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1.
Front Immunol ; 11: 2014, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849666

RESUMO

To date the pathophysiology of COVID-19 remains unclear: this represents a factor determining the current lack of effective treatments. In this paper, we hypothesized a complex host response to SARS-CoV-2, with the Contact System (CS) playing a pivotal role in innate immune response. CS is linked with different proteolytic defense systems operating in human vasculature: the Kallikrein-Kinin (KKS), the Coagulation/Fibrinolysis and the Renin-Angiotensin (RAS) Systems. We investigated the role of the mediators involved. CS consists of Factor XII (FXII) and plasma prekallikrein (complexed to high-molecular-weight kininogen-HK). Autoactivation of FXII by contact with SARS-CoV-2 could lead to activation of intrinsic coagulation, with fibrin formation (microthrombosis), and fibrinolysis, resulting in increased D-dimer levels. Activation of kallikrein by activated FXII leads to production of bradykinin (BK) from HK. BK binds to B2-receptors, mediating vascular permeability, vasodilation and edema. B1-receptors, binding the metabolite [des-Arg9]-BK (DABK), are up-regulated during infections and mediate lung inflammatory responses. BK could play a relevant role in COVID-19 as already described for other viral models. Angiotensin-Converting-Enzyme (ACE) 2 displays lung protective effects: it inactivates DABK and converts Angiotensin II (Ang II) into Angiotensin-(1-7) and Angiotensin I into Angiotensin-(1-9). SARS-CoV-2 binds to ACE2 for cell entry, downregulating it: an impaired DABK inactivation could lead to an enhanced activity of B1-receptors, and the accumulation of Ang II, through a negative feedback loop, may result in decreased ACE activity, with consequent increase of BK. Therapies targeting the CS, the KKS and action of BK could be effective for the treatment of COVID-19.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Fibrinólise/imunologia , Sistema Calicreína-Cinina/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Sistema Renina-Angiotensina/imunologia , Bradicinina/metabolismo , Permeabilidade Capilar , Proteína Inibidora do Complemento C1 , Infecções por Coronavirus/virologia , Fator XIIa/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Cininogênio de Alto Peso Molecular/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Calicreína Plasmática/metabolismo , Pneumonia Viral/virologia , Pré-Calicreína/metabolismo , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/metabolismo , Vasodilatação
3.
Proc Natl Acad Sci U S A ; 117(25): 14482-14492, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32518112

RESUMO

Cerebral amyloid angiopathy (CAA), where beta-amyloid (Aß) deposits around cerebral blood vessels, is a major contributor of vascular dysfunction in Alzheimer's disease (AD) patients. However, the molecular mechanism underlying CAA formation and CAA-induced cerebrovascular pathology is unclear. Hereditary cerebral amyloid angiopathy (HCAA) is a rare familial form of CAA in which mutations within the (Aß) peptide cause an increase in vascular deposits. Since the interaction between Aß and fibrinogen increases CAA and plays an important role in cerebrovascular damage in AD, we investigated the role of the Aß-fibrinogen interaction in HCAA pathology. Our work revealed the most common forms of HCAA-linked mutations, Dutch (E22Q) and Iowa (D23N), resulted in up to a 50-fold stronger binding affinity of Aß for fibrinogen. In addition, the stronger interaction between fibrinogen and mutant Aßs led to a dramatic perturbation of clot structure and delayed fibrinolysis. Immunofluorescence analysis of the occipital cortex showed an increase of fibrin(ogen)/Aß codeposition, as well as fibrin deposits in HCAA patients, compared to early-onset AD patients and nondemented individuals. Our results suggest the HCAA-type Dutch and Iowa mutations increase the interaction between fibrinogen and Aß, which might be central to cerebrovascular pathologies observed in HCAA.


Assuntos
Peptídeos beta-Amiloides/genética , Encéfalo/patologia , Angiopatia Amiloide Cerebral Familiar/patologia , Fibrina/metabolismo , Fibrinogênio/metabolismo , Fragmentos de Peptídeos/genética , Peptídeos beta-Amiloides/metabolismo , Angiopatia Amiloide Cerebral Familiar/genética , Feminino , Fibrinogênio/isolamento & purificação , Fibrinólise/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo
4.
J Trauma Acute Care Surg ; 89(1): 87-95, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32574484

RESUMO

BACKGROUND: While tissue injury provokes fibrinolysis shutdown in trauma, the mechanism remains elusive. Cellular death causes release of structural proteins, including actin and myosin, which may interact with clot formation and structure. We hypothesized that tissue injury is associated with high circulating actin and that actin produces a hypercoagulable profile with decreased fibrinolysis in vitro. METHODS: Blood was collected from trauma activation patients at a single Level I trauma center for thrombelastography and proteomics. Proteomic analyses were performed through targeted liquid chromatography coupled with mass spectrometry using isotope-labeled standards for quantification of actin and its endogenous inhibitor gelsolin. Based on the results, we added physiologic concentrations of cytoskeletal G-actin to whole blood from healthy volunteers and analyzed changes in thrombelastography, as well as to plasma and examined clot architecture using confocal microscopy of fluorescently labeled fibrinogen. RESULTS: Overall, 108 trauma patients were included: majority (71%) men, median age of 32.7 years, 66% blunt mechanism, median New Injury Severity Score (NISS) of 41. Compared with patients without severe tissue injury (NISS < 15, n = 10), patients with severe tissue injury (NISS > 15, n = 98) had higher levels of circulating actin (0.0428 vs. 0.0301, p = 0.02). Further, there was a trend toward lower gelsolin levels in patients with fibrinolysis shutdown (0.1844 vs. 0.2052, p = 0.17) and tissue plasminogen activator resistance (0.1676 vs. 0.2188, p = 0.06).Ten healthy volunteers were included in the in vitro experiments (50% male; median age, 31.3 years). Actin significantly increased angle (40.0° to 52.9°, p = 0.002) and decreased fibrinolysis (percent clot lysis 30 minutes after reaching maximum amplitude, 4.0% to 1.6%; p = 0.002), provoking fibrinolytic shutdown in three patients. The addition of actin to control plasma decreased fiber resolvability of fibrin clots, monitored by microscopy, and decreased plasmin-mediated fibrinolysis. CONCLUSION: Actin increases clot propagation and provokes fibrinolysis shutdown in vitro, through a mechanism of plasmin inhibition. High circulating levels of actin are present in trauma patients with severe tissue injury, suggesting actin contributes to fibrinolysis shutdown in the setting of tissue injury.


Assuntos
Actinas/sangue , Fibrinólise , Ferimentos e Lesões/sangue , Adulto , Cromatografia Líquida , Feminino , Gelsolina/sangue , Humanos , Técnicas In Vitro , Escala de Gravidade do Ferimento , Masculino , Espectrometria de Massas , Microscopia Confocal , Proteômica , Tromboelastografia , Centros de Traumatologia
5.
PLoS One ; 15(6): e0234844, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32579572

RESUMO

BACKGROUND: To study central hypovolemia in humans, lower body negative pressure (LBNP) is a recognized alternative to blood removal (HEM). While LBNP mimics the cardiovascular responses of HEM in baboons, similarities in hemostatic responses to LBNP and HEM remain unknown in this species. METHODS: Thirteen anesthetized baboons were exposed to progressive hypovolemia by HEM and, four weeks later, by LBNP. Hemostatic activity was evaluated by plasma markers, thromboelastography (TEG), flow cytometry, and platelet aggregometry at baseline (BL), during and after hypovolemia. RESULTS: BL values were indistinguishable for most parameters although platelet count, maximal clot strength (MA), protein C, thrombin anti-thrombin complex (TAT), thrombin activatable fibrinolysis inhibitor (TAFI) activity significantly differed between HEM and LBNP. Central hypovolemia induced by either method activated coagulation; TEG R-time decreased and MA increased during and after hypovolemia compared to BL. Platelets displayed activation by flow cytometry; platelet count and functional aggregometry were unchanged. TAFI activity and protein, Factors V and VIII, vWF, Proteins C and S all demonstrated hemodilution during HEM and hemoconcentration during LBNP, whereas tissue plasminogen activator (tPA), plasmin/anti-plasmin complex, and plasminogen activator inhibitor-1 did not. Fibrinolysis (TEG LY30) was unchanged by either method; however, at BL, fibrinolysis varied greatly. Post-hoc analysis separated baboons into low-lysis (LY30 <2%) or high-lysis (LY30 >2%) whose fibrinolytic state matched at both HEM and LBNP BL. In high-lysis, BL tPA and LY30 correlated strongly (r = 0.95; P<0.001), but this was absent in low-lysis. In low-lysis, BL TAFI activity and tPA correlated (r = 0.88; P<0.050), but this was absent in high-lysis. CONCLUSIONS: Central hypovolemia induced by either LBNP or HEM resulted in activation of coagulation; thus, LBNP is an adjunct to study hemorrhage-induced pro-coagulation in baboons. Furthermore, this study revealed a subset of baboons with baseline hyperfibrinolysis, which was strongly coupled to tPA and uncoupled from TAFI activity.


Assuntos
Fibrinólise , Hemorragia/complicações , Hemostasia , Hipovolemia/tratamento farmacológico , Hipovolemia/fisiopatologia , Pressão Negativa da Região Corporal Inferior/efeitos adversos , Animais , Masculino , Papio
8.
Thromb Haemost ; 120(5): 758-767, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32369847

RESUMO

BACKGROUND: Ligneous conjunctivitis (LC) is a rare disorder associated with plasminogen deficiency characterized by chronic fibrin deposits in the eyelids. All patients with plasminogen deficiency do not develop LC, whose underlying mechanisms remain unknown. OBJECTIVE: We investigated whether fibrinolytic activity was correlated with phenotype and/or genotype in patients suffering from LC and their relatives. METHODS: Plasminogen activity/antigen levels and PLG mutations were determined in 10 patients with LC, 17 of their asymptomatic relatives, and 10 healthy individuals used as a control group. Plasma fibrinolytic activity was evaluated using three different assays: (1) tissue-plasminogen activator (t-PA) front lysis, (2) cell-based urokinase-dependent euglobulin clot lysis (ECLT) at the surface of corneal cells, and (3) urokinase-dependent plasminogen activation. RESULTS: Plasminogen activity varied from <10 to 40% in patients, 36 to 105% in relatives, and >80% in control healthy individuals. Homozygous K19E mutation was associated with normal antigenic plasminogen levels. In front-lysis experiments, all patients had a lower fibrinolysis rate as compared with their relatives and to control individuals. The cell-based ECLT and plasminogen activation assay demonstrated that urokinase-mediated fibrinolysis was not impaired in patients with homozygous K19E mutation compared with the other mutants. CONCLUSION: We confirm that plasminogen levels fail to predict LC occurrence. In these conditions, t-PA clot lysis front is useful to predict clinical outcome in plasminogen deficiency. Moreover, we provide evidence that occurrence of LC overlaps quantitative and qualitative plasminogen deficiencies. The homozygous K19E mutation is associated with isolated impaired t-PA-mediated fibrinolysis compared with other mutants.


Assuntos
Testes de Coagulação Sanguínea , Conjuntivite/diagnóstico , Olho/metabolismo , Fibrina/metabolismo , Fibrinólise , Plasminogênio/deficiência , Dermatopatias Genéticas/diagnóstico , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Conjuntivite/genética , Conjuntivite/metabolismo , Feminino , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Homozigoto , Humanos , Cinética , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Plasminogênio/genética , Plasminogênio/metabolismo , Valor Preditivo dos Testes , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/metabolismo , Ativador de Plasminogênio Tecidual/metabolismo , Adulto Jovem
9.
PLoS One ; 15(5): e0233640, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32453766

RESUMO

Understanding the coagulation process is critical to developing treatments for trauma and coagulopathies. Clinical studies on tranexamic acid (TXA) have resulted in mixed reports on its efficacy in improving outcomes in trauma patients. The largest study, CRASH-2, reported that TXA improved outcomes in patients who received treatment prior to 3 hours after the injury, but worsened outcomes in patients who received treatment after 3 hours. No consensus has been reached about the mechanism behind the duality of these results. In this paper we use a computational model for coagulation and fibrinolysis to propose that deficiencies or depletions of key anti-fibrinolytic proteins, specifically antiplasmin, a1-antitrypsin and a2-macroglobulin, can lead to worsened outcomes through urokinase-mediated hyperfibrinolysis.


Assuntos
Transtornos da Coagulação Sanguínea/tratamento farmacológico , Ácido Tranexâmico/uso terapêutico , Ativador de Plasminogênio Tipo Uroquinase/genética , Ferimentos e Lesões/tratamento farmacológico , Antifibrinolíticos/uso terapêutico , Coagulação Sanguínea/genética , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/genética , Transtornos da Coagulação Sanguínea/patologia , Simulação por Computador , Fibrina/genética , Tempo de Lise do Coágulo de Fibrina , Fibrinolisina/genética , Fibrinólise/efeitos dos fármacos , Hemorragia/sangue , Hemorragia/tratamento farmacológico , Hemorragia/genética , Humanos , Proteínas de Membrana/genética , Mortalidade , alfa 2-Macroglobulinas Associadas à Gravidez/genética , Trombina/genética , Trombina/metabolismo , Ferimentos e Lesões/sangue , Ferimentos e Lesões/genética , Ferimentos e Lesões/patologia , alfa 1-Antitripsina/genética
10.
J Am Coll Surg ; 231(2): 193-203.e1, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32422349

RESUMO

BACKGROUND: COVID-19 predisposes patients to a prothrombotic state with demonstrated microvascular involvement. The degree of hypercoagulability appears to correlate with outcomes; however, optimal criteria to assess for the highest-risk patients for thrombotic events remain unclear; we hypothesized that deranged thromboelastography measurements of coagulation would correlate with thromboembolic events. STUDY DESIGN: Patients admitted to an ICU with COVID-19 diagnoses who had thromboelastography analyses performed were studied. Conventional coagulation assays, d-dimer levels, and viscoelastic measurements were analyzed using a receiver operating characteristic curve to predict thromboembolic outcomes and new-onset renal failure. RESULTS: Forty-four patients with COVID-19 were included in the analysis. Derangements in coagulation laboratory values, including elevated d-dimer, fibrinogen, prothrombin time, and partial thromboplastin time, were confirmed; viscoelastic measurements showed an elevated maximum amplitude and low lysis of clot at 30 minutes. A complete lack of lysis of clot at 30 minutes was seen in 57% of patients and predicted venous thromboembolic events with an area under the receiver operating characteristic curve of 0.742 (p = 0.021). A d-dimer cutoff of 2,600 ng/mL predicted need for dialysis with an area under the receiver operating characteristic curve of 0.779 (p = 0.005). Overall, patients with no lysis of clot at 30 minutes and a d-dimer > 2,600 ng/mL had a venous thromboembolic event rate of 50% compared with 0% for patients with neither risk factor (p = 0.008), and had a hemodialysis rate of 80% compared with 14% (p = 0.004). CONCLUSIONS: Fibrinolysis shutdown, as evidenced by elevated d-dimer and complete failure of clot lysis at 30 minutes on thromboelastography predicts thromboembolic events and need for hemodialysis in critically ill patients with COVID-19. Additional clinical trials are required to ascertain the need for early therapeutic anticoagulation or fibrinolytic therapy to address this state of fibrinolysis shutdown.


Assuntos
Testes de Coagulação Sanguínea , Infecções por Coronavirus/sangue , Fibrinólise/fisiologia , Pneumonia Viral/sangue , Tromboembolia/sangue , Tromboembolia/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Feminino , Tempo de Lise do Coágulo de Fibrina , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pandemias , Tempo de Tromboplastina Parcial , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Diálise Renal , Fatores de Risco , Tromboelastografia , Tromboembolia/fisiopatologia , Tromboembolia/terapia
11.
Lab Invest ; 100(6): 794-800, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-143924

RESUMO

Timely analysis of the laboratory characteristics associated with 2019 novel coronavirus pneumonia (COVID-19) can assist with clinical diagnosis and prognosis. This study is a collection of clinical data from 54 hospitalized adult patients diagnosed with COVID-19 in the Zhongfa Xincheng district of China at Tongji Hospital of Huazhong University of Science and Technology from January 28, 2020 to February 11, 2020. The average age of the patients was 61.8 ± 14.5 years, and the predominant age group was 50-79. The proportion of critical-type patients with comorbidities was higher than that of severe-type patients. Lymphocyte counts were significantly reduced in routine bloodwork for all patients, but significantly lower in critical-type patients than that in severe-type patients. Prolongation of prothrombin times (PT) and elevation of fibrinogen degradation products (FDPs) and D-dimers (D-Ds) were detected in coagulation function tests, and more significant changes were observed in critical-type patients compared to severe-type patients. Serum ferritin levels were sensitive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but could not be used for disease assessment. In addition, levels of two inflammatory factors, soluble interleukin-2 receptor (sIL-2R) and interleukin-6 (IL-6) were significantly increased in all patients, but higher in critical-type patients than in severe-type patients. Moreover, kidney injury was the second-most common organ affected by COVID-19 followed by heart and liver. Kidney and heart injury were more severe in critical-type patients than in severe-type patients. All of the 31 severe-type patients recovered. Of the critical-type patients, six died and 17 recovered. The length of hospital stay for critical-type patients was significantly longer for severe-type patients. In summary, increased lymphocyte counts, prolonged PT, secondary increases in fibrinolytic activity and increases in sIL-2R and IL-6 are typical features of COVID-19 and are associated with disease severity.


Assuntos
Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Comorbidade , Infecções por Coronavirus/diagnóstico , Feminino , Ferritinas/sangue , Fibrinólise , Cardiopatias/virologia , Humanos , Interleucina-6/sangue , Nefropatias/virologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Receptores de Interleucina-2/sangue , Estudos Retrospectivos , Adulto Jovem
12.
J Thromb Haemost ; 18(7): 1752-1755, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32267998

RESUMO

A prothrombotic coagulopathy is commonly found in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). A unique feature of COVID-19 respiratory failure is a relatively preserved lung compliance and high Alveolar-arterial oxygen gradient, with pathology reports consistently demonstrating diffuse pulmonary microthrombi on autopsy, all consistent with a vascular occlusive etiology of respiratory failure rather than the more classic findings of low-compliance in ARDS. The COVID-19 pandemic is overwhelming the world's medical care capacity with unprecedented needs for mechanical ventilators and high rates of mortality once patients progress to needing mechanical ventilation, and in many environments including in parts of the United States the medical capacity is being exhausted. Fibrinolytic therapy has previously been used in a Phase 1 clinical trial that led to reduced mortality and marked improvements in oxygenation. Here we report a series of three patients with severe COVID-19 respiratory failure who were treated with tissue plasminogen activator. All three patients had a temporally related improvement in their respiratory status, with one of them being a durable response.


Assuntos
Betacoronavirus/patogenicidade , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Fibrinólise/efeitos dos fármacos , Fibrinolíticos/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/administração & dosagem , Idoso , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/virologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Evolução Fatal , Feminino , Fibrinolíticos/efeitos adversos , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Recuperação de Função Fisiológica , Terapia Trombolítica/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do Tratamento
13.
Lab Invest ; 100(6): 794-800, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32341519

RESUMO

Timely analysis of the laboratory characteristics associated with 2019 novel coronavirus pneumonia (COVID-19) can assist with clinical diagnosis and prognosis. This study is a collection of clinical data from 54 hospitalized adult patients diagnosed with COVID-19 in the Zhongfa Xincheng district of China at Tongji Hospital of Huazhong University of Science and Technology from January 28, 2020 to February 11, 2020. The average age of the patients was 61.8 ± 14.5 years, and the predominant age group was 50-79. The proportion of critical-type patients with comorbidities was higher than that of severe-type patients. Lymphocyte counts were significantly reduced in routine bloodwork for all patients, but significantly lower in critical-type patients than that in severe-type patients. Prolongation of prothrombin times (PT) and elevation of fibrinogen degradation products (FDPs) and D-dimers (D-Ds) were detected in coagulation function tests, and more significant changes were observed in critical-type patients compared to severe-type patients. Serum ferritin levels were sensitive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but could not be used for disease assessment. In addition, levels of two inflammatory factors, soluble interleukin-2 receptor (sIL-2R) and interleukin-6 (IL-6) were significantly increased in all patients, but higher in critical-type patients than in severe-type patients. Moreover, kidney injury was the second-most common organ affected by COVID-19 followed by heart and liver. Kidney and heart injury were more severe in critical-type patients than in severe-type patients. All of the 31 severe-type patients recovered. Of the critical-type patients, six died and 17 recovered. The length of hospital stay for critical-type patients was significantly longer for severe-type patients. In summary, increased lymphocyte counts, prolonged PT, secondary increases in fibrinolytic activity and increases in sIL-2R and IL-6 are typical features of COVID-19 and are associated with disease severity.


Assuntos
Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Comorbidade , Infecções por Coronavirus/diagnóstico , Feminino , Ferritinas/sangue , Fibrinólise , Cardiopatias/virologia , Humanos , Interleucina-6/sangue , Nefropatias/virologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Receptores de Interleucina-2/sangue , Estudos Retrospectivos , Adulto Jovem
14.
J Thromb Haemost ; 18(7): 1548-1555, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32329246

RESUMO

The global pandemic of coronavirus disease 2019 (COVID-19) is associated with the development of acute respiratory distress syndrome (ARDS), which requires ventilation in critically ill patients. The pathophysiology of ARDS results from acute inflammation within the alveolar space and prevention of normal gas exchange. The increase in proinflammatory cytokines within the lung leads to recruitment of leukocytes, further propagating the local inflammatory response. A consistent finding in ARDS is the deposition of fibrin in the air spaces and lung parenchyma. COVID-19 patients show elevated D-dimers and fibrinogen. Fibrin deposits are found in the lungs of patients due to the dysregulation of the coagulation and fibrinolytic systems. Tissue factor (TF) is exposed on damaged alveolar endothelial cells and on the surface of leukocytes promoting fibrin deposition, while significantly elevated levels of plasminogen activator inhibitor 1 (PAI-1) from lung epithelium and endothelial cells create a hypofibrinolytic state. Prophylaxis treatment of COVID-19 patients with low molecular weight heparin (LMWH) is important to limit coagulopathy. However, to degrade pre-existing fibrin in the lung it is essential to promote local fibrinolysis. In this review, we discuss the repurposing of fibrinolytic drugs, namely tissue-type plasminogen activator (tPA), to treat COVID-19 associated ARDS. tPA is an approved intravenous thrombolytic treatment, and the nebulizer form has been shown to be effective in plastic bronchitis and is currently in Phase II clinical trial. Nebulizer plasminogen activators may provide a targeted approach in COVID-19 patients to degrade fibrin and improving oxygenation in critically ill patients.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Fibrinólise/efeitos dos fármacos , Fibrinolíticos/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/administração & dosagem , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos , Fibrinolíticos/efeitos adversos , Interações Hospedeiro-Patógeno , Humanos , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Terapia Trombolítica/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do Tratamento
15.
Anesth Analg ; 130(6): 1594-1604, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32224832

RESUMO

Bleeding and coagulation management are essential aspects in the management of neonates and children undergoing cardiac surgery. The use of point-of-care tests (POCTs) in a pediatric setting is not as widely used as in the adult setting. This systematic review aims to summarize the evidence showed by the literature regarding the use of POCTs in children undergoing cardiac surgery. We included all studies examining the pediatric population (<18 years old) undergoing cardiac surgery in which the coagulation profile was assessed with POCTs. Three electronic databases (PubMed, Embase, and the Cochrane Controlled Clinical Trials register) were searched. Tests involved were heparin effect tests, viscoelastic tests, and platelet function tests. Due to the wide heterogeneity of the patients and tests studied, a formal meta-analysis was impossible, and the results are therefore presented through a systematic review. Eighty articles were found, of which 47 are presented in this review. At present, literature data are too weak to define POCTs as a "gold standard" for the treatment of perioperative bleeding in pediatric cardiac surgery. Nevertheless, introduction of POCTs into postoperative algorithms has shown to improve bleeding management, patient outcome, and cost efficiency.


Assuntos
Anticoagulantes/uso terapêutico , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Testes Imediatos , Hemorragia Pós-Operatória/prevenção & controle , Adolescente , Algoritmos , Coagulação Sanguínea/efeitos dos fármacos , Testes de Coagulação Sanguínea , Perda Sanguínea Cirúrgica , Criança , Pré-Escolar , Cianose/complicações , Elasticidade , Fibrinólise , Heparina/química , Heparina/uso terapêutico , Humanos , Lactente , Recém-Nascido , Testes de Função Plaquetária , Hemorragia Pós-Operatória/sangue , Tromboelastografia , Viscosidade
16.
Tohoku J Exp Med ; 250(2): 121-128, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32115494

RESUMO

The fibrinolytic system plays an important role in breast cancer, favoring progression through extracellular-matrix degradation, angiogenesis, apoptosis and cellular proliferation. The expression of urokinase-type plasminogen activator (uPA) in breast cancer tissue is widely recognized as an unfavorable prognostic factor. However, fibrinolytic activity associated with uPA cannot be reliably measured in the blood because of the rapid inhibition of uPA by plasminogen activator inhibitor-1 (PAI-1). By contrast, circulating microvesicles (Mvs) in peripheral blood protect bound enzymes from inhibition. Mvs are extracellular vesicles, released from various types of cells, and their size fluctuates between 100 and 1,000 nm. Mvs carry DNA, RNA, miRNA, and proteins, thereby serving as a source of horizontal communication between cells. We investigated whether fibrinolytic activity on circulating Mvs reflects breast cancer progression. The study population consisted of 13 patients with breast cancer and 13 healthy women. The cancer patients included 4 patients in remission, 3 patients with locally advanced cancer, and 6 with metastatic disease. Mvs were isolated from peripheral blood, quantified by a protein concentration method, and their fibrinolytic potential was measured by their capacity to generate plasmin. Although the quantity of Mvs found in patients with cancer and healthy individuals was similar, plasmin generated on Mvs was twice the amount in patients with metastasis than in healthy women (P < 0.05), underlying the value of this distinctive parameter. The data suggest that in breast cancer patients, higher fibrinolytic activity of circulating Mvs could be related to progression and metastasis of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Micropartículas Derivadas de Células/metabolismo , Progressão da Doença , Fibrinólise , Adulto , Neoplasias da Mama/tratamento farmacológico , Feminino , Fibrinolisina/metabolismo , Fluorescência , Humanos , Pessoa de Meia-Idade , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
17.
Prague Med Rep ; 121(1): 42-48, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32191619

RESUMO

A male patient with a history of immobilization due to motor weakness, was transferred to our emergency department after syncope during physiotherapy, with recorded hypotension. Transthoracic echocardiography showed severe dilatation of the right ventricle (RV), with apex hypercontractility and almost akinetic RV free wall. The above findings, in addition to the unexpected visualization of a large, free-floating, right atrial thrombus, a rare finding associated with high mortality, readily confirmed the clinical suspicion of acute pulmonary embolism (PE) causing circulatory collapse. Intravenous fibrinolysis and vasopressor therapy were successfully administered, and hemodynamic instability was soon alleviated.


Assuntos
Cardiopatias , Embolia Pulmonar , Trombose , Ecocardiografia , Fibrinólise , Humanos , Masculino , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/tratamento farmacológico
18.
Int J Nanomedicine ; 15: 1549-1568, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32210551

RESUMO

Background: Thrombotic events continue to be a major cause of morbidity and mortality worldwide. Tissue plasminogen activator (tPA) is used for the treatment of acute ischemic stroke and other thrombotic disorders. Use of tPA is limited by its narrow therapeutic time window, hemorrhagic complications, and insufficient delivery to the location of the thrombus. Magnetic nanoparticles (MNPs) have been proposed for targeting tPA delivery. It would be advantageous to develop an improved in vitro model of clot formation, to screen thrombolytic therapies that could be enhanced by addition of MNPs, and to test magnetic drug targeting at human-sized distances. Methods: We utilized commercially available blood and endothelial cells to construct 1/8th inch (and larger) biomimetic vascular channels in acrylic trays. MNP clusters were moved at a distance by a rotating permanent magnet and moved along the channels by surface walking. The effect of different transport media on MNP velocity was studied using video photography. MNPs with and without tPA were analyzed to determine their velocities in the channels, and their fibrinolytic effect in wells and the trays. Results: MNP clusters could be moved through fluids including blood, at human-sized distances, down straight or branched channels, using the rotating permanent magnet. The greatest MNP velocity was closest to the magnet: 0.76 ± 0.03 cm/sec. In serum, the average MNP velocity was 0.10 ± 0.02 cm/sec. MNPs were found to enhance tPA delivery, and cause fibrinolysis in both static and dynamic studies. Fibrinolysis was observed to occur in 85% of the dynamic MNP + tPA experiments. Conclusion: MNPs hold great promise for use in augmenting delivery of tPA for the treatment of stroke and other thrombotic conditions. This model system facilitates side by side comparisons of MNP-facilitated drug delivery, at a human scale.


Assuntos
Biomimética/métodos , Fibrinolíticos/farmacocinética , Nanopartículas de Magnetita/análise , Ativador de Plasminogênio Tecidual/administração & dosagem , Animais , Biomimética/instrumentação , Sistemas de Liberação de Medicamentos , Células Endoteliais/efeitos dos fármacos , Desenho de Equipamento , Fibrinólise/efeitos dos fármacos , Fibrinolíticos/administração & dosagem , Nanopartículas de Magnetita/administração & dosagem , Coelhos , Trombose/tratamento farmacológico , Gravação em Vídeo
19.
Int J Hematol ; 111(4): 550-558, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31897889

RESUMO

Abnormal bleeding is sometimes observed in patients with immunoglobulin light chain (AL) amyloidosis. Although several theories have been proposed regarding the pathological causes of the bleeding tendency in AL amyloidosis, many lacked sufficient evidence and full consensus. We conducted a retrospective survey at a single institution to assess bleeding manifestations, methods for evaluating hematological abnormalities, and treatments for bleeding in patients with systemic AL amyloidosis over the past 13 years. The participants were 10 men and 14 women, aged 39-84 years (mean 65 years). The prevalence of bleeding was 29%. Prolonged prothrombin time (PT), elevated plasmin-α2-antiplasmin complex, and factor X deficiency were distinctive to the bleeding group. Two case studies showed that tranexamic acid was effective for treating this hematological condition. However, two patients with normal PT and activated partial thromboplastin time (APTT) also had a bleeding manifestation. The rates of administration of coagulation and fibrinolytic tests were relatively low in the non-bleeding group. Therefore, a close investigation concerning coagulation and fibrinolysis should be performed in every patient with AL amyloidosis regardless of the PT/APTT values. A more careful, comprehensive, and large-scale study is required to reinforce these findings.


Assuntos
Coagulação Sanguínea , Fibrinólise , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Amiloidose de Cadeia Leve de Imunoglobulina/sangue , Ácido Tranexâmico/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/complicações , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
20.
Plast Reconstr Surg ; 145(2): 392-401, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31985629

RESUMO

BACKGROUND: Sequential compression devices are often considered a mainstay of prophylaxis against deep venous thromboses in surgical patients. The devices are believed to produce a milking action on the deep veins to prevent venous stasis. A systemic fibrinolytic effect has also been proposed, adding a second mechanism of action. The plasma levels of tissue plasminogen activator and plasminogen activator inhibitor-1 reflect fibrinolytic activity. METHODS: A randomized trial was conducted among 50 consecutive plastic surgery outpatients undergoing cosmetic surgery performed by the author under total intravenous anesthesia and without paralysis. Patients were randomized to receive calf-length sequential compression devices or no sequential compression devices during surgery. Blood samples were obtained from the upper extremity preoperatively and at hourly intervals until the patient was discharged from the postanesthesia care unit. Tissue plasminogen activator and plasminogen activator inhibitor-1 levels were measured. Ultrasound surveillance was used in all patients. There was no outside funding for the study. RESULTS: All patients agreed to participate (inclusion rate, 100 percent). No patient developed clinical signs or ultrasound evidence of a deep venous thrombosis. There were no significant changes in tissue plasminogen activator levels or plasminogen activator inhibitor-1 levels from the preoperative measurements at any hourly interval and no differences in levels comparing patients treated with or without sequential compression devices. CONCLUSIONS: No significant change in systemic fibrinolytic activity occurs during outpatient plastic surgery under total intravenous anesthesia. Sequential compression devices do not affect tissue plasminogen activator or plasminogen activator inhibitor-1 levels, suggesting no fibrinolytic benefit. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.


Assuntos
Fibrinólise/fisiologia , Dispositivos de Compressão Pneumática Intermitente , Adulto , Idoso , Técnicas Cosméticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Inativadores de Plasminogênio/metabolismo , Estudos Prospectivos , Procedimentos Cirúrgicos Reconstrutivos/métodos , Ativador de Plasminogênio Tecidual/metabolismo , Trombose Venosa/sangue , Trombose Venosa/prevenção & controle , Adulto Jovem
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