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1.
PLoS One ; 17(1): e0262352, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34986205

RESUMO

INTRODUCTION: COVID-19 infection has been hypothesized to precipitate venous and arterial clotting events more frequently than other illnesses. MATERIALS AND METHODS: We demonstrate this increased risk of blood clots by comparing rates of venous and arterial clotting events in 4400 hospitalized COVID-19 patients in a large multisite clinical network in the United States examined from April through June of 2020, to patients hospitalized for non-COVID illness and influenza during the same time period and in 2019. RESULTS: We demonstrate that COVID-19 increases the risk of venous thrombosis by two-fold compared to the general inpatient population and compared to people with influenza infection. Arterial and venous thrombosis were both common occurrences among patients with COVID-19 infection. Risk factors for thrombosis included male gender, older age, and diabetes. Patients with venous or arterial thrombosis had high rates of admission to the ICU, re-admission to the hospital, and death. CONCLUSION: Given the ongoing scientific discussion about the impact of clotting on COVID-19 disease progression, these results highlight the need to further elucidate the role of anticoagulation in COVID-19 patients, particularly outside the intensive care unit setting. Additionally, concerns regarding clotting and COVID-19 vaccines highlight the importance of addressing the alarmingly high rate of clotting events during actual COVID-19 infection when weighing the risks and benefits of vaccination.


Assuntos
COVID-19/patologia , Trombose/patologia , Idoso , COVID-19/mortalidade , Estudos de Coortes , Comorbidade , Feminino , Hospitalização , Humanos , Masculino , New Jersey , Estudos Retrospectivos , Trombose/mortalidade , Estados Unidos
2.
Curr Opin Nephrol Hypertens ; 31(1): 36-46, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34846312

RESUMO

PURPOSE OF REVIEW: Severe COVID-19 disease is often complicated by acute kidney injury (AKI), which may transition to chronic kidney disease (CKD). Better understanding of underlying mechanisms is important in advancing therapeutic approaches. RECENT FINDINGS: SARS-CoV-2-induced endothelial injury initiates platelet activation, platelet-neutrophil partnership and release of neutrophil extracellular traps. The resulting thromboinflammation causes ischemia-reperfusion (I/R) injury to end organs. Severe COVID-19 induces a lipid-mediator storm with massive increases in thromboxane A2 (TxA2) and PGD2, which promote thromboinflammation and apoptosis of renal tubular cells, respectively, and thereby enhance renal fibrosis. COVID-19-associated AKI improves rapidly in the majority. However, 15-30% have protracted renal injury, raising the specter of transition from AKI to CKD. SUMMARY: In COVID-19, the lipid-mediator storm promotes thromboinflammation, ischemia-reperfusion injury and cytotoxicity. The thromboxane A2 and PGD2 signaling presents a therapeutic target with potential to mitigate AKI and transition to CKD. Ramatroban, the only dual antagonist of the thromboxane A2/TPr and PGD2/DPr2 signaling could potentially mitigate renal injury in acute and long-haul COVID. Urgent studies targeting the lipid-mediator storm are needed to potentially reduce the heavy burden of kidney disease emerging in the wake of the current pandemic.


Assuntos
Injúria Renal Aguda , COVID-19 , Insuficiência Renal Crônica , Trombose , Injúria Renal Aguda/etiologia , COVID-19/complicações , Fibrose , Humanos , Inflamação , Rim/patologia , Lipídeos , Insuficiência Renal Crônica/patologia , SARS-CoV-2 , Trombose/patologia
3.
Am J Surg Pathol ; 46(1): 89-96, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34081038

RESUMO

Approximately 20% of patients with symptomatic syndrome-associated coronavirus-2 (SARS-CoV-2) infection have gastrointestinal bleeding and/or diarrhea. Most are managed without endoscopic evaluation because the risk of practitioner infection outweighs the value of biopsy analysis unless symptoms are life-threatening. As a result, much of what is known about the gastrointestinal manifestations of coronavirus disease-2019 (COVID-19) has been gleaned from surgical and autopsy cases that suffer from extensive ischemic injury and/or poor preservation. There are no detailed reports describing any other gastrointestinal effects of SARS-CoV-2 even though >3,000,000 people have died from COVID-19 worldwide. The purpose of this study is to report the intestinal findings related to SARS-CoV-2 infection by way of a small case series including one with evidence of direct viral cytopathic effect and 2 with secondary injury attributed to viral infection. Infection can be confirmed by immunohistochemical stains directed against SARS-CoV-2 spike protein, in situ hybridization for spike protein-encoding RNA, and ultrastructural visualization of viruses within the epithelium. It induces cytoplasmic blebs and tufted epithelial cells without inflammation and may not cause symptoms. In contrast, SARS-CoV-2 infection can cause gastrointestinal symptoms after the virus is no longer detected, reflecting systemic activation of cytokine and complement cascades rather than direct viral injury. Reversible mucosal ischemia features microvascular injury with hemorrhage, small vessel thrombosis, and platelet-rich thrombi. Systemic cytokine elaboration and dysbiosis likely explain epithelial cell injury that accompanies diarrheal symptoms. These observations are consistent with clinical and in vitro data and contribute to our understanding of the protean manifestations of COVID-19.


Assuntos
COVID-19/patologia , Enteropatias/patologia , Enteropatias/virologia , Intestinos/patologia , Intestinos/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Biópsia , COVID-19/diagnóstico , COVID-19/imunologia , Citocinas/metabolismo , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/imunologia , Hemorragia Gastrointestinal/patologia , Hemorragia Gastrointestinal/virologia , Humanos , Enteropatias/diagnóstico , Enteropatias/imunologia , Intestinos/imunologia , Isquemia/diagnóstico , Isquemia/imunologia , Isquemia/patologia , Isquemia/virologia , Masculino , Trombose/diagnóstico , Trombose/imunologia , Trombose/patologia , Trombose/virologia
4.
Cancer Treat Rev ; 102: 102322, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34922151

RESUMO

Advances in understanding the molecular mechanisms of tumor progression have achieved impressive progress in the treatment of cancer and so-called immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Indeed, antibody-based drugs blocking immune escape of tumor cells by modulation of T cell responses are increasingly utilized for a wide range of tumor entities. Nonetheless, response rates remain limited, and the development of secondary resistance is a common problem. In addition, by increasing the immune response a variety of severe side effects are provoked. Next to autoimmune responses, activation of the complement system and skin toxicity, an increased incidence for thrombotic complications has been observed associated with an increased mortality rate. Based on this, it can be postulated that the interplay of coagulation with inflammation in the tumor microenvironment is relevant for each step in the tumor life cycle. This review focuses on the coagulation as central player fostering mechanisms associated with tumor progression. Thus, a better understanding of the molecular pathways involved in the complex interaction of circulating tumor cells, the plasmatic coagulation and immune cells may help to improve therapeutic concepts reducing mortality and morbidity associated with cancer.


Assuntos
Coagulação Sanguínea/imunologia , Heparina de Baixo Peso Molecular/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Inflamação/sangue , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Anticoagulantes/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Humanos , Inflamação/imunologia , Inflamação/patologia , Neoplasias/imunologia , Trombose/sangue , Trombose/tratamento farmacológico , Trombose/patologia , Evasão Tumoral/efeitos dos fármacos
5.
Int J Mol Sci ; 22(24)2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34948438

RESUMO

COVID-19 infection is associated with a broad spectrum of presentations, but alveolar capillary microthrombi have been described as a common finding in COVID-19 patients, appearing as a consequence of a severe endothelial injury with endothelial cell membrane disruption. These observations clearly point to the identification of a COVID-19-associated coagulopathy, which may contribute to thrombosis, multi-organ damage, and cause of severity and fatality. One significant finding that emerges in prothrombotic abnormalities observed in COVID-19 patients is that the coagulation alterations are mainly mediated by the activation of platelets and intrinsically related to viral-mediated endothelial inflammation. Beyond the well-known role in hemostasis, the ability of platelets to also release various potent cytokines and chemokines has elevated these small cells from simple cell fragments to crucial modulators in the blood, including their inflammatory functions, that have a large influence on the immune response during infectious disease. Indeed, platelets are involved in the pathogenesis of acute lung injury also by promoting NET formation and affecting vascular permeability. Specifically, the deposition by activated platelets of the chemokine platelet factor 4 at sites of inflammation promotes adhesion of neutrophils on endothelial cells and thrombogenesis, and it seems deeply involved in the phenomenon of vaccine-induced thrombocytopenia and thrombosis. Importantly, the hyperactivated platelet phenotype along with evidence of cytokine storm, high levels of P-selectin, D-dimer, and, on the other hand, decreased levels of fibrinogen, von Willebrand factor, and thrombocytopenia may be considered suitable biomarkers that distinguish the late stage of COVID-19 progression in critically ill patients.


Assuntos
Plaquetas/fisiologia , COVID-19/sangue , Trombose/patologia , Coagulação Sanguínea , Transtornos da Coagulação Sanguínea/etiologia , Plaquetas/metabolismo , Plaquetas/virologia , COVID-19/metabolismo , Síndrome da Liberação de Citocina , Células Endoteliais/patologia , Produtos de Degradação da Fibrina e do Fibrinogênio , Hemostasia , Humanos , Inflamação , Fenótipo , Ativação Plaquetária/fisiologia , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Trombocitopenia/metabolismo , Trombose/metabolismo , Trombose/virologia
6.
Cells ; 10(12)2021 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-34943852

RESUMO

Depression is an independent risk factor for cardiovascular disease (CVD). We have previously shown that repeated social defeat (RSD) exaggerates atherosclerosis development by enhancing neutrophil extracellular trap (NET) formation. In this study, we investigated the impact of RSD on arterial thrombosis. Eight-week-old male wild-type mice (C57BL/6J) were exposed to RSD by housing with larger CD-1 mice in a shared home cage. They were subjected to vigorous physical contact daily for 10 consecutive days. After confirming depression-like behaviors, mice underwent FeCl3-induced carotid arterial injury and were analyzed after 3 h. Although the volume of thrombi was comparable between the two groups, fibrin(ogen)-positive areas were significantly increased in defeated mice, in which Ly-6G-positive cells were appreciably co-localized with Cit-H3-positive staining. Treatment with DNase I completely diminished exaggerated fibrin-rich clot formation in defeated mice. Flow cytometric analysis showed that neutrophil CD11b expression before FeCl3 application was significantly higher in defeated mice than in control mice. In vitro NET formation induced by activated platelets was significantly augmented in defeated mice, which was substantially inhibited by anti-CD11b antibody treatment. Our findings demonstrate that RSD enhances fibrin-rich clot formation after arterial injury by enhancing NET formation, suggesting that NET can be a new therapeutic target in depression-related CVD.


Assuntos
Coagulação Sanguínea , Plaquetas/metabolismo , Comunicação Celular , Armadilhas Extracelulares/metabolismo , Fibrina/metabolismo , Neutrófilos/metabolismo , Derrota Social , Animais , Anticorpos/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Antígeno CD11b/metabolismo , Comunicação Celular/efeitos dos fármacos , Cloretos/farmacologia , Desoxirribonuclease I/metabolismo , Armadilhas Extracelulares/efeitos dos fármacos , Compostos Férricos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Selectina-P/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Trombose/patologia
7.
Clin Appl Thromb Hemost ; 27: 10760296211051764, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34755565

RESUMO

The precise mechanisms of pathology in severe COVID-19 remains elusive. Current evidence suggests that inflammatory mediators are responsible for the manifestation of clinical symptoms that precedes a fatal response to infection. This review examines the nature of platelet activating factor and emphasizes the similarities between the physiological effects of platelet activating factor and the clinical complications of severe COVID-19.


Assuntos
COVID-19/metabolismo , Fator de Ativação de Plaquetas/metabolismo , Animais , COVID-19/complicações , COVID-19/mortalidade , COVID-19/patologia , Humanos , Inflamação/complicações , Inflamação/metabolismo , Inflamação/mortalidade , Inflamação/patologia , Insuficiência de Múltiplos Órgãos/complicações , Insuficiência de Múltiplos Órgãos/metabolismo , Insuficiência de Múltiplos Órgãos/mortalidade , Insuficiência de Múltiplos Órgãos/patologia , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/mortalidade , Síndrome do Desconforto Respiratório/patologia , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Trombose/complicações , Trombose/metabolismo , Trombose/mortalidade , Trombose/patologia
8.
Nat Commun ; 12(1): 5760, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34608135

RESUMO

Metastasis is the principal cause of cancer related deaths. Tumor invasion is essential for metastatic spread. However, determinants of invasion are poorly understood. We addressed this knowledge gap by leveraging a unique attribute of kidney cancer. Renal tumors invade into large vessels forming tumor thrombi (TT) that migrate extending sometimes into the heart. Over a decade, we prospectively enrolled 83 ethnically-diverse patients undergoing surgical resection for grossly invasive tumors at UT Southwestern Kidney Cancer Program. In this study, we perform comprehensive histological analyses, integrate multi-region genomic studies, generate in vivo models, and execute functional studies to define tumor invasion and metastatic competence. We find that invasion is not always associated with the most aggressive clone. Driven by immediate early genes, invasion appears to be an opportunistic trait attained by subclones with diverse oncogenomic status in geospatial proximity to vasculature. We show that not all invasive tumors metastasize and identify determinants of metastatic competency. TT associated with metastases are characterized by higher grade, mTOR activation and a particular immune contexture. Moreover, TT grade is a better predictor of metastasis than overall tumor grade, which may have implications for clinical practice.


Assuntos
Carcinoma de Células Renais/secundário , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/patologia , Trombose/genética , Idoso , Animais , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Feminino , Humanos , Rim/irrigação sanguínea , Rim/patologia , Neoplasias Renais/complicações , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Estudos Prospectivos , RNA-Seq , Fatores de Risco , Trombose/patologia , Sequenciamento Completo do Exoma , Ensaios Antitumorais Modelo de Xenoenxerto
9.
PLoS One ; 16(10): e0258192, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34614035

RESUMO

OBJECTIVES: Acquired coagulopathy may be associated with bleeding risk. Approaches to restore haemostasis include administration of coagulation factor concentrates, but there are concerns regarding potential prothrombotic risk. The present study assessed the prothrombotic potential of four-factor prothrombin complex concentrate (4F-PCC) versus activated PCC (aPCC) and recombinant factor VIIa (rFVIIa), using three preclinical animal models. METHODS: The first model was a modified Wessler model of venous stasis-induced thrombosis in rabbit, focusing on dilutional coagulopathy; the second model employed the same system but focused on direct oral anticoagulant reversal (i.e. edoxaban). The third model assessed the prothrombotic impact of 4F-PCC, aPCC and rFVIIa in a rat model of ferric chloride-induced arterial thrombosis. RESULTS: In the first model, thrombi were observed at aPCC doses ≥10 IU/kg (therapeutic dose 100 IU/kg) and rFVIIa doses ≥50 µg/kg (therapeutic dose 90 µg/kg), but not 4F-PCC 50 IU/kg (therapeutic dose 50 IU/kg). The impact of 4F-PCC (up to 300 IU/kg) on thrombus formation was evident from 10 minutes post-administration, but not at 24 hours post-administration; this did not change with addition of tranexamic acid and/or fibrinogen concentrate. 4F-PCC-induced thrombus formation was lower after haemodilution versus non-haemodilution. In the second model, no prothrombotic effect was confirmed at 4F-PCC 50 IU/kg. The third model showed lower incidence of thrombus formation for 4F-PCC 50 IU/kg versus aPCC (50 U/kg) and rFVIIa (90 µg/kg). CONCLUSIONS: These results suggest that 4F-PCC has a low thrombotic potential versus aPCC or rFVIIa, supporting the clinical use of 4F-PCC for the treatment of coagulopathy-mediated bleeding.


Assuntos
Fatores de Coagulação Sanguínea/metabolismo , Trombose/metabolismo , Animais , Artérias/efeitos dos fármacos , Artérias/patologia , Fator VIIa/farmacologia , Feminino , Hemodiluição , Coelhos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Trombose/patologia , Fatores de Tempo , Ácido Tranexâmico/farmacologia
10.
Anticancer Res ; 41(10): 5241-5247, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593477

RESUMO

AIM: To clarify the clinical and radiological features of isolated tumor thrombi in the inferior vena cava (IVC)/right atrium in patients with hepatocellular carcinoma (HCC) without hepatic vein invasion. PATIENTS AND METHODS: In this retrospective study, from January 2007 to December 2019, a total of 35,163 chemoembolization sessions were performed in 7,704 patients with HCC. Among them, 10 (0.13%) patients had tumor thrombi in the IVC/right atrium without definitive hepatic vein invasion. Computed tomographic (CT) scans, digital subtraction angiograms, and cone-beam CT images were retrospectively reviewed and interpreted. RESULTS: The tumor thrombi were supplied by the right inferior phrenic artery (n=8) or the right internal mammary artery (n=2). Follow-up CT scans in eight patients showed linear accumulation of iodized oil along the diaphragm, which was presumed to be a thrombosis of the phrenic vein. Retrospective review of formal radiological reports of pre-procedural CT scans revealed that a correct diagnosis of tumor thrombi of the IVC/right atrium was made in only three cases. CONCLUSION: HCC invading the phrenic vein may have tumor thrombi in the IVC/right atrium without hepatic vein invasion.


Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/mortalidade , Átrios do Coração/patologia , Cardiopatias/terapia , Veias Hepáticas/patologia , Trombose/terapia , Veia Cava Inferior/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/métodos , Feminino , Seguimentos , Cardiopatias/etiologia , Cardiopatias/patologia , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Trombose/etiologia , Trombose/patologia
11.
Eur Rev Med Pharmacol Sci ; 25(19): 5904-5912, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34661248

RESUMO

OBJECTIVE: Liver injury has been reported in patients with COVID-19. This condition is characterized by severe outcome and could be related with the ability of SARS-CoV-2 to activate cytotoxic T cells. The purpose of this study is to show the histological and scanning electron microscopy features of liver involvement in COVID-19 to characterize the liver changes caused by the activation of multiple molecular pathways following this infection. PATIENTS AND METHODS: Liver biopsies from 4 patients (3 post-mortems and 1 in vivo) with COVID-19 were analyzed with histology and by scanning electron microscopy. RESULTS: The liver changes showed significant heterogeneity. The first case showed ground glass hepatocytes and scattered fibrin aggregates in the sinusoidal lumen. The second evidenced intra-sinusoidal thrombi. The third was characterized by sinusoidal dilatation, atrophy of hepatocytes, Disse's spaces dilatation and intra-sinusoidal aggregates of fibrin and red blood cells. The fourth case exhibited diffuse fibrin aggregates in the dilated Disse spaces and microthrombi in the sinusoidal lumen. CONCLUSIONS: In COVID-19-related liver injury, a large spectrum of pathological changes was observed. The most peculiar features were very mild inflammation, intra-sinusoidal changes, including sinusoidal dilatation, thrombotic sinusoiditis and diffuse intra-sinusoidal fibrin deposition. These findings suggested that a thrombotic sinusoiditis followed by a local diffuse intra-vascular (intra-sinusoidal) coagulation could be the typical features of the SARS-CoV-2-related liver injury.


Assuntos
Transtornos da Coagulação Sanguínea/patologia , COVID-19/patologia , Hepatopatias/patologia , Fígado/patologia , Trombose/patologia , Idoso , Autopsia , Biópsia , Eritrócitos/patologia , Fibrina , Hepatócitos/patologia , Humanos , Masculino , Microscopia Eletrônica de Varredura , Pessoa de Meia-Idade , Trombose/complicações , Adulto Jovem
12.
Curr Gastroenterol Rep ; 23(12): 24, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34654971

RESUMO

PURPOSE OF REVIEW: Portal vein thrombosis (PVT) is a frequent consequence of cirrhosis and its management is variable and controversial. Herein we highlight interventional treatment options and outcomes, together with mention of the physiology, presentation and imaging of PVT. RECENT FINDINGS: Utilization of transjugular intrahepatic portosystemic shunt (TIPS) for acute and chronic PVT is expanding. In acute PVT, TIPS improves hepatopetal flow which promotes thrombus resorption and prevents rethrombosis. The TIPS also functions as a conduit for thrombectomy devices and allows for embolization of variceal shunts. Chronic PVT is a relative contraindication to liver transplant. Portal vein recanalization (PVR) TIPS restores flow in a previously occluded portal vein, allowing for a conventional end-to-end portal vein anastomosis at transplant. PVR TIPS is technically demanding and often requires percutaneous splenic vein access for portal venous recanalization. Selection of endovascular PVT treatment varies with the age (acute or chronic) and the extent of thrombus, along with presenting symptoms and transplant candidacy.


Assuntos
Derivação Portossistêmica Transjugular Intra-Hepática , Trombose , Humanos , Cirrose Hepática/complicações , Veia Porta , Trombose/patologia , Resultado do Tratamento
13.
Front Immunol ; 12: 735922, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34671353

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. COVID-19 is considered an airway/multi-systemic disease, and demise has been associated with an uncontrolled immune response and a cytokine storm in response to the virus. However, the lung pathology, immune response, and tissue damage associated with COVID-19 demise are poorly described and understood due to safety concerns. Using post-mortem lung tissues from uninfected and COVID-19 deadly cases as well as an unbiased combined analysis of histology, multi-viral and host markers staining, correlative microscopy, confocal, and image analysis, we identified three distinct phenotypes of COVID-19-induced lung damage. First, a COVID-19-induced hemorrhage characterized by minimal immune infiltration and large thrombus; Second, a COVID-19-induced immune infiltration with excessive immune cell infiltration but no hemorrhagic events. The third phenotype correspond to the combination of the two previous ones. We observed the loss of alveolar wall integrity, detachment of lung tissue pieces, fibroblast proliferation, and extensive fibrosis in all three phenotypes. Although lung tissues studied were from lethal COVID-19, a strong immune response was observed in all cases analyzed with significant B cell and poor T cell infiltrations, suggesting an exhausted or compromised immune cellular response in these patients. Overall, our data show that SARS-CoV-2-induced lung damage is highly heterogeneous. These individual differences need to be considered to understand the acute and long-term COVID-19 consequences.


Assuntos
COVID-19/mortalidade , COVID-19/patologia , Lesão Pulmonar/patologia , Alvéolos Pulmonares/patologia , Fibrose Pulmonar/patologia , Idoso , Idoso de 80 Anos ou mais , Autopsia , Linfócitos T CD8-Positivos/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/patologia , Células Epiteliais/patologia , Feminino , Hemorragia/patologia , Humanos , Inflamação/patologia , Pulmão/patologia , Lesão Pulmonar/virologia , Linfopenia/patologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/patologia , Neutrófilos/imunologia , SARS-CoV-2 , Trombose/patologia
14.
Clin Appl Thromb Hemost ; 27: 10760296211042940, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34693754

RESUMO

The world is in a hard battle against COVID-19. Endothelial cells are among the most critical targets of SARS-CoV-2. Dysfunction of endothelium leads to vascular injury following by coagulopathies and thrombotic conditions in the vital organs increasing the risk of life-threatening events. Growing evidences revealed that endothelial dysfunction and consequent thrombotic conditions are associated with the severity of outcomes. It is not yet fully clear that these devastating sequels originate directly from the virus or a side effect of virus-induced cytokine storm. Due to endothelial dysfunction, plasma levels of some biomarkers are changed and relevant clinical manifestations appear as well. Stabilization of endothelial integrity and supporting its function are among the promising therapeutic strategies. Other than respiratory, COVID-19 could be called a systemic vascular disease and this aspect should be scrutinized in more detail in order to reduce related mortality. In the present investigation, the effects of COVID-19 on endothelial function and thrombosis formation are discussed. In this regard, critical players, laboratory findings, clinical manifestation, and suggestive therapies are presented.


Assuntos
Coagulação Sanguínea , COVID-19/virologia , Células Endoteliais/virologia , Endotélio Vascular/virologia , SARS-CoV-2/patogenicidade , Trombose/virologia , Animais , COVID-19/sangue , COVID-19/patologia , COVID-19/fisiopatologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Interações Hospedeiro-Patógeno , Humanos , Transdução de Sinais , Trombose/sangue , Trombose/patologia , Trombose/fisiopatologia
15.
Int J Mol Sci ; 22(20)2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34681689

RESUMO

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has infected >235 million people and killed over 4.8 million individuals worldwide. Although vaccines have been developed for prophylactic management, there are no clinically proven antivirals to treat the viral infection. Continuous efforts are being made all over the world to develop effective drugs but these are being delayed by periodic outbreak of mutated SARS-CoV-2 and a lack of knowledge of molecular mechanisms underlying viral pathogenesis and post-infection complications. In this regard, the involvement of Annexin A2 (AnxA2), a lipid-raft related phospholipid-binding protein, in SARS-CoV-2 attachment, internalization, and replication has been discussed. In addition to the evidence from published literature, we have performed in silico docking of viral spike glycoprotein and RNA-dependent RNA polymerase with human AnxA2 to find the molecular interactions. Overall, this review provides the molecular insights into a potential role of AnxA2 in the SARS-CoV-2 pathogenesis and post-infection complications, especially thrombosis, cytokine storm, and insulin resistance.


Assuntos
Anexina A2/metabolismo , COVID-19/patologia , Anexina A2/química , COVID-19/virologia , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/patologia , Humanos , Simulação de Acoplamento Molecular , RNA Polimerase Dependente de RNA/química , RNA Polimerase Dependente de RNA/metabolismo , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Trombose/metabolismo , Trombose/patologia , Internalização do Vírus
16.
Int J Mol Sci ; 22(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34502228

RESUMO

Extracellular vesicles (EVs) compose a heterogenous group of membrane-derived particles, including exosomes, microvesicles and apoptotic bodies, which are released into the extracellular environment in response to proinflammatory or proapoptotic stimuli. From earlier studies suggesting that EV shedding constitutes a cellular clearance mechanism, it has become evident that EV formation, secretion and uptake represent important mechanisms of intercellular communication and exchange of a wide variety of molecules, with relevance in both physiological and pathological situations. The putative role of EVs in hemostasis and thrombosis is supported by clinical and experimental studies unraveling how these cell-derived structures affect clot formation (and resolution). From those studies, it has become clear that the prothrombotic effects of EVs are not restricted to the exposure of tissue factor (TF) and phosphatidylserines (PS), but also involve multiplication of procoagulant surfaces, cross-linking of different cellular players at the site of injury and transfer of activation signals to other cell types. Here, we summarize the existing and novel clinical and experimental evidence on the role and function of EVs during arterial and venous thrombus formation and how they may be used as biomarkers as well as therapeutic vectors.


Assuntos
Biomarcadores/metabolismo , Comunicação Celular , Vesículas Extracelulares/metabolismo , Tromboplastina/metabolismo , Trombose/patologia , Animais , Humanos , Trombose/metabolismo
17.
Int Heart J ; 62(5): 1182-1185, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34544989

RESUMO

A 20-year-old man with arrhythmogenic right ventricular cardiomyopathy (ARVC) was resuscitated from ventricular fibrillation. He was transferred to our hospital because of progressive multiorgan dysfunction despite mechanical circulatory support with peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) and intra-aortic balloon pump (IABP). At admission to our hospital, chest X-ray showed bilateral complete lung opacification, and echocardiography revealed a massive thrombus occupying the left atrium (LA) and left ventricle (LV). Conversion to central ECMO with transapical LV venting and thrombectomy were performed. The huge LA thrombus occluded all pulmonary veins (PVs). Despite the surgery and intensive care, complete lung opacity remained, and he died of multiorgan failure associated with sepsis. Autopsy demonstrated bilateral pulmonary multiple red infarctions, and histopathology showed alveolar wall necrosis with extensive hemorrhage, confirming a diagnosis of pulmonary hemorrhagic infarction. Extensive pulmonary infarction was attributable to PV occlusion due to massive LA thrombus. PV thrombosis should be considered when refractory lung opacities are encountered during VA-ECMO and necessitates early intervention.


Assuntos
Displasia Arritmogênica Ventricular Direita/complicações , Oxigenação por Membrana Extracorpórea/métodos , Insuficiência de Múltiplos Órgãos/complicações , Trombose/diagnóstico , Fibrilação Ventricular/etiologia , Autopsia/métodos , Ecocardiografia/métodos , Evolução Fatal , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/patologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Hemorragia/complicações , Hemorragia/diagnóstico , Humanos , Balão Intra-Aórtico/métodos , Masculino , Infarto Pulmonar/diagnóstico , Veias Pulmonares/diagnóstico por imagem , Veias Pulmonares/patologia , Pneumopatia Veno-Oclusiva/complicações , Pneumopatia Veno-Oclusiva/diagnóstico , Ressuscitação/métodos , Sepse/complicações , Trombectomia/métodos , Trombose/patologia , Trombose/cirurgia , Fibrilação Ventricular/terapia , Adulto Jovem
19.
Biomolecules ; 11(7)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34356618

RESUMO

The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune cells. Being part of the blood-brain barrier, endothelial cells of the brain have specialized morphology, physiology, and phenotypes due to their unique microenvironment. Known cardiovascular risk factors facilitate cerebral endothelial dysfunction, leading to impaired vasodilation, an aggravated inflammatory response, as well as increased oxidative stress and vascular proliferation. This culminates in the thrombo-inflammatory response, an underlying cause of ischemic stroke and cerebral small vessel disease (CSVD). These events are further exacerbated when blood flow is returned to the brain after a period of ischemia, a phenomenon termed ischemia-reperfusion injury. Purinergic signaling is an endogenous molecular pathway in which the enzymes CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia and CSVD, eATP is released from dying neurons as a damage molecule, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Evidently, therapies that promote adenosine generation or boost CD39 activity at the site of endothelial injury have promising benefits in the context of atherothrombotic stroke and can be extended to current CSVD known pathomechanisms. Here, we have reviewed the rationale and benefits of CD39 and CD39 therapies to treat endothelial dysfunction in the brain.


Assuntos
Trifosfato de Adenosina/metabolismo , Doenças de Pequenos Vasos Cerebrais/metabolismo , Endotélio Vascular/metabolismo , AVC Isquêmico/metabolismo , Transdução de Sinais , Trombose/metabolismo , Animais , Doenças de Pequenos Vasos Cerebrais/patologia , Endotélio Vascular/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , AVC Isquêmico/patologia , Trombose/patologia
20.
Thromb Res ; 206: 133-136, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34464871

RESUMO

Acute non-cirrhotic and non-malignant portal vein thrombosis (aPVT) is a rare and heterogenous condition. Current guidelines recommend early initiation of therapeutic anticoagulation to prevent extension of thrombosis, and favor recanalization. Although not formally defined, a poor outcome in the acute setting would include thrombosis extension with progression to intestinal infarction. Patients are also at risk of negative long-term outcomes related to complications of portal hypertension, such as variceal bleeding, ascites, and portal cholangiopathy. Identifying patients at risk of these events despite early initiation of anticoagulation remains challenging. Trials comparing treatment strategies in those failing standard therapy with meaningful radiological and clinical endpoints, whether in the short or long term, are desperately needed. The objective of this review will be to discuss a real-life clinical case and propose a treatment approach for aPVT based on the available evidence. We will mainly focus on management strategies including anticoagulation, prognostic factors, and options beyond anticoagulation, such as thrombolysis, thrombectomy, and transjugular intrahepatic portosystemic shunts. This review will not cover tumor portal vein thrombosis or thrombosis associated with cirrhosis.


Assuntos
Varizes Esofágicas e Gástricas , Trombose , Anticoagulantes/uso terapêutico , Hemorragia Gastrointestinal , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Veia Porta/patologia , Trombose/patologia , Resultado do Tratamento
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