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1.
Res Pract Thromb Haemost ; 8(3): 102395, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38699410

RESUMO

The University of North Carolina Symposia on Hemostasis began in 2002, with The First Symposium on Hemostasis with a Special Focus on FVIIa and Tissue Factor. They have occurred biannually since and have maintained the primary goal of establishing a forum for the sharing of outstanding advances made in the basic sciences of hemostasis. The 2024 11th Symposium on Hemostasis will bring together leading scientists from around the globe to present and discuss the latest research related to coagulation factors and platelet biology. In keeping with the tradition of the conference, we expect novel cross-disciplinary collaborations to result from bringing together fundamental scientists and physician-scientists from different backgrounds and perspectives. The aim of these collaborations is to springboard the next generation of important advances in the field. This year's program was designed to discuss Coagulation and Platelet Biology at the Intersection of Health and Disease. The goal is to develop a better understanding of the pathophysiologic mechanisms leading to hemostatic and thrombotic disorders as this understanding is critical for the continued development of safe and efficacious therapeutics. Included in this review article are illustrated capsules provided by our speakers that highlight the main conclusions of the invited talks.

2.
Res Pract Thromb Haemost ; 7(6): 102197, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37822706

RESUMO

Gender-affirming hormonal therapies are a critical component of the care of transgender individuals. Transgender people are commonly prescribed estrogen or testosterone to promote male-to-female or female-to-male transitions and to preserve gender-specific characteristics long-term. However, some exogenous hormones, especially certain estrogen preparations, are an established risk factor of thrombosis. As the number of individuals seeking gender-based care is rising, there is an urgent need to identify and characterize the mechanisms underlying hormone-associated thrombosis and incorporate this information into clinical algorithms for diagnosis and management. Herein, we discuss historical evidence on the incidence of thrombosis and changes in plasma composition in transgender and cisgender cohorts. We present 3 case studies to demonstrate knowledge gaps in thrombosis risk stratification and prediction tools. We also present data from in vitro coagulation and fibrinolysis assays and discuss how information from these kinds of assays may be used to help guide the clinical management of transgender individuals.

4.
Front Immunol ; 14: 1181761, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37287977

RESUMO

Background: Neutrophil Extracellular Traps (NETs) are key mediators of immunothrombotic mechanisms and defective clearance of NETs from the circulation underlies an array of thrombotic, inflammatory, infectious, and autoimmune diseases. Efficient NET degradation depends on the combined activity of two distinct DNases, DNase1 and DNase1-like 3 (DNase1L3) that preferentially digest double-stranded DNA (dsDNA) and chromatin, respectively. Methods: Here, we engineered a dual-active DNase with combined DNase1 and DNase1L3 activities and characterized the enzyme for its NET degrading potential in vitro. Furthermore, we produced a mouse model with transgenic expression of the dual-active DNase and analyzed body fluids of these animals for DNase1 and DNase 1L3 activities. We systematically substituted 20 amino acid stretches in DNase1 that were not conserved among DNase1 and DNase1L3 with homologous DNase1L3 sequences. Results: We found that the ability of DNase1L3 to degrade chromatin is embedded into three discrete areas of the enzyme's core body, not the C-terminal domain as suggested by the state-of-the-art. Further, combined transfer of the aforementioned areas of DNase1L3 to DNase1 generated a dual-active DNase1 enzyme with additional chromatin degrading activity. The dual-active DNase1 mutant was superior to native DNase1 and DNase1L3 in degrading dsDNA and chromatin, respectively. Transgenic expression of the dual-active DNase1 mutant in hepatocytes of mice lacking endogenous DNases revealed that the engineered enzyme was stable in the circulation, released into serum and filtered to the bile but not into the urine. Conclusion: Therefore, the dual-active DNase1 mutant is a promising tool for neutralization of DNA and NETs with potential therapeutic applications for interference with thromboinflammatory disease states.


Assuntos
Endodesoxirribonucleases , Armadilhas Extracelulares , Camundongos , Animais , Endodesoxirribonucleases/genética , Armadilhas Extracelulares/metabolismo , Desoxirribonuclease I/genética , Desoxirribonuclease I/metabolismo , Cromatina , DNA/metabolismo , Desoxirribonucleases/genética
5.
J Thromb Haemost ; 21(4): 814-827, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36990522

RESUMO

BACKGROUND: Human serum albumin (HSA) is the most abundant plasma protein and is sensitive to glycation in vivo. The chronic hyperglycemic conditions in patients with diabetes mellitus (DM) induce a nonenzymatic Maillard reaction that denatures plasma proteins and forms advanced glycation end products (AGEs). HSA-AGE is a prevalent misfolded protein in patients with DM and is associated with factor XII activation and downstream proinflammatory kallikrein-kinin system activity without any associated procoagulant activity of the intrinsic pathway. OBJECTIVES: This study aimed to determine the relevance of HSA-AGE toward diabetic pathophysiology. METHODS: The plasma obtained from patients with DM and euglycemic volunteers was probed for activation of FXII, prekallikrein (PK), and cleaved high-molecular-weight kininogen by immunoblotting. Constitutive plasma kallikrein activity was determined via chromogenic assay. Activation and kinetic modulation of FXII, PK, FXI, FIX, and FX via in vitro-generated HSA-AGE were explored using chromogenic assays, plasma-clotting assays, and an in vitro flow model using whole blood. RESULTS: Plasma obtained from patients with DM contained increased plasma AGEs, activated FXIIa, and resultant cleaved cleaved high-molecular-weight kininogen. Elevated constitutive plasma kallikrein enzymatic activity was identified, which positively correlated with glycated hemoglobin levels, representing the first evidence of this phenomenon. HSA-AGE, generated in vitro, triggered FXIIa-dependent PK activation but limited the intrinsic coagulation pathway activation by inhibiting FXIa and FIXa-dependent FX activation in plasma. CONCLUSION: These data indicate a proinflammatory role of HSA-AGEs in the pathophysiology of DM via FXII and kallikrein-kinin system activation. A procoagulant effect of FXII activation was lost through the inhibition of FXIa and FIXa-dependent FX activation by HSA-AGEs.


Assuntos
Calicreínas , Calicreína Plasmática , Humanos , Calicreínas/metabolismo , Calicreína Plasmática/metabolismo , Cininas , Fator XIIa/metabolismo , Cininogênio de Alto Peso Molecular/metabolismo , Pré-Calicreína/metabolismo , Albuminas , Produtos Finais de Glicação Avançada
6.
Blood ; 141(15): 1871-1883, 2023 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-36706361

RESUMO

A hypercoagulable state, chronic inflammation, and increased risk of venous thrombosis and stroke are prominent features in patients with sickle cell disease (SCD). Coagulation factor XII (FXII) triggers activation of the contact system that is known to be involved in both thrombosis and inflammation, but not in physiological hemostasis. Therefore, we investigated whether FXII contributes to the prothrombotic and inflammatory complications associated with SCD. We found that when compared with healthy controls, patients with SCD exhibit increased circulating biomarkers of FXII activation that are associated with increased activation of the contact pathway. We also found that FXII, but not tissue factor, contributes to enhanced thrombin generation and systemic inflammation observed in sickle cell mice challenged with tumor necrosis factor α. In addition, FXII inhibition significantly reduced experimental venous thrombosis, congestion, and microvascular stasis in a mouse model of SCD. Moreover, inhibition of FXII attenuated brain damage and reduced neutrophil adhesion to the brain vasculature of sickle cell mice after ischemia/reperfusion induced by transient middle cerebral artery occlusion. Finally, we found higher FXII, urokinase plasminogen activator receptor, and αMß2 integrin expression in neutrophils of patients with SCD compared with healthy controls. Our data indicate that targeting FXII effectively reduces experimental thromboinflammation and vascular complications in a mouse model of SCD, suggesting that FXII inhibition may provide a safe approach for interference with inflammation, thrombotic complications, and vaso-occlusion in patients with SCD.


Assuntos
Anemia Falciforme , Fator XII , Animais , Camundongos , Anemia Falciforme/complicações , Anemia Falciforme/metabolismo , Fator XII/metabolismo , Inflamação , Acidente Vascular Cerebral , Trombose/metabolismo
7.
Biosens Bioelectron ; 222: 114921, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36521205

RESUMO

Neutrophil recruitment to the inflamed endothelium is a multistep process and is of utmost importance in the development of the hallmark vaso-occlusive crisis in sickle cell disease (SCD). However, there lacks a standardized, clinically feasible approach for assessing neutrophil recruitment to the inflamed endothelium for individualized risk stratification and therapeutic response prediction in SCD. Here, we describe a microfluidic device functionalized with E-selectin, a critical endothelial receptor for the neutrophil recruitment process, as a strategy to assess neutrophil binding under physiologic flow in normoxia and clinically relevant hypoxia in SCD. We show that hypoxia significantly enhances neutrophil binding to E-selectin and promotes the formation of neutrophil-platelet aggregates. Moreover, we identified two distinct patient populations: a more severe clinical phenotype with elevated lactate dehydrogenase levels and absolute reticulocyte counts but lowered fetal hemoglobin levels associated with constitutively less neutrophil binding to E-selectin. Mechanistically, we demonstrate that the extent of neutrophil activation correlates with membrane L-selectin shedding, resulting in the loss of ligand interaction sites with E-selectin. We also show that inhibition of E-selectin significantly reduces leukocyte recruitment to activated endothelial cells. Our findings add mechanistic insight into neutrophil-endothelial interactions under hypoxia and provide a clinically feasible means for assessing neutrophil binding to E-selectin using clinical whole blood samples, which can help guide therapeutic decisions for SCD patients.


Assuntos
Anemia Falciforme , Técnicas Biossensoriais , Humanos , Selectina E/uso terapêutico , Células Endoteliais/metabolismo , Infiltração de Neutrófilos , Adesão Celular , Endotélio/metabolismo , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/metabolismo , Dispositivos Lab-On-A-Chip , Hipóxia
8.
Nat Nanotechnol ; 17(9): 1004-1014, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35851383

RESUMO

Targeted drug delivery to disease-associated activated neutrophils can provide novel therapeutic opportunities while avoiding systemic effects on immune functions. We created a nanomedicine platform that uniquely utilizes an α1-antitrypsin-derived peptide to confer binding specificity to neutrophil elastase on activated neutrophils. Surface decoration with this peptide enabled specific anchorage of nanoparticles to activated neutrophils and platelet-neutrophil aggregates, in vitro and in vivo. Nanoparticle delivery of a model drug, hydroxychloroquine, demonstrated significant reduction of neutrophil activities in vitro and a therapeutic effect on murine venous thrombosis in vivo. This innovative approach of cell-specific and activation-state-specific targeting can be applied to several neutrophil-driven pathologies.


Assuntos
Elastase de Leucócito , Deficiência de alfa 1-Antitripsina , Animais , Humanos , Hidroxicloroquina/farmacologia , Elastase de Leucócito/metabolismo , Camundongos , Nanomedicina , Neutrófilos
9.
Blood ; 138(22): 2256-2268, 2021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34587242

RESUMO

SARS-CoV-2 vaccine ChAdOx1 nCoV-19 (AstraZeneca) causes a thromboembolic complication termed vaccine-induced immune thrombotic thrombocytopenia (VITT). Using biophysical techniques, mouse models, and analysis of VITT patient samples, we identified determinants of this vaccine-induced adverse reaction. Super-resolution microscopy visualized vaccine components forming antigenic complexes with platelet factor 4 (PF4) on platelet surfaces to which anti-PF4 antibodies obtained from VITT patients bound. PF4/vaccine complex formation was charge-driven and increased by addition of DNA. Proteomics identified substantial amounts of virus production-derived T-REx HEK293 proteins in the ethylenediaminetetraacetic acid (EDTA)-containing vaccine. Injected vaccine increased vascular leakage in mice, leading to systemic dissemination of vaccine components known to stimulate immune responses. Together, PF4/vaccine complex formation and the vaccine-stimulated proinflammatory milieu trigger a pronounced B-cell response that results in the formation of high-avidity anti-PF4 antibodies in VITT patients. The resulting high-titer anti-PF4 antibodies potently activated platelets in the presence of PF4 or DNA and polyphosphate polyanions. Anti-PF4 VITT patient antibodies also stimulated neutrophils to release neutrophil extracellular traps (NETs) in a platelet PF4-dependent manner. Biomarkers of procoagulant NETs were elevated in VITT patient serum, and NETs were visualized in abundance by immunohistochemistry in cerebral vein thrombi obtained from VITT patients. Together, vaccine-induced PF4/adenovirus aggregates and proinflammatory reactions stimulate pathologic anti-PF4 antibody production that drives thrombosis in VITT. The data support a 2-step mechanism underlying VITT that resembles the pathogenesis of (autoimmune) heparin-induced thrombocytopenia.


Assuntos
Complexo Antígeno-Anticorpo/imunologia , Autoanticorpos/imunologia , COVID-19/prevenção & controle , Proteínas do Capsídeo/efeitos adversos , ChAdOx1 nCoV-19/efeitos adversos , Contaminação de Medicamentos , Vetores Genéticos/efeitos adversos , Células HEK293/imunologia , Imunoglobulina G/imunologia , Fator Plaquetário 4/imunologia , Púrpura Trombocitopênica Idiopática/etiologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/efeitos adversos , Adenoviridae/imunologia , Animais , Complexo Antígeno-Anticorpo/ultraestrutura , Autoanticorpos/biossíntese , Síndrome de Vazamento Capilar/etiologia , Proteínas do Capsídeo/imunologia , Linhagem Celular Transformada , ChAdOx1 nCoV-19/química , ChAdOx1 nCoV-19/imunologia , ChAdOx1 nCoV-19/toxicidade , Difusão Dinâmica da Luz , Epitopos/química , Epitopos/imunologia , Armadilhas Extracelulares/imunologia , Extravasamento de Materiais Terapêuticos e Diagnósticos/etiologia , Vetores Genéticos/imunologia , Células HEK293/química , Humanos , Imageamento Tridimensional , Imunoglobulina G/biossíntese , Inflamação , Camundongos , Microscopia/métodos , Ativação Plaquetária , Proteômica , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/imunologia , Trombose dos Seios Intracranianos/diagnóstico por imagem , Trombose dos Seios Intracranianos/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Cultura de Vírus
10.
Nat Commun ; 12(1): 5596, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34552086

RESUMO

Contact activation refers to the process of surface-induced activation of factor XII (FXII), which initiates blood coagulation and is captured by the activated partial thromboplastin time (aPTT) assay. Here, we show the mechanism and diagnostic implications of FXII contact activation. Screening of recombinant FXII mutants identified a continuous stretch of residues Gln317-Ser339 that was essential for FXII surface binding and activation, thrombin generation and coagulation. Peptides spanning these 23 residues competed with surface-induced FXII activation. Although FXII mutants lacking residues Gln317-Ser339 were susceptible to activation by plasmin and plasma kallikrein, they were ineffective in supporting arterial and venous thrombus formation in mice. Antibodies raised against the Gln317-Ser339 region induced FXII activation and triggered controllable contact activation in solution leading to thrombin generation by the intrinsic pathway of coagulation. The antibody-activated aPTT allows for standardization of particulate aPTT reagents and for sensitive monitoring of coagulation factors VIII, IX, XI.


Assuntos
Coagulação Sanguínea , Fator XII/química , Fator XII/metabolismo , Sequência de Aminoácidos , Animais , Anticorpos/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/metabolismo , Fator XII/genética , Fator XII/imunologia , Fator XIIa/metabolismo , Camundongos , Mutação , Tempo de Tromboplastina Parcial/normas , Peptídeos/química , Peptídeos/genética , Peptídeos/imunologia , Peptídeos/metabolismo , Trombose/diagnóstico , Trombose/genética , Trombose/metabolismo
11.
JMIR Pediatr Parent ; 4(2): e27958, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34106080

RESUMO

BACKGROUND: Resilience is a person's mental ability to deal with challenging situations adaptively and is a crucial stress management skill. Psychological resilience and finding ways to cope in crises is a highly relevant topic considering the COVID-19 pandemic, which enforced quarantine, social distancing measures, and school closures worldwide. Parents and children are currently living with increased stress due to COVID-19. We need to respond with immediate ways to strengthen children's resilience. Internet-based cognitive behavioral therapy interventions for children's stress management overcome accessibility issues such as the inability to visit mental health experts owing to COVID-19 movement restrictions. An interactive learning environment was created, based on the preventive program "Friends," to overcome accessibility issues associated with delivering cognitive behavioral therapy-based interventions in formal and informal education settings. OBJECTIVE: This study aimed to examine the effectiveness of a web-based learning environment on resilience in (1) reducing anxiety symptoms and (2) increasing emotion recognition and recognition of stress management techniques among 9-10-year-old children. We also aimed to evaluate the learning environment's usability. METHODS: A quasi-experimental pretest-posttest control group design was used. In total, 20 fourth graders in the experimental group interacted with the learning environment over 6 weekly 80-minute sessions. Further, 21 fourth graders constituted the control group. The main data sources were (1) a psychometric tool to measure children's anxiety symptoms, namely the Greek translation of the original Spence Children's Anxiety Scale, (2) 3 open-ended questions assessing emotion recognition and recognition of stress management techniques, and (3) the System Usability Scale to measure the usability of the learning environment. RESULTS: In both groups, there was a small but nonsignificant postintervention reduction in reported anxiety symptoms, except for obsessive-compulsive disorder symptoms in the experimental group. A paired samples t test revealed that students' reported symptom scores of obsessive-compulsive disorder significantly decreased from 1.06 (SD 0.68) to 0.76 (SD 0.61) (t19= 5.16; P=.01). The experimental group revealed a significant increase in emotion recognition (t19=-6.99; P<.001), identification of somatic symptoms of stress (t19=-7.31; P<.001), and identification of stress management techniques (t19=-6.85; P<.001). The learning environment received a satisfactory usability score. The raw average system usability score was 76.75 (SD 8.28), which is in the 80th percentile rank and corresponds to grade B. CONCLUSIONS: This study shows that interactive learning environments might deliver resilience interventions in an accessible and cost-effective manner in formal education, potentially even in distance-learning conditions owing to the COVID-19 pandemic. Interactive learning environments on resilience are also valuable tools for parents who can use them with their children at home, for informal learning, using mobile devices. As such, they could be a promising first-step, low-intensity intervention that children and the youth can easily access.

12.
EBioMedicine ; 67: 103382, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34000623

RESUMO

BACKGROUND: Coagulopathy and inflammation are hallmarks of Coronavirus disease 2019 (COVID-19) and are associated with increased mortality. Clinical and experimental data have revealed a role for neutrophil extracellular traps (NETs) in COVID-19 disease. The mechanisms that drive thrombo-inflammation in COVID-19 are poorly understood. METHODS: We performed proteomic analysis and immunostaining of postmortem lung tissues from COVID-19 patients and patients with other lung pathologies. We further compared coagulation factor XII (FXII) and DNase activities in plasma samples from COVID-19 patients and healthy control donors and determined NET-induced FXII activation using a chromogenic substrate assay. FINDINGS: FXII expression and activity were increased in the lung parenchyma, within the pulmonary vasculature and in fibrin-rich alveolar spaces of postmortem lung tissues from COVID-19 patients. In agreement with this, plasmaaac acafajföeFXII activation (FXIIa) was increased in samples from COVID-19 patients. Furthermore, FXIIa colocalized with NETs in COVID-19 lung tissue indicating that NETs accumulation leads to FXII contact activation in COVID-19. We further showed that an accumulation of NETs is partially due to impaired NET clearance by extracellular DNases as DNase substitution improved NET dissolution and reduced FXII activation in vitro. INTERPRETATION: Collectively, our study supports that the NET/FXII axis contributes to the pathogenic chain of procoagulant and proinflammatory responses in COVID-19. Targeting both NETs and FXIIa may offer a potential novel therapeutic strategy. FUNDING: This study was supported by the European Union (840189), the Werner Otto Medical Foundation Hamburg (8/95) and the German Research Foundation (FR4239/1-1, A11/SFB877, B08/SFB841 and P06/KFO306).


Assuntos
COVID-19/metabolismo , Armadilhas Extracelulares/metabolismo , Fator XII/metabolismo , Autopsia , Estudos de Casos e Controles , Desoxirribonucleases/sangue , Desoxirribonucleases/metabolismo , Humanos , Pulmão/metabolismo , Ativação de Neutrófilo , Pneumonia , Proteômica
13.
Blood ; 137(10): 1392-1405, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32932519

RESUMO

Polyphosphate is a procoagulant inorganic polymer of linear-linked orthophosphate residues. Multiple investigations have established the importance of platelet polyphosphate in blood coagulation; however, the mechanistic details of polyphosphate homeostasis in mammalian species remain largely undefined. In this study, xenotropic and polytropic retrovirus receptor 1 (XPR1) regulated polyphosphate in platelets and was implicated in thrombosis in vivo. We used bioinformatic analyses of omics data to identify XPR1 as a major phosphate transporter in platelets. XPR1 messenger RNA and protein expression inversely correlated with intracellular polyphosphate content and release. Pharmacological interference with XPR1 activity increased polyphosphate stores, led to enhanced platelet-driven coagulation, and amplified thrombus formation under flow via the polyphosphate/factor XII pathway. Conditional gene deletion of Xpr1 in platelets resulted in polyphosphate accumulation, accelerated arterial thrombosis, and augmented activated platelet-driven pulmonary embolism without increasing bleeding in mice. These data identify platelet XPR1 as an integral regulator of platelet polyphosphate metabolism and reveal a fundamental role for phosphate homeostasis in thrombosis.


Assuntos
Plaquetas/metabolismo , Polifosfatos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Virais/metabolismo , Trombose/metabolismo , Animais , Transporte Biológico , Coagulação Sanguínea , Fator XII/metabolismo , Feminino , Masculino , Camundongos , Trombose/sangue , Receptor do Retrovírus Politrópico e Xenotrópico
14.
Thromb Haemost ; 121(1): 58-69, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32877954

RESUMO

BACKGROUND: There are acute settings where assessing the anticoagulant effect of direct oral anticoagulants (DOACs) can be useful. Due to variability among routine coagulation tests, there is an unmet need for an assay that detects DOAC effects within minutes in the laboratory or at the point of care. METHODS: We developed a novel dielectric microsensor, termed ClotChip, and previously showed that the time to reach peak permittivity (T peak) is a sensitive parameter of coagulation function. We conducted a prospective, single-center, pilot study to determine its clinical utility at detecting DOAC anticoagulant effects in whole blood. RESULTS: We accrued 154 individuals: 50 healthy volunteers, 49 rivaroxaban patients, 47 apixaban, and 8 dabigatran patients. Blood samples underwent ClotChip measurements and plasma coagulation tests. Control mean T peak was 428 seconds (95% confidence interval [CI]: 401-455 seconds). For rivaroxaban, mean T peak was 592 seconds (95% CI: 550-634 seconds). A receiver operating characteristic curve showed that the area under the curve (AUC) predicting rivaroxaban using T peak was 0.83 (95% CI: 0.75-0.91, p < 0.01). For apixaban, mean T peak was 594 seconds (95% CI: 548-639 seconds); AUC was 0.82 (95% CI: 0.73-0.91, p < 0.01). For dabigatran, mean T peak was 894 seconds (95% CI: 701-1,086 seconds); AUC was 1 (p < 0.01). Specificity for all DOACs was 88%; sensitivity ranged from 72 to 100%. CONCLUSION: This diagnostic study using samples from "real-world" DOAC patients supports that ClotChip exhibits high sensitivity at detecting DOAC anticoagulant effects in a disposable portable platform, using a miniscule amount of whole blood (<10 µL).


Assuntos
Testes de Coagulação Sanguínea/instrumentação , Monitoramento de Medicamentos/instrumentação , Inibidores do Fator Xa/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Coagulação Sanguínea/efeitos dos fármacos , Testes de Coagulação Sanguínea/métodos , Dabigatrana/farmacologia , Dabigatrana/uso terapêutico , Monitoramento de Medicamentos/métodos , Desenho de Equipamento , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridonas/farmacologia , Piridonas/uso terapêutico , Rivaroxabana/farmacologia , Rivaroxabana/uso terapêutico
15.
Exp Biol Med (Maywood) ; 245(17): 1543-1551, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32762265

RESUMO

IMPACT STATEMENT: Aging is associated with DNA methylation (DNAm) changes. Recent advancement of the whole-genome DNAm analysis technology allowed scientists to develop DNAm-based age estimators. A majority of these estimators use DNAm data from a single tissue type such as blood. In 2013, a multi-tissue age estimator using DNAm pattern of 353 CpGs was developed by Steve Horvath. This estimator was named "epigenetic clock", and the improved version using DNAm pattern of 391 CpGs was developed in 2018. The estimated age by epigenetic clock is named DNAmAge. DNAmAge can be used as a biomarker of aging predicting the risk of age-associated diseases and mortality. Although the DNAm-based age estimators were developed, the mechanism of epigenetic aging is still enigmatic. The biological significance of epigenetic aging is not well understood, either. This minireview discusses the current understanding of the mechanism of epigenetic aging and the future direction of aging research.


Assuntos
Envelhecimento/genética , Epigênese Genética , Animais , Relógios Biológicos/genética , Hipóxia Celular/genética , Metilação de DNA/genética , Células-Tronco Hematopoéticas/metabolismo , Humanos
16.
AACN Adv Crit Care ; 31(2): 129-137, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32526007

RESUMO

BACKGROUND: The VA Northeast Ohio Healthcare System introduced a new nurse-driven anti-factor Xa (anti-Xa) protocol for monitoring unfractionated heparin to replace the previous activated partial thromboplastin time protocol. OBJECTIVE: To design, implement, and evaluate the efficacy of the anti-Xa monitoring protocol. METHODS: An interdisciplinary team of providers collaborated to develop and implement a nurse-driven, facility-wide anti-factor Xa protocol for monitoring unfractionated heparin therapy. The effectiveness of this protocol was evaluated by retrospective analysis. RESULTS: We reviewed 100 medical records for compliance with the new anti-Xa monitoring protocol. We then evaluated 178 patients whose anticoagulation was monitored with the anti-Xa assay to determine the time to therapeutic range. We found that 80% of patients receiving the anti-Xa protocol achieved therapeutic anticoagulation within 24 hours, as compared with 54% of patients receiving the activated partial thromboplastin time protocol (P < .001). Protocol conversion also yielded a decrease in blood draws, dose adjustments, and potential calculation errors. CONCLUSIONS: Monitoring intravenous heparin therapy with the anti-Xa assay rather than activated partial thromboplastin time resulted in a shorter time to therapeutic anticoagulation, longer maintenance of therapeutic levels, and fewer laboratory tests and heparin dosage changes. We believe the current practice of monitoring heparin treatment with activated partial thromboplastin time assays should be reexamined.


Assuntos
Anticoagulantes/uso terapêutico , Testes de Coagulação Sanguínea/métodos , Coagulação Sanguínea/efeitos dos fármacos , Fator X/análise , Heparina/análise , Heparina/uso terapêutico , Trombose/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Protocolos Clínicos , Feminino , Heparina/administração & dosagem , Hospitais de Veteranos , Humanos , Masculino , Pessoa de Meia-Idade , Ohio , Tempo de Tromboplastina Parcial , Estudos Retrospectivos , Estados Unidos
18.
Res Pract Thromb Haemost ; 3(4): 599-606, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31624779

RESUMO

Factor XII (FXII) becomes a serine protease when blood is exposed to artificial medical surfaces or when pathologic surfaces arise in disease states leading to its autoactivation. Initiation of the blood coagulation cascade was the first recognized activity of FXIIa. Blocking FXIIa activity formed on artificial medical surfaces should reduce induced blood coagulation leading to thrombosis. In contrast to FXII enzymatic activities, less is known about zymogen FXII functions. Studies show that zymogen FXII has biologic activity in various cells in vivo. In endothelium, FXII stimulates cell growth and proliferation and, in vivo, neoangiogenesis after injury. In fibroblasts, transforming growth factor-ß increases FXII expression, which in turn stimulates fibroblast proliferation, contributing to tissue fibrosis. In neutrophils, FXII stimulates Akt2 to initiate neutrophil adhesion, migration, and chemotaxis, priming events leading to NETosis. Factor FXII deficiency leads to decreased neutrophil recruitment and improved wound healing. In dendritic cells, FXII contributes to neuroinflammation, and its deficiency or pharmacologic inhibition renders mice less susceptible to autoimmune encephalomyelitis. These combined studies indicate that FXII also contributes to multiple components of the inflammatory response. In sum, targeting FXII's biologic activities may provide novel approaches to reduce thrombosis and the inflammatory response in various disease states.

19.
Front Immunol ; 10: 2011, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507606

RESUMO

Factor XII (FXII) is the zymogen of serine protease, factor XIIa (FXIIa). FXIIa enzymatic activities have been extensively studied and FXIIa inhibition is emerging as a promising target to treat or prevent thrombosis without creating a hemostatic defect. FXII and plasma prekallikrein reciprocally activate each other and result in liberation of bradykinin. Due to its unique structure among coagulation factors, FXII exerts mitogenic activity in endothelial and smooth muscle cells, indicating that zymogen FXII has activities independent of its protease function. A growing body of evidence has revealed that both FXII and FXIIa upregulate neutrophil functions, contribute to macrophage polarization and induce T-cell differentiation. In vivo, these signaling activities contribute to host defense against pathogens, mediate the development of neuroinflammation, influence wound repair and may facilitate cancer maintenance and progression. Here, we review the roles of FXII in innate immunity as they relate to non-sterile and sterile immune responses.


Assuntos
Fator XII/metabolismo , Imunidade Inata , Animais , Coagulação Sanguínea , Bradicinina/metabolismo , Suscetibilidade a Doenças , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Humanos , Imunomodulação , Neutrófilos/imunologia , Neutrófilos/metabolismo , Calicreína Plasmática , Cicatrização
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