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1.
J Cardiovasc Pharmacol Ther ; 26(1): 12-24, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32924567

RESUMO

Coronavirus-2019 (COVID-19) predisposes patients to arterial and venous thrombosis commonly complicating the clinical course of hospitalized patients and attributed to the inflammatory state, endothelial dysfunction, platelet activation and blood stasis. This viral coagulopathy may occur despite thromboprophylaxis and raises mortality; the risk appears highest among critically ill inpatients monitored in the intensive care unit. The prevalence of venous thromboembolism in COVID-19 patients has been reported to reach ∼10-35%, while autopsies raise it to nearly 60%. The most common thrombotic complication is pulmonary embolism, which though may occur in the absence of a recognizable deep venous thrombosis and may be due to pulmonary arterial thrombosis rather than embolism, resulting in thrombotic occlusion of small- to mid-sized pulmonary arteries and subsequent infarction of lung parenchyma. This micro-thrombotic pattern seems more specific for COVID-19 and is associated with an intense immuno-inflammatory reaction that results in diffuse occlusive thrombotic micro-angiopathy with alveolar damage and vascular angiogenesis. Furthermore, thrombosis has also been observed in various arterial sites, including coronary, cerebral and peripheral arteries. Biomarkers related to coagulation, platelet activation and inflammation have been suggested as useful diagnostic and prognostic tools for COVID-19-associated coagulopathy; among them, D-dimer remains a key biomarker employed in clinical practice. Various medical societies have issued guidelines or consensus statements regarding thromboprophylaxis and treatment of these thrombotic complications specifically adapted to COVID-19 patients. All these issues are detailed in this review, data from meta-analyses and current guidelines are tabulated, while the relevant mechanisms of this virus-associated coagulopathy are pictorially illustrated.


Assuntos
Anticoagulantes/administração & dosagem , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Alarminas/metabolismo , Biomarcadores , Proteínas do Sistema Complemento/biossíntese , Estado Terminal , Citocinas/biossíntese , Produtos de Degradação da Fibrina e do Fibrinogênio/biossíntese , Humanos , Unidades de Terapia Intensiva , Pandemias , Ativação Plaquetária/fisiologia , Embolia Pulmonar/mortalidade , Embolia Pulmonar/prevenção & controle , Tromboembolia Venosa/fisiopatologia
3.
Int J Mol Sci ; 21(24)2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33327658

RESUMO

Patients affected by the rare Glanzmann thrombasthenia (GT) suffer from defective or low levels of the platelet-associated glycoprotein (GP) IIb/IIIa, which acts as a fibrinogen receptor, and have therefore an impaired ability to aggregate platelets. Because the procoagulant activity is a dichotomous facet of platelet activation, diverging from the aggregation endpoint, we were interested in characterizing the ability to generate procoagulant platelets in GT patients. Therefore, we investigated, by flow cytometry analysis, platelet functions in three GT patients as well as their ability to generate procoagulant collagen-and-thrombin (COAT) platelets upon combined activation with convulxin-plus-thrombin. In addition, we further characterized intracellular ion fluxes during the procoagulant response, using specific probes to monitor by flow cytometry kinetics of cytosolic calcium, sodium, and potassium ion fluxes. GT patients generated higher percentages of procoagulant COAT platelets compared to healthy donors. Moreover, they were able to mobilize higher levels of cytosolic calcium following convulxin-plus-thrombin activation, which is congruent with the greater procoagulant activity. Further investigations will dissect the role of GPIIb/IIIa outside-in signalling possibly implicated in the regulation of platelet procoagulant activity.


Assuntos
Plaquetas/metabolismo , Trombastenia/metabolismo , Plaquetas/fisiologia , Cálcio/metabolismo , Colágeno/metabolismo , Citometria de Fluxo , Humanos , Ativação Plaquetária/fisiologia , Potássio/metabolismo , Sódio/metabolismo , Trombina/metabolismo
4.
Nat Commun ; 11(1): 3479, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32661250

RESUMO

Genetic factors contribute to the risk of thrombotic diseases. Recent genome wide association studies have identified genetic loci including SLC44A2 which may regulate thrombosis. Here we show that Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial energetics. We find that Slc44a2 null mice (Slc44a2(KO)) have increased bleeding times and delayed thrombosis compared to wild-type (Slc44a2(WT)) controls. Platelets from Slc44a2(KO) mice have impaired activation in response to thrombin. We discover that Slc44a2 mediates choline transport into mitochondria, where choline metabolism leads to an increase in mitochondrial oxygen consumption and ATP production. Platelets lacking Slc44a2 contain less ATP at rest, release less ATP when activated, and have an activation defect that can be rescued by exogenous ADP. Taken together, our data suggest that mitochondria require choline for maximum function, demonstrate the importance of mitochondrial metabolism to platelet activation, and reveal a mechanism by which Slc44a2 influences thrombosis.


Assuntos
Proteínas de Membrana Transportadoras/metabolismo , Mitocôndrias/metabolismo , Ativação Plaquetária/fisiologia , Trombose/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Estudo de Associação Genômica Ampla , Masculino , Espectrometria de Massas , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Ativação Plaquetária/genética , Agregação Plaquetária/genética , Agregação Plaquetária/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Trombose/genética
5.
PLoS One ; 15(6): e0234501, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32525962

RESUMO

Shear-induced conformational changes of von Willebrand factor (VWF) play an important role in platelet activation. A novel approach describing VWF unfolding on the platelet surface under dynamic shear stress is proposed. Cumulative effect of dynamic shear on platelet activation via conformational changes of VWF is analysed. The critical condition of shear-induced platelet activation is formulated. The explicit expression for the threshold value of cumulative shear stress as a function of VWF multimer size is derived. The results open novel prospects for pharmacological regulation of shear-induced platelet activation through control of VWF multimers size distribution.


Assuntos
Plaquetas/fisiologia , Modelos Biológicos , Ativação Plaquetária/fisiologia , Estrutura Quaternária de Proteína/fisiologia , Fator de von Willebrand/metabolismo , Humanos , Simulação de Dinâmica Molecular , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Multimerização Proteica/fisiologia , Estabilidade Proteica , Estresse Mecânico , Relação Estrutura-Atividade
6.
Am J Pathol ; 190(9): 1833-1842, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32473917

RESUMO

Cholestatic liver injury leads to liver dysfunction. The available evidence suggests that platelets can either promote or reduce liver injury and fibrosis. This study focused on the functions of the C-type lectin-like receptor 2 (CLEC-2), a new special platelet receptor that binds with podoplanin-activating platelets. The role of CLEC-2 and podoplanin in cholestatic liver injury was investigated. Mice were injected intraperitoneally with weekly doses of anti-CLEC-2 antibody (2A2B10) to achieve effective CLEC-2 inhibition in their platelets. Next, left and middle hepatic bile duct ligation (BDL) procedures were performed, and mice were euthanized 1 week later (2A2B10-BDL group). In addition, mice were prepared for control groups, and relevant histological and laboratory variables were compared among these groups. The inhibition of CLEC-2 resulted in increasing hepatocellular necrosis, hepatic inflammation, and liver fibrosis. In addition, podoplanin was strongly expressed in hepatic sinusoidal endothelial cells in BDL-treated mice. Moreover, in 2A2B10-BDL mice, total plasma bile acid levels were significantly increased. In summary, podoplanin is expressed on hepatic sinusoidal endothelial cells upon BDL. Platelets bind with podoplanin via CLEC-2 and become activated. As a result, the total bile acid pool is decreased. Therefore, the CLEC-2-podoplanin interaction promotes liver protection and inhibits liver fibrosis after cholestatic liver injury.


Assuntos
Plaquetas/metabolismo , Colestase/metabolismo , Lectinas Tipo C/metabolismo , Glicoproteínas de Membrana/metabolismo , Animais , Colestase/patologia , Células Endoteliais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ativação Plaquetária/fisiologia
7.
Platelets ; 31(4): 423-431, 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32297542

RESUMO

A confluence of technological advances in genetic manipulation and molecular-based fluorescence imaging has led to the widespread adoption of laser injury models to study hemostasis and thrombosis in mice. In all animal models of hemostasis and thrombosis, detailing the nature of experimentally induced vascular injury is paramount in enabling appropriate interpretation of experimental results. A careful appraisal of the literature shows that direct laser-induced injury can result in variable degrees of vascular damage. This review will compare and contrast models of laser injury utilized in the field, with an emphasis on the mechanism and extent of injury, the use of laser injury in different vascular beds and the molecular mechanisms regulating the response to injury. All of these topics will be discussed in the context of how distinct applications of laser injury models may be viewed as representing thrombosis and/or hemostasis.


Assuntos
Modelos Animais de Doenças , Terapia a Laser , Camundongos , Lesões do Sistema Vascular/etiologia , Lesões do Sistema Vascular/patologia , Animais , Células Endoteliais/patologia , Artéria Femoral/lesões , Artéria Femoral/patologia , Artéria Femoral/efeitos da radiação , Hemostasia/fisiologia , Humanos , Microscopia Intravital , Terapia a Laser/métodos , Ativação Plaquetária/fisiologia , Veia Safena/lesões , Veia Safena/patologia , Veia Safena/efeitos da radiação , Trombose/metabolismo , Trombose/patologia , Tromboxano A2/metabolismo , Lesões do Sistema Vascular/metabolismo
8.
Medicine (Baltimore) ; 99(10): e19336, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32150071

RESUMO

BACKGROUND: VerifyNow (VN; Accumetrics, San Diego, CA) P2Y12 reaction unit (PRU) has an inverse relation with hemoglobin level (Hb). Chronic kidney disease (CKD) is associated with low response to clopidogrel and low Hb. Our aim is to investigate the relation between PRU and Hb, and to assess whether Hb directly affects PRU or not in patients with CKD undergoing hemodialysis (HD). METHODS: We analyzed the relation between PRU and Hb in 43 HD patients and compared it with a control group of 127 patients with normal renal function. Both groups underwent percutaneous coronary intervention for stable coronary artery disease. We also compared PRU between the 2 groups considering Hb as a confounding factor. RESULTS: In the control group, Hb and PRU showed a significant inverse correlation (correlation coefficient r = -0.340; P < .001), but not in the HD group (correlation coefficient r = -0.099; P = .53). PRU was higher in the HD group than the control group after adjusting for the influence of Hb (299.2 [95% confidence interval: 278.4-316.7] vs 248.7 [95% confidence interval: 227.7-269.0]; P < .001), even after propensity score matching (299.2 [95% confidence interval: 278.4-316.7] vs 241.7 [95% confidence interval: 221.8-262.2]; P < .001). CONCLUSIONS: PRU was higher regardless of lower Hb in CKD on HD patients than normal renal function patients. Therefore, Hb was not crucial factor to decide PRU in CKD on HD patients in this study.


Assuntos
Clopidogrel/farmacologia , Hemoglobinas/análise , Hemoglobinas/fisiologia , Ativação Plaquetária/fisiologia , Idoso , Clopidogrel/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Testes de Função Plaquetária/métodos , Estudos Prospectivos , Diálise Renal/métodos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia
9.
Transfusion ; 60(3): 613-621, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32017135

RESUMO

BACKGROUND: Cold (4°C)-stored platelets are currently under investigation for transfusion in bleeding patients. It is currently unknown how long cold-stored platelets can be stored for clinical applications. STUDY DESIGN AND METHODS: Twenty three subjects were recruited. Twenty-one subjects were available for in vivo assessment and received indium-111 radiolabeled, cold-stored platelets. We investigated 5- (n = 5), 10- (n = 6), 15- (n = 5), and 20-day-stored (n = 5) platelets and obtained samples for in vitro testing at baseline and after the designated storage time. Twenty three units were available for in vitro testing. Five- and 7-day (n = 5 each), room temperature (RT)-stored platelets served as the current clinical standard control. RESULTS: In vivo, we found a continuous decline in platelet recovery from 5 to 20 days. Platelet survival reached a low nadir after 10 days of storage. Ex vivo, we observed the maximum platelet αIIbß3 integrin response to collagen at 5 days of cold storage, and we saw a continuous decline thereafter. However, platelet integrin activation and mitochondrial membrane integrity were better preserved after 20 days at 4°C, compared to 5 days at RT. Platelet metabolic parameters suggest comparable results between 20-day cold-stored platelets and 5- or 7-day RT-stored platelets. CONCLUSION: In summary, we performed the first studies with extended, cold-stored, apheresis platelets in plasma for up to 20 days with a fresh comparator. Storing cold-stored platelets up to 20 days yields better results in vitro, but further studies in actively bleeding patients are needed to determine the best compromise between hemostatic efficacy and storage prolongation.


Assuntos
Plaquetas/fisiologia , Preservação de Sangue/métodos , Criopreservação , Humanos , Ativação Plaquetária/fisiologia , Transfusão de Plaquetas , Plaquetoferese/métodos , Fatores de Tempo
10.
Biochem Pharmacol ; 174: 113827, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31987853

RESUMO

Adenosine analogues have high affinity and selectivity for adenosine receptors (AR), and exhibit anti-platelet activity. Plasma proteins play an important role in the regulation of platelet function and may influence the action of anti-platelet compounds. Little is known about the interactions of AR agonists with plasma proteins. This study investigates the interplay between AR agonists and plasma proteins and the consequences of those interactions. Surface plasmon resonance was employed together with molecular docking study to determine the binding kinetics of four selected ARagonists (PSB0777, Cl-Ado, MRE0094, UK432097) to several carrier proteins and to clarify the nature of these interactions. The influence of a whole plasma and of some plasma components on the effectiveness of ARagonists in the inhibition of platelet function was assessed by flow cytometry (platelet activation) and ELISA (platelet adhesion). Plasma proteins remarkably diminished the effectiveness of ARagonists in inhibiting platelet activation and adhesion in vitro. ARagonists were found to strongly bind to human serum albumin (HSA) and the protein components of lipoproteins - apolipoproteins; HSA was essential for the binding of water-soluble PSB0777, whereas apolipoproteins were needed for interactions with poorly-water soluble compounds such as UK432097 and MRE0094. In addition, HSA was shown to significantly reduce the effectiveness of PSB0777 in inhibiting ADP-induced platelet activation. In conclusion, HSA and lipoproteins are important carriers for ARagonists, which can affect pharmacodynamics of ARagonists used as platelet inhibitors.


Assuntos
Agonistas do Receptor A2 de Adenosina/farmacologia , Adenosina/farmacologia , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Adenosina/análogos & derivados , Adenosina/química , Agonistas do Receptor A2 de Adenosina/química , Adulto , Feminino , Furanos/química , Furanos/farmacologia , Humanos , Masculino , Simulação de Acoplamento Molecular/métodos , Ativação Plaquetária/fisiologia , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/fisiologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Receptores Purinérgicos P1/metabolismo , Adulto Jovem
11.
Arterioscler Thromb Vasc Biol ; 40(2): 335-349, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31941383

RESUMO

OBJECTIVE: Cardiovascular disease is a major public health problem. Among cardiovascular disease's risk factors, tobacco smoking is considered the single most preventable cause of death, with thrombosis being the main mechanism of cardiovascular disease mortality in smokers. While tobacco smoking has been on the decline, the use of waterpipes/hookah has been rising, mainly due to the perception that they are less harmful than regular cigarettes. Strikingly, there are few studies on the negative effects of waterpipes on the cardiovascular system, and none regarding their direct contribution to thrombus formation. Approach and Results: We used a waterpipe whole-body exposure protocol that mimics real-life human exposure scenarios and investigated its effects, relative to clean air, on platelet function, hemostasis, and thrombogenesis. We found that waterpipe smoke (WPS)-exposed mice exhibited both shortened thrombus occlusion and bleeding times. Further, our results show that platelets from WPS-exposed mice are hyperactive, with enhanced agonist-induced aggregation, dense and α-granule secretion, αIIbß3 integrin activation, phosphatidylserine expression, and platelet spreading, when compared with clean air-exposed platelets. Finally, at the molecular level, it was found that Akt (protein kinase B) and ERK (extracellular signal-regulated kinases) phosphorylation are enhanced in the WPS and in nicotine-treated platelets. CONCLUSIONS: Our findings demonstrate that WPS exposure directly modulates hemostasis and increases the risk of thrombosis and that this is mediated, in part, via a state of platelet hyperactivity. The negative health impact of WPS/hookah, therefore, should not be underestimated. Moreover, this study should also help in raising public awareness of the toxic effects of waterpipe/hookah.


Assuntos
Plaquetas/efeitos dos fármacos , Artérias Carótidas/efeitos dos fármacos , Ativação Plaquetária/fisiologia , Cachimbos de Água , Fumar/efeitos adversos , Trombose/metabolismo , Animais , Plaquetas/metabolismo , Artérias Carótidas/patologia , Cotinina/toxicidade , Modelos Animais de Doenças , Citometria de Fluxo , Seguimentos , Immunoblotting , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nicotina/toxicidade , Contagem de Plaquetas , Fumaça/efeitos adversos , Trombose/induzido quimicamente , Fatores de Tempo
13.
Am J Sports Med ; 48(1): 197-209, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31765237

RESUMO

BACKGROUND: Meniscal injury is very common, and injured meniscal tissue has a limited healing ability because of poor vascularity. Platelets contain both pro- and anti-angiogenic factors, which can be released by platelet selective activation. HYPOTHESIS: Platelets release a high level of vascular endothelial growth factor (VEGF) when they are activated by protease-activated receptor 1 (PAR1), whereas the platelets release endostatin when they are activated by protease-activated receptor 4 (PAR4). The PAR1-treated platelets enhance the proliferation of meniscal cells in vitro and promote in vivo healing of wounded meniscal tissue. STUDY DESIGN: Controlled laboratory study. METHOD: Platelets were isolated from human blood and activated with different reagents. The released growth factors from the activated platelets were determined by immunostaining and enzyme-linked immunosorbent assay. The effects of the platelets with different treatments on meniscal cells were tested by an in vitro model of cell culture and an in vivo model of wounded meniscal healing. RESULTS: The results indicated that platelets contained both pro- and antiangiogenic factors including VEGF and endostatin. In unactivated platelets, VEGF and endostatin were contained inside of the platelets. Both VEGF and endostatin were released from the platelets when they were activated by thrombin. However, only VEGF was released from the platelets when they were activated by PAR1, and only endostatin was released from the platelets when they were activated by PAR4. The rat meniscal cells grew much faster in the medium that contained PAR1-activated platelets than in the medium that contained either PAR4-activated platelets or unactivated platelets. The wounds treated with PAR1-activated platelets healed faster than those treated with either PAR4-activated platelets or unactivated platelets. Many blood vessel-like structures were found in the wounded menisci treated with PAR1-activated platelets. CONCLUSION: The PAR1-activated platelets released high levels of VEGF, which increased the proliferation of rat meniscal cells in vitro, enhanced the vascularization of menisci in vivo, and promoted healing of wounded menisci. CLINICAL RELEVANCE: Our results suggested that selective activated platelets can be used clinically to enhance healing of wounded meniscal tissue.


Assuntos
Plaquetas/metabolismo , Menisco/lesões , Neovascularização Fisiológica/fisiologia , Ativação Plaquetária/fisiologia , Animais , Endostatinas/metabolismo , Feminino , Humanos , Ratos , Ratos Nus , Receptor PAR-1/metabolismo , Receptores de Trombina/metabolismo , Trombina/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Cardiovasc Intervent Radiol ; 43(1): 140-146, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31410532

RESUMO

BACKGROUND: Dual antiplatelet therapy is a pre-requisite for flow diverter (FD) implantation. The purpose of this study was to assess the thrombogenicity of the p48 FD, coated with the newly developed phenox Hydrophilic Polymer Coating (p48_HPC, phenox GmbH, Germany) in comparison with uncoated p48 FDs in an in vitro flow model (Chandler Loop). METHODS: p48 and p48_HPC FDs were implanted into silicon tubes filled with whole human blood and incubated at 37 °C under pulsating flow. After 120 min, platelet count was determined in the blood. Platelet activation markers (PAR1) and formation of microparticles were analyzed in a flow cytometer. Fluorescence microscopy of CD42a positive cells and scanning electron microscopy was used to detect adherent platelets on the wire surface. RESULTS: Platelets in contact with the uncoated p48 FDs are significantly more activated than those incubated with p48_HPC (73 ± 9% vs. 65 ± 6%, p < 0.05) and release more microparticles (1.8 ± 0.5 vs. 1.4 ± 0.4, p < 0.05). The platelet count after 120-min circulation in the Chandler Loop was significantly lower for the uncoated p48 compared to the p48_HPC indicating significantly greater adherence of the platelets to the p48 (71 ± 8% vs. 87 ± 5%, p < 0.05). SEM and fluorescent antibody imaging revealed minimal platelet adherence to the surface of the p48_HPC compared to the uncoated p48. CONCLUSION: The pHPC coating significantly reduces thrombogenicity of the p48 FD. This may help to reduce the risk of thromboembolic complications when using these devices. A reduction in antiplatelet therapy may be possible.


Assuntos
Plaquetas/fisiologia , Ativação Plaquetária/fisiologia , Stents , Trombose/prevenção & controle , Citometria de Fluxo , Humanos , Técnicas In Vitro , Microscopia Eletrônica de Varredura , Microscopia de Fluorescência , Polímeros
15.
Ther Apher Dial ; 24(1): 26-33, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31058456

RESUMO

Because hemofilters used for continuous renal replacement therapy contact with blood over a prolonged period during treatments, platelet activation may occur stronger. The purpose of this study is to clarify the blood compatibility in three hemofilters mostly used in Japan. We compared the blood compatibility of the two polysulfone (AEF: Asahi Kasei Medical Co., Tokyo, Japan and SHG: Toray Medical Co., Ltd., Tokyo, Japan) and one polymethylmethacrylate membranes (CH: Toray Medical Co., Ltd.). First, test blood was collected from healthy volunteers. Subsequently, the blood was circulated by a roller pump at the rate of 100 mL/min. We measured the platelet counts and platelet factor 4 (PF4). The platelet counts at 48 h in polymethylmethacrylate membrane were significantly less than that in polysulfone membranes. Levels of the PF4 after the circulation were 978.5 ± 200.0 ng/dL with AEF, 863.0 ± 233.9 ng/dL with SHG and 1780.0 ± 465.1 ng/dL with CH, respectively. Hemofilters with polysulfone membranes showed less platelet activation. It was inferred that the amount of PVP, the smoothness of the membrane surface, and the inner diameter of the hollow fiber affect the blood compatibility in the hemofilter.


Assuntos
Terapia de Substituição Renal Contínua/instrumentação , Membranas Artificiais , Polímeros/química , Polimetil Metacrilato/química , Sulfonas/química , Materiais Biocompatíveis/química , Feminino , Humanos , Japão , Masculino , Ativação Plaquetária/fisiologia , Contagem de Plaquetas , Fator Plaquetário 4/metabolismo
16.
Med Sci Monit ; 25: 9882-9886, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31868169

RESUMO

BACKGROUND Platelets are considered to be essential in proinflammatory environments, including atherosclerosis. The degree of platelet activation has been demonstrated to be correlated with plateletcrit and platelet distribution width. The main purpose of this study was to assess the relationship between plateletcrit (PCT), platelet distribution, and the degree of hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD). MATERIAL AND METHODS We enrolled 225 biopsy-proven NAFLD patients and 142 control subjects without NAFLD. NAFLD patients were separated into 2 groups according to percentage of steatosis. Demographic and clinical data were collected retrospectively. RESULTS PCT level was significantly higher in NAFLD group I and group II than in the control group. PCT was higher in the NAFLD groups than in the control group. However, there was no difference according to PCT and PDW levels between NAFLD groups. CONCLUSIONS In this study, a relationship was found between PCT and hepatosteatosis, but no relationship was found with PDW. PCT might be a useful biomarker for early detection of steatohepatitis in patients with nan-alcoholic fatty liver disease.


Assuntos
Plaquetas/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Adulto , Biomarcadores , Estudos de Casos e Controles , Fígado Gorduroso/sangue , Fígado Gorduroso/metabolismo , Feminino , Humanos , Masculino , Volume Plaquetário Médio/métodos , Pessoa de Meia-Idade , Ativação Plaquetária/fisiologia , Contagem de Plaquetas/métodos , Curva ROC , Estudos Retrospectivos
17.
Int J Mol Sci ; 20(23)2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31783490

RESUMO

Dysregulation of platelet function can contribute to the disease progression in sepsis. The proteasome represents a critical and vital element of cellular protein metabolism in platelets and its proteolytic activity has been associated with platelet function. However, the role of the platelet proteasome as well as its response to infection under conditions of sepsis have not been studied so far. We measured platelet proteasome activity by fluorescent substrates, degradation of poly-ubiquitinated proteins and cleavage of the proteasome substrate Talin-1 in the presence of living E. coli strains and in platelets isolated from sepsis patients. Upregulation of the proteasome activator PA28 (PSME1) was assessed by quantitative real-time PCR in platelets from sepsis patients. We show that co-incubation of platelets with living E. coli (UTI89) results in increased degradation of poly-ubiquitinated proteins and cleavage of Talin-1 by the proteasome. Proteasome activity and cleavage of Talin-1 was significantly increased in α-hemolysin (HlyA)-positive E. coli strains. Supporting these findings, proteasome activity was also increased in platelets of patients with sepsis. Finally, the proteasome activator PA28 (PSME1) was upregulated in this group of patients. In this study we demonstrate for the first time that the proteasome in platelets is activated in the septic milieu.


Assuntos
Plaquetas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Sepse/metabolismo , Sepse/microbiologia , Regulação para Cima/fisiologia , Escherichia coli/patogenicidade , Proteínas Hemolisinas/metabolismo , Humanos , Proteínas Musculares/metabolismo , Ativação Plaquetária/fisiologia , Agregação Plaquetária/fisiologia , Talina/metabolismo , Ativação Transcricional/fisiologia
18.
Thromb Res ; 184: 115-121, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31731068

RESUMO

INTRODUCTION: Red blood cell (RBC) transfusion is associated with an increased risk of pro-thrombotic events, but the underlying mechanism is poorly understood. We hypothesized that RBC transfusion modulates platelet activity in critically ill patients with and without sepsis. METHODS: In a prospective cohort study, 37 critically ill patients receiving a single RBC unit to correct for anemia were sampled prior to and 1 h after transfusion. Platelet exposure of P-selectin, CD63 and binding of PAC-1 as well as formation of platelet-leukocyte complexes were measured by flow cytometry. The ability of plasma from critically ill patients to induce ex vivo platelet aggregation was assessed by flow cytometry after incubation with platelets from a healthy donor. RESULTS: RBC transfusion neither triggered the expression of platelet activation markers nor the formation of platelet-leukocyte complexes. Plasma from critically ill patients induced more spontaneous platelet aggregation prior to RBC transfusion compared to healthy controls, which was further augmented following RBC transfusion. Also collagen-induced platelet aggregation was already increased prior to RBC transfusion compared to healthy controls, and this response was unaffected by RBC transfusion. In contrast, ristocetin-induced platelet agglutination was decreased when compared to controls, suggesting impaired vWF-dependent platelet agglutination, even in the presence of high vWF levels. Following RBC transfusion, ristocetin-induced platelet agglutination further decreased. There were no differences between septic and non-septic recipients in all assays. CONCLUSION: Ex vivo platelet aggregation is disturbed in the critically ill. Transfusion of a RBC unit may further increase the spontaneous platelet aggregatory response.


Assuntos
Plaquetas/metabolismo , Transfusão de Eritrócitos/métodos , Ativação Plaquetária/fisiologia , Idoso , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
19.
Bull Exp Biol Med ; 167(6): 732-734, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31655993

RESUMO

Generation of ROS (including free radicals) in rat platelets during physical exercises of different intensities was evaluated by the chemiluminescent method. The acute or chronic submaximal exercises increased the platelet chemiluminescence by 2.5-3.0 times. In the control, platelet activation with physiological aggregant ADP enhanced their chemiluminescence by 7.5 times. Addition of ADP to platelets isolated from animals subjected to exercise of any intensity increased chemiluminescence by 4-5 times. In a trained organism, functional reserve of the platelets is preserved during long-term physical exercise of any intensity, but is exhausted after acute physical exercise. Thus, intensive physical exercises enhanced the hemostatic potential of the blood, which is associated with the risk of thrombohemorrhagic complications, especially in acute or submaximal long-term exercises.


Assuntos
Plaquetas/fisiologia , Luminescência , Condicionamento Físico Animal/fisiologia , Animais , Animais não Endogâmicos , Radicais Livres/metabolismo , Masculino , Condicionamento Físico Animal/métodos , Esforço Físico/fisiologia , Ativação Plaquetária/fisiologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Natação/fisiologia
20.
BMC Nephrol ; 20(1): 395, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664940

RESUMO

BACKGROUND: Major Depressive Disorder (MDD) can lead to adverse cardiovascular outcomes in patients with chronic kidney disease (CKD). Although one of the proposed mechanisms is heightened platelet activation, effects of MDD and its treatment with a selective serotonin reuptake inhibitor (SSRI) on platelet function in patients with CKD remain unclear. METHODS: In a pre-specified analysis, changes from baseline to 12 weeks in whole blood platelet aggregation (WBPA) and plasma levels of E-selectin and P-selectin on treatment with sertraline vs. placebo were investigated in 175 patients with CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73m2) and MDD (MDD+/CKD+) in a randomized, double-blind trial. Correlations between severity of depressive symptoms and platelet function were also analyzed. In order to investigate whether differences in platelet function were due to presence of CKD or MDD, we compared a subgroup of 49 MDD+/CKD+ patients with eGFR < 30 ml/min/1.73m2 to 43 non-depressed CKD controls (28 CKD with eGFR < 30 ml/min/1.73m2 [MDD-/CKD+] and 15 individuals with eGFR ≥90 ml/min/1.73m2 [MDD-/CKD-]. RESULTS: In MDD+/CKD+ individuals, there were no significant correlations between severity of depressive symptoms and platelet function, and no significant changes in platelet function after 12 weeks of treatment with sertraline vs. placebo. There were no significant differences in platelet function among MDD+/CKD+ patients and controls without MDD except in WBPA to 10 µM ADP (P = 0.03). WBPA to ADP was lower in the MDD-/CKD- group (8.0 Ω [5.0 Ω, 11.0 Ω]) as compared to the MDD-/CKD+ group (12.5 Ω [8.0 Ω, 14.5 Ω]), P = 0.01, and the MDD+/CKD+ group (11.0 Ω [8.0 Ω, 15.0 Ω]), P < 0.01. CONCLUSIONS: Heightened ADP-induced platelet aggregability was observed in CKD patients compared to controls with normal kidney function, regardless of presence of comorbid MDD, and treatment with sertraline did not affect platelet function. These findings suggest that increased platelet activation may not be a major contributory underlying mechanism by which depression may lead to worse cardiovascular outcomes in patients with CKD. Future studies should include positive MDD controls without CKD to confirm our findings. TRIAL REGISTRATION: ClinicalTrials.gov identifier numbers: CAST Study: NCT00946998 (Recruitment Status: Completed. First Posted: July 27, 2009. Results First Posted: January 30, 2018). WiCKDonASA Study: NCT01768637 (Recruitment Status: Completed. First Posted: January 15, 2013. Results First Posted: April 19, 2019).


Assuntos
Plaquetas/efeitos dos fármacos , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Insuficiência Renal Crônica/sangue , Inibidores de Captação de Serotonina/uso terapêutico , Sertralina/uso terapêutico , Ácido Araquidônico/sangue , Plaquetas/fisiologia , Transtorno Depressivo Maior/complicações , Método Duplo-Cego , Selectina E/sangue , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Selectina-P/sangue , Placebos/uso terapêutico , Ativação Plaquetária/efeitos dos fármacos , Ativação Plaquetária/fisiologia , Agregação Plaquetária , Insuficiência Renal Crônica/complicações , Inibidores de Captação de Serotonina/sangue , Sertralina/sangue , Fatores de Tempo
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