Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.317
Filtrar
1.
Scand J Immunol ; 94(5): e13097, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34940978

RESUMO

COVID-19 is a global pandemic with a daily increasing number of affected individuals. Thrombosis is a severe complication of COVID-19 that leads to a worse clinical course with higher rates of mortality. Multiple lines of evidence suggest that hyperinflammation plays a crucial role in disease progression. This review compiles clinical data of COVID-19 patients who developed thrombotic complications to investigate the possible role of hyperinflammation in inducing hypercoagulation. A systematic literature search was performed using PubMed, Embase, Medline and Scopus to identify relevant clinical studies that investigated thrombotic manifestations and reported inflammatory and coagulation biomarkers in COVID-19 patients. Only 54 studies met our inclusion criteria, the majority of which demonstrated significantly elevated inflammatory markers. In the cohort studies with control, D-dimer was significantly higher in COVID-19 patients with thrombosis as compared to the control. Pulmonary embolism, deep vein thrombosis and strokes were frequently reported which could be attributed to the hyperinflammatory response associated with COVID-19 and/or to the direct viral activation of platelets and endothelial cells, two mechanisms that are discussed in this review. It is recommended that all admitted COVID-19 patients should be assessed for hypercoagulation. Furthermore, several studies have suggested that anticoagulation may be beneficial, especially in hospitalized non-ICU patients. Although vaccines against SARS-CoV-2 have been approved and distributed in several countries, research should continue in the field of prevention and treatment of COVID-19 and its severe complications including thrombosis due to the emergence of new variants against which the efficacy of the vaccines is not yet clear.


Assuntos
Artérias/patologia , Plaquetas/imunologia , COVID-19/imunologia , Endotélio Vascular/imunologia , Inflamação/imunologia , SARS-CoV-2/fisiologia , Trombose Venosa/imunologia , Animais , Anticoagulantes/uso terapêutico , Plaquetas/virologia , COVID-19/complicações , Endotélio Vascular/virologia , Humanos , Inflamação/complicações , Fenótipo , Trombose , Trombose Venosa/etiologia , Trombose Venosa/prevenção & controle
2.
Hamostaseologie ; 41(5): 379-385, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34695854

RESUMO

In 2019 first reports about a new human coronavirus emerged, which causes common cold symptoms as well as acute respiratory distress syndrome. The virus was identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and severe thrombotic events including deep vein thrombosis, pulmonary embolism, and microthrombi emerged as additional symptoms. Heart failure, myocardial infarction, myocarditis, and stroke have also been observed. As main mediator of thrombus formation, platelets became one of the key aspects in SARS-CoV-2 research. Platelets may also directly interact with SARS-CoV-2 and have been shown to carry the SARS-CoV-2 virus. Platelets can also facilitate the virus uptake by secretion of the subtilisin-like proprotein convertase furin. Cleavage of the SARS-CoV-2 spike protein by furin enhances binding capabilities and virus entry into various cell types. In COVID-19 patients, platelet count differs between mild and serious infections. Patients with mild symptoms have a slightly increased platelet count, whereas thrombocytopenia is a hallmark of severe COVID-19 infections. Low platelet count can be attributed to platelet apoptosis and the incorporation of platelets into microthrombi (peripheral consumption) and severe thrombotic events. The observed excessive formation of thrombi is due to hyperactivation of platelets caused by the infection. Various factors have been suggested in the activation of platelets in COVID-19, such as hypoxia, vessel damage, inflammatory factors, NETosis, SARS-CoV-2 interaction, autoimmune reactions, and autocrine activation. COVID-19 does alter chemokine and cytokine plasma concentrations. Platelet chemokine profiles are altered in COVID-19 and contribute to the described chemokine storms observed in severely ill COVID-19 patients.


Assuntos
Plaquetas/fisiologia , Plaquetas/virologia , COVID-19/sangue , Plaquetas/imunologia , COVID-19/complicações , COVID-19/imunologia , Quimiocinas/sangue , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Modelos Biológicos , Pandemias , Ativação Plaquetária/imunologia , Ativação Plaquetária/fisiologia , SARS-CoV-2/patogenicidade , Trombose/sangue , Trombose/etiologia
3.
Virol J ; 18(1): 211, 2021 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-34715884

RESUMO

BACKGROUND: The SARS-CoV-2 virus is the causing agent of the Coronavirus disease 2019 (COVID-19) characterized by a huge pro-inflammatory response and coagulation disorders that may lead to for its severe forms, in organ failure or even death. As major players of thrombo-inflammation, platelets release large amounts of immunomodulatory molecules and regulate leukocyte and endothelial activity, which are both altered in COVID-19. Altogether, this makes platelets a very likely actor of the thrombo-inflammatory complications of COVID-19. Thus, we propose to identify a platelet inflammatory signature of severe COVID-19 specifically modulated throughout the course of the disease. METHODS: Luminex technology and enzyme-linked immunosorbent assay were used to assess plasma levels of platelet inflammatory markers in patients with severe acute respiratory syndrome coronavirus 2 infection on admission and for 14 days afterwards. RESULTS: In accordance with the observations of other teams, we evidence that the plasma levels of the platelet soluble (s)CD40L is significantly elevated in the early stages of the disease. Interestingly we observe that the plasma level of sCD40L decreases overtime while that of sCD62P increases significantly. CONCLUSIONS: Our data suggest that there is a platelet signature of inflammatory response to SARS-COv-2 infection which varies overtime and could serve as monitoring biomarkers of patient inflammatory state. CLINICAL TRIAL REGISTRATION NUMBER: 2020-A01100-39; title: Human Ab Response & immunoMONItoring of COVID-19 Patients, registration date: 05/25/2020; URL of the registry: https://clinicaltrials.gov/ct2/history/NCT04373200?V_5=View .


Assuntos
Biomarcadores/sangue , Plaquetas/imunologia , COVID-19 , Inflamação , Adulto , Idoso , COVID-19/sangue , COVID-19/imunologia , Feminino , Humanos , Inflamação/sangue , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
4.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638568

RESUMO

The conventional function described for platelets is maintaining vascular integrity. Nevertheless, increasing evidence reveals that platelets can additionally play a crucial role in responding against microorganisms. Activated platelets release molecules with antimicrobial activity. This ability was first demonstrated in rabbit serum after coagulation and later in rabbit platelets stimulated with thrombin. Currently, multiple discoveries have allowed the identification and characterization of PMPs (platelet microbicidal proteins) and opened the way to identify kinocidins and CHDPs (cationic host defense peptides) in human platelets. These molecules are endowed with microbicidal activity through different mechanisms that broaden the platelet participation in normal and pathologic conditions. Therefore, this review aims to integrate the currently described platelet molecules with antimicrobial properties by summarizing the pathways towards their identification, characterization, and functional evaluation that have promoted new avenues for studying platelets based on kinocidins and CHDPs secretion.


Assuntos
Anti-Infecciosos/sangue , Plaquetas/química , Plaquetas/microbiologia , Animais , Anti-Infecciosos/química , Anti-Infecciosos/classificação , Anti-Infecciosos/imunologia , Peptídeos Catiônicos Antimicrobianos/imunologia , Antiparasitários/imunologia , Antivirais/imunologia , Plaquetas/imunologia , Humanos , Ribonucleases/imunologia
5.
Molecules ; 26(17)2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34500771

RESUMO

Vincristine is a clinically used antimicrotubule drug for treating patients with lymphoma. Due to its property of increasing platelet counts, vincristine is also used to treat patients with immune thrombocytopenia. Moreover, antiplatelet agents were reported to be beneficial in thrombotic thrombocytopenic purpura (TTP). Therefore, we investigated the detailed mechanisms underlying the antiplatelet effect of vincristine. Our results revealed that vincristine inhibited platelet aggregation induced by collagen, but not by thrombin, arachidonic acid, and the thromboxane A2 analog U46619, suggesting that vincristine exerts higher inhibitory effects on collagen-mediated platelet aggregation. Vincristine also reduced collagen-mediated platelet granule release and calcium mobilization. In addition, vincristine inhibited glycoprotein VI (GPVI) signaling, including Syk, phospholipase Cγ2, protein kinase C, Akt, and mitogen-activated protein kinases. In addition, the in vitro PFA-100 assay revealed that vincristine did not prolong the closure time, and the in vivo study tail bleeding assay showed that vincristine did not prolong the tail bleeding time; both findings suggested that vincristine may not affect normal hemostasis. In conclusion, we demonstrated that vincristine exerts antiplatelet effects at least in part through the suppression of GPVI signaling. Moreover, this property of antiplatelet activity of vincristine may provide additional benefits in the treatment of TTP.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Plaquetas/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Trombocitopenia/tratamento farmacológico , Vincristina/farmacologia , Antineoplásicos Fitogênicos/química , Plaquetas/imunologia , Colágeno/antagonistas & inibidores , Colágeno/farmacologia , Humanos , Conformação Molecular , Neoplasias/imunologia , Agregação Plaquetária/efeitos dos fármacos , Trombocitopenia/imunologia , Vincristina/química
6.
Front Immunol ; 12: 728513, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484238

RESUMO

VITT is a rare, life-threatening syndrome characterized by thrombotic symptoms in combination with thrombocytopenia, which may occur in individuals receiving the first administration of adenoviral non replicating vectors (AVV) anti Covid19 vaccines. Vaccine-induced immune thrombotic thrombocytopenia (VITT) is characterized by high levels of serum IgG that bind PF4/polyanion complexes, thus triggering platelet activation. Therefore, identification of the fine pathophysiological mechanism by which vaccine components trigger platelet activation is mandatory. Herein, we propose a multistep mechanism involving both the AVV and the neo-synthetized Spike protein. The former can: i) spread rapidly into blood stream, ii), promote the early production of high levels of IL-6, iii) interact with erythrocytes, platelets, mast cells and endothelia, iv) favor the presence of extracellular DNA at the site of injection, v) activate platelets and mast cells to release PF4 and heparin. Moreover, AVV infection of mast cells may trigger aberrant inflammatory and immune responses in people affected by the mast cell activation syndrome (MCAS). The pre-existence of natural antibodies binding PF4/heparin complexes may amplify platelet activation and thrombotic events. Finally, neosynthesized Covid 19 Spike protein interacting with its ACE2 receptor on endothelia, platelets and leucocyte may trigger further thrombotic events unleashing the WITT syndrome.


Assuntos
Anticorpos/efeitos adversos , Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Púrpura Trombocitopênica Idiopática/fisiopatologia , Adenoviridae/genética , Animais , Plaquetas/imunologia , Plaquetas/patologia , Vacinas contra COVID-19/imunologia , Modelos Animais de Doenças , Vetores Genéticos , Humanos , Camundongos , Ativação Plaquetária/imunologia , Fator Plaquetário 4 , Coelhos
7.
Int J Mol Sci ; 22(18)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34576172

RESUMO

Global data correlate severe vitamin D deficiency with COVID-19-associated coagulopathy, further suggesting the presence of a hypercoagulable state in severe COVID-19 patients, which could promote thrombosis in the lungs and in other organs. The feedback loop between COVID-19-associated coagulopathy and vitamin D also involves platelets (PLTs), since vitamin D deficiency stimulates PLT activation and aggregation and increases fibrinolysis and thrombosis. Vitamin D and PLTs share and play specific roles not only in coagulation and thrombosis but also during inflammation, endothelial dysfunction, and immune response. Additionally, another 'fil rouge' between vitamin D and PLTs is represented by their role in mineral metabolism and bone health, since vitamin D deficiency, low PLT count, and altered PLT-related parameters are linked to abnormal bone remodeling in certain pathological conditions, such as osteoporosis (OP). Hence, it is possible to speculate that severe COVID-19 patients are characterized by the presence of several predisposing factors to bone fragility and OP that may be monitored to avoid potential complications. Here, we hypothesize different pervasive actions of vitamin D and PLT association in COVID-19, also allowing for potential preliminary information on bone health status during COVID-19 infection.


Assuntos
Plaquetas/imunologia , COVID-19/complicações , Osteoporose/imunologia , Trombose/imunologia , Deficiência de Vitamina D/imunologia , Vitamina D/metabolismo , Plaquetas/metabolismo , Remodelação Óssea/imunologia , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/imunologia , Retroalimentação Fisiológica , Humanos , Osteoporose/sangue , Ativação Plaquetária/imunologia , Contagem de Plaquetas , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Trombose/sangue , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicações
9.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360659

RESUMO

Platelets are hematopoietic cells whose main function has for a long time been considered to be the maintenance of vascular integrity. They have an essential role in the hemostatic response, but they also have functional capabilities that go far beyond it. This review will provide an overview of platelet functions. Indeed, stress signals may induce platelet apoptosis through proapoptotis or hemostasis receptors, necrosis, and even autophagy. Platelets also interact with immune cells and modulate immune responses in terms of activation, maturation, recruitment and cytokine secretion. This review will also show that platelets, thanks to their wide range of innate immune receptors, and in particular toll-like receptors, and can be considered sentinels actively participating in the immuno-surveillance of the body. We will discuss the diversity of platelet responses following the engagement of these receptors as well as the signaling pathways involved. Finally, we will show that while platelets contribute significantly, via their TLRs, to immune response and inflammation, these receptors also participate in the pathophysiological processes associated with various pathogens and diseases, including cancer and atherosclerosis.


Assuntos
Aterosclerose/patologia , Plaquetas/patologia , Imunidade Inata/imunologia , Neoplasias/patologia , Ativação Plaquetária , Receptores Imunológicos/metabolismo , Receptores Toll-Like/metabolismo , Animais , Aterosclerose/imunologia , Aterosclerose/metabolismo , Plaquetas/imunologia , Plaquetas/metabolismo , Humanos , Neoplasias/imunologia , Neoplasias/metabolismo
10.
Cells ; 10(8)2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34440764

RESUMO

OBJECTIVE: platelets possess not only haemostatic but also inflammatory properties, which combined are thought to play a detrimental role in thromboinflammatory diseases such as acute coronary syndromes and stroke. Phosphodiesterase (PDE) 3 and -5 inhibitors have demonstrated efficacy in secondary prevention of arterial thrombosis, partially mediated by their antiplatelet action. Yet it is unclear whether such inhibitors also affect platelets' inflammatory functions. Here, we aimed to examine the effect of the PDE3A inhibitor cilostazol and the PDE5 inhibitor tadalafil on platelet function in various aspects of thromboinflammation. Approach and results: cilostazol, but not tadalafil, delayed ex vivo platelet-dependent fibrin formation under whole blood flow over type I collagen at 1000 s-1. Similar results were obtained with blood from Pde3a deficient mice, indicating that cilostazol effects are mediated via PDE3A. Interestingly, cilostazol specifically reduced the release of phosphatidylserine-positive extracellular vesicles (EVs) from human platelets while not affecting total EV release. Both cilostazol and tadalafil reduced the interaction of human platelets with inflamed endothelium under arterial flow and the release of the chemokines CCL5 and CXCL4 from platelets. Moreover, cilostazol, but not tadalafil, reduced monocyte recruitment and platelet-monocyte interaction in vitro. CONCLUSIONS: this study demonstrated yet unrecognised roles for platelet PDE3A and platelet PDE5 in platelet procoagulant and proinflammatory responses.


Assuntos
Anti-Inflamatórios/farmacologia , Plaquetas/efeitos dos fármacos , Cilostazol/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Fibrinolíticos/farmacologia , Inibidores da Fosfodiesterase 3/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Animais , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/enzimologia , Plaquetas/imunologia , Células Cultivadas , Quimiocinas/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Fibrina/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Inibidores da Fosfodiesterase 5/farmacologia , Adesividade Plaquetária/efeitos dos fármacos , Transdução de Sinais , Tadalafila/farmacologia
11.
Blood ; 138(14): 1269-1277, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34280256

RESUMO

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse effect of ChAdOx1 nCoV-19 COVID-19 vaccine (Vaxzevria) and Janssen Ad26.COV2.S COVID-19 vaccine, and it is associated with unusual thrombosis. VITT is caused by anti-platelet factor 4 (PF4) antibodies activating platelets through their FcγRIIa receptors. Antibodies that activate platelets through FcγRIIa receptors have also been identified in patients with COVID-19. These findings raise concern that vaccination-induced antibodies against anti-SARS-CoV-2 spike protein cause thrombosis by cross-reacting with PF4. Immunogenic epitopes of PF4 and SARS-CoV-2 spike protein were compared using in silico prediction tools and 3D modeling. The SARS-CoV-2 spike protein and PF4 share at least 1 similar epitope. Reactivity of purified anti-PF4 antibodies from patients with VITT was tested against recombinant SARS-CoV-2 spike protein. However, none of the affinity-purified anti-PF4 antibodies from 14 patients with VITT cross-reacted with SARS-CoV-2 spike protein. Sera from 222 polymerase chain reaction-confirmed patients with COVID-19 from 5 European centers were tested by PF4-heparin enzyme-linked immunosorbent assays and PF4-dependent platelet activation assays. We found anti-PF4 antibodies in sera from 19 (8.6%) of 222 patients with COVID-19. However, only 4 showed weak to moderate platelet activation in the presence of PF4, and none of those patients developed thrombotic complications. Among 10 (4.5%) of 222 patients who had COVID-19 with thrombosis, none showed PF4-dependent platelet-activating antibodies. In conclusion, antibodies against PF4 induced by vaccination do not cross-react with the SARS-CoV-2 spike protein, indicating that the intended vaccine-induced immune response against SARS-CoV-2 spike protein is not the trigger of VITT. PF4-reactive antibodies found in patients with COVID-19 in this study were not associated with thrombotic complications.


Assuntos
Anticorpos/efeitos adversos , Vacinas contra COVID-19/efeitos adversos , Reações Cruzadas/imunologia , Fator Plaquetário 4/imunologia , Púrpura Trombocitopênica Idiopática/etiologia , Púrpura Trombocitopênica Idiopática/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Plaquetas/imunologia , COVID-19/imunologia , Estudos de Coortes , Epitopos/imunologia , Feminino , Heparina/metabolismo , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Domínios Proteicos , Púrpura Trombocitopênica Idiopática/sangue , Glicoproteína da Espícula de Coronavírus/química , Adulto Jovem
12.
Sci Rep ; 11(1): 13754, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215804

RESUMO

Diseases and injuries that compromise the ocular surface cause considerable patient distress and have long term consequences for their quality of life. Treatment modalities that can address the delicate balance of tissue regeneration, inflammation and maintenance of corneal transparency are therefore needed. We have recently formulated two novel eye drops from placental tissues: cord blood platelet lysate (CBED) and amniotic membrane extract eye drops (AMED), which can be used to treat severe ocular disorders. Here we characterise these two preparations by measuring: (a) growth factors (GF) and cytokines composition, (b) promotion of human corneal epithelial cell (HCEC) growth and (c) effects on immune cells in a lymphocyte culture assay. Finally, their bioavailability was assayed in an ex vivo porcine corneal model. We show that both preparations contain GF and cytokines that were able to promote the in vitro growth of HCEC and support repair in an in vitro scratch test. When assessed in a lymphocyte culture, both favoured immune suppression reducing the cellular expression of NKG2D and CD107a as well as the production of interferon gamma (IFN-γ) in natural killer, NKT and T cells. Regarding bioavailability, CBED active molecules were found mainly in the pre-corneal fraction with some penetration into the corneal fraction, in an ex vivo model. In summary, both placental-derived allogeneic preparations, CBED and AMED, display regenerative and immunomodulatory capabilities. These results will help define mechanisms of action and the best indications and doses of each product for use in a particular patient and support the development of off-the-shelf therapies for ocular surface pathologies in which wound healing defects and inflammatory events are contributing factors.


Assuntos
Córnea/efeitos dos fármacos , Doenças da Córnea/tratamento farmacológico , Soluções Oftálmicas/farmacologia , Regeneração/efeitos dos fármacos , Âmnio/química , Animais , Plaquetas/imunologia , Proliferação de Células/efeitos dos fármacos , Córnea/crescimento & desenvolvimento , Doenças da Córnea/patologia , Células Epiteliais/efeitos dos fármacos , Feminino , Sangue Fetal/química , Sangue Fetal/imunologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Soluções Oftálmicas/química , Placenta/química , Placenta/imunologia , Gravidez , Qualidade de Vida , Suínos , Cicatrização
13.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205175

RESUMO

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


Assuntos
Doença de Crohn/tratamento farmacológico , Imunoglobulina G/genética , Infliximab/administração & dosagem , Receptores de IgG/genética , Adulto , Complexo Antígeno-Anticorpo/genética , Complexo Antígeno-Anticorpo/imunologia , Plaquetas/efeitos dos fármacos , Plaquetas/imunologia , Doença de Crohn/sangue , Doença de Crohn/genética , Doença de Crohn/imunologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina G/imunologia , Infliximab/farmacocinética , Masculino , Ativação Plaquetária/efeitos dos fármacos , Contagem de Plaquetas , Polimorfismo Genético/genética
14.
Blood ; 138(16): 1481-1489, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34315173

RESUMO

A subset of patients with coronavirus disease 2019 (COVID-19) become critically ill, suffering from severe respiratory problems and also increased rates of thrombosis. The causes of thrombosis in severely ill patients with COVID-19 are still emerging, but the coincidence of critical illness with the timing of the onset of adaptive immunity could implicate an excessive immune response. We hypothesized that platelets might be susceptible to activation by anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antibodies and might contribute to thrombosis. We found that immune complexes containing recombinant SARS-CoV-2 spike protein and anti-spike immunoglobulin G enhanced platelet-mediated thrombosis on von Willebrand factor in vitro, but only when the glycosylation state of the Fc domain was modified to correspond with the aberrant glycosylation previously identified in patients with severe COVID-19. Furthermore, we found that activation was dependent on FcγRIIA, and we provide in vitro evidence that this pathogenic platelet activation can be counteracted by the therapeutic small molecules R406 (fostamatinib) and ibrutinib, which inhibit tyrosine kinases Syk and Btk, respectively, or by the P2Y12 antagonist cangrelor.


Assuntos
Plaquetas/patologia , COVID-19/complicações , Imunoglobulina G/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Trombose/patologia , Fator de von Willebrand/metabolismo , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Complexo Antígeno-Anticorpo/imunologia , Plaquetas/imunologia , Plaquetas/metabolismo , COVID-19/imunologia , COVID-19/virologia , Glicosilação , Humanos , Ativação Plaquetária/imunologia , Trombose/imunologia , Trombose/virologia , Fator de von Willebrand/genética
15.
Front Immunol ; 12: 631696, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093524

RESUMO

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


Assuntos
Ativação Plaquetária/imunologia , Tuberculose/imunologia , Plaquetas/efeitos dos fármacos , Plaquetas/imunologia , Matriz Extracelular/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Tuberculose/tratamento farmacológico
16.
Transfusion ; 61(8): 2307-2316, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34075590

RESUMO

BACKGROUND: Donor specific antibody sum mean fluorescence intensity (MFI) values have been successfully used in transplant medicine to assess risk for organ rejection. However, little is known regarding whether MFI values could be similarly used to aid in platelet product selection. We have developed a novel protocol where MFI values are used to offer human leukocyte antigen (HLA)-incompatible platelet products when HLA antigen-matched products are not available. We aimed to evaluate the efficacy of this protocol. METHODS: We performed a 4-year retrospective chart review for all patients who received at least one MFI-selected platelet product. A corrected count increment (CCI) was calculated for each transfusion event. A mixed effects model was used to investigate the association between CCIs for MFI-selected, HLA antigen matched, and random donor platelet transfusions. A random effects expectation-maximization regression tree was used to define the extent to which other patient variables, such as age, sex, and diagnosis impacted the CCI for each platelet transfusion. RESULTS: Twenty highly HLA alloimmunized patients received a total of 591 platelets. MFI-selected platelet (low MFI) transfusions had a significantly higher median CCI 0-6 hour post-transfusion (13,559, interquartile range [IQR]: 8275-18,736) compared to random donor platelets (2121, IQR: 0-10,368, p < 0.0001). There was no significant difference in median CCI between HLA antigen matched and MFI selected platelet transfusions (p = 0.2). Mixed effects and regression modeling revealed that MFI-selected platelet products had a significantly higher CCI than non-matched platelets, even when accounting for other significant patient variables. CONCLUSION: MFI-selected HLA-incompatible platelet products could provide a comparable alternative to traditional HLA antigen-matched platelet products.


Assuntos
Plaquetas/imunologia , Antígenos HLA/imunologia , Transfusão de Plaquetas , Idoso , Feminino , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Transfusão de Plaquetas/efeitos adversos , Transfusão de Plaquetas/métodos , Estudos Retrospectivos
17.
Front Immunol ; 12: 629167, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122402

RESUMO

Neutrophil extracellular traps (NETs) are increasingly recognized to play a role in the pathogenesis of viral infections, including dengue. NETs can be formed NADPH oxidase (NOX)-dependently or NOX-independently. NOX-independent NETs can be induced by activated platelets and are very potent in activating the endothelium. Platelet activation with thrombocytopenia and endothelial dysfunction are prominent features of dengue virus infection. We postulated that dengue infection is associated with NOX-independent NET formation, which is related to platelet activation, endothelial perturbation and increased vascular permeability. Using our specific NET assays, we investigated the time course of NET formation in a cohort of Indonesian dengue patients. We found that plasma levels of NETs were profoundly elevated and that these NETs were predominantly NOX-independent NETs. During early recovery phase (7-13 days from fever onset), total NETs correlated negatively with platelet number and positively with platelet P-selectin expression, the binding of von Willebrand factor to platelets and levels of Syndecan-1. Patients with gall bladder wall thickening, an early marker of plasma leakage, had a higher median level of total NETs. Ex vivo, platelets induced NOX-independent NET formation in a dengue virus non-structural protein 1 (NS1)-dependent manner. We conclude that NOX-independent NET formation is enhanced in dengue, which is most likely mediated by NS1 and activated platelets.


Assuntos
Plaquetas/metabolismo , Vírus da Dengue/patogenicidade , Dengue/enzimologia , Armadilhas Extracelulares/metabolismo , NADPH Oxidases/metabolismo , Neutrófilos/enzimologia , Ativação Plaquetária , Adolescente , Adulto , Plaquetas/imunologia , Plaquetas/virologia , Estudos de Casos e Controles , Células Cultivadas , Dengue/sangue , Dengue/imunologia , Dengue/virologia , Vírus da Dengue/imunologia , Vírus da Dengue/metabolismo , Armadilhas Extracelulares/virologia , Feminino , Interações Hospedeiro-Patógeno , Humanos , Indonésia , Masculino , Neutrófilos/imunologia , Neutrófilos/virologia , Estudos Prospectivos , Proteínas não Estruturais Virais/metabolismo , Adulto Jovem
18.
J Stroke Cerebrovasc Dis ; 30(9): 105942, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34175640

RESUMO

Vaccine-induced immune thrombotic thrombocytopenia is a rare syndrome following the ChAdOx1 nCov-19 or Ad26.COV2.S vaccine. Reported patients developed mainly venous thrombosis. We describe a case of a young healthy women suffering from acute ischemic stroke due to large vessel occlusion without cerebral venous thrombosis 8 days after vaccination and its consequences on recanalization strategy. Considering the thrombocytopenia, intravenous thrombolysis was contraindicated. She underwent mechanical thrombectomy with complete recanalization and dramatically improved clinically. Positive detection of anti-PF4-heparin-antibodies confirmed vaccine-induced immune thrombotic thrombocytopenia diagnosis. In case of acute ischemic stroke after recent ChAdOx1 nCov-19 or Ad26.COV2.S vaccine, platelet count should be systematically checked before giving thrombolysis, and direct mechanical thrombectomy should be proposed in patients with large vessel occlusion.


Assuntos
Vacinas contra COVID-19/efeitos adversos , AVC Isquêmico/terapia , Púrpura Trombocitopênica Trombótica/terapia , Trombectomia , Vacinação/efeitos adversos , Adulto , Anticorpos/sangue , Plaquetas/imunologia , Vacinas contra COVID-19/administração & dosagem , Feminino , Heparina/imunologia , Humanos , AVC Isquêmico/sangue , AVC Isquêmico/induzido quimicamente , AVC Isquêmico/diagnóstico , Fator Plaquetário 4/imunologia , Púrpura Trombocitopênica Trombótica/sangue , Púrpura Trombocitopênica Trombótica/induzido quimicamente , Púrpura Trombocitopênica Trombótica/diagnóstico , Resultado do Tratamento
19.
J Biomed Sci ; 28(1): 46, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34116654

RESUMO

Dysregulated formation of neutrophil extracellular traps (NETs) is observed in acute viral infections. Moreover, NETs contribute to the pathogenesis of acute viral infections, including those caused by the dengue virus (DV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Furthermore, excessive NET formation (NETosis) is associated with disease severity in patients suffering from SARS-CoV-2-induced multiple organ injuries. Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and other members of C-type lectin family (L-SIGN, LSECtin, CLEC10A) have been reported to interact with viral glycans to facilitate virus spreading and exacerbates inflammatory reactions. Moreover, spleen tyrosine kinase (Syk)-coupled C-type lectin member 5A (CLEC5A) has been shown as the pattern recognition receptor for members of flaviviruses, and is responsible for DV-induced cytokine storm and Japanese encephalomyelitis virus (JEV)-induced neuronal inflammation. Moreover, DV activates platelets via CLEC2 to release extracellular vesicles (EVs), including microvesicles (MVs) and exosomes (EXOs). The DV-activated EXOs (DV-EXOs) and MVs (DV-MVs) stimulate CLEC5A and Toll-like receptor 2 (TLR2), respectively, to enhance NET formation and inflammatory reactions. Thus, EVs from virus-activated platelets (PLT-EVs) are potent endogenous danger signals, and blockade of C-type lectins is a promising strategy to attenuate virus-induced NETosis and intravascular coagulopathy.


Assuntos
COVID-19/imunologia , Vírus da Encefalite Japonesa (Espécie)/imunologia , Encefalite Japonesa/imunologia , Armadilhas Extracelulares/imunologia , Lectinas Tipo C/imunologia , SARS-CoV-2/imunologia , Plaquetas/imunologia , Plaquetas/patologia , COVID-19/patologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Encefalite Japonesa/patologia , Humanos , Ativação Plaquetária/imunologia , Transdução de Sinais/imunologia
20.
Transfusion ; 61(9): 2788-2794, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34156106

RESUMO

BACKGROUND: Neonatal alloimmune thrombocytopenia (NAIT) is a potentially serious clinical condition caused by maternal alloantibodies directed to human platelet antigens (HPA), inherited from the father and expressed on fetal/neonatal platelets. We report a case of an otherwise well, full term child, with a profound thrombocytopenia (33 x 109/L). There was no bleeding or obvious explanation for the low platelet count. Samples were sent for the investigation of NAIT. METHOD: Serological investigations were performed on maternal serum taken at day (D)+4 and D+78. The platelet immunofluorescence test (PIFT) and monoclonal antibody immobilization of platelet antigens (MAIPA) assays were performed with a panel of HPA typed donor platelets and against paternal platelets in a crossmatch. HPA 1-6, -9 and -15 and HLA genotyping was performed by in-house PCR-sequence based typing (SBT) and next generation sequencing (NGS). RESULTS: HPA antibody screening of D+4 maternal serum indicated that platelet-specific antibodies were absent. HPA genotyping of the father and child revealed the presence of the low frequency HPA antigen (LFHPA), HPA-6b, which was absent in the mother. Maternal samples were crossmatched against paternal platelets and were positive by PIFT and glycoprotein (GP) IIb/IIIa and HLA class I in the MAIPA assay. The infant required no platelet transfusion support as the thrombocytopenia resolved spontaneously. DISCUSSION: We conclude that the positive crossmatch reaction was due to anti-HPA-6b alloantibodies. This case further emphasizes the importance of platelet crossmatching and HPA genotyping of LFHPA in cases where there is a high clinical suspicion of NAIT but initial screening is negative.


Assuntos
Antígenos de Plaquetas Humanas/imunologia , Isoanticorpos/imunologia , Trombocitopenia Neonatal Aloimune/imunologia , Adulto , Plaquetas/imunologia , Feminino , Humanos , Recém-Nascido , Masculino , Reino Unido
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...