Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.473
Filtrar
1.
Medicine (Baltimore) ; 98(39): e17130, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574813

RESUMO

Animal studies have demonstrated that autophagy was involved in neuronal damage after intracerebral hemorrhage (ICH). Several studies showed thrombin-antithrombin (TAT) plasma levels were elevated in patients with ICH. In this study, we aimed to evaluate if autophagy occurred in patients with ICH; and the relationship between the severity of brain injury and plasma TAT levels.A novel tissue harvesting device was used during hematoma removal surgery to collect loose fragments of tissue surrounding the affected brain area in 27 ICH patients with hematoma volumes of >30 mL in the basal ganglia. Control tissues were obtained from patients who underwent surgery for arteriovenous malformation (n = 25). Transmission electron microscopy (TEM) and immunohistochemistry for autophagy-related proteins were used to evaluate the ultrastructural and morphologic cellular characteristics; and the extent of autophagy in the recovered tissue specimens. Stroke severity was assessed by using the Glasgow Coma Scale (GCS) and the National Institutes of Health Stroke Scale (NIHSS). An enzyme-linked immunosorbent assay (ELISA) was used to measure plasma TAT levels.Transmission electron microscopy showed autophagosomes and autolysosomes exist in neurons surrounding the hematoma, but not in the control tissues. The number of cells containing autophagic vacuoles correlated with the severity of brain injury. Immunohistochemistry showed strong LC3, beclin 1, and cathepsin D staining in ICH tissue specimens. Plasma TAT levels correlated positively with autophagic cells and ICH severity (P < .01).Autophagy was induced in perihematomal neurons after ICH. Autophagy and plasma TAT levels correlated positively with severity of brain injury. These results suggest that autophagy and increased plasma TAT levels may contribute to the secondary damage in ICH patients.


Assuntos
Autofagia , Hemorragia Cerebral/sangue , Hematoma/sangue , Neurônios/fisiologia , Peptídeo Hidrolases/sangue , Adulto , Idoso , Antitrombina III , Gânglios da Base/metabolismo , Hemorragia Cerebral/fisiopatologia , Hemorragia Cerebral/cirurgia , Feminino , Escala de Coma de Glasgow , Hematoma/fisiopatologia , Hematoma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade
2.
Geriatr Gerontol Int ; 19(8): 804-808, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31264332

RESUMO

AIM: This study aimed to examine the relationship between blood coagulability and sense of burden among caregivers of patients with senile dementia of the Alzheimer type. METHODS: A cross-sectional study was carried out involving healthy older caregivers who lived with their patients with senile dementia of the Alzheimer type. We evaluated the Zarit Burden Interview score, levels of von Willebrand factor antigen, D-dimer, thrombin-antithrombin III complex, tissue plasminogen activator/plasminogen activator inhibitor type 1 complex, number of chronic diseases, body mass index and number of medications. A linear regression model was used to estimate adjusted associations. RESULTS: Thrombin-antithrombin III complex levels were higher in female caregivers than in male caregivers (P = 0.07). Headaches were significantly more frequent in female caregivers than in male caregivers, as assessed by a visual analog scale (P < 0.01). The number of chronic diseases and body mass index were positively associated with levels of tissue plasminogen activator/plasminogen activator inhibitor type 1 complex (P < 0.05). Similarly, the number of medications was positively associated with levels of D-dimer (P < 0.05). However, the Zarit Burden Interview score was not associated with blood coagulability (P > 0.05). CONCLUSIONS: The present study found that the number of chronic diseases and body mass index were associated with blood coagulability, and that female caregivers were more prone to headaches and higher blood coagulability than male caregivers. These findings highlight the essential nature of health management during caregiving. The impact of caregiver burden on blood coagulability is likely to differ depending on the long-term or short-term psychological stress associated with caregiving conditions. Geriatr Gerontol Int 2019; 19: 804-808.


Assuntos
Doença de Alzheimer , Cuidadores , Doença Crônica/epidemiologia , Fadiga por Compaixão , Transtornos da Cefaleia , Peptídeo Hidrolases/sangue , Estresse Psicológico , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Antitrombina III , Coagulação Sanguínea , Índice de Massa Corporal , Cuidadores/psicologia , Cuidadores/estatística & dados numéricos , Fadiga por Compaixão/sangue , Fadiga por Compaixão/diagnóstico , Fadiga por Compaixão/etiologia , Fadiga por Compaixão/psicologia , Efeitos Psicossociais da Doença , Estudos Transversais , Feminino , Transtornos da Cefaleia/diagnóstico , Transtornos da Cefaleia/epidemiologia , Humanos , Japão/epidemiologia , Masculino , Fatores Sexuais , Estresse Psicológico/sangue , Estresse Psicológico/diagnóstico , Estresse Psicológico/etiologia , Escala Visual Analógica
3.
J Clin Lab Anal ; 33(6): e22913, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31090232

RESUMO

BACKGROUND: To conduct a comprehensive performance evaluation of a fully automated analyzer for measuring thrombomodulin (TM), thrombin-antithrombin complex (TAT), plasmin-α2-antiplasmin complex (PAP), and t-PA: PAI-1 complex (tPAI-C). METHODS: According to the Clinical and Laboratory Standards Institute (CLSI) EP05-A2, EP06-A specifications, TM, TAT, PAP, and tPAI-C were analyzed to evaluate intraassay variability and interassay variability, linear range, carryover rate, reference range, sample stability, and interferences. RESULTS: The intraassay variability and interassay variability of the four factors were all below 5%. The carryover rates were below 1%. Linear verification analysis revealed correlation coefficients of 0.998-0.999. The recommended reference ranges of TM, TAT, and PAP were appropriate for our laboratory, whereas the reference of tPAI-C should be established by each laboratory. Stability assessment revealed that TM is stable for 2 days at room temperature but lacks stability at colder temperatures. In contrast, TAT is stable for 5 days at 4°C and -20°C but has poor stability at room temperature. PAP and tPAI-C are stable for 3 days at all three temperatures. The measurement of TM, TAT, PAP, and tPAI-C is not altered by the presence of 510 mg/dL hemoglobin, 1490 FTU triglycerides, or 21.1 mg/dL conjugated and free bilirubin. CONCLUSION: The determination of TM, TAT, PAP, and tPAI-C using a high-sensitivity chemiluminescence analyzer performs well in terms of precision, carryover rate, linear range, and interference. Thus, this method is suitable for the detection of these substances in clinical specimens.


Assuntos
Análise Química do Sangue/instrumentação , Fibrinolisina/análise , Peptídeo Hidrolases/sangue , Inibidor 1 de Ativador de Plasminogênio/sangue , Trombomodulina/sangue , Ativador de Plasminogênio Tecidual/sangue , alfa 2-Antiplasmina/análise , Antitrombina III , Automação , Análise Química do Sangue/métodos , Calibragem , Humanos , Medições Luminescentes/instrumentação , Medições Luminescentes/métodos , Valores de Referência
4.
Intern Emerg Med ; 14(3): 459-466, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30535649

RESUMO

To evaluate if the assessment of coagulation abnormalities at ED admission could improve prognostic assessment of septic patients. This report utilizes a portion of the data collected in a prospective study, with the aim to identify reliable biomarkers for an early sepsis diagnosis. In the period November 2011-December 2016, we enrolled 268 patients, admitted to our High-Dependency Unit with a diagnosis severe sepsis/septic shock. Study-related blood samplings were performed at ED-HDU admission (T0), after 6 h (T6) and 24 h (T24): D-dimer, thrombin-antithrombin complex (TAT) and prothrombin fragment F1 + 2 levels were analyzed. The primary end-points were day-7 and in-hospital mortality. Day-7 mortality rate was 16%. D-dimer (T0: 4661 ± 4562 µg/ml vs 3190 ± 7188 µg/ml; T6: 4498 ± 4931 µg/ml vs 2822 ± 5623 µg/ml; T24 2905 ± 2823 µg/ml vs 2465 ± 4988 µg/ml, all p < 0.05) and TAT levels (T0 29 ± 45 vs 22 ± 83; T6 21 ± 22 vs 15 ± 35; T24 16 ± 19 vs 13 ± 30, all p < 0.05) were higher among non-survivors compared to survivors. We defined an abnormal coagulation activation (COAG+) as D-dimer > 500 µg/ml and TAT > 8 ng/ml (for both, twice the upper normal value). Compared to COAG-, COAG+ patients showed higher lactate levels at the earliest evaluations (T0: 3.3 ± 2.7 vs 2.5 ± 2.3, p = 0.041; T6: 2.8 ± 3.4 vs 1.8 ± 1.6, p = 0.015); SOFA score was higher after 24 h (T24: 6.7 ± 3.1 vs 5.4 ± 2.9, p = 0.008). At T0, COAG+ patients showed a higher day-7 mortality rate (HR 2.64; 95% CI 1.14-6.11, p = 0.023), after adjustment for SOFA score and lactate level. Presence of abnormal coagulation at ED admission shows an independent association with an increased short-term mortality rate.


Assuntos
Transtornos da Coagulação Sanguínea/etiologia , Valor Preditivo dos Testes , Sepse/complicações , Idoso , Idoso de 80 Anos ou mais , Antitrombina III/análise , Biomarcadores/análise , Biomarcadores/sangue , Serviço Hospitalar de Emergência/organização & administração , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Peptídeo Hidrolases/análise , Peptídeo Hidrolases/sangue , Prognóstico , Estudos Prospectivos
5.
Thromb Res ; 173: 20-26, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30458338

RESUMO

BACKGROUND: Accurate and early diagnosis is important in the management of disseminated intravascular coagulation (DIC). We employed new automation technology to detect plasma biomarkers, including thrombin-antithrombin complex (TAT), α2-plasmininhibitor-plasmin complex (PIC), soluble thrombomodulin (sTM), and tissue plasminogen activator-inhibitor complex (tPAIC), and evaluated their diagnostic performance and prognostic value for DIC in Chinese population. METHODS: This prospective observational study included 444 patients with suspected DIC and 137 healthy people. The molecular markers were measured by qualitative chemiluminescence enzyme immunoassay performed on HISCL automated analyzers. All patients with suspected DIC were followed for 7 days to screen for the development of overt-DIC and 28 days for mortality. RESULTS: According to the International Society of Thrombosis and Haemostasis (ISTH) scoring system, 157 patients were diagnosed as overt-DIC and 36 were diagnosed as pre-DIC. All four biomarkers were significantly higher in DIC patients than in non-overt DIC patients; TAT, tPAIC, and sTM were significantly higher in pre-DIC patients than in non-overt DIC patients. Four molecular markers behaved differently among various underlying diseases. TAT, tPAIC, and sTM were also good predictors of 28-day mortality, high levels were associated with poor outcomes. CONCLUSIONS: TAT, PIC, tPAIC, and sTM demonstrated good diagnostic performance and prognostic value in DIC patients with different underlying diseases. Besides, TAT, tPAIC and sTM have certain implications in pre-DIC stage. Combination of four makers was demonstrated better behavior than single one.


Assuntos
Coagulação Intravascular Disseminada/sangue , Fibrinolisina/análise , Peptídeo Hidrolases/sangue , Trombomodulina/sangue , Ativador de Plasminogênio Tecidual/sangue , alfa 2-Antiplasmina/análise , Adulto , Antitrombina III , Biomarcadores/sangue , China/epidemiologia , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
6.
J Vasc Surg ; 69(1): 174-180.e2, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29914835

RESUMO

OBJECTIVE: For patients with end-stage renal disease on hemodialysis, the durability of vascular access (VA) is still far from optimal, and access survival after intervention for access failure is an important aspect. Procoagulant status is a leading cause of access failure. Coagulation-fibrinolysis imbalance can occur in hemodialyzed patients, but the influence of the imbalance has not been fully elucidated. METHODS: We prospectively examined coagulation-fibrinolysis balance to assess the risk of access failure after the intervention of revascularization in a cohort of 462 hemodialysis patients. Thrombin-antithrombin complex (TAT) and plasmin-α2-plasmin inhibitor complex (PIC) are markers for coagulation and fibrinolysis. Median follow-up was 243 days. The end point was clinical access failure: revascularization or access revision. The survival curve for VA patency was assessed using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards regression models that allowed adjustment for baseline differences in age, sex, dialysis vintage, diabetes mellitus, and various factors (quantity of blood flow, prothrombin time-international normalized ratio, fibrin degradation products, C-reactive protein, interleukin-6, tumor necrosis factor-α, and pentraxin-3) were used. RESULTS: The 162 patients who reached an end point had smaller access flow volume and smaller percentage of arteriovenous fistula and higher TAT/PIC ratio. Kaplan-Meier analysis indicated that the patients with elevated TAT/PIC ratio showed poorer outcome (P < .001). On Cox regression modeling, elevated TAT/PIC was an independent risk factor for access failure (hazard ratio, 1.58; P = .03). CONCLUSIONS: Our results suggest that coagulation-fibrinolysis imbalance is a significant risk factor for access failure and may predict VA failure in hemodialyzed patients after access intervention.


Assuntos
Derivação Arteriovenosa Cirúrgica/efeitos adversos , Coagulação Sanguínea , Fibrinólise , Oclusão de Enxerto Vascular/etiologia , Diálise Renal , Trombose/etiologia , Idoso , Idoso de 80 Anos ou mais , Antitrombina III , Biomarcadores/sangue , Feminino , Fibrinolisina/metabolismo , Oclusão de Enxerto Vascular/sangue , Oclusão de Enxerto Vascular/diagnóstico , Oclusão de Enxerto Vascular/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Hidrolases/sangue , Estudos Prospectivos , Fatores de Risco , Trombose/sangue , Trombose/diagnóstico , Trombose/fisiopatologia , Fatores de Tempo , Falha de Tratamento , Grau de Desobstrução Vascular , alfa 2-Antiplasmina/metabolismo
7.
Medicine (Baltimore) ; 97(51): e13830, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30572550

RESUMO

We evaluated the utility of left atrial volume index (LAVI) and markers of coagulation and hemostatic activation (MOCHA) in cryptogenic stroke (CS) patients to identify those more likely to have subsequent diagnosis of atrial fibrillation (AF), malignancy or recurrent stroke during follow-up.Consecutive CS patients who met embolic stroke of undetermined source (ESUS) who underwent transthoracic echocardiography and outpatient cardiac monitoring following stroke were identified from the Emory cardiac registry. In a subset of consecutive patients, d-dimer, prothrombin fragment 1.2, thrombin-antithrombin complex and fibrin monomer (MOCHA panel) were obtained ≥2 weeks post-stroke and repeated ≥4 weeks later if abnormal; abnormal MOCHA panel was defined as ≥2 elevated markers which did not normalize when repeated. We assessed the predictive abilities of LAVI and the MOCHA panel to identify patients with subsequent diagnosis of AF, malignancy, recurrent stroke or the composite outcome during follow-up.Of 94 CS patients (mean age 64 ± 15 years, 54% female, 63% non-white, mean follow-up 1.4 ± 0.8 years) who underwent prolonged cardiac monitoring, 15 (16%) had new AF. Severe LA enlargement (vs normal) was associated with AF (P < .06). In 42 CS patients with MOCHA panel testing (mean follow-up 1.1 ± 0.6 years), 14 (33%) had the composite outcome and all had abnormal MOCHA. ROC analysis showed LAVI and abnormal MOCHA together outperformed either test alone with good predictive ability for the composite outcome (AUC 0.84).We report the novel use of the MOCHA panel in CS patients to identify a subgroup of patients more likely to have occult AF, occult malignancy or recurrent stroke during follow-up. A normal MOCHA panel identified a subgroup of CS patients at low risk for recurrent stroke on antiplatelet therapy. Further study is warranted to evaluate whether the combination of an elevated LAVI and abnormal MOCHA panel identifies a subgroup of CS patients who may benefit from early anticoagulation for secondary stroke prevention.


Assuntos
Fibrilação Atrial/complicações , Isquemia Encefálica/complicações , Neoplasias/complicações , Idoso , Antitrombina III , Biomarcadores/sangue , Coagulação Sanguínea , Ecocardiografia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Peptídeo Hidrolases/sangue , Estudos Prospectivos , Protrombina , Curva ROC , Recidiva , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco
8.
Blood Adv ; 2(22): 3088-3096, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30442686

RESUMO

Abdominal aortic aneurysm (AAA) is associated with high morbidity and mortality and is an established cause of unbalanced hemostasis. A number of hemostatic biomarkers have been associated with AAA; however, the utility of hemostatic biomarkers in AAA diagnosis and prognosis is unclear. The aim of the present study was to characterize the potential prognostic value of D-dimer and markers of altered hemostasis in a large cohort of patients with AAAs characterized by either fast or slow aneurysm growth (frequency matched for baseline diameter) and subaneurysmal dilations. We measured plasma concentrations of thrombin-antithrombin (TAT) complex, platelet factor 4 (PF4), and D-dimer in 352 patients with either fast-growing AAAs (>2 mm/y), slow-growing AAAs (<2 mm/y), subaneurysmal aortic dilations, or nonaneurysmal aortas. Plasma D-dimer and TAT were significantly elevated in both AAA and subaneurysmal dilation patients compared with controls. Individuals with D-dimer levels ≥500 ng/mL had 3.09 times the odds of subaneurysms, 6.23 times the odds of slow-growing AAAs, and 7.19 times the odds of fast-growing AAAs than individuals with D-dimer level <500 ng/mL. However, no differences in D-dimer concentration were noted between fast- and slow-growing aneurysms. Plasma D-dimer and TAT were strong independent predictors of AAA growth rate with multivariate analysis revealing a 500-ng/mL increase in D-dimer or 1-µg/mL increase in TAT led to additional 0.21-mm and 0.24-mm changes in aortic diameter per year, respectively. Rising levels of plasma TAT, in addition to D-dimer, may predict disease progression and aneurysm growth in patients with AAA or subaneurysmal dilation.


Assuntos
Aneurisma da Aorta Abdominal/diagnóstico , Biomarcadores/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Idoso , Antitrombina III , Aneurisma da Aorta Abdominal/patologia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Modelos Logísticos , Masculino , Razão de Chances , Peptídeo Hidrolases/sangue , Fator Plaquetário 4/sangue , Prognóstico , Fatores de Risco
9.
PLoS One ; 13(10): e0205511, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30304025

RESUMO

Reference interval for thrombin-antithrombin complex (TAT) level was determined using an in-house TAT measurement device, and its validity for diagnosis of disseminated intravascular coagulation (DIC) was evaluated in dogs. One hundred and two clinically healthy dogs and 247 diseased dogs with conditions that potentially caused DIC were recruited in the study. Six diagnostic testing for DIC were evaluated in diseased dogs and the diseased dogs were categorized into five groups depending on abnormal findings. TAT was measured in all study animals and between-group differences were evaluated. TAT level was positively associated with severity of DIC. There were no significant differences in TAT levels among clinically healthy dogs, diseased dogs without any abnormal finding and diseased dogs with one abnormal finding in the DIC diagnostic testing. TAT levels in groups with two or more abnormal findings were significantly higher than clinically healthy dogs. Reference interval of TAT level for clinically healthy dogs was ≤ 0.25 ng/ml. Validity of using TAT for early detection of DIC was evaluated. In-house TAT measurement was suggested to be a clinically relevant and useful tool for early detection of canine DIC.


Assuntos
Coagulação Intravascular Disseminada/veterinária , Doenças do Cão/sangue , Peptídeo Hidrolases/sangue , Testes Imediatos , Animais , Antitrombina III , Biomarcadores/sangue , Estudos de Casos e Controles , Coagulação Intravascular Disseminada/sangue , Cães , Diagnóstico Precoce , Feminino , Masculino , Índice de Gravidade de Doença
10.
Thromb Haemost ; 118(9): 1545-1555, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30086574

RESUMO

BACKGROUND: Neonates undergoing cardiopulmonary bypass (CPB) surgery to correct congenital heart defects often experience excessive bleeding. Exposure of blood to artificial materials during CPB may activate coagulation, complement and inflammatory pathways. In addition, the surgical stress placed on the haemostatic system may result in cross-activation of other plasma proteolytic cascades, which could further complicate physiological responses to the surgical procedure and post-operative recovery. Plasma protease inhibitors undergo distinct conformational changes upon interaction with proteases, and, thereby, can serve as endogenous biosensors to identify activation of the different proteolytic cascades. We tested the hypothesis that changes in the concentration and conformation of protease inhibitors regulating plasma proteolytic cascades during neonatal CPB are associated with post-operative bleeding. PATIENTS AND METHODS: Plasma samples from 44 neonates were obtained at four time points across the surgical procedure. Anti-thrombin, antitrypsin, anti-chymotrypsin, anti-plasmin, C1-inhibitor and tissue factor pathway inhibitor (TFPI) concentrations and conformations were evaluated by enzyme-linked immunosorbent assay, transverse urea gradient gel electrophoresis and sodium dodecyl sulphate-polyacrylamide gel electrophoresis. RESULTS/CONCLUSION: The most striking changes were observed following heparin administration and were associated with the appearance of inactive forms of anti-thrombin and an increase in the plasma concentration of TFPI. Changes in anti-thrombin and TFPI remained evident throughout surgery and into the post-operative period but were not different between patients with or without post-operative bleeding. The concentration of antitrypsin decreased across surgery, but there was no significant accumulation of inactive conformations of any inhibitor besides anti-thrombin, indicating that widespread cross-activation of other plasma proteolytic cascades by coagulation proteases did not occur.


Assuntos
Anticoagulantes/sangue , Coagulação Sanguínea/efeitos dos fármacos , Ponte Cardiopulmonar , Heparina/uso terapêutico , Lipoproteínas/sangue , Feminino , Hemorragia/etiologia , Humanos , Recém-Nascido , Masculino , Peptídeo Hidrolases/sangue , Plasma/metabolismo , Complicações Pós-Operatórias , Ligação Proteica , Trombina/metabolismo
11.
J Stroke Cerebrovasc Dis ; 27(11): 2951-2961, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30072172

RESUMO

BACKGROUND: Intracerebral hemorrhage (ICH) causes death or disability and the incidence increases with age. Knowledge of acute hemostatic function in patients with ICH without anticoagulant and antiplatelet therapy is sparse. Increased knowledge of the coagulation profile in the acute phase of ICH could improve acute treatment and recovery. We investigated coagulation at admission and changes in coagulation during the first 24hours after symptom onset. METHODS: Enrolled were 41 ICH patients without anticoagulant or antiplatelet therapy admitted to Aarhus University Hospital, Denmark. Blood samples were collected at admission, 6, and 24hours after symptom onset. Thromboelastometry (ROTEM), thrombin generation, and thrombin-antithrombin (TAT) complex were analyzed. Clinical outcome was evaluated using the National Institute of Health Stroke Scale, the Modified Rankin Score, and mortality. RESULTS: At admission, compared with healthy individuals, ICH patients had increased maximum clot firmness (EXTEM P < .0001; INTEM P < .0001; FIBTEM P < .0001), increased platelet maximum clot elasticity (P < .0001) in ROTEM, higher peak thrombin (P < .0001) and endogenous thrombin potential (P = .01) in thrombin generation, and elevated TAT complex levels. During 24hours after significantly, while thrombin generation showed decreased peak thrombin (P < .0001) and endogenous thrombin potential (P < .0001). Coagulation test results did not differ between patients when stratified according to clinical outcome. CONCLUSIONS: ICH patients without anticoagulant or antiplatelet therapy demonstrated activated coagulation at admission and within 24hours after symptom onset.


Assuntos
Coagulação Sanguínea , Hemorragia Cerebral/sangue , Peptídeo Hidrolases/sangue , Tromboelastografia , Trombina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antitrombina III , Biomarcadores/sangue , Estudos de Casos e Controles , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/mortalidade , Hemorragia Cerebral/fisiopatologia , Dinamarca , Avaliação da Deficiência , Feminino , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Tempo
12.
Am J Cardiovasc Drugs ; 18(6): 503-511, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30144017

RESUMO

BACKGROUND: The aim was to compare the peri-procedural biomarkers of coagulation and platelet activation in patients randomly allocated to intravenous enoxaparin or unfractionated heparin (UFH) in the ATOLL randomized trial (NCT00718471). METHODS AND RESULTS: A total of 129 patients (n = 58 enoxaparin and n = 71 UFH) admitted for ST-segment elevation myocardial infarction (STEMI) treated by percutaneous coronary intervention (PCI) were included in this substudy of the ATOLL trial. Activated partial thromboplastin time ratio, anti-Xa activity, von Willebrand factor antigen, prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT), tissue factor pathway inhibitor and soluble CD40 ligand were measured at sheath insertion (T1) and at the end of the PCI (T2) and correlated with 1-month clinical outcomes. Target anticoagulation levels at T2 were more readily achieved in patients receiving enoxaparin compared to those receiving UFH (80.3 vs 18.2%, p < 0.0001). Increased levels of F1 + 2 and TAT measured at T2 were associated with the incidence of the composite ischemic endpoint (p = 0.04 and p = 0.03) and all-cause mortality (p < 0.0001 and p = 0.002). Release of F1 + 2 between T1 and T2 also predicted the composite ischemic endpoint (312 ± 513 vs 37 ± 292, p = 0.04) and net clinical outcome (185 ± 405 vs 3.2 ± 278, p = 0.03). CONCLUSIONS: During primary PCI, enoxaparin achieved therapeutic levels more frequently than UFH. Higher level of thrombin generation measured at the end of the PCI procedure was associated with more frequent ischemic events.


Assuntos
Anticoagulantes/uso terapêutico , Enoxaparina/uso terapêutico , Heparina/uso terapêutico , Intervenção Coronária Percutânea/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Antitrombina III , Biomarcadores , Ligante de CD40/sangue , Enoxaparina/administração & dosagem , Enoxaparina/efeitos adversos , Fator Xa/análise , Feminino , Heparina/administração & dosagem , Heparina/efeitos adversos , Humanos , Lipoproteínas/análise , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Peptídeo Hidrolases/sangue , Protrombina/análise , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Fator de von Willebrand/análise
13.
J Thromb Haemost ; 16(9): 1800-1813, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29971917

RESUMO

Essentials Tumor-bearing mice were employed to follow oncogenic HRAS sequences in plasma, and blood cells. Cancer DNA accumulated in leukocytes above levels detected in exosomes, platelets and plasma. Extracellular vesicles and nucleosomes are required for uptake of tumor DNA by leukocytes. Uptake of tumor-derived extracellular vesicles by leukocytes triggers coagulant phenotype. SUMMARY: Background Tumor-derived extracellular vesicles (EVs) and free nucleosomes (NSs) carry into the circulation a wealth of cancer-specific, bioactive and poorly understood molecular cargoes, including genomic DNA (gDNA). Objective Here we investigated the distribution of extracellular oncogenic gDNA sequences (HRAS and HER2) in the circulation of tumor-bearing mice. Methods and Results Surprisingly, circulating leukocytes (WBCs), especially neutrophils, contained the highest levels of mutant gDNA, which exceeded the amount of this material recovered from soluble fractions of plasma, circulating EVs, platelets, red blood cells (RBCs) and peripheral organs, as quantified by digital droplet PCR (ddPCR). Tumor excision resulted in disappearance of the WBC-associated gDNA signal within 2-9 days, which is in line with the expected half-life of these cells. EVs and nucleosomes were essential for the uptake of tumor-derived extracellular DNA by neutrophil-like cells and impacted their phenotype. Indeed, the exposure of granulocytic HL-60 cells to EVs from HRAS-driven cancer cells resulted in a selective increase in tissue factor (TF) procoagulant activity and interleukin 8 (IL-8) production. The levels of circulating thrombin-antithrombin complexes (TAT) were markedly elevated in mice harboring HRAS-driven xenografts. Conclusions Myeloid cells may represent a hitherto unrecognized reservoir of cancer-derived, EV/NS-associated oncogenic gDNA in the circulation, and a possible novel platform for liquid biopsy in cancer. In addition, uptake of this material alters the phenotype of myeloid cells, induces procoagulant and proinflammatory activity and may contribute to systemic effects associated with cancer.


Assuntos
DNA de Neoplasias/sangue , Vesículas Extracelulares/química , Genes erbB-2 , Genes ras , Células Mieloides/química , Neutrófilos/química , Animais , Antitrombina III , Plaquetas/química , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular , Transformação Celular Neoplásica , DNA de Neoplasias/farmacocinética , Exossomos/química , Feminino , Células HL-60 , Xenoenxertos , Humanos , Interleucina-8/biossíntese , Camundongos , Camundongos SCID , Células Mieloides/metabolismo , Transplante de Neoplasias , Neutrófilos/metabolismo , Nucleossomos/química , Peptídeo Hidrolases/sangue , Plasma/química , Ratos , Células THP-1 , Tromboplastina/biossíntese , Carga Tumoral
14.
Ann Rheum Dis ; 77(10): 1516-1523, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29945920

RESUMO

OBJECTIVES: IKZF1 and IKZF3 (encoding transcription factors Ikaros and Aiolos) are susceptibility loci for systemic lupus erythematosus (SLE). The pharmacology of iberdomide (CC-220), a cereblon (CRBN) modulator targeting Ikaros and Aiolos, was studied in SLE patient cells and in a phase 1 healthy volunteer study. METHODS: CRBN, IKZF1 and IKZF3 gene expression was measured in peripheral blood mononuclear cells (PBMC) from patients with SLE and healthy volunteers. Ikaros and Aiolos protein levels were measured by Western blot and flow cytometry. Anti-dsDNA and anti-phospholipid autoantibodies were measured in SLE PBMC cultures treated for 7 days with iberdomide. Fifty-six healthy volunteers were randomised to a single dose of iberdomide (0.03-6 mg, n=6 across seven cohorts) or placebo (n=2/cohort). CD19+ B cells, CD3+ T cells and intracellular Aiolos were measured by flow cytometry. Interleukin (IL)-2 and IL-1ß production was stimulated with anti-CD3 and lipopolysaccharide, respectively, in an ex vivo whole blood assay. RESULTS: SLE patient PBMCs expressed significantly higher CRBN (1.5-fold), IKZF1 (2.1-fold) and IKZF3 (4.1-fold) mRNA levels compared with healthy volunteers. Iberdomide significantly reduced Ikaros and Aiolos protein levels in B cells, T cells and monocytes. In SLE PBMC cultures, iberdomide inhibited anti-dsDNA and anti-phospholipid autoantibody production (IC50 ≈10 nM). Single doses of iberdomide (0.3-6 mg) in healthy volunteers decreased intracellular Aiolos (minimum mean per cent of baseline: ≈12%-28% (B cells); ≈0%-33% (T cells)), decreased absolute CD19+ B cells, increased IL-2 and decreased IL-1ß production ex vivo. CONCLUSIONS: These findings demonstrate pharmacodynamic activity of iberdomide and support its further clinical development for the treatment of SLE. TRIAL REGISTRATION NUMBER: NCT01733875; Results.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Fator de Transcrição Ikaros/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Peptídeo Hidrolases/efeitos dos fármacos , Autoanticorpos/sangue , Autoanticorpos/imunologia , Western Blotting , Método Duplo-Cego , Citometria de Fluxo , Voluntários Saudáveis , Humanos , Fator de Transcrição Ikaros/sangue , Imunomodulação/efeitos dos fármacos , Leucócitos Mononucleares , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Peptídeo Hidrolases/sangue , RNA Mensageiro/sangue , RNA Mensageiro/efeitos dos fármacos
15.
Fish Shellfish Immunol ; 80: 416-425, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29920384

RESUMO

The present study was conducted to evaluate the supplementation of three autochthonous Bacillus strains (B. subtilis, B. amyloliquefaciens and B. cereus) and a commercial B. amyloliquefaciensin doses of 1 × 1010 CFU/kg on the growth performance, hematology, antioxidant activities, digestive enzyme levels, immune status and disease resistance of Clarias gariepinus. A total of 300 fish (75.23 ±â€¯1.6 g) were randomly divided into 5 groups (each group was subdivided into 2 subgroups, 30 fish/each). The control group was fed basal diet (D0). Diets D1, D2, D3 and D4were supplemented with B. subtilis, B. amyloliquefaciens, B. cereus and a commercial B. amyloliquefaciens, respectively. During the course of the experiment, D3 showed the best body weight, weight gain, specific growth rate and food conversion ratio. The measured hemogram blood parameters had the highest significant increase in D3. WBCs and monocyte counts had no significant differences among the experimental groups. The serum antioxidant and digestive enzymes were the highest in D3 and were the lowest in D0. After 15 d, the non-specific immune parameters were markedly increased in fish fed probiotic-containing diet compared with the control. After 30 d, the highest significant immune parameters were observed in D3; D1 and D2 had no significant differences in serum lysozyme activity, nitric oxide and IgM compared with D0. Myostatin cDNA levels were adversely affected by probiotic supplements compare with the control. The PACAP expression showed the highest significant value in D3 followed by D1and D4then D2. The relative survival percentages of the Aeromonas sobria challenged C. gariepinus were the highest in D3, D2, D4 and then D1. Among the three isolated Bacillus species, dietary supplementation with the B. cereus had the highest performance in C. gariepinus compared with the commercial B. amyloliquefaciens and the control group.


Assuntos
Bacillus , Peixes-Gato , Probióticos , Aeromonas , Amilases/sangue , Ração Animal , Animais , Peso Corporal , Peixes-Gato/genética , Peixes-Gato/crescimento & desenvolvimento , Peixes-Gato/imunologia , Peixes-Gato/microbiologia , Resistência à Doença , Contagem de Eritrócitos , Doenças dos Peixes , Microbioma Gastrointestinal , Infecções por Bactérias Gram-Negativas/veterinária , Lipase/sangue , Miostatina/genética , Peptídeo Hidrolases/sangue , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , RNA Mensageiro/metabolismo , Superóxido Dismutase/metabolismo
16.
PLoS One ; 13(5): e0196084, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29718943

RESUMO

In Chile, agriculture is a relevant economic activity and is concomitant with the use of pesticides to improve the yields. Acute intoxications of agricultural workers occur with some frequency and they must be reported to the surveillance system of the Ministry of Health. However the impacts of chronic and environmental pesticide exposure have been less studied. Among pesticides frequently used in Chile for insects control are organophosphates (OP) and carbamates (CB). They are inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). In this study we determined the pattern of both biomarkers activity in three populations with different type of chronic exposure to OP/CB: environmentally exposed (EE), occupationally exposed (OE) and a reference group (RG) without exposure. Besides this, we also measured the activity of acylpeptide hydrolase (APEH), an enzyme involved in relevant functions in the central synapses that is also expressed in erythrocytes and previously reported to be highly inhibited by some OP. A baseline measurement was done in both exposure groups and then a second measurement was done during the spraying season. The RG was measured only once at any time of the year. Our results indicate that people under chronic OP/CB exposure showed an adaptive response through an increase of basal BChE activity. During the spray season only BChE activity was decreased in the EE and OE groups (p<0.05 and p<0.01, respectively) and the higher magnitude of BChE inhibition was observed in the EE group. The analysis of the frequencies of inhibition above 30% (biological tolerance limit declared by Chilean legislation) indicated that BChE was most frequently inhibited in the EE group (53% of the individuals displayed inhibition) and AChE in the OE group (55% of the individuals displayed AChE inhibition). APEH activity showed the highest frequency of inhibition in the EE group independent of its magnitude (64%). Our results demonstrate that the rural population living nearby agricultural settings displays high levels of environmental exposure. APEH activity seems to be a sensitive biomarker for acute low-level exposure and its usefulness as a routine biomarker must to be explored in future studies. Systematic biomonitoring and health outcomes studies are necessary as well as obtaining the baseline for BChE and AChE activity levels with the aim to improve environmental and occupational health policies in Chile.


Assuntos
Butirilcolinesterase/sangue , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Monitoramento Ambiental , Peptídeo Hidrolases/sangue , Praguicidas/toxicidade , População Rural/estatística & dados numéricos , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Butirilcolinesterase/metabolismo , Chile , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Hidrolases/metabolismo , Adulto Jovem
17.
Arterioscler Thromb Vasc Biol ; 38(7): 1528-1536, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29724819

RESUMO

OBJECTIVE: We investigated the coregulation of thrombin and fibrin as blood flows over a procoagulant surface. APPROACH AND RESULTS: Using microfluidic perfusion of factor XIIa-inhibited human whole blood (200 s-1 wall shear rate) over a 250-µm long patch of collagen/TF (tissue factor; ≈1 molecule per µm2) and immunoassays of the effluent for F1.2 (prothrombin fragment 1.2), TAT (thrombin-antithrombin complex), and D-dimer (post-end point plasmin digest), we sought to establish the transient mass balance for clotting under venous flow. F1.2 (but almost no free thrombin detected via TAT assay) continually eluted from clots when fibrin was allowed to form. Low-dose fluorescein-Phe-Pro-Arg-chloromethylketone stained fibrin-bound thrombin-a staining ablated by anti-γ'-fibrinogen or the fibrin inhibitor glypro-arg-pro but highly resistant to 7-minute buffer rinse, demonstrating tight binding of thrombin to γ'-fibrin. With fibrin polymerizing for 500 seconds, 92 000 thrombin molecules and 203 000 clot-associated fibrin monomer equivalents were generated per TF molecule (or per µm2). Fibrin reached 15 mg/mL in the pore space (porosity ≈0.5) of a 15-µm-thick thrombus core by 500 seconds and 30 mg/mL by 800 seconds. For a known rate of ≈60 FPA (fibrinopeptide-A) per thrombin per second, each thrombin molecule generated only 3 fibrin monomer equivalents during 500 seconds, indicating an intraclot thrombin half-life of ≈70 ms, much shorter than its diffusional escape time (≈10 seconds). By 800 seconds, gly-pro-arg-pro allowed 4-fold more F1.2 generation, consistent with gly-pro-arg-pro ablating fibrin's antithrombin-I activity and facilitating thrombin-mediated FXIa activation. CONCLUSIONS: Under flow, fibrinogen continually penetrates the clot, and γ'-fibrin regulates thrombin.


Assuntos
Coagulação Sanguínea , Fibrina/metabolismo , Hemodinâmica , Trombina/metabolismo , Tromboplastina/metabolismo , Trombose/sangue , Antitrombina III , Velocidade do Fluxo Sanguíneo , Fator XIIa/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinogênios Anormais/metabolismo , Humanos , Cinética , Técnicas Analíticas Microfluídicas , Fragmentos de Peptídeos/sangue , Peptídeo Hidrolases/sangue , Porosidade , Protrombina , Trombose/fisiopatologia
18.
Clin Rheumatol ; 37(8): 2087-2093, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29675623

RESUMO

The aim of this study is to assess the relationship between autoimmunity and endothelial activation/damage (ICAM-1 and vWF serum levels) and the degree of prothrombotic activity (thrombin-antithrombin complexes-TAT serum levels) in SLE. In 60 clinically stable SLE patients, levels of the following parameters were estimated in their serum: lupus anticoagulant (LA), anticardiolipin antibodies in both IgG and IgM classes (aCL-IgG and aCL-IgM, respectively), antiß2GPI antibodies in both IgG and IgM classes (antiß2GPI-IgG and antiß2GPI-IgM, respectively), ICAM, von Willebrand factor (vWF), TAT, CRP, C3c, C4, and IL-6. ICAM-1 values exceeded the upper reference limit in 9 (15%) patients. vWF levels were increased in 21 (35%) patients. In all patients with elevated ICAM-1 values, vWF were also increased. TAT concentrations were elevated in 12 (20%) people. ICAM-1 were significantly higher in patients with elevated aCL-IgM (> 30 MPL vs ≤ 30 MPL; p < 0.05). Similarly, ICAM-1 were significantly higher in patients with elevated antiß2-GPI-IgM (> 20 SMU vs ≤ 20 SMU; p < 0.05). There was no significant difference in ICAM-1 levels in relation to LA-positivity. vWF were not significantly different in relation to antiphospholipid antibodies nor the inflammation marker levels. TAT were significantly higher in patients with elevated aCL-IgM (> 30 MPL vs ≤ 30 MPL; p < 0.05). In one third of young patients with stable SLE, signs of endothelial activation/damage were found, as shown by elevated plasma ICAM-1 or vWF. Increased prothrombotic tendency manifested by elevated TAT was found in one fifth of the patients. Elevated anticardiolipin (IgM) and anti-ß2-glycoprotein I (IgM) antibodies influence endothelial dysfunction and enhance prothrombotic state.


Assuntos
Autoimunidade , Endotélio Vascular/fisiopatologia , Molécula 1 de Adesão Intercelular/sangue , Lúpus Eritematoso Sistêmico/sangue , Peptídeo Hidrolases/sangue , Trombose/sangue , Fator de von Willebrand/análise , Adulto , Idoso , Anticorpos Anticardiolipina , Antitrombina III , Feminino , Humanos , Inflamação/fisiopatologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
J Artif Organs ; 21(2): 196-200, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29383543

RESUMO

A circuit clot is one of the most frequent complications during extracorporeal membrane oxygenation (ECMO) support. We identify coagulation/fibrinolysis markers for predicting ECMO circuit exchange because of circuit clots during ECMO support. Ten patients with acute pulmonary failure who underwent veno-venous ECMO were enrolled between January 2014 and December 2016. ECMO support lasted 106 days. The 6 days on which the ECMO circuits were exchanged were considered as circuit clot (+) group, while the remaining 100 days were considered as circuit clot (-) group. The predictors of ECMO circuit exchange because of circuit clots were identified. The mean duration of ECMO support was 10 ± 13 days, and the mean number of ECMO circuit exchange was 0.6 ± 1.1 times per patient. Thrombin-antithrombin complex (TAT) and soluble fibrin (SF) were higher in the circuit clot (+) group than in the circuit clot (-) group (both P < 0.01). According to a multivariate analysis, SF was the only independent predictor of ECMO circuit exchange (P < 0.01). The odds ratio (confidence intervals) for SF (10 µg/ml) was 1.20 (1.06-1.36). The area under the curve and optimal cut-off value were 0.95 and 101 ng/ml for SF (sensitivity, 100%; specificity, 89%). SF may be useful in predicting ECMO circuit exchange because of circuit clots.


Assuntos
Oxigenação por Membrana Extracorpórea/efeitos adversos , Fibrina/metabolismo , Insuficiência Respiratória/terapia , Trombose/sangue , Trombose/etiologia , Idoso , Antitrombina III , Biomarcadores/sangue , Coagulação Sanguínea , Feminino , Humanos , Pulmão , Masculino , Pessoa de Meia-Idade , Peptídeo Hidrolases/sangue , Estudos Retrospectivos
20.
Probiotics Antimicrob Proteins ; 10(3): 399-407, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29064058

RESUMO

An 8-week study was conducted to evaluate three different diets supplemented with bovine lactoferrin (LF) at 0 (control), 800, and 1200 mg LF kg-1 diet on somatic growth, hemato-immunological parameters, antioxidant status, and digestive enzyme activities in silvery-black porgy (Sparidentex hasta) juveniles. Fish fed the 800 mg LF kg-1 diet had higher growth performance and feed utilization parameters than the other groups. Hematological and liver antioxidant parameters were not affected by dietary LF supplementation. Fish fed the 800 mg LF kg-1 diet had higher plasma lysozyme activity values than the other groups. Total protease activity was higher in fish fed LF-supplemented diets than the control group. Results indicated that diet supplemented with 800 mg kg-1 for 8 weeks enhanced somatic growth performance, lysozyme activity, and proteolytic digestive enzyme activities in S. hasta, as well as improving feed efficiency parameters like the protein efficiency and feed conversion ratios.


Assuntos
Ração Animal/análise , Lactoferrina/metabolismo , Perciformes/crescimento & desenvolvimento , Perciformes/metabolismo , Animais , Antioxidantes/metabolismo , Bovinos , Dieta/veterinária , Digestão , Fígado/metabolismo , Muramidase/sangue , Peptídeo Hidrolases/sangue , Perciformes/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA