RESUMO
Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating disease characterized by thrombotic occlusion of pulmonary arteries and vasculopathy, leading to increased pulmonary vascular resistance and progressive right-sided heart failure. Thrombotic lesions in CTEPH contain CD68+ macrophages, and increasing evidence supports their role in disease pathogenesis. Macrophages are classically divided into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages, which are involved in wound healing and tissue repair. Currently, the phenotype of macrophages and their localization within thrombotic lesions of CTEPH are largely unknown. In our study, we subclassified thrombotic lesions of CTEPH patients into developing fresh thrombi (FT) and organized thrombi (OT), based on the degree of fibrosis and remodeling. We used multiplex immunofluorescence histology to identify immune cell infiltrates in thrombotic lesions of CPTEH patients. Utilizing software-assisted cell detection and quantification, increased proportions of macrophages were observed in immune cell infiltrates of OT lesions, compared with FT. Strikingly, the proportions with a CD206+INOS- M2 phenotype were significantly higher in OT than in FT, which mainly contained unpolarized macrophages. Taken together, we observed a shift from unpolarized macrophages in FT toward an expanded population of M2 macrophages in OT, indicating a dynamic role of macrophages during CTEPH pathogenesis.
Assuntos
Hipertensão Pulmonar , Macrófagos , Embolia Pulmonar , Trombose , Humanos , Macrófagos/imunologia , Hipertensão Pulmonar/imunologia , Hipertensão Pulmonar/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/imunologia , Embolia Pulmonar/patologia , Doença Crônica , Trombose/imunologia , Trombose/patologia , Idoso , Antígenos CD/metabolismoRESUMO
The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.
Assuntos
Injúria Renal Aguda/complicações , COVID-19/complicações , Síndrome da Liberação de Citocina/complicações , Coagulação Intravascular Disseminada/complicações , Linfopenia/complicações , Miocardite/complicações , Embolia Pulmonar/complicações , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/virologia , Anticoagulantes/uso terapêutico , Antivirais/uso terapêutico , COVID-19/imunologia , COVID-19/virologia , Ensaios Clínicos como Assunto , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/imunologia , Coagulação Intravascular Disseminada/virologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Células Endoteliais/virologia , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Linfopenia/tratamento farmacológico , Linfopenia/imunologia , Linfopenia/virologia , Miocardite/tratamento farmacológico , Miocardite/imunologia , Miocardite/virologia , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/imunologia , Embolia Pulmonar/virologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/imunologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/patogenicidade , Tratamento Farmacológico da COVID-19Assuntos
Anticorpos/sangue , ChAdOx1 nCoV-19/efeitos adversos , Fator Plaquetário 4/imunologia , Embolia Pulmonar/induzido quimicamente , Trombocitopenia/induzido quimicamente , Vacinação/efeitos adversos , Tromboembolia Venosa/induzido quimicamente , Trombose Venosa/induzido quimicamente , Idoso , Biomarcadores/sangue , ChAdOx1 nCoV-19/administração & dosagem , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/imunologia , Trombocitopenia/diagnóstico , Trombocitopenia/tratamento farmacológico , Trombocitopenia/imunologia , Resultado do Tratamento , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/imunologia , Trombose Venosa/diagnóstico , Trombose Venosa/tratamento farmacológico , Trombose Venosa/imunologiaRESUMO
OBJECTIVE: We evaluated which aPL combinations increase the risk of future thrombosis in patients with SLE. METHODS: This prospective cohort study consisted of SLE patients who had been tested for all seven aPL (LA, aCL isotypes IgM, IgG and IgA, and anti-ß2-glycoprotein I isotypes IgM, IgG and IgA). Pooled logistic regression was used to assess the relationship between aPL and thrombosis. RESULTS: There were 821 SLE patients with a total of 75 048 person-months of follow-up. During the follow-up we observed 88 incident cases of thrombosis: 48 patients with arterial, 37 with venous and 3 with both arterial and venous thrombosis. In individual models, LA was the most predictive of any [age-adjusted rate ratio 3.56 (95% CI 2.01, 6.30), P < 0.0001], venous [4.89 (2.25, 10.64), P < 0.0001] and arterial [3.14 (1.41, 6.97), P = 0.005] thrombosis. Anti-ß2-glycoprotein I IgA positivity was a significant risk factor for any [2.00 (1.22, 3.3), P = 0.0065] and venous [2.8 (1.42, 5.51), P = 0.0029] thrombosis. Only anti-ß2-glycoprotein I IgA appeared to add significant risk to any [1.73 (1.04, 2.88), P = 0.0362] and venous [2.27 (1.13, 4.59), P = 0.0218] thrombosis among those with LA. We created an interaction model with four categories based on combinations of LA and other aPL to look at the relationships between combinations and the risk of thrombosis. In this model LA remained the best predictor of thrombosis. CONCLUSION: Our study demonstrated that in SLE, LA remained the best predictor of thrombosis and adding additional aPL did not add to the risk, with the exception of anti-ß2-glycoprotein I IgA.
Assuntos
Anticorpos Anticardiolipina/imunologia , Inibidor de Coagulação do Lúpus/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Trombose/imunologia , beta 2-Glicoproteína I/imunologia , Adulto , Anticorpos Antifosfolipídeos/imunologia , Estudos de Coortes , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Isquemia/epidemiologia , Isquemia/imunologia , Modelos Logísticos , Masculino , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/imunologia , Estudos Prospectivos , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/imunologia , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/imunologia , Trombose/epidemiologia , Trombose Venosa/epidemiologia , Trombose Venosa/imunologiaRESUMO
ABSTRACT: There is increasing evidence that novel coronavirus disease 2019 (COVID-19) leads to a significant coagulopathy, a phenomenon termed "COVID-19 associated coagulopathy." COVID-19 has been associated with increased rates of both venous and arterial thromboembolic events, a source of significant morbidity and mortality in this disease. Further evidence suggests a link between the inflammatory response and coagulopathy associated with COVID-19. This presents a unique set of challenges for diagnosis, prevention, and treatment of thrombotic complications. In this review, we summarize and discuss the current literature on laboratory coagulation disruptions associated with COVID-19 and the clinical effects of thromboembolic events including pulmonary embolism, deep vein thrombosis, peripheral arterial thrombosis, and acute ischemic stroke in COVID-19. Endothelial injury and augmented innate immune response are implicated in the development of diffuse macro- and microvascular thrombosis in COVID-19. The pathophysiology of COVID-19 associated coagulopathy is an important determinant of appropriate treatment and monitoring of these complications. We highlight the importance of diagnosis and management of dysregulated coagulation in COVID-19 to improve outcomes in COVID-19 patients with thromboembolic complications.
Assuntos
Transtornos da Coagulação Sanguínea , Coagulação Sanguínea/imunologia , COVID-19 , Imunidade Inata , SARS-CoV-2/imunologia , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/imunologia , Transtornos da Coagulação Sanguínea/patologia , Transtornos da Coagulação Sanguínea/terapia , COVID-19/complicações , COVID-19/patologia , COVID-19/terapia , Humanos , AVC Isquêmico/complicações , AVC Isquêmico/metabolismo , AVC Isquêmico/patologia , Embolia Pulmonar/etiologia , Embolia Pulmonar/imunologia , Embolia Pulmonar/patologia , Embolia Pulmonar/terapia , Trombose/etiologia , Trombose/imunologia , Trombose/patologia , Trombose/terapiaRESUMO
BACKGROUND: There is a close relationship between neutrophil extracellular traps (NETs) and venous thromboembolism (VTE). The regulatory role and mechanism of glucocorticoids (GC) in the formation of NETs are unclear. OBJECTIVE: This study was conducted to assess the effect of GC on the formation of NETs. METHODS: We constructed a mouse VTE model and treated them with GC to observe the effect of GC on the formation of NETs. In this regard, peripheral blood neutrophils were isolated, and the effect and mechanism of GC in neutrophil activation were analyzed. RESULTS: Following LPS treatment, the colony-forming ability of neutrophils and their ability to form NETs increased significantly. The analysis of cytokine changes by RT-PCR combined with ELISA showed that the level of inflammatory factors in LPS-activated neutrophils increased significantly; however, these factors were significantly inhibited after GC treatment, and the inhibitory effect was positively correlated with the concentration of GC. LPS treatment was able to activate the production of ROS and lipid peroxides, however, this activation was significantly inhibited after GC treatment, and the inhibition increased with increasing doses of GC. Further examination of the changes in NF-κB signaling activation revealed that LPS-induced NF-κB signaling was significantly inhibited after GC treatment, and this inhibition increased with increasing the GC concentration. CONCLUSION: Glucocorticoids were able to inhibit neutrophil activation and reduce the formation of NETs. The research results provided a new research direction for clinical antithrombotic treatment.
Assuntos
Armadilhas Extracelulares/metabolismo , Glucocorticoides/metabolismo , Pulmão/imunologia , Neutrófilos/imunologia , Embolia Pulmonar/imunologia , Tromboembolia Venosa/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Fibrinolíticos/uso terapêutico , Glucocorticoides/uso terapêutico , Humanos , Lipopolissacarídeos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Ativação de Neutrófilo , Embolia Pulmonar/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Tromboembolia Venosa/tratamento farmacológicoRESUMO
Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in SMARCAL1. A phenotype-genotype correlation has been attempted and variable expressivity of biallelic SMARCAL1 variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the SMARCAL1 gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD-both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with SMARCAL1 mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.
Assuntos
Arteriosclerose , DNA Helicases , Rim , Células Matadoras Naturais/imunologia , Mutação de Sentido Incorreto , Nefroma Mesoblástico , Síndrome Nefrótica , Osteocondrodisplasias , Fenótipo , Doenças da Imunodeficiência Primária , Embolia Pulmonar , Sistema Urinário , Substituição de Aminoácidos , Arteriosclerose/diagnóstico por imagem , Arteriosclerose/genética , Arteriosclerose/imunologia , DNA Helicases/genética , DNA Helicases/imunologia , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/imunologia , Rim/anormalidades , Rim/diagnóstico por imagem , Rim/imunologia , Masculino , Nefroma Mesoblástico/diagnóstico por imagem , Nefroma Mesoblástico/genética , Nefroma Mesoblástico/imunologia , Síndrome Nefrótica/diagnóstico por imagem , Síndrome Nefrótica/genética , Síndrome Nefrótica/imunologia , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Osteocondrodisplasias/imunologia , Doenças da Imunodeficiência Primária/diagnóstico por imagem , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/imunologia , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/genética , Embolia Pulmonar/imunologia , Sistema Urinário/anormalidades , Sistema Urinário/diagnóstico por imagem , Sistema Urinário/imunologia , Sequenciamento Completo do GenomaRESUMO
Coronavirus disease 2019 (COVID-19) patients with pre-existing cardiovascular disease (CVD) or with cardiovascular complications have a higher risk of mortality. The main cardiovascular complications of COVID-19 include acute cardiac injury, acute myocardial infarction (AMI), myocarditis, arrhythmia, heart failure, shock, and venous thromboembolism (VTE)/pulmonary embolism (PE). COVID-19 can cause cardiovascular complications or deterioration of coexisting CVD through direct or indirect mechanisms, including viral toxicity, dysregulation of the renin-angiotensin-aldosterone system (RAAS), endothelial cell damage and thromboinflammation, cytokine storm, and oxygen supply-demand mismatch. We systematically review cardiovascular manifestations, histopathology, and mechanisms of COVID-19, to help to formulate future research goals and facilitate the development of therapeutic management strategies.
Assuntos
COVID-19/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Enzima de Conversão de Angiotensina 2/metabolismo , Arritmias Cardíacas/imunologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , COVID-19/imunologia , COVID-19/metabolismo , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/metabolismo , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/fisiopatologia , Cardiopatias/imunologia , Cardiopatias/metabolismo , Cardiopatias/fisiopatologia , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipóxia/imunologia , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miocardite/imunologia , Miocardite/metabolismo , Miocardite/fisiopatologia , Embolia Pulmonar/imunologia , Embolia Pulmonar/metabolismo , Embolia Pulmonar/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , Choque/imunologia , Choque/metabolismo , Choque/fisiopatologia , Troponina/metabolismo , Tromboembolia Venosa/imunologia , Tromboembolia Venosa/metabolismo , Tromboembolia Venosa/fisiopatologiaRESUMO
Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.
Assuntos
Infecções por Coronavirus/imunologia , Epigênese Genética/imunologia , Fibrose Pulmonar Idiopática/imunologia , Mecanotransdução Celular/imunologia , Pneumonia Viral/imunologia , Embolia Pulmonar/imunologia , Insuficiência Respiratória/imunologia , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/patologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Fenômenos Biomecânicos , COVID-19 , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Fibroblastos/imunologia , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/virologia , Pulmão/irrigação sanguínea , Pulmão/imunologia , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/patologia , Mecanotransdução Celular/genética , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Embolia Pulmonar/genética , Embolia Pulmonar/patologia , Embolia Pulmonar/virologia , Insuficiência Respiratória/genética , Insuficiência Respiratória/patologia , Insuficiência Respiratória/virologia , SARS-CoV-2 , Estresse MecânicoRESUMO
A subset of patients with coronavirus 2 disease (COVID-19) experience neurological complications. These complications include loss of sense of taste and smell, stroke, delirium, and neuromuscular signs and symptoms. The etiological agent of COVID-19 is SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), an RNA virus with a glycoprotein-studded viral envelope that uses ACE2 (angiotensin-converting enzyme 2) as a functional receptor for infecting the host cells. Thus, the interaction of the envelope spike proteins with ACE2 on host cells determines the tropism and virulence of SARS-CoV-2. Loss of sense of taste and smell is an initial symptom of COVID-19 because the virus enters the nasal and oral cavities first and the epithelial cells are the receptors for these senses. Stroke in COVID-19 patients is likely a consequence of coagulopathy and injury to cerebral vascular endothelial cells that cause thrombo-embolism and stroke. Delirium and encephalopathy in acute and post COVID-19 patients are likely multifactorial and secondary to hypoxia, metabolic abnormalities, and immunological abnormalities. Thus far, there is no clear evidence that coronaviruses cause inflammatory neuromuscular diseases via direct invasion of peripheral nerves or muscles or via molecular mimicry. It appears that most of neurologic complications in COVID-19 patients are indirect and as a result of a bystander injury to neurons.
Assuntos
Betacoronavirus/patogenicidade , Encefalopatias/complicações , Infecções por Coronavirus/complicações , Transtornos do Olfato/complicações , Pneumonia Viral/complicações , Embolia Pulmonar/complicações , Acidente Vascular Cerebral/complicações , Enzima de Conversão de Angiotensina 2 , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Encéfalo/virologia , Encefalopatias/imunologia , Encefalopatias/patologia , Encefalopatias/virologia , Efeito Espectador , COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Pulmão/irrigação sanguínea , Pulmão/patologia , Pulmão/virologia , Neurônios/patologia , Neurônios/virologia , Transtornos do Olfato/imunologia , Transtornos do Olfato/patologia , Transtornos do Olfato/virologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Embolia Pulmonar/imunologia , Embolia Pulmonar/patologia , Embolia Pulmonar/virologia , SARS-CoV-2 , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/virologiaRESUMO
Since the initial description in 2019, the novel coronavirus SARS-Cov-2 infection (COVID-19) pandemic has swept the globe. The most severe form of the disease presents with fever and shortness of breath, which rapidly deteriorates to respiratory failure and acute lung injury (ALI). COVID-19 also presents with a severe coagulopathy with a high rate of venous thromboembiolism. In addition, autopsy studies have revealed co-localized thrombosis and inflammation, which is the signature of thromboinflammation, within the pulmonary capillary vasculature. While the majority of published data is on adult patients, there are parallels to pediatric patients. In our experience as a COVID-19 epicenter, children and young adults do develop both the coagulopathy and the ALI of COVID-19. This review will discuss COVID-19 ALI from a hematological perspective with discussion of the distinct aspects of coagulation that are apparent in COVID-19. Current and potential interventions targeting the multiple thromboinflammatory mechanisms will be discussed.
Assuntos
Lesão Pulmonar Aguda/sangue , Infecções por Coronavirus/sangue , Inflamação/sangue , Pneumonia Viral/sangue , Trombose/sangue , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/fisiopatologia , Anticoagulantes/uso terapêutico , Antitrombinas/uso terapêutico , Betacoronavirus , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/imunologia , Transtornos da Coagulação Sanguínea/fisiopatologia , COVID-19 , Capilares/imunologia , Capilares/fisiopatologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Endotélio Vascular/imunologia , Endotélio Vascular/fisiopatologia , Inibidores do Fator Xa/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/fisiopatologia , Pandemias , Ativação Plaquetária , Inibidores da Agregação Plaquetária/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Embolia Pulmonar/sangue , Embolia Pulmonar/imunologia , Embolia Pulmonar/fisiopatologia , SARS-CoV-2 , Trombina/imunologia , Trombina/metabolismo , Trombose/tratamento farmacológico , Trombose/imunologia , Trombose/fisiopatologia , Tratamento Farmacológico da COVID-19RESUMO
OBJECTIVES: Non-conventional aPL have been described in patients presenting clinical manifestations of antiphospholipid syndrome but negative for conventional markers. Among them, detection of autoantibodies against prothrombin has been proposed to improve diagnosis and management of these patients. However autoantibodies against prothrombin are heterogeneous and their use in clinical practice still remains unclear. The aim of this study was to evaluate the interest of IgG and IgM autoantibodies directed against the prothrombin only (aPT). METHODS: We retrospectively studied IgM and IgG aPT results, conventional antiphospholipid syndrome markers and clinical data of a large cohort of 441 patients referred for antiphospholipid syndrome exploration with aPT detection over a period of 5 years. RESULTS: We observed a total prevalence of 17% of aPT-positive patients (75/441). A significant association was found between aPT and thrombosis (P = 0.035), with 70% of patients having unexplained thrombosis, aPT representing the sole aPL detected. aPT positivity was significantly more frequent in venous thrombosis than in arterial thrombosis (P = 0.004). Interestingly, we demonstrated for the first time that aPT IgG levels were higher in recurrent thrombosis than in isolated thrombosis (P = 0.013), leading us to propose a predictive level of recurrence for thrombosis. CONCLUSION: Our results show that aPT are associated with thrombosis and demonstrate the interest of assessing both IgG and IgM aPT, in particular in venous thrombosis when conventional markers are negative. Quantification of aPT could predict recurrence of thrombosis and influence subsequent treatment strategy. Prospective clinical studies are now required to confirm these results.
Assuntos
Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Protrombina/imunologia , Embolia Pulmonar/imunologia , Trombose Venosa/imunologia , Adulto , Anticorpos Anticardiolipina/imunologia , Síndrome Antifosfolipídica/complicações , Artérias , Autoanticorpos/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Ataque Isquêmico Transitório/etiologia , Ataque Isquêmico Transitório/imunologia , Inibidor de Coagulação do Lúpus/imunologia , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/etiologia , Recidiva , Estudos Retrospectivos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/imunologia , Trombose/etiologia , Trombose/imunologia , Trombose Venosa/etiologia , beta 2-Glicoproteína I/imunologiaRESUMO
While circulating autoantibodies have been detected in patients with several cardiovascular diseases, such studies have not been performed for chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Here we investigated the production of certain auto-antibodies in CTEPH patients. Initial screening was performed in 5 CTEPH patients and 5 healthy donors (HDs) using a ProtoArray Human Protein Microarray v5.1 containing 9,375 human proteins, and we selected 34 antigens recognized by IgG antibodies more strongly in the sera of CTEPH patients than in the sera of HDs. In subsequent second/third analyses, we validated the auto-antibody level using amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) in 96 CTEPH patients and 96 HDs as follows: At the second screening, we used 63 crude peptides derived from those selected 34 antigens and found that the serum levels of autoantibodies for 4 peptides seemed higher in CTEPH patients than in HDs. In third analysis, we used the purified peptides of those selected in second screening and found that serum antibodies against peptides derived from exonuclease 3'-5' domain-containing 2 (EXD2) and phosphorylated adaptor for RNA export (PHAX) were significantly higher in CTEPH patients than in HDs. The serum antibody levels to these antigens were also elevated in PAH patients. The titers against EXD2 peptide decreased after surgical treatment in CTEPH patients. These autoantibodies may be useful as biomarkers of CTEPH and PAH, and further investigations may provide novel insight into the etiology.
Assuntos
Autoanticorpos/sangue , Hipertensão Pulmonar/imunologia , Embolia Pulmonar/imunologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/imunologia , Síndromes da Apneia do Sono/imunologiaRESUMO
OBJECTIVES: The aim of this study was to investigate association between pulmonary and skin manifestations in a large group of patients with primary antiphospholipid syndrome (PAPS) as well as their connection with antiphospholipid antibodies. METHODS: Our prospective study comprises of 390 patients with primary APS. Antiphospholipid antibody (aPL) analysis included detection of aCL (IgG/IgM), ß2GPI (IgG/IgM) and LA. Distinct pulmonary and skin associations were determined, as well as their associations with aPL. RESULTS: In PAPS patients the presence of LA was more common in PTE (p=0.005) and in pulmonary microthrombosis (p=0.003). We revealed statistical significance considering the presence of aCL IgM and pulmonary microthrombosis (p=0.05). Skin ulcerations correlated with positive titres aCL IgM and ß2 GPI IgM (p=0.03 and 0.04, respectively), while pseudovasculitis correlated with positive titres ß2 GPI IgM (p=0.02). PAPS patients were more more likely to develop pulmonary thromboembolisam if they had livedo reticularis (p=0.005), skin ulcerations (p=0.007), pseudovasculitic lesions (p=0.01), superficial cutaneous necrosis (p=0.005), and digital gangrene (p=0.02). Patients were also more prone to pulmonary microthrombosis if they already had livedo reticularis (p=0.03), skin ulcerations (p=0.007), pseudovasculitic lesions (p=0.05), superficial cutaneous necrosis (p=0.006), and digital gangrene (p=0.02). CONCLUSIONS: There is strong link between some pulmonary and skin manifestations in PAPS patients, suggesting complexity and evolutionary nature of APS. The presence of skin manifestations may be a high risk factor for several types of serious pulmonary manifestations in PAPS. Certain aPL types are associated with distinct pulmonary and skin manifestation, suggesting their predictive role.
Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/imunologia , Pneumopatias/imunologia , Dermatopatias/imunologia , Adulto , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/epidemiologia , Biomarcadores/sangue , Feminino , Humanos , Pneumopatias/sangue , Pneumopatias/diagnóstico , Pneumopatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Embolia Pulmonar/sangue , Embolia Pulmonar/imunologia , Fatores de Risco , Sérvia/epidemiologia , Testes Sorológicos , Dermatopatias/sangue , Dermatopatias/diagnóstico , Dermatopatias/epidemiologia , Dermatopatias Vasculares/sangue , Dermatopatias Vasculares/imunologia , Úlcera Cutânea/sangue , Úlcera Cutânea/imunologiaRESUMO
The present study aimed to explore the influence of aspirin on the CX3CL1/CX3CR1 signaling pathway in acute pulmonary embolism (APE) in rats. Our previous study found that CX3CL1/CX3CR1 was increased in APE. However, the effect of this signaling pathway on APE remains unclear. CX3CL1-shRNA adenovirus and CX3CL1-overexpression vector were constructed. Male Sprague-Dawley rats were randomly divided into 9 groups (n=10): normal group (group N), sham operation group (group Sham), sham operation + aspirin group (group ASP), model group (group M), model + ASP group (group M+A), model + shRNA group (group M+SH), sham operation + CX3CL1-overexpression vector group (group Sham+Cx3), model + ASP + shRNA group (group M+A+SH), and model + ASP + CX3CL1-overexpression vector group (group M+A+CX3). Arterial pressure detection, hematoxylin and eosin staining, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and laser confocal scanning microscopy were applied. Aspirin significantly decreased pulmonary artery pressure, improve pathological changes in the embolism, and decreased the expression of CX3CL1/CX3CR1 and CX3CL1/NF-κB. Moreover, the adenovirus-overexpression CX3CL1 vector aggravated the inflammatory changes in APE, which were improved by aspirin. However, the intervention of the adenovirus CX3CL1 vector reduced the change, while its combination with aspirin significantly improved the change. In conclusion, aspirin improved pathological changes in rats with APE via the CX3CL1/CX3CR1 signaling pathway.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Receptor 1 de Quimiocina CX3C/imunologia , Quimiocina CX3CL1/imunologia , Embolia Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Doença Aguda , Animais , Receptor 1 de Quimiocina CX3C/análise , Quimiocina CX3CL1/análise , Masculino , NF-kappa B/análise , NF-kappa B/imunologia , Embolia Pulmonar/imunologia , Embolia Pulmonar/patologia , Ratos Sprague-DawleyRESUMO
BACKGROUND AND AIMS: Pulmonary thromboembolism (PTE) is a common cardiovascular emergency. Activated leukocytes may produce free oxygen radicals and endothelial damage, and, thereby, increased inflammation and thrombogenesis. In this study, we aimed to investigate endothelial dysfunction in patients with PTE. METHODS: Between May 2012 and July 2013, a total of 71 patients with acute PTE (32 males, 39 females; mean age: 64.94 ± 15.27 years; range: 33 to 87 years) who were admitted to the Emergency and Thoracic Diseases Departments and 56 healthy controls (44 males, 12 females; mean age: 62.52 ± 9.80 years; range: 46 to 79 years) were included. Brachial artery flow-mediated dilation (BFMD) was performed. Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) were calculated. RESULTS: Significantly higher BFMD values were observed in patients with PTE (P < 0.05). Patients with PTE also had significantly higher NLR and PLR values, compared with the healthy control group (P < 0.05). CONCLUSION: The results of our study suggest that using non-invasive method such as ultrasonography combined with NLR and PLR in endothelial dysfunction diagnosis in PTE patients are both effective and inexpensive. We believe in PTE patients endothelial dysfunction may play a role in the development of probable cardiovascular events in future.
Assuntos
Linfócitos/patologia , Neutrófilos/patologia , Embolia Pulmonar/sangue , Embolia Pulmonar/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Endotélio/imunologia , Endotélio/patologia , Feminino , Humanos , Contagem de Linfócitos , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Contagem de Plaquetas , Prognóstico , Índice de Gravidade de Doença , UltrassonografiaRESUMO
OBJECTIVE: To investigate the clinical characteristics in patients with primary antiphospholipid syndrome (PAPS) and to identify potential predictors of thrombotic events. METHODS: A total of 107 patients with PAPS were enrolled in our study, who were admitted in Peking Union Medical College Hospital from January 2004 to December 2014. Demographic data, age at onset, disease duration, past history of hypertension and regular cigarette smoking, clinical manifestations, imaging characteristics, management and prognosis were retrospectively collected. Bivariate statistical analysis and logistical regression test were performed to compare the discrepancy between patients with or without thromboembolic events. RESULTS: In 107 patients, there were 65 female and 42 male patients, with mean age (39.8±15.8) years old, median disease duration 10.5 (2.0, 48.0) months. A total of 72(67.3%) patients reported episodes of thromboembolic events, including 72 venous thromboses and 29 arterial thromboses. The most frequent venous thromboses were deep vein thromboses (35.5%), pulmonary embolism the second common (29.9%), with cranial venous sinus thromboses the following (8.4%). In arterial thromboembolic events, the incidence of transient ischemic attack (TIA) and ischemic stoke was the highest(14.0%), embolism of lower extremities the second (6.5%), and 4 patients (3.7%) with acute myocardial infarction. Sixty seven patients(62.6%)had positive lupus anticoagulant, 60 patients(56.1%)with positive anticardiolipin antibody, 32 patients(29.9%, 32/74) with positive ß2 glycoprotein â (ß2GPâ ). Forty patients(37.4%)had double positive antibodies, while 19 cases(17.8%)with triple positive. In logistical regression, aging (per 10 years) and hypocomplementemia were significantly related to venous thrombosis (OR=1.421, 95%CI 1.066-1.894, P<0.05, and OR=6.435, 95%CI 1.374-30.130, P<0.05, respectively). Cigarette smoking and triple positive antibodies were independent risk factors of arterial thrombosis (OR=3.996, 95%CI 1.079-14.795, P<0.05 and OR=3.166, 95%CI 1.102-9.097, P<0.05, respectively). CONCLUSION: APS is an autoimmune disorder characterized by recurrent arterial and venous thromboembolic events. Venous thromboembolism is more common than the arterial. Age and hypocomplementemia are predictors of venous thromboembolism; while smoking and triple positive antibodies are independent risk factors of arterial thromboembolism.
Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/complicações , Trombina/metabolismo , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Trombose Venosa/epidemiologia , Adulto , Anticorpos Antifosfolipídeos/análise , Feminino , Humanos , Incidência , Inibidor de Coagulação do Lúpus/sangue , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/imunologia , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/imunologia , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Trombose , Tromboembolia Venosa/complicações , Trombose Venosa/imunologia , Adulto JovemRESUMO
Proteus syndrome (PS) is an extremely rare and complex disease characterized by malformations and overgrowth of different tissues. Prognosis of affected patients may be complicated by premature death, mostly due to pulmonary embolism and respiratory failure. To date, immunological data in Proteus syndrome are scarse.We report on the novel immunologic findings of a 15 years old girl affected with PS. Detailed T and B cell evaluation revealed maturational alterations for both subsets and functional hyperactivation for the latter. Such findings have not been reported previously in PS and may be the spy of more complex immune abnormalities in this syndrome.
Assuntos
Síndrome de Proteu/diagnóstico , Síndrome de Proteu/imunologia , Adolescente , Linfócitos B/imunologia , Feminino , Humanos , Síndrome de Proteu/complicações , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/etiologia , Embolia Pulmonar/imunologia , Linfócitos T/imunologiaRESUMO
Raised plasma levels of the soluble urokinase plasminogen activator receptor (suPAR) have been associated with increased incidence of cardiovascular diseases. Whether suPAR is associated with venous thromboembolism (VTE) is largely unknown. The purpose of the present study was to investigate the relationship between suPAR and incidence of VTE in a cohort study. suPAR was measured in 5,203 subjects (aged 46-68 years, 58 % women) from the general population, who participated in the Malmö Diet and Cancer (MDC) study between 1991 and 1994. Incident cases of VTE were identified from the Swedish patient register during a mean follow-up of 15.7 years. Of 5,203 subjects with measurements of suPAR, 239 had VTE during follow-up (127 venous thrombosis, 86 lung embolism, 26 both). Incidence of VTE was significantly higher in subjects with suPAR levels in the top quartile. Adjusted for age and sex, the HR (4th vs 1st quartile) was 1.74 (95 %CI: 1.2-2.6, p for trend=0.003). After adjustments for risk factors, the HR was 1.66 (95 %CI: 1.1-2.5, p for trend=0.016). High level of suPAR was a risk indicator for incidence of VTE in this population-based cohort study. The causal relationships between suPAR and VTE remain to be explored.
Assuntos
Receptores de Ativador de Plasminogênio Tipo Uroquinase/química , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/imunologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Proteína C-Reativa/química , Estudos de Coortes , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Ativadores de Plasminogênio/química , Embolia Pulmonar/imunologia , Receptores de Ativador de Plasminogênio Tipo Uroquinase/sangue , Sistema de Registros , Fatores de Risco , Suécia , Tromboembolia Venosa/sangueRESUMO
OBJECTIVE: The high morbidity, mortality and misdiagnosis rate render pulmonary embolism (PE) as a worldwide health problem. However, the etiology and pathogenesis of this disease have not been well characterized. Increasing studies indicate infection and immunity play a crucial role in PE. Natural killer (NK) cells act as a bridge between the innate immune and acquired immune. This study aimed to investigate the possible function of NK cells in PE. METHODS: Human cDNA microarray analysis was employed to detect genes associated with NK cells in peripheral blood mononuclear cells (PBMCs). Random variance model corrected t-test was used for statistical analysis of differential gene expression. Flow cytometry was performed to detect the CD16+CD56+ NK cells. RESULTS: In the present study, based on gene expression microarray analysis, we showed four inhibitory receptors (KLRB1, KLRD1, KLRF1, KLRG1) and four activating receptors (KLRC1, KLRC3, KLRK1 and NCR1) on NK cells were remarkably down-regulated and the cytological experiment demonstrated the proportion of CD16+CD56+ NK cells among PBMCs decreased in the PE group. CONCLUSIONS: We confirmed the presence of reduced expression of critical activating as well as inhibitory NK cell receptors and low proportion of CD16+CD56+ NK cells in PE. The consistence between genomic and cytological examination suggests compromised NK cells may contribute to the pathogenesis of PE.