1 brings about an increase in collagen- and epinephrine­induced aggregation values by 1.5 and 4, respectively. CONCLUSION: Administration of warfarin does not produce a significant reduction in platelet aggregation. On the contrary, prolonged INR evokes a mild increase in aggregation induced by collagen or epinephrine (Tab. 2, Fig. 3, Ref. 32). Text in PDF www.elis.sk Keywords: platelet aggregation, anticoagulation, warfarin, platelet function tests, chronic ischemic heart disease.


Assuntos
Agregação Plaquetária , Varfarina , Plaquetas , Humanos , Inibidores da Agregação de Plaquetas/farmacologia , Testes de Função Plaquetária , Varfarina/farmacologia
5.
Nat Commun ; 12(1): 2360, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33883551

RESUMO

Von Willebrand factor (VWF) activates in response to shear flow to initiate hemostasis, while aberrant activation could lead to thrombosis. Above a critical shear force, the A1 domain of VWF becomes activated and captures platelets via the GPIb-IX complex. Here we show that the shear-responsive element controlling VWF activation resides in the discontinuous autoinhibitory module (AIM) flanking A1. Application of tensile force in a single-molecule setting induces cooperative unfolding of the AIM to expose A1. The AIM-unfolding force is lowered by truncating either N- or C-terminal AIM region, type 2B VWD mutations, or binding of a ristocetin-mimicking monoclonal antibody, all of which could activate A1. Furthermore, the AIM is mechanically stabilized by the nanobody that comprises caplacizumab, the only FDA-approved anti-thrombotic drug to-date that targets VWF. Thus, the AIM is a mechano-regulator of VWF activity. Its conformational dynamics may define the extent of VWF autoinhibition and subsequent activation under force.


Assuntos
Fator de von Willebrand/química , Fator de von Willebrand/metabolismo , Anticorpos Monoclonais/farmacologia , Fenômenos Biomecânicos , Cristalografia por Raios X , Humanos , Técnicas In Vitro , Modelos Moleculares , Mutação , Agregação Plaquetária/efeitos dos fármacos , Conformação Proteica , Domínios Proteicos , Estabilidade Proteica , Desdobramento de Proteína , Ristocetina/farmacologia , Imagem Individual de Molécula , Anticorpos de Domínio Único/farmacologia , Resistência à Tração , Fator de von Willebrand/genética
6.
Adv Exp Med Biol ; 1286: 145-161, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33725352

RESUMO

Aging is a biological process with effects at the molecular, cellular, tissue, organ, system, and organismal levels and is characterized by decline in physical function and higher risks of age-related diseases. The use of anti-aging drugs for disease prevention has become a high priority for science and is a new biomedicine trend. Geroprotectors are compounds which slow aging and increase lifespan of the organism in question. The common painkiller aspirin, a member of the non-steroidal anti-inflammatory drug (NSAID) family, is one of the potential geroprotective agents. Aspirin is often used in treatment of mild to moderate pain. It has anti-inflammatory and anti-pyretic properties and acts as an inhibitor of cyclooxygenase which results in inhibition of prostaglandin. Acetylsalicylic acid as an active compound of aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Aspirin has shown life-extending effects in numerous model organisms. This chapter reviews the evidence for clinical efficacy of aspirin including cardiovascular disease prevention, anti-cancer effects, and improvement of cognitive function. However, there are some limitations of these therapies, including the risk of excessive bleeding. We have also summarized numerous experimental and analytical data that support health and longevity benefits of aspirin treatment by affecting pro-longevity pathways.


Assuntos
Anti-Inflamatórios não Esteroides , Aspirina , Anti-Inflamatórios , Ciclo-Oxigenase 2 , Agregação Plaquetária
7.
Medicine (Baltimore) ; 100(8): e24932, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663130

RESUMO

BACKGROUND: Exercise test (ET) may have adverse effects on platelet function and induce acute thrombotic events in patients with coronary artery disease (CAD). The aim of this study is to investigate the platelet function and evaluate the risk of thrombotic events in CAD patients during ET. METHODS: Pubmed, Embase, Cochrane Library, and Web of Science were searched for a systematic review from initiation to October 2019. The inclusion criteria were controlled clinical trails as study design; investigating platelet function in CAD patients during ET; with ET carried out by treadmill or bicycle ergometer; written in English. Included articles were screened based on title/abstract and full-text review by 2 independent reviewers. Platelet aggregation (PA), platelet surface expression of CD62p and PAC-1, plasma levels of platelet factor 4 (PF4) and beta-thromboglobulin (ß-TG) were evaluated before and after ET. RESULTS: Eighteen articles were included out of the 427 references initially identified. In most of the studies included ET was terminated because of limited symptoms. Prior to ET, no difference in platelet aggregation was observed in CAD patients compared with healthy controls in majority of the studies, with or without the treatment with Aspirin. Dual anti-platelet therapy suppressed adenosine diphosphate (ADP)-induced platelet aggregation at rest. After ET, platelet aggregation, the serum levels of ß-thromboglobulin were found unchanged in majority of studies and platelet factor-4 were found unchanged in half of studies. The expression of platelet surface markers were elevated by ET in a few study. CONCLUSION: Symptom-limited exercise test did not affect platelet function in patients with coronary artery disease; however exercise to higher intensity may induce platelet activation.


Assuntos
Doença da Artéria Coronariana/sangue , Teste de Esforço/efeitos adversos , Agregação Plaquetária , Reabilitação Cardíaca , Doença da Artéria Coronariana/terapia , Humanos , Inibidores da Agregação de Plaquetas/uso terapêutico , Testes de Função Plaquetária
8.
Zhonghua Er Ke Za Zhi ; 59(2): 113-118, 2021 Feb 02.
Artigo em Chinês | MEDLINE | ID: mdl-33548957

RESUMO

Objective: To explore the predictive value of platelet aggregation rate in patent ductus arteriosus in preterm infants. Methods: This prospective nested case-control study enrolled 72 preterm infants with gestational age<32 weeks, who were admitted to Neonatal Intensive Care Unit of Xuzhou Central Hospital from August 2017 to October 2019. The echocardiography was performed on the 4th to 5th day after birth, and the preterm infants who met the diagnostic criteria of hemodynamically significant patent ductus arteriosus (hsPDA) were included into hsPDA group, and the control group was comprised of matched preterm infants with non-hsPDA according to the proportion of 1∶2. The basic characteristics of the preterm infants were recorded, and their complete blood counts and platelet aggregation function were examined. Clinical data were compared by student's t test and chi-square test between the two groups. The risk factors and their predictive values were analyzed by binary logistic regression analysis and receiver operating characteristic curve. Results: There were 24 preterm infants (16 boys) in the hsPDA group, and 48 (30 boys) in the control group. The incidence of neonatal respiratory distress syndrome (NRDS) grade II-IV in the hsPDA group was higher than that in the control group (67% (16/24) vs. 27% (13/48), χ²=10.422, P=0.001). The thrombocytocrit and adenosine diphosphate-induced platelet aggregation rate in the hsPDA group were lower than those in the control group (0.002 1±0.000 9 vs. 0.002 8±0.000 9, 0.21±0.10 vs. 0.32±0.07, t=-3.043 and -5.093, P=0.004 and <0.01, respectively); while the platelet volume in the hsPDA group was greater than that in the control group ((10.3±2.4) vs. (9.2±2.0) fl, t = 2.713, P = 0.033). The other platelet parameters (platelet count, platelet distribution width, and large platelet ratio) and platelet aggregation rate induced by other inducers (collagen, epinephrine and arachidonic acid) were not significantly different between the two groups (all P>0.05). The low platelet aggregation rate induced by adenosine diphosphate and low thrombocytocrit were independent risk factors for hsPDA in preterm infants (OR=4.525 and 3.994, 95%CI: 1.305-15.689 and 1.143-13.958, respectively). And the adenosine diphosphate-induced platelet aggregation rate had moderate predictive value for hsPDA in preterm infants, as the area under the receiver operating characteristic curve was 0.809, and the cutoff value was 0.245 with 0.67 sensitivity and 0.86 specificity. Conclusions: Poor platelet aggregation function and low thrombocytocrit are independent risk factors for hsPDA in preterm infants with gestational age<32 weeks. Low platelet aggregation rate induced by adenosine diphosphate has moderate predictive value for hsPDA patency.


Assuntos
Permeabilidade do Canal Arterial , Estudos de Casos e Controles , Permeabilidade do Canal Arterial/diagnóstico por imagem , Permeabilidade do Canal Arterial/epidemiologia , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Agregação Plaquetária , Estudos Prospectivos
9.
J Med Food ; 24(2): 135-144, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33617365

RESUMO

Thrombosis causes poor blood circulation, which may lead to several cardiovascular disorders. Antiplatelet aggregation and antihyperlipidemia are the key processes that improve blood circulation. The antiplatelet aggregation and antihyperlipidemic effects of ACG-1, a mixture of Angelica gigas, Cynanchum wilfordii, and Ginkgo biloba extracts, were investigated in this study. The antiplatelet aggregation activity of ACG-1 was determined by studying its effects on collagen-induced platelet aggregation in human platelet-rich plasma (PRP). In addition, the effects of ACG-1 were investigated in a thromboembolism mouse model. The high-fat diet (HFD)-fed mouse model was used to investigate the antihyperlipidemic effects of ACG-1 and western blotting assay was performed to elucidate its mechanism of action. It was observed that ACG-1 significantly inhibited platelet aggregation in human PRP. Furthermore, ACG-1 showed protective effects in a thromboembolism mouse model induced by administering a mixed collagen and epinephrine intravenous injection. Oral administration of ACG-1 also significantly ameliorated blood lipid profiles in the HFD-fed mouse model. In conclusion, ACG-1 should be considered a powerful functional food to improve blood circulation.


Assuntos
Angelica , Circulação Sanguínea , Cynanchum , Ginkgo biloba , Extratos Vegetais , Agregação Plaquetária , Angelica/química , Animais , Circulação Sanguínea/efeitos dos fármacos , Cynanchum/química , Modelos Animais de Doenças , Ginkgo biloba/química , Humanos , Camundongos , Extratos Vegetais/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Tromboembolia/tratamento farmacológico
10.
Nutr Metab Cardiovasc Dis ; 31(4): 1276-1285, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33549433

RESUMO

BACKGROUND AND AIMS: Dual antiplatelet therapy (DAPT) and Renin-angiotensin system inhibitors (RASi) represent the cornerstone in the treatment of patients undergoing percutaneous coronary interventions (PCI), mainly after an acute ischemic event. However, high-on treatment residual platelet reactivity (HRPR), is not infrequent despite optimal medical treatment. Homocysteine (Hcy) is a metabolite of methionine catabolism linked to atherothrombosis. Recently, a potential crosstalk between RAS and Hcy has been suggested, potentially favouring platelet aggregation and cardiovascular disease.Therefore, we aimed to investigate the impact of RASi on Hcy levels and platelet aggregation in patients on DAPT after PCI. METHODS AND RESULTS: Patients undergoing PCI on DAPT with ASA plus an ADP-antagonist (clopidogrel, ticagrelor or prasugrel), were included. RASi comprised angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). Aggregation tests were performed by Multiple Electrode Aggregometry. We included 1210 patients, of whom 862 (71.2%) were on treatment with RASi. Overall, DAPT composition was ASA+clopidogrel in 566 (46.8%) patients, ASA+ticagrelor in 428 (35.4%) and ASA+prasugrel in 216 (17.9%). Median values of Hcy were higher in RASi patients (p = 0.006), who displayed a higher percentage of Hcy above the median value (52.4% vs. 44.8%, p = 0.019, adjustedOR [95%CI] = 1.40 [1.04-1.88], p = 0.027). No differences in HRPR rate were found according to RASi use for ASPI test (3.6% vs. 3.3%, p = 0.88) and ADP test (25.6% vs. 24.3%,p = 0.62; adjustedOR [95%CI] = 1.23 [0.89-1.70], p = 0.220) and according to ADP-antagonist type. A direct linear relationship was observed between platelet reactivity and Hcy in both patients receiving RASi and untreated ones, with higher values of platelet aggregation being observed in patients with Hcy above the median, independently from RASi administration and DAPT strategy. CONCLUSION: In patients on DAPT after PCI, RASi treatment did not emerge as an independent predictor of HRPR. However, the levels of Hcy were significantly elevated in patients on RASi and related to higher values of platelet reactivity, independently from the DAPT strategy.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Plaquetas/efeitos dos fármacos , Doença da Artéria Coronariana/terapia , Terapia Antiplaquetária Dupla , Homocisteína/sangue , Intervenção Coronária Percutânea , Agregação Plaquetária/efeitos dos fármacos , Idoso , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Biomarcadores/sangue , Plaquetas/metabolismo , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Terapia Antiplaquetária Dupla/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
11.
Klin Lab Diagn ; 66(1): 35-41, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33567171

RESUMO

Platelet function testing is widely used to diagnose disorders of the cellular link of hemostasis. The study of platelet aggregation activity is relevant for the prevention of thromboembolic complications in atrial fibrillation and monitoring the effectiveness and safety of therapy. In this study, a comparative analysis of spontaneous and stimulated platelet aggregation in groups of patients with two types of atrial fibrillation was performed - paroxysmal and persistent. The effect of ß-adrenoblocker therapy on platelet aggregation activity in patients with atrial fibrillation was also studied. Platelet aggregation activity was studied using the method of G. Born in the modification of Z.A. Gabbasov on a two-channel laser analyzer "Biola". Collagen at a concentration of 2 mg / ml and adrenaline in a concentration range of 2.5-10 µg / ml were used as aggregation-promoting agents. It has been established that spontaneous aggregation potential and collagen-induced platelet aggregation depend on the type of atrial fibrillation, as well as on the presence or absence of ß-blockers in therapy. The response of platelets to stimulation with adrenaline depends, first of all, on the type of atrial fibrillation and the concentration of adrenaline in the reaction medium. The most significant changes were noted in the group of patients with a paroxysmal form atrial fibrillation, taking ß-blockers in therapy.


Assuntos
Fibrilação Atrial , Fibrilação Atrial/tratamento farmacológico , Plaquetas , Hemostasia , Humanos , Agregação Plaquetária , Testes de Função Plaquetária
13.
Nutrients ; 13(2)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498445

RESUMO

Fish consumption beneficially affects coagulation markers. Few dietary intervention studies have investigated differently fed farmed fish against these cardio-metabolic risk factors in humans. This double-blind randomized crossover trial evaluated differently fed farmed gilthead sea bream consumption against platelet aggregation and circulating haemostatic markers among apparently healthy adults. Subjects aged 30-65 years, with a body mass index 24.0-31.0 kg/m2, consuming less than 150 g cooked fish per week, were recruited in Attica, Greece. Participants were randomized (n = 38, 1:1) to one of two sequences; consumption of fish fed with fish oil diet (conventional fish, CF)/fish fed with olive pomace-enriched diet (enriched fish, EF) versus EF/CF. The primary outcomes were ex vivo human platelet aggregation and circulating plasminogen activator inhibitor-1 (PAI-1) and P-selectin (sP-selectin) concentrations. EF consumption had no significant effect on platelet sensitivity or haemostatic markers compared to CF. Platelet sensitivity to platelet-activating factor (PAF) decreased after CF consumption during the second period (p < 0.01). Plasma PAI-1 and sP-selectin concentrations increased after CF consumption during both periods (p < 0.01 for both). Based on current findings, consumption of enriched farmed gilthead sea bream had no greater effect on coagulation markers in adults compared to the conventionally fed fish.


Assuntos
Ração Animal , Coagulação Sanguínea , Dieta , Pesqueiros , Agregação Plaquetária , Dourada , Alimentos Marinhos , Adulto , Idoso , Animais , Biomarcadores/sangue , Estudos Cross-Over , Método Duplo-Cego , Óleos de Peixe , Hemostasia , Humanos , Pessoa de Meia-Idade
14.
PLoS One ; 16(1): e0244736, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33411760

RESUMO

Galectin-1 (gal-1) is a carbohydrate-binding lectin with important functions in angiogenesis, immune response, hemostasis and inflammation. Comparable functions are exerted by platelet factor 4 (CXCL4), a chemokine stored in the α-granules of platelets. Previously, gal-1 was found to activate platelets through integrin αIIbß3. Both gal-1 and CXCL4 have high affinities for polysaccharides, and thus may mutually influence their functions. The aim of this study was to investigate a possible synergism of gal-1 and CXCL4 in platelet activation. Platelets were treated with increasing concentrations of gal-1, CXCL4 or both, and aggregation, integrin activation, P-selectin and phosphatidyl serine (PS) exposure were determined by light transmission aggregometry and by flow cytometry. To investigate the influence of cell surface sialic acid, platelets were treated with neuraminidase prior to stimulation. Gal-1 and CXCL4 were found to colocalize on the platelet surface. Stimulation with gal-1 led to integrin αIIbß3 activation and to robust platelet aggregation, while CXCL4 weakly triggered aggregation and primarily induced P-selectin expression. Co-incubation of gal-1 and CXCL4 potentiated platelet aggregation compared with gal-1 alone. Whereas neither gal-1 and CXCL4 induced PS-exposure on platelets, prior removal of surface sialic acid strongly potentiated PS exposure. In addition, neuraminidase treatment increased the binding of gal-1 to platelets and lowered the activation threshold for gal-1. However, CXCL4 did not affect binding of gal-1 to platelets. Taken together, stimulation of platelets with gal-1 and CXCL4 led to distinct and complementary activation profiles, with additive rather than synergistic effects.


Assuntos
Plaquetas/efeitos dos fármacos , Galectina 1/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Fator Plaquetário 4/farmacologia , Plaquetas/metabolismo , Humanos , Ácido N-Acetilneuramínico/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Anesthesiology ; 134(3): 457-467, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33417674

RESUMO

BACKGROUND: The hemostatic balance in patients with coronavirus disease 2019 (COVID-19) seems to be shifted toward a hypercoagulable state. The aim of the current study was to assess the associated coagulation alterations by point-of-care-diagnostics, focusing on details of clot formation and lysis in these severely affected patients. METHODS: The authors' prospective monocentric observational study included critically ill patients diagnosed with COVID-19. Demographics and biochemical data were recorded. To assess the comprehensive hemostatic profile of this patient population, aggregometric (Multiplate) and viscoelastometric (CloPro) measures were performed in the intensive care unit of a university hospital at a single occasion. Coagulation analysis and assessment of coagulation factors were performed. Data were compared to healthy controls. RESULTS: In total, 27 patients (21 male; mean age, 60 yr) were included. Impedance aggregometry displayed no greater platelet aggregability in COVID-19 in comparison with healthy controls (area under the curve [AUC] in adenosine diphosphate test, 68 ± 37 U vs. 91 ± 29 U [-27 (Hodges-Lehmann 95% CI, -48 to -1); P = 0.043]; AUC in arachidonic acid test, 102 ± 54 U vs. 115 ± 26 U [-21 (Hodges-Lehmann 95% CI, -51 to 21); P = 0.374]; AUC in thrombin receptor activating peptide 6 test, 114 ± 61 U vs. 144 ± 31 U [-31 (Hodges-Lehmann 95% CI, -69 to -7); P = 0.113]). Comparing the thromboelastometric results of COVID-19 patients to healthy controls, the authors observed significant differences in maximum clot firmness in fibrin contribution to maximum clot firmness assay (37 ± 11 mm vs. 15 ± 4 mm [21 (Hodges-Lehmann 95% CI, 17 to 26); P < 0.001]) and lysis time in extrinsic activation and activation of fibrinolysis by tissue plasminogen activator assay (530 ± 327 s vs. 211 ± 80 s [238 (Hodges-Lehmann 95% CI, 160 to 326); P < 0.001]). CONCLUSIONS: Thromboelastometry in COVID-19 patients revealed greater fibrinolysis resistance. The authors did not find a greater platelet aggregability based on impedance aggregometric tests. These findings may contribute to our understanding of the hypercoagulable state of critically ill patients with COVID-19.


Assuntos
Fibrinólise , Estado Terminal , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária , Estudos Prospectivos , Tromboelastografia , Ativador de Plasminogênio Tecidual
16.
Arterioscler Thromb Vasc Biol ; 41(3): 1092-1104, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33472402

RESUMO

OBJECTIVE: GPVI (glycoprotein VI) is a key molecular player in collagen-induced platelet signaling and aggregation. Recent evidence indicates that it also plays important role in platelet aggregation and thrombus growth through interaction with fibrin(ogen). However, there are discrepancies in the literature regarding whether the monomeric or dimeric form of GPVI binds to fibrinogen at high affinity. The mechanisms of interaction are also not clear, including which region of fibrinogen is responsible for GPVI binding. We aimed to gain further understanding of the mechanisms of interaction at molecular level and to identify the regions on fibrinogen important for GPVI binding. Approach and Results: Using multiple surface- and solution-based protein-protein interaction methods, we observe that dimeric GPVI binds to fibrinogen with much higher affinity and has a slower dissociation rate constant than the monomer due to avidity effects. Moreover, our data show that the highest affinity interaction of GPVI is with the αC-region of fibrinogen. We further show that GPVI interacts with immobilized fibrinogen and fibrin variants at a similar level, including a nonpolymerizing fibrin variant, suggesting that GPVI binding is independent of fibrin polymerization. CONCLUSIONS: Based on the above findings, we conclude that the higher affinity of dimeric GPVI over the monomer for fibrinogen interaction is achieved by avidity. The αC-region of fibrinogen appears essential for GPVI binding. We propose that fibrin polymerization into fibers during coagulation will cluster GPVI through its αC-region, leading to downstream signaling, further activation of platelets, and potentially stimulating clot growth. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Fibrinogênio/metabolismo , Fragmentos de Peptídeos/sangue , Glicoproteínas da Membrana de Plaquetas/metabolismo , Animais , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/química , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinogênio/química , Humanos , Técnicas In Vitro , Camundongos , Microscopia de Força Atômica , Fragmentos de Peptídeos/química , Peptídeos/química , Peptídeos/metabolismo , Agregação Plaquetária/fisiologia , Glicoproteínas da Membrana de Plaquetas/química , Domínios e Motivos de Interação entre Proteínas , Estrutura Quaternária de Proteína , Transdução de Sinais , Ressonância de Plasmônio de Superfície
17.
J Vet Diagn Invest ; 33(2): 300-307, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33353486

RESUMO

In addition to maintaining hemostasis, platelets have an important role in modulating innate and adaptive immune responses. A low platelet count has been found to be a negative prognostic factor for survival in humans and horses with critical illnesses, such as sepsis or systemic inflammatory response syndrome (SIRS). Decreased platelet aggregation, caused by in vivo activation, has been found in human patients with severe sepsis. In our prospective controlled study, we assessed platelet biology in blood samples from 20 equine SIRS cases and 120 healthy control horses. Platelet variables such as platelet count, large platelet count, clumps, plateletcrit, mean platelet volume, and mean platelet component concentration were analyzed by laser flow cytometry (Advia 2120) from K3EDTA blood and from citrate blood. Hirudin blood samples were analyzed by impedance aggregometry (Multiplate analyzer; Roche) for platelet aggregation, including spontaneous aggregation and aggregation by 4 different agonists: adenosine diphosphate (ADPtest), ADP + prostaglandin E1 (ADPtestHS), arachidonic acid (ASPItest), and collagen (COLtest). SIRS cases had significantly lower platelet counts in K3EDTA blood (p < 0.0001) compared to control horses. There were no significant differences in aggregation values between SIRS cases and controls. Non-surviving SIRS horses did not have statistically significant lower platelet counts or lower aggregation values for COLtest, ADPtest, or ADPtestHS compared to surviving SIRS horses, although 5 non-survivors were thrombocytopenic.


Assuntos
Plaquetas/fisiologia , Doenças dos Cavalos/fisiopatologia , Agregação Plaquetária , Contagem de Plaquetas/veterinária , Síndrome de Resposta Inflamatória Sistêmica/veterinária , Animais , Estudos de Casos e Controles , Feminino , Alemanha , Doenças dos Cavalos/sangue , Cavalos , Masculino , Estudos Prospectivos , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia
18.
Carbohydr Polym ; 254: 117291, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33357860

RESUMO

Anti-inflammatory drugs such as dexamethasone (DEX) are commonly administered to cancer patients along with anticancer drugs, however, the effect of DEX on human cancers is poorly understood. In this article, we have tailored self-assembled nanoparticles derived from hyaluronic acid (HA) wherein, anti-inflammatory DEX was used as a hydrophobic moiety for inducing amphiphilicity. The HA-DEX micelles were subsequently loaded with chemotherapeutic agent, doxorubicin (DOX) (HA-DEX-DOX) and was utilized to deliver drug cargo to human cancer cells expressing different levels of CD44 receptors. We found that DEX suppressed the cytotoxicity of DOX in HCT116, while it synergistically enhanced cytotoxicity in MCF-7 cells. When we tested DOX and HA-DEX-DOX in an ex-vivo human whole blood, we found activation of complement and the coagulation cascade in one group of donors. Encapsulation of DOX within the nanoparticle core eliminated such deleterious side-effects. The HA-DEX-DOX also polarized bone-marrow-derived anti-inflammatory M2 macrophages, to pro-inflammatory M1 phenotype with the upregulation of the cytokines TNF-α, iNOS and IL-1ß.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antibióticos Antineoplásicos/administração & dosagem , Polaridade Celular/efeitos dos fármacos , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Ácido Hialurônico/química , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Nanopartículas/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Combinação de Medicamentos , Liberação Controlada de Fármacos , Células HCT116 , Humanos , Receptores de Hialuronatos/antagonistas & inibidores , Ácido Hialurônico/farmacologia , Inflamação/tratamento farmacológico , Células MCF-7 , Camundongos , Camundongos Endogâmicos C57BL , Micelas , Fenótipo , Agregação Plaquetária/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
19.
Phytomedicine ; 80: 153363, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33070081

RESUMO

BACKGROUND: The ingestion of flavonoids has been reported to be associated with reduced cardiovascular disease risk. Quercitrin is a common flavonoid in nature, and it exhibits antioxidant properties. Although the process of thrombogenesis is intimately related to cardiovascular disease risk, it is unclear whether quercitrin plays a role in thrombogenesis. PURPOSE: The aim of this study was to examine the antiplatelet effect of quercitrin in platelet activation. METHODS: Platelet aggregation, granule secretion, calcium mobilization, and integrin activation were used to assess the antiplatelet activity of quercitrin. Antithrombotic effect was determined in mouse using ferric chloride (FeCl3)-induced arterial thrombus formation in vivo and thrombus formation on collagen-coated surfaces under arteriolar shear in vitro. Transection tail bleeding time was used to evaluate whether quercitrin inhibited primary hemostasis. RESULTS: Quercitrin significantly impaired collagen-related peptide-induced platelet aggregation, granule secretion, reactive oxygen species generation, and intracellular calcium mobilization. Outside-in signaling of αIIbß3 integrin was significantly inhibited by quercitrin in a concentration-dependent manner. The inhibitory effect of quercitrin resulted from inhibition of the glycoprotein VI-mediated platelet signal transduction during cell activation. Further, the antioxidant effect is derived from decreased phosphorylation of components of the TNF receptor-associated factor 4/p47phox/Hic5 axis signalosome. Oral administration of quercitrin efficiently blocked FeCl3-induced arterial thrombus formation in vivo and thrombus formation on collagen-coated surfaces under arteriolar shear in vitro, without prolonging bleeding time. Studies using a mouse model of ischemia/reperfusion-induced stroke indicated that treatment with quercitrin reduced the infarct volume in stroke. CONCLUSIONS: Our results demonstrated that quercitrin could be an effective therapeutic agent for the treatment of thrombotic diseases.


Assuntos
Fibrinolíticos/farmacologia , Hemostasia/efeitos dos fármacos , Quercetina/análogos & derivados , Trombose/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Artérias , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Quercetina/efeitos adversos , Quercetina/farmacologia , Traumatismo por Reperfusão/induzido quimicamente , Trombose/induzido quimicamente , Trombose/metabolismo
20.
Methods Mol Biol ; 2217: 237-249, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33215384

RESUMO

Platelets are small, anucleate cells that play oversized roles in hemostasis, immunity, and inflammation. An important mediator of platelet function is integrin αIIbß3, which is required for fibrinogen-dependent platelet aggregation during hemostasis. This platelet response is dependent on conformational changes in the integrin induced by "inside-out" biochemical signals that are triggered by platelet agonists. In turn, fibrinogen binding to αIIbß3 initiates "outside-in" biochemical and mechanical signals that regulate the platelet cytoskeleton and help to promote full platelet aggregation and secretory responses. Without a nucleus, there is a limited range of experimental manipulations that are possible with human platelets to study the molecular basis of integrin signaling in these primary cells. Consequently, many studies of αIIbß3 function use genetic approaches that rely on heterologous expression systems or platelets from gene-targeted mice, sometimes with uncertain applicability to human platelets. This chapter will detail a method for genetic manipulation of megakaryocytes and platelets derived from human induced pluripotent stem cells for molecular studies of αIIbß3 signaling and for modeling of human platelet functions potentially relevant to hemostasis, immunity, and inflammation.


Assuntos
Plaquetas/metabolismo , Engenharia Celular/métodos , Megacariócitos/metabolismo , Agregação Plaquetária/genética , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Glicoproteína IIb da Membrana de Plaquetas/genética , Plaquetas/citologia , Diferenciação Celular , Linhagem Celular , Citoesqueleto/metabolismo , Citoesqueleto/ultraestrutura , Fibrinogênio/genética , Fibrinogênio/metabolismo , Regulação da Expressão Gênica , Hemostasia/genética , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Megacariócitos/citologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Glicoproteína IIb da Membrana de Plaquetas/metabolismo , Ligação Proteica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Ubiquitinas/antagonistas & inibidores , Ubiquitinas/genética , Ubiquitinas/metabolismo
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