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1.
Interv Cardiol Clin ; 13(4): 451-467, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39245546

RESUMO

Antiplatelet and anticoagulant therapies are cornerstones of secondary prevention in high-risk cardiovascular patients. Whereas in former days the focus was set on effective antithrombotic effects, more recent trials and guidelines placed emphasis on a more balanced approach, thus including the bleeding risk for an individualized therapy. Type, strength, combination, and duration are important components to modify the individual bleeding risk. Novel antiplatelet and anticoagulant agents have shown promising results that might offer safer options in the future for high-risk cardiovascular patients. This review aims to give an overview about established drug target and pharmacologic approaches that are currently in the pipeline.


Assuntos
Anticoagulantes , Coagulação Sanguínea , Ativação Plaquetária , Inibidores da Agregação Plaquetária , Humanos , Ativação Plaquetária/efeitos dos fármacos , Ativação Plaquetária/fisiologia , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/fisiologia , Anticoagulantes/uso terapêutico , Anticoagulantes/farmacologia , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia
2.
Front Immunol ; 15: 1441637, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39229275

RESUMO

Background: Chronic obstructive pulmonary disease (COPD), usually caused by long-term tobacco smoking, is independently associated with systemic inflammation. However, little is known about the systemic inflammatory status of patients with early-stage COPD (classified as GOLD 1) and long-term smokers with normal lung function (LF). Here, we characterised the early changes in the associated inflammatory state in patients with GOLD 1 and in long-term smokers with normal LF. Methods: Fresh blood samples from 27 patients with GOLD 1, 27 long-term smokers and 14 non-smokers were analysed. Results: Ex vivo blood analysis revealed greater leucocyte-platelet adhesion to TNFα-stimulated pulmonary endothelium in patients with GOLD 1 than in smokers and non-smokers. In addition, platelet reactivity (platelet count and activation, and fibrinogen levels) and the frequency of leucocyte-platelet aggregates were higher in the GOLD 1 group than in the other groups. Some of these findings correlated with the severity of lung dysfunction, while platelet hyperactivity correlated positively with leucocyte-platelet adhesion. The GOLD 1 group also had a higher Th17/Treg ratio and higher circulating levels of IL-17C and C-reactive protein than the other groups. However, long-term smokers also had higher leucocyte counts and activation, and higher plasma levels of TNFα and IL-6 than non-smokers. Conclusion: Our data suggest that the altered inflammatory parameters in long-term smokers may represent early biomarkers of COPD. Accordingly, peripheral immune monitoring based on the above parameters may be useful to prevent disease progression in long-term smokers with normal LF and early COPD.


Assuntos
Plaquetas , Leucócitos , Ativação Plaquetária , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Leucócitos/imunologia , Leucócitos/metabolismo , Plaquetas/metabolismo , Plaquetas/imunologia , Idoso , Adesão Celular , Fumar/efeitos adversos , Biomarcadores/sangue
3.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(8): 1605-1611, 2024 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-39276057

RESUMO

OBJECTIVE: To investigate the effects of platelet-specific Rictor knockout on platelet activation and thrombus formation in mice. METHODS: PF4-Cre and Rictorfl/fl transgenic mice were crossed to obtain platelet-specific Rictor knockout (Rictor-KO) mice and wild-type mice (n=65), whose expression levels of Rictor, protein kinase B (AKT) and p-AKT were detected using Western blotting. Platelet counts of the mice were determined using routine blood tests, and hemostatic function was assessed by tail vein hemorrhage test. Venous thrombosis models were established in the mice to evaluate the effect of Rictor knockout on thrombosis. Platelet aggregation induced by ADP and thrombin was observed in Rictor-KO and wild-type mice, and flow cytometry was used to analyze the expression levels of integrin αIIbß3 and CD62P in resting and activated platelets. Plasma PF4 levels were determined with ELISA. Megakaryocytes from Rictor-KO and wild-type mice were incubated by vWF immunohistochemical antibody and APC-CD41 antibody to detect the number and ploidy of megakaryocytes, respectively. Platelet elongation on collagen surface was observed with scanning electron microscopy. RESULTS: Compared with the wild-type mice, Rictor-KO mice showed significantly decreased AKT phosphorylation, decreased platelet production, reduced thrombosis, and decreased platelet activation in response to ADP and thrombin stimulation. The Rictor-KO mice also showed lowered expression level of P-selectin protein and activation of integrin αIIbß3 with suppression of platelet extension, reduced plasma PF4 level and decreased number of megakaryocytes in the bone marrow. The ploidy of megakaryocytes and the mean area of proplatelets were both significantly decreased in Rictor-KO mice. CONCLUSION: Platelet-specific Rictor knockout inhibits platelet generation and activation to result in decreased thrombus formation in mice, suggesting the potential of mTORC2 activity inhibition as an efficient antithrombotic strategy.


Assuntos
Plaquetas , Megacariócitos , Camundongos Knockout , Ativação Plaquetária , Proteínas Proto-Oncogênicas c-akt , Proteína Companheira de mTOR Insensível à Rapamicina , Trombose , Animais , Camundongos , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Proteína Companheira de mTOR Insensível à Rapamicina/genética , Plaquetas/metabolismo , Trombose/metabolismo , Trombose/prevenção & controle , Megacariócitos/metabolismo , Megacariócitos/citologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Agregação Plaquetária , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Selectina-P/metabolismo , Contagem de Plaquetas
4.
Clin Immunol ; 267: 110350, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39218194

RESUMO

Platelets are crucial for thrombosis and hemostasis. Importantly, they contain mitochondria that are responsible for energy generation and therefore vital for platelet survival and activation. Activated platelets can release mitochondria that may be free or encapsulated in platelet extracellular vesicles (EVs). Extruded mitochondria are a well-known source of mitochondrial DNA, and mitochondrial antigens that can be targeted by autoantibodies forming immune complexes (IC). Interaction of IC with the platelet cell surface FcγRIIA receptor results in platelet activation and release of platelet granule components. In this review, we summarize how platelets and mitochondria may contribute to the pathogenesis of different autoimmune and musculoskeletal diseases. Targeting key drivers of mitochondrial extrusion may ultimately lead to urgently needed targeted pharmacological interventions for treating inflammation and thrombotic diathesis, and halting organ damage in some of these rheumatological conditions.


Assuntos
Doenças Autoimunes , Plaquetas , Mitocôndrias , Doenças Musculoesqueléticas , Humanos , Plaquetas/imunologia , Plaquetas/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/imunologia , Doenças Autoimunes/imunologia , Doenças Musculoesqueléticas/imunologia , Animais , Ativação Plaquetária/imunologia , Autoanticorpos/imunologia
5.
Immunity ; 57(9): 2140-2156.e10, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39226900

RESUMO

Venous thromboembolism (VTE) is a common, deadly disease with an increasing incidence despite preventive efforts. Clinical observations have associated elevated antibody concentrations or antibody-based therapies with thrombotic events. However, how antibodies contribute to thrombosis is unknown. Here, we show that reduced blood flow enabled immunoglobulin M (IgM) to bind to FcµR and the polymeric immunoglobulin receptor (pIgR), initiating endothelial activation and platelet recruitment. Subsequently, the procoagulant surface of activated platelets accommodated antigen- and FcγR-independent IgG deposition. This leads to classical complement activation, setting in motion a prothrombotic vicious circle. Key elements of this mechanism were present in humans in the setting of venous stasis as well as in the dysregulated immunothrombosis of COVID-19. This antibody-driven thrombosis can be prevented by pharmacologically targeting complement. Hence, our results uncover antibodies as previously unrecognized central regulators of thrombosis. These findings carry relevance for therapeutic application of antibodies and open innovative avenues to target thrombosis without compromising hemostasis.


Assuntos
Plaquetas , COVID-19 , Ativação do Complemento , Imunoglobulina M , Trombose , Humanos , Trombose/imunologia , Animais , Imunoglobulina M/imunologia , Ativação do Complemento/imunologia , Camundongos , Plaquetas/imunologia , Plaquetas/metabolismo , COVID-19/imunologia , COVID-19/complicações , SARS-CoV-2/imunologia , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Ativação Plaquetária/imunologia , Imunoglobulina G/imunologia , Masculino
6.
Sci Rep ; 14(1): 20569, 2024 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-39232077

RESUMO

Depression is a common psychiatric disorder among patients undergoing maintenance haemodialysis (MHD). Depression may reportedly contribute to poor prognosis in several ways, including its effects on platelet function. We hypothesised that depression contributes to the occurrence of cardiocerebral vascular events (CCVE) and dysfunction of arteriovenous fistula (DAVF) in patients undergoing MHD through its effects on platelets. In this prospective cohort study, patients undergoing MHD were recruited and divided into depression and non-depression groups according to their Hamilton Depression Scale (HAMD) scores. The 286 enrolled patients had 103 occurrences of depressive symptoms (prevalence = 36.01%). Compared with the non-depression group, depression group had a significantly higher cumulative prevalence of CCVE and DAVF during follow-up. Cox regression analysis indicated that higher HAMD scores and lower plasma platelet distribution width (PDW) were common risk factors for CCVE and DAVF. Furthermore, HAMD scores were significantly negatively correlated with plasma PDW and was the main variable affecting changes in PDW, as indicated by multiple linear regression analysis. Depression may increase the risk of CCVE and DAVF in patients undergoing MHD by activating platelets. Plasma PDW may be a convenient indicator of platelet activation status and may predict the risk of CCVE and DAVF.


Assuntos
Depressão , Ativação Plaquetária , Diálise Renal , Humanos , Masculino , Feminino , Diálise Renal/efeitos adversos , Depressão/sangue , Depressão/etiologia , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Fístula Arteriovenosa , Fatores de Risco , Plaquetas
7.
J Immunol Methods ; 533: 113746, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39181235

RESUMO

Platelets are enucleated fragments of cells with a diversity of internal granules. They are responsible for functions related to hemostasis, coagulation, and inflammation. The activation of these processes depends on a cascade coordinated by cytokines, chemokines, and components of purinergic signaling, such as ATP, ADP, and adenosine. Platelets express distinct components of the purinergic system: P2X1, P2Y1, PY12, and P2Y14 receptors; and the ectonucleotidases NTPDase, NPP, and 5NTE (ecto-5'-nucleotidase). Except for P2Y14, which has not yet exhibited a known function, all other components relate to the biological processes mentioned before. Platelets are known to display specific responses to microorganisms, being capable of recognizing pathogen-associated molecular patterns (PAMPs), engulfing certain classes of viruses, and participating in NETosis. Platelet function dysregulation implicates various pathophysiological processes, including cardiovascular diseases (CVDs) and infections. In COVID-19 patients, platelets exhibit altered purinergic signaling and increased activation, contributing to inflammation. Excessive platelet activation can lead to complications from thrombosis, which can affect the circulation of vital organs. Therefore, controlling the activation is necessary to end the inflammatory process and restore homeostasis. Ectonucleotidases, capable of hydrolyzing ATP, ADP, and AMP, are of fundamental importance in activating platelets, promising pharmacological targets for clinical use as cardiovascular protective drugs. In this review, we revisit platelet biology, the purinergic receptors and ectonucleotidases on their surface, and their importance in platelet activity. Additionally, we describe methods for isolating platelets in humans and murine, as well as the main techniques for detecting the activity of ectonucleotidases in platelets. Considering the multitude of functions revealed by platelets and their potential use as potent bioreactors able to secrete and present molecules involved in the communication of the vasculature with the immune system, it is crucial to deeply understand platelet biology and purinergic signaling participation to contribute to the developing of therapeutic strategies in diseases of the cardiovascular, inflammatory, and immune systems.


Assuntos
Plaquetas , COVID-19 , Ativação Plaquetária , Humanos , Plaquetas/metabolismo , Plaquetas/imunologia , COVID-19/imunologia , COVID-19/sangue , 5'-Nucleotidase/metabolismo , Transdução de Sinais , SARS-CoV-2/imunologia , Animais , Separação Celular/métodos , Adenosina Trifosfatases/metabolismo
8.
Nat Cardiovasc Res ; 3(2): 166-185, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-39196196

RESUMO

Inherited bleeding disorders such as Glanzmann thrombasthenia (GT) lack prophylactic treatment options. As a result, serious bleeding episodes are treated acutely with blood product transfusions or frequent, repeated intravenous administration of recombinant activated coagulation factor VII (rFVIIa). Here we describe HMB-001, a bispecific antibody designed to bind and accumulate endogenous FVIIa and deliver it to sites of vascular injury by targeting it to the TREM (triggering receptor expressed on myeloid cells)-like transcript-1 (TLT-1) receptor that is selectively expressed on activated platelets. In healthy nonhuman primates, HMB-001 prolonged the half-life of endogenous FVIIa, resulting in its accumulation. Mouse bleeding studies confirmed antibody-mediated potentiation of FVIIa hemostatic activity by TLT-1 targeting. In ex vivo models of GT, HMB-001 localized FVIIa on activated platelets and potentiated fibrin-dependent platelet aggregation. Taken together, these results indicate that HMB-001 has the potential to offer subcutaneous prophylactic treatment to prevent bleeds in people with GT and other inherited bleeding disorders, with a low-frequency dosing regimen.


Assuntos
Anticorpos Biespecíficos , Animais , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/imunologia , Humanos , Fator VIIa , Plaquetas/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/imunologia , Camundongos , Modelos Animais de Doenças , Hemorragia/prevenção & controle , Hemorragia/tratamento farmacológico , Agregação Plaquetária/efeitos dos fármacos , Trombastenia/tratamento farmacológico , Trombastenia/imunologia , Camundongos Endogâmicos C57BL , Feminino , Masculino , Macaca fascicularis , Ativação Plaquetária/efeitos dos fármacos
9.
Int J Mol Sci ; 25(16)2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39201591

RESUMO

Caffeine is the most popular and widely consumed behaviourally active substance in the world. This review describes the influence of caffeine on the cardiovascular system, with a special focus on blood platelets. For many years, caffeine was thought to have a negative effect on the cardiovascular system mainly due to increasing blood pressure. However, more recent data suggest that habitual caffeine consumption may reduce the risk of cardiovascular disease and hypertension. This could be a significant finding as cardiovascular disease is the leading cause of death worldwide. Caffeine is known to inhibit A1 adenosine receptors, through which it is believed to modulate inter alia coronary blood flow, total peripheral resistance, diuresis, and heart rate. It has been shown that coffee possesses antiplatelet activity, but depending on the dose and the term of its use, caffeine may stimulate or inhibit platelet reactivity. Also, chronic exposure to caffeine may sensitize or upregulate the adenosine receptors in platelets causing increased cAMP accumulation and anti-aggregatory effects and decrease calcium levels elicited by AR agonists. The search for new, selective, and safe AR agonists is one of the new strategies for improving antiplatelet therapy involving targeting multiple pathways of platelet activation. Therefore, this review examines the AR-dependent impact of caffeine on blood platelets in the presence of adenosine receptor agonists.


Assuntos
Plaquetas , Cafeína , Receptores Purinérgicos P1 , Humanos , Cafeína/farmacologia , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Receptores Purinérgicos P1/metabolismo , Animais , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Ativação Plaquetária/efeitos dos fármacos
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 32(4): 1264-1270, 2024 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-39192429

RESUMO

OBJECTIVE: To optimize the technical parameters related to the preparation of novel frozen human platelets and formulate corresponding protocol for its preparation. METHODS: Novel frozen human platelets were prepared with O-type bagged platelet-rich plasma (PRP), the key technical parameters (DMSO addition, incubation time, centrifugation conditions, etc.) of the preparation process were optimized, and the quality of the frozen platelets was evaluated by routine blood tests, apoptosis rate, platelet activation rate and surface protein expression level. RESULTS: In the preparation protocol of novel frozen human platelets, the operation of centrifugation to remove supernatant was adjusted to before the procedure of platelets freezing, and the effect of centrifugation on platelets was minimal when the centrifugation condition was 800×g for 8 min. In addition, platelets incubated with DMSO for 30 min before centrifugation exhibited better quality after freezing and thawing. The indexes of novel frozen human platelets prepared with this protocol remained stable after long-term cryopreservation. CONCLUSION: The preparation technique of novel frozen human platelets was established and the protocol was formulated. It was also confirmed that the quality of frozen platelets could be improved by incubating platelets with DMSO for 30 min and then centrifuging them at 800×g for 8 min in the preparation of novel frozen human platelets.


Assuntos
Plaquetas , Criopreservação , Humanos , Preservação de Sangue/métodos , Plasma Rico em Plaquetas , Centrifugação , Dimetil Sulfóxido , Congelamento , Ativação Plaquetária
11.
Nat Commun ; 15(1): 6902, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39164233

RESUMO

Platelets are key mediators of atherothrombosis, yet, limited tools exist to identify individuals with a hyperreactive platelet phenotype. In this study, we investigate the association of platelet hyperreactivity and cardiovascular events, and introduce a tool, the Platelet Reactivity ExpreSsion Score (PRESS), which integrates platelet aggregation responses and RNA sequencing. Among patients with peripheral artery disease (PAD), those with a hyperreactive platelet response (>60% aggregation) to 0.4 µM epinephrine had a higher incidence of the 30 day primary cardiovascular endpoint (37.2% vs. 15.3% in those without hyperreactivity, adjusted HR 2.76, 95% CI 1.5-5.1, p = 0.002). PRESS performs well in identifying a hyperreactive phenotype in patients with PAD (AUC [cross-validation] 0.81, 95% CI 0.68 -0.94, n = 84) and in an independent cohort of healthy participants (AUC [validation] 0.77, 95% CI 0.75 -0.79, n = 35). Following multivariable adjustment, PAD individuals with a PRESS score above the median are at higher risk for a future cardiovascular event (adjusted HR 1.90, CI 1.07-3.36; p = 0.027, n = 129, NCT02106429). This study derives and validates the ability of PRESS to discriminate platelet hyperreactivity and identify those at increased cardiovascular risk. Future studies in a larger independent cohort are warranted for further validation. The development of a platelet reactivity expression score opens the possibility for a personalized approach to antithrombotic therapy for cardiovascular risk reduction.


Assuntos
Plaquetas , Doenças Cardiovasculares , Doença Arterial Periférica , Agregação Plaquetária , Humanos , Doença Arterial Periférica/sangue , Doença Arterial Periférica/epidemiologia , Masculino , Feminino , Plaquetas/metabolismo , Pessoa de Meia-Idade , Idoso , Agregação Plaquetária/efeitos dos fármacos , Doenças Cardiovasculares/sangue , Fatores de Risco de Doenças Cardíacas , Ativação Plaquetária , Epinefrina/sangue , Fatores de Risco
12.
Thromb Res ; 241: 109111, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39098189

RESUMO

Thrombosis is the primary cause of death in patients with cancer. Resveratrol inhibits platelet activation, a crucial pathophysiological basis of thrombosis, in healthy individuals. However, its effects and mechanisms of action in patients with colon cancer remain unknown. Here, we investigated the effect of resveratrol on platelet adhesion and aggregation in patients with colon cancer. Through numerous in vitro and in vivo analyses, including flow cytometry, western blotting, ELISA, and immunofluorescence and colon cancer rat models, we demonstrated that resveratrol reduced thrombosis in patients with colon cancer by inhibiting the phosphorylation of the MAPK and activating the cyclic-GMP/vasodilator-stimulated phosphoprotein pathway. These findings demonstrate the potential of resveratrol in reducing thrombosis in patients with colon cancer and could be used to develop novel therapeutic strategies for this condition.


Assuntos
Moléculas de Adesão Celular , Neoplasias do Colo , GMP Cíclico , Fosfoproteínas , Ativação Plaquetária , Resveratrol , Trombose , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Trombose/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/complicações , Humanos , Animais , Ativação Plaquetária/efeitos dos fármacos , Masculino , Ratos , GMP Cíclico/metabolismo , Moléculas de Adesão Celular/metabolismo , Fosfoproteínas/metabolismo , Feminino , Estilbenos/farmacologia , Estilbenos/uso terapêutico , Ratos Sprague-Dawley , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Proteínas dos Microfilamentos
13.
Cell Biol Toxicol ; 40(1): 67, 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39110362

RESUMO

BACKGROUND: Titanium dioxide nanoparticles (TiO2NPs) are widely used in medical application. However, the relevant health risk has not been completely assessed, the potential of inducing arterial thrombosis (AT) in particular. METHODS: Alterations in platelet function and susceptibility to arterial thrombosis induced by TiO2NPs were examined using peripheral blood samples from healthy adult males and an in vivo mouse model, respectively. RESULTS: Here, using human platelets (hPLTs) freshly isolated from health volunteers, we demonstrated TiO2NP treatment triggered the procoagulant activity of hPLTs through phosphatidylserine exposure and microvesicles generation. In addition, TiO2NP treatment increased the levels of glycoprotein IIb/IIIa and P-selectin leading to aggregation and activation of hPLTs, which were exacerbated by providing physiology-mimicking conditions, including introduction of thrombin, collagen, and high shear stress. Interestingly, intracellular calcium levels in hPLTs were increased upon TiO2NP treatment, which were crucial in TiO2NP-induced hPLT procoagulant activity, activation and aggregation. Moreover, using mice in vivo models, we further confirmed that TiO2NP treatment a reduction in mouse platelet (mPLT) counts, disrupted blood flow, and exacerbated carotid arterial thrombosis with enhanced deposition of mPLT. CONCLUSIONS: Together, our study provides evidence for an ignored health risk caused by TiO2NPs, specifically TiO2NP treatment augments procoagulant activity, activation and aggregation of PLTs via calcium-dependent mechanism and thus increases the risk of AT.


Assuntos
Plaquetas , Ativação Plaquetária , Agregação Plaquetária , Trombose , Titânio , Titânio/toxicidade , Animais , Humanos , Agregação Plaquetária/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Masculino , Trombose/induzido quimicamente , Camundongos , Ativação Plaquetária/efeitos dos fármacos , Adulto , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Coagulação Sanguínea/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Selectina-P/metabolismo , Cálcio/metabolismo , Cálcio/sangue , Nanopartículas/toxicidade , Nanopartículas Metálicas/toxicidade
14.
Clin Oral Investig ; 28(9): 470, 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39110266

RESUMO

OBJECTIVE: This study assessed the cellular composition and effects of leukocyte-platelet-rich fibrin (L-PRF) exudate on whole blood platelets from healthy volunteers. Key objectives included evaluating leukocyte subpopulations, platelet activation markers, platelet-leukocyte interactions and quantifying inflammatory cytokines within the L-PRF exudate. MATERIALS AND METHODS: L-PRF was obtained from 20 healthy donors. Flow cytometry methodologies were used to assess intracellular calcium kinetics and activated GPIIbIIIa, and P-selectin expression. Leukocyte subpopulations and platelet-leukocyte interactions were characterized using monoclonal antibodies. Inflammatory cytokines (IL-8, IL-1ß, IL-6, IL-10, TNF, IL-12p70) within L-PRF exudate were quantified using a cytometric bead array. RESULTS: The expression of activated GPIIbIIIa, and P-selectin exhibited a significant increase (p < 0.001) when L-PRF exudate was added to platelets of whole blood. Regarding intracellular Ca2+ mobilization, the L-PRF exudate elicited significant responses (p < 0.001). L-PRF exudate contained different leukocytes populations, being TCD4 + the most representative of T cells. It was possible to stablish a profile of cytokines produced by the L-PRF exudate, with human IL-8 cytokine exhibiting the highest average (16.90 pg/mL). CONCLUSIONS: Despite the study limitations, the research yielded important insights: 1- L-PRF exudate can stimulate platelet activation, essential in healing, tissue inflammation and remodeling. 2-The presence of leukocyte subpopulations within L-PRF exudate reflexes its complexity and potential to enhance immune responses. 3-The analysis of inflammatory cytokines within L-PRF exudate revealed its immunomodulatory potential. These findings are valuable evidences for understanding the potential role of L-PRF exudate in regenerative dentistry and medicine, offering innovative therapeutic strategies. CLINICAL RELEVANCE: This research highlights crucial aspects that could significantly influence the clinical use of L-PRF exudate in the oral cavity. The findings support the application of L-PRF exudate in both surgical and regenerative dentistry, facilitating the development of innovative therapeutic strategies to enhance patient outcomes.


Assuntos
Plaquetas , Citocinas , Exsudatos e Transudatos , Citometria de Fluxo , Fibrina Rica em Plaquetas , Humanos , Masculino , Citocinas/metabolismo , Feminino , Adulto , Voluntários Saudáveis , Ativação Plaquetária , Leucócitos , Biomarcadores/sangue
15.
Vaccine ; 42(25): 126175, 2024 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-39107160

RESUMO

INTRODUCTION: The Ad26.COV2·S (Janssen/Johnson & Johnson) COVID-19 vaccine, has been rarely associated with vaccine-induced immune thrombocytopenia and thrombosis (VITT). We investigated the prevalence of anti-PF4 antibody positivity, thrombocytopenia, D-dimer elevation, plasmatic thromboinflammatory markers, and platelet functional assays following Ad26.COV2·S vaccination in Rio de Janeiro, Brazil. METHODS: From July to September 2021, participants were assessed prior, 1, and 3 weeks post-vaccination. Platelet count and D-dimer were measured at each visit and anti-PF4 at week 3. A positive anti-PF4 prompted retrospective testing of the sample from week 0. Individuals with new thrombocytopenia or elevated D-dimer, positive anti-PF4, and 38 matched controls without laboratory abnormalities were evaluated for plasmatic p-selectin, tissue factor, and functional platelet activation assays. RESULTS: 630 individuals were included; 306 (48.57%) females, median age 28 years. Forty-two (6.67%) presented ≥1 laboratory abnormality in week 1 or 3. Five (0.79%) had thrombocytopenia, 31 (4.91%) elevated D-dimer, and 9 (1.57%) had positive anti-PF4 at week 3. Individuals with laboratory abnormalities and controls showed a slight increase in plasmatic p-selectin and tissue factor. Ten individuals with laboratory abnormalities yielded increased surface expression of p-selectin, and their ability to activate platelets in a FcγRIIa dependent manner was further evaluated. Two were partially inhibited by high concentrations of heparin and blockage of FcγRII with IV.3 antibody. Plasma obtained before vaccination produced similar results, suggesting a lack of association with vaccination. CONCLUSIONS: Vaccination with Ad26.COV2·S vaccine led to a very low frequency of low-titer positive anti-PF4 antibodies, elevation of D-dimer, and mild thrombocytopenia, with no associated clinically relevant increase in thromboinflammatory markers and platelet activation.


Assuntos
COVID-19 , Produtos de Degradação da Fibrina e do Fibrinogênio , Ativação Plaquetária , Fator Plaquetário 4 , Humanos , Feminino , Masculino , Brasil/epidemiologia , Adulto , Fator Plaquetário 4/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Pessoa de Meia-Idade , Trombocitopenia/induzido quimicamente , SARS-CoV-2/imunologia , Adulto Jovem , Ad26COVS1 , Contagem de Plaquetas , Vacinação , Estudos Retrospectivos , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/efeitos adversos , Adolescente , Trombose/imunologia , Trombose/prevenção & controle
16.
Int J Mol Sci ; 25(15)2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-39125586

RESUMO

The correlation between obesity and cardiovascular disease has long been understood, yet scant investigations endeavored to determine the impact of an obesogenic diet on platelet activation or function. As platelets drive clot formation, the terminus of cardiovascular events, we aimed to elucidate the longitudinal effect of an obesogenic diet on platelet phenotype by assessing markers of platelet activation using flow cytometry. Male, weanling mice were fed either a Western diet (30% kcal sucrose, 40% kcal fat, 8.0% sodium) or Control diet (7% kcal sucrose, 10% kcal fat, 0.24% sodium). At 12, 16 and 20 weeks on diets, platelets were collected and stained to visualize glycoprotein Ibα (GPIbα), P-selectin and the conformationally active state of αIIbß3 (a platelet specific integrin) after collagen stimulation. At all time points, a Western diet reduced GPIbα and αIIbß3 expression in platelets broadly while P-selectin levels were unaffected. However, P-selectin was diminished by a Western diet in the GPIbα- subpopulation. Thus, a Western diet persistently primed platelets towards a blunted activation response as indicated by reduced active αIIbß3 and P-selectin surface expression. This study provides a first look at the influence of diet on platelet activation and revealed that platelet activation is susceptible to dietary intervention.


Assuntos
Plaquetas , Dieta Ocidental , Selectina-P , Ativação Plaquetária , Complexo Glicoproteico GPIIb-IIIa de Plaquetas , Animais , Masculino , Dieta Ocidental/efeitos adversos , Camundongos , Plaquetas/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Selectina-P/metabolismo , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/sangue , Obesidade/etiologia
17.
Int J Biol Sci ; 20(10): 3956-3971, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39113702

RESUMO

Platelet extracellular vesicles (PEVs) play an important role in tumor development. However, the mechanisms underlying their biogenesis have not been fully elucidated. Protein kinase Cα (PKCα) is an important regulator of platelet activation, but the effect of PKCα on EV generation is unclear. We used small-particle flow cytometry and found that the number of PEVs was increased in patients with breast cancer compared to those with benign breast disease. This was accompanied by increased levels of activated PKCα in breast cancer platelets. Treating platelets with the PKCα agonist phorbol 12-myristate 13-acetate (PMA) increased the phosphorylation PKCα and induced PEV production, while the PKCα inhibitor GÖ6976 showed the opposite effects. Notably, incubating platelets from patients with benign tumors with the culture supernatant of MDA-MB-231 cells induced PKCα phosphorylation in the platelets. Mass spectrometry and coimmunoprecipitation assays showed that Dynamin 2 (DNM2), a member of the guanosine-triphosphate-binding protein family, might cooperate with activated PKCα to regulate PEV production by breast cancer platelets. Similar results were observed in a mouse model of lung metastasis. In addition, PEVs were engulfed by breast cancer cells and promoted cancer cell migration and invasion via miR-1297 delivery. These findings suggested that PKCα cooperates with DNM2 to induce PEV generation, and PEV release might triggered by factors in the breast cancer environment.


Assuntos
Plaquetas , Neoplasias da Mama , Vesículas Extracelulares , Proteína Quinase C-alfa , Proteína Quinase C-alfa/metabolismo , Vesículas Extracelulares/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Humanos , Plaquetas/metabolismo , Feminino , Animais , Camundongos , Linhagem Celular Tumoral , Ativação Plaquetária , Metástase Neoplásica , Fosforilação , Movimento Celular , Acetato de Tetradecanoilforbol/farmacologia
18.
Int J Mol Sci ; 25(16)2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39201499

RESUMO

BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) represents a major comorbidity in the elderly and is associated with cognitive impairment (CoI) and type 2 diabetes mellitus (T2DM). In this context, there is an increase in oxidative stress and platelet activation biomarkers. The aim of this study was to evaluate the effects of 6 months' treatment with SGLT2i on functional, mood-related, and cognitive aspects, assessed by performing a comprehensive geriatric assessment (CGA), and on oxidative stress and platelet activation biomarkers, in a cohort of HFpEF elderly patients with T2DM. We recruited 150 elderly outpatients (mean age 75.8 ± 7.4 years). RESULTS: At six-month follow-up, there was a significant improvement in MMSE (p < 0.0001), MoCA (p < 0.0001), GDS score (p < 0.0001), and SPPB (p < 0.0001). Moreover, we observed a significant reduction in Nox-2 (p < 0.0001), 8-Isoprostane (p < 0.0001), Sp-Selectin (p < 0.0001), and Gp-VI (p < 0.0001). Considering ΔMMSE as the dependent variable, ΔE/e', ΔNox-2, ΔHOMA, Δ8-Isoprostane, and ΔUricemia were associated for 59.6% with ΔMMSE. When ΔMoCA was considered as the dependent variable, ΔHOMA, ΔE/e', Δ8-Isoprostane, ΔNox-2 and ΔUricemia were associated for 59.2%. Considering ΔGDS as the dependent variable, ΔHOMA, ΔNox-2, Δ8-Isoprostane, and ΔUricemia were associated with 41.6% of ΔGDS variation. Finally, ΔHOMA was the main predictor of ΔSPPB, which was associated with 21.3% with ΔSPPB, Δ8-Isoprostane, ΔNox-2, ΔE/e', and ΔUricemia added another 24.1%. CONCLUSION: The use of SGLT2i in elderly patients with T2DM and HFpEF significantly contributes to improving CGA scales and biomarkers of OS and PA.


Assuntos
Biomarcadores , Diabetes Mellitus Tipo 2 , Avaliação Geriátrica , Insuficiência Cardíaca , Estresse Oxidativo , Ativação Plaquetária , Inibidores do Transportador 2 de Sódio-Glicose , Volume Sistólico , Humanos , Idoso , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/sangue , Feminino , Masculino , Ativação Plaquetária/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Idoso de 80 Anos ou mais , Avaliação Geriátrica/métodos , Dinoprosta/análogos & derivados , Dinoprosta/sangue
19.
Clin Lab Med ; 44(3): 511-526, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39089755

RESUMO

Clinical assessment of platelet activation by flow cytometry is useful in the characterization and diagnosis of platelet-specific disorders and as a measure of risk for thrombosis or bleeding. Platelets circulate in a resting, "unactivated" state, but when activated they undergo alterations in surface glycoprotein function and/or expression level, exposure of granule membrane proteins, and exposure of procoagulant phospholipids. Flow cytometry provides the means to detect these changes and, unlike other platelet tests, is appropriate for measuring platelet function in samples from patients with low platelet counts. The present review will focus on flow cytometric tests for platelet activation markers.


Assuntos
Plaquetas , Citometria de Fluxo , Ativação Plaquetária , Humanos , Testes de Função Plaquetária , Transtornos Plaquetários/diagnóstico , Transtornos Plaquetários/sangue , Biomarcadores/sangue
20.
Curr Opin Hematol ; 31(5): 230-237, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39087372

RESUMO

PURPOSE OF REVIEW: Thromboembolic complications are a major contributor to global mortality. The relationship between inflammation and coagulation pathways has become an emerging research topic where the role of the innate immune response, and specifically neutrophils in "immunothrombosis" are receiving much attention. This review aims to dissect the intricate interplay between histones (from neutrophils or cellular damage) and the haemostatic pathway, and to explore mechanisms that may counteract the potentially procoagulant effects of those histones that have escaped their nuclear localization. RECENT FINDINGS: Extracellular histones exert procoagulant effects via endothelial damage, platelet activation, and direct interaction with coagulation proteins. Neutralization of histone activities can be achieved by complexation with physiological molecules, through pharmacological compounds, or via proteolytic degradation. Details of neutralization of extracellular histones are still being studied. SUMMARY: Leveraging the understanding of extracellular histone neutralization will pave the way for development of novel pharmacological interventions to treat and prevent complications, including thromboembolism, in patients in whom extracellular histones contribute to their overall clinical status.


Assuntos
Histonas , Humanos , Histonas/metabolismo , Neutrófilos/metabolismo , Coagulação Sanguínea , Animais , Ativação Plaquetária , Trombose/metabolismo , Tromboembolia/etiologia , Tromboembolia/metabolismo , Espaço Extracelular/metabolismo
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