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1.
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
2.
Int J Mol Sci ; 22(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34502228

RESUMO

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


Assuntos
Biomarcadores/metabolismo , Comunicação Celular , Vesículas Extracelulares/metabolismo , Tromboplastina/metabolismo , Trombose/patologia , Animais , Humanos , Trombose/metabolismo
3.
Int J Mol Sci ; 22(18)2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34576303

RESUMO

Thrombosis is a major comorbidity of obesity and type-2 diabetes mellitus (T2DM). Despite the development of numerous effective treatments and preventative strategies to address thrombotic disease in such individuals, the incidence of thrombotic complications remains high. This suggests that not all the pathophysiological mechanisms underlying these events have been identified or targeted. Non-esterified fatty acids (NEFAs) are increasingly regarded as a nexus between obesity, insulin resistance, and vascular disease. Notably, plasma NEFA levels are consistently elevated in obesity and T2DM and may impact hemostasis in several ways. A potentially unrecognized route of NEFA-mediated thrombotic activity is their ability to disturb Zn2+ speciation in the plasma. Zn2+ is a potent regulator of coagulation and its availability in the plasma is monitored carefully through buffering by human serum albumin (HSA). The binding of long-chain NEFAs such as palmitate and stearate, however, trigger a conformational change in HSA that reduces its ability to bind Zn2+, thus increasing the ion's availability to bind and activate coagulation proteins. NEFA-mediated perturbation of HSA-Zn2+ binding is thus predicted to contribute to the prothrombotic milieu in obesity and T2DM, representing a novel targetable disease mechanism in these disorders.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos não Esterificados/sangue , Obesidade/metabolismo , Trombose/metabolismo , Zinco/sangue , Animais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Ácidos Graxos não Esterificados/metabolismo , Humanos , Obesidade/sangue , Obesidade/epidemiologia , Trombose/sangue , Trombose/epidemiologia , Zinco/metabolismo
5.
FASEB J ; 35(9): e21835, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34449927

RESUMO

Circulating neutrophil extracellular traps (NETs) resistant to t-PA have not been studied completely although NETs in thrombi may contribute to tissue plasminogen activator (t-PA) resistance. This research intended to elucidate whether circulating NETs are associated with t-PA resistance and the underlying mechanism. The levels of NETs were detected in the circulating neutrophils, ischemic brain tissue of acute ischemic stroke (AIS) patients, and transient middle cerebral artery occlusion (tMCAO) models. NET formation in blood, thrombi, and ischemic brain tissue of mice were analyzed by immunofluorescence. Exposed phosphatidylserine (PS) was assessed using flow cytometry and confocal microscopy. Procoagulant activity (PCA) was evaluated using fibrin formation assays, thrombin, and purified coagulation complex. The plasma levels of NETs in AIS patients were significantly higher than those in healthy individuals. After thrombolysis, a significant increase was noted in NET markers in no-improvement patients, while the changes in improvement patients were not significant. Importantly, NETs were decorated with von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) in the blood and thrombi, which could reverse the fibrinolytic effects. In addition, NETs activated platelets (PLTs) and endothelial cells (ECs), stimulating a procoagulant phenotype and facilitating vWF and PAI-1 release. DNase I, activated protein C (APC), and sivelestat markedly inhibited these effects. Furthermore, targeting NETs protected mice from tMCAO-induced cerebral ischemia, possibly by regulating vWF and PAI-1. In summary, NETs may contribute to t-PA resistance in AIS through activation of PLTs and ECs. Strategies against NETs may present a promising therapeutic approach to improve the thrombolysis efficiency of t-PA in AIS patients.


Assuntos
Isquemia Encefálica/metabolismo , Armadilhas Extracelulares/metabolismo , AVC Isquêmico/metabolismo , Neutrófilos/metabolismo , Acidente Vascular Cerebral/metabolismo , Ativador de Plasminogênio Tecidual/metabolismo , Idoso , Animais , Coagulação Sanguínea/fisiologia , Plaquetas/metabolismo , Células Endoteliais/metabolismo , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fosfatidilserinas/metabolismo , Trombina/metabolismo , Trombose/metabolismo
6.
Biomolecules ; 11(7)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34356618

RESUMO

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


Assuntos
Trifosfato de Adenosina/metabolismo , Doenças de Pequenos Vasos Cerebrais/metabolismo , Endotélio Vascular/metabolismo , AVC Isquêmico/metabolismo , Transdução de Sinais , Trombose/metabolismo , Animais , Doenças de Pequenos Vasos Cerebrais/patologia , Endotélio Vascular/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , AVC Isquêmico/patologia , Trombose/patologia
7.
Cytokine ; 146: 155634, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34247039

RESUMO

Thrombopoietin (TPO) is most recognized for its function as the primary regulator of megakaryocyte (MK) expansion and differentiation. MKs, in turn, are best known for their role in platelet production. Research indicates that MKs and platelets play an extensive role in the pathologic thrombosis at sites of high inflammation. TPO, therefore, is a key mediator of thromboinflammation. Silencing of TPO has been shown to decrease platelets levels and rates of pathologic thrombosis in patients with various inflammatory disorders (Barrett et al, 2020; Bunting et al, 1997; Desai et al, 2018; Kaser et al, 2001; Shirai et al, 2019). Given the high rates of thromboinflammmation in the novel coronavirus 2019 (COVID-19), as well as the well-documented aberrant MK activity in affected patients, TPO silencing offers a potential therapeutic modality in the treatment of COVID-19 and other pathologies associated with thromboinflammation. The current review explores the current clinical applications of TPO silencing and offers insight into a potential role in the treatment of COVID-19.


Assuntos
COVID-19/terapia , Inativação Gênica , Inflamação/genética , Trombocitose/genética , Trombopoetina/genética , Trombose/genética , COVID-19/complicações , COVID-19/virologia , Humanos , Inflamação/complicações , Inflamação/metabolismo , Megacariócitos/metabolismo , SARS-CoV-2/fisiologia , Trombocitose/complicações , Trombocitose/metabolismo , Trombopoese/genética , Trombopoetina/metabolismo , Trombose/complicações , Trombose/metabolismo
8.
Arterioscler Thromb Vasc Biol ; 41(9): 2370-2383, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34261330

RESUMO

Thrombosis is a major complication of cardiovascular disease, leading to myocardial infarction, acute ischemic stroke, or venous thromboembolism. Thrombosis occurs when a thrombus forms inside blood vessels disrupting blood flow. Developments in thrombectomy to remove thrombi from vessels have provided new opportunities to study thrombus composition which may help to understand mechanisms of disease and underpin improvements in treatments. We aimed to review thrombus compositions, roles of components in thrombus formation and stability, and methods to investigate thrombi. Also, we summarize studies on thrombus structure obtained from cardiovascular patients and animal models. Thrombi are composed of fibrin, red blood cells, platelets, leukocytes, and neutrophil extracellular traps. These components have been analyzed by several techniques, including scanning electron microscopy, laser scanning confocal microscopy, histochemistry, and immunohistochemistry; however, each technique has advantages and limitations. Thrombi are heterogenous in composition, but overall, thrombi obtained from myocardial infarction are composed of mainly fibrin and other components, including platelets, red blood cells, leukocytes, and cholesterol crystals. Thrombi from patients with acute ischemic stroke are characterized by red blood cell- and platelet-rich regions. Thrombi from patients with venous thromboembolism contain mainly red blood cells and fibrin with some platelets and leukocytes. Thrombus composition from patients with myocardial infarction is influenced by ischemic time. Animal thrombosis models are crucial to gain further mechanistic information about thrombosis and thrombus structure, with thrombi being similar in composition compared with those from patients. Further studies on thrombus composition and function are key to improve treatment and clinical outcome of thrombosis.


Assuntos
Coagulação Sanguínea , Plaquetas/metabolismo , Eritrócitos/metabolismo , Fibrina/metabolismo , Trombose/metabolismo , Animais , Plaquetas/patologia , Colesterol/metabolismo , Modelos Animais de Doenças , Eritrócitos/patologia , Humanos , Leucócitos/metabolismo , Trombectomia , Trombose/patologia , Trombose/terapia
9.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199319

RESUMO

Inflammation is an old concept that has started to be considered as an important factor in infection and chronic diseases. The role of leukocytes, the plasmatic components, then of the mediators such as prostaglandins, cytokines, and, in recent decades, of the endothelium has completed the concept of the inflammation process. The function of the endothelium appeared to be crucial as a regulator or the initiator of the inflammatory process. Culture of human endothelial cells and experimental systems made it possible to define the molecular basis of inflammation in vascular diseases, in diabetes mellitus, atherosclerosis, vasculitis and thromboembolic complications. Advanced glycation end product receptor (RAGE), present on endothelial cells (ECs) and monocytes, participates in the activation of these cells in inflammatory conditions. Inflammasome is a cytosolic multiprotein that controls the response to diverse microorganisms. It is positively regulated by stimulator of interferon response CGAMP interactor-1 (STING1). Angiogenesis and thrombotic events are dysregulated during inflammation. ECs appear to be a protector, but also a possible initiator of thrombosis.


Assuntos
Aterosclerose/patologia , Endotélio Vascular/metabolismo , Trombose/patologia , Aterosclerose/metabolismo , Endotélio Vascular/citologia , Humanos , Inflamassomos/metabolismo , Proteínas de Membrana/metabolismo , Neovascularização Fisiológica , Óxido Nítrico/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Trombose/metabolismo
10.
Nutrients ; 13(6)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207745

RESUMO

It has recently been hypothesized that vitamin K could play a role in COVID-19. We aimed to test the hypotheses that low vitamin K status is a common characteristic of patients hospitalized with COVID-19 compared to population controls and that low vitamin K status predicts mortality in COVID-19 patients. In a cohort of 138 COVID-19 patients and 138 population controls, we measured plasma dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP), which reflects the functional vitamin K status in peripheral tissue. Forty-three patients died within 90 days from admission. In patients, levels of dp-ucMGP differed significantly between survivors (mean 877; 95% CI: 778; 995) and non-survivors (mean 1445; 95% CI: 1148; 1820). Furthermore, levels of dp-ucMGP (pmol/L) were considerably higher in patients (mean 1022; 95% CI: 912; 1151) compared to controls (mean 509; 95% CI: 485; 540). Cox regression survival analysis showed that increasing levels of dp-ucMGP (reflecting low vitamin K status) were associated with higher mortality risk (sex- and age-adjusted hazard ratio per doubling of dp-ucMGP was 1.49, 95% CI: 1.03; 2.24). The association attenuated and became statistically insignificant after adjustment for co-morbidities (sex, age, CVD, diabetes, BMI, and eGFR adjusted hazard ratio per doubling of dp-ucMGP was 1.22, 95% CI: 0.82; 1.80). In conclusion, we found that low vitamin K status was associated with mortality in patients with COVID-19 in sex- and age-adjusted analyses, but not in analyses additionally adjusted for co-morbidities. Randomized clinical trials would be needed to clarify a potential role, if any, of vitamin K in the course of COVID-19.


Assuntos
COVID-19/mortalidade , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Hospitalização , Deficiência de Vitamina K/mortalidade , Vitamina K/sangue , Adulto , Idoso , Biomarcadores/sangue , Coagulação Sanguínea , COVID-19/complicações , COVID-19/metabolismo , Proteínas de Ligação ao Cálcio/sangue , Estudos de Coortes , Proteínas da Matriz Extracelular/sangue , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise de Regressão , SARS-CoV-2 , Trombose/metabolismo , Deficiência de Vitamina K/sangue , Deficiência de Vitamina K/complicações , Adulto Jovem
11.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203139

RESUMO

Fibrinogen is one of the key molecular players in haemostasis. Thrombin-mediated release of fibrinopeptides from fibrinogen converts this soluble protein into a network of fibrin fibres that form a building block for blood clots. Thrombin-activated factor XIII further crosslinks the fibrin fibres and incorporates antifibrinolytic proteins into the network, thus stabilising the clot. The conversion of fibrinogen to fibrin also exposes binding sites for fibrinolytic proteins to limit clot formation and avoid unwanted extension of the fibrin fibres. Altered clot structure and/or incorporation of antifibrinolytic proteins into fibrin networks disturbs the delicate equilibrium between clot formation and lysis, resulting in either unstable clots (predisposing to bleeding events) or persistent clots that are resistant to lysis (increasing risk of thrombosis). In this review, we discuss the factors responsible for alterations in fibrin(ogen) that can modulate clot stability, in turn predisposing to abnormal haemostasis. We also explore the mechanistic pathways that may allow the use of fibrinogen as a potential therapeutic target to treat vascular thrombosis or bleeding disorders. Better understanding of fibrinogen function will help to devise future effective and safe therapies to modulate thrombosis and bleeding risk, while maintaining the fine balance between clot formation and lysis.


Assuntos
Fator XIIIa/metabolismo , Fibrina/metabolismo , Fibrinogênio/metabolismo , Trombose/metabolismo , Animais , Fator XIIIa/genética , Fibrina/genética , Fibrinogênio/genética , Fibrinólise/genética , Fibrinólise/fisiologia , Humanos , Trombose/genética
12.
Int J Mol Sci ; 22(12)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205443

RESUMO

Factor XIII (FXIII) is a transglutaminase that promotes thrombus stability by cross-linking fibrin. The cellular form, a homodimer of the A subunits, denoted FXIII-A, lacks a classical signal peptide for its release; however, we have shown that it is exposed on activated platelets. Here we addressed whether monocytes expose intracellular FXIII-A in response to stimuli. Using flow cytometry, we demonstrate that FXIII-A antigen and activity are up-regulated on human monocytes in response to stimulation by IL-4 and IL-10. Higher basal levels of the FXIII-A antigen were noted on the membrane of the monocytic cell line THP-1, but activity was significantly enhanced following stimulation with IL-4 and IL-10. In contrast, treatment with lipopolysaccharide did not upregulate exposure of FXIII-A in THP-1 cells. Quantification of the FXIII-A activity revealed a significant increase in THP-1 cells in total cell lysates following stimulation with IL-4 and IL-10. Following fractionation, the largest pool of FXIII-A was membrane associated. Monocytes were actively incorporated into the fibrin mesh of model thrombi. We found that stimulation of monocytes and THP-1 cells with IL-4 and IL-10 stabilized FXIII-depleted thrombi against fibrinolytic degradation, via a transglutaminase-dependent mechanism. Our data suggest that monocyte-derived FXIII-A externalized in response to stimuli participates in thrombus stabilization.


Assuntos
Fator XIIIa/metabolismo , Monócitos/metabolismo , Trombose/metabolismo , Voluntários Saudáveis , Humanos , Células THP-1/metabolismo
13.
ACS Appl Mater Interfaces ; 13(24): 27814-27824, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34102839

RESUMO

Early spontaneous detection of thrombin activation benefits precise theranostics for thrombotic vascular disease. Herein, a thrombin-responsive nanoprobe conjugated by a FITC dye, PEGylated Fe3O4 nanoparticles, and a thrombin-sensitive peptide (LASG) was constructed to visualize thrombin activation and subsequent thrombosis in vivo. The FITC dye was linked to the LASG coated on the Fe3O4 nanoparticles for sensing the thrombin activity via the Förster resonance energy transfer effect. In vitro fluorescence imaging showed that the fluorescence signal intensity increased significantly after incubation with thrombin in contrast to that of the control group (p < 0.05), and the signal intensity was enhanced with the increase in thrombin concentration. Further in vivo fluorescence imaging also revealed that the signal elevated markedly in the left common carotid artery (LCCA) lesion of the mice thrombosis model after nanoprobe injection, in contrast to that of the control + nanoprobe group (p < 0.05). Moreover, the thrombin inhibitor bivalirudin could decrease the filling defect of the LCCA. Three-dimensional fusion images of micro-CT and fluorescence confirmed that filling defects in the LCCA were nicely colocalized with fluorescence signal caused by nanoprobes. The nanoplatform based on a thrombin-activatable visualization system could provide smart responsive and dynamic imaging of thrombosis in vivo.


Assuntos
Nanopartículas de Magnetita/química , Trombose/diagnóstico por imagem , Trombose/metabolismo , Sequência de Aminoácidos , Animais , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Fluoresceína-5-Isotiocianato/química , Corantes Fluorescentes/química , Imageamento por Ressonância Magnética , Masculino , Camundongos , Microscopia Confocal , Microscopia de Fluorescência , Imagem Multimodal , Peptídeos/química , Trombose/patologia , Tomografia Computadorizada por Raios X
14.
Nat Commun ; 12(1): 3972, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172735

RESUMO

Recovery after stroke is thought to be mediated by adaptive circuit plasticity, whereby surviving neurons assume the roles of those that died. However, definitive longitudinal evidence of neurons changing their response selectivity after stroke is lacking. We sought to directly test whether such functional "remapping" occurs within mouse primary somatosensory cortex after a stroke that destroys the C1 barrel. Using in vivo calcium imaging to longitudinally record sensory-evoked activity under light anesthesia, we did not find any increase in the number of C1 whisker-responsive neurons in the adjacent, spared D3 barrel after stroke. To promote plasticity after stroke, we also plucked all whiskers except C1 (forced use therapy). This led to an increase in the reliability of sensory-evoked responses in C1 whisker-responsive neurons but did not increase the number of C1 whisker-responsive neurons in spared surround barrels over baseline levels. Our results argue against remapping of functionality after barrel cortex stroke, but support a circuit-based mechanism for how rehabilitation may improve recovery.


Assuntos
Córtex Somatossensorial/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Trombose/fisiopatologia , Animais , Cálcio/metabolismo , Potenciais Somatossensoriais Evocados , Feminino , Masculino , Camundongos Transgênicos , Imagem Molecular , Plasticidade Neuronal/fisiologia , Neurônios/patologia , Córtex Somatossensorial/fisiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/terapia , Trombose/metabolismo , Trombose/terapia , Vibrissas/fisiologia
15.
Int J Biol Macromol ; 185: 122-133, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34147523

RESUMO

Photothermal-responsive (PTR) and anti-oxidative silk fibroin/dopamine nanoparticles (SD NPs) mediated by tyrosinase were produced, and decorated either by curcumin or albumin (BSA) to produce SD/curcumin or SD/BSA NPs as drug delivery vehicles, respectively. Both drug loaded NPs were further blended into SF solutions to produce SD films, as a depot-based drug delivery. The reaction mechanisms for producing new SD NPs were proposed. Anti-oxidative activities for SD NPs were examined by H2O2 scavenge capacities of NPs. NPs were not cytotoxic at concentration of 1000µg/mL. Moreover, heparin was coated to SD films to produce SDH films for temporary implants. Cumulative release profiles for drugs loaded SDH films showed fast releases and then sustained releases stages. Furthermore, the releases of curcumin in sustained stages for varying SD/curcumin NPs loaded into SDH films were dependent on amounts of NPs. BSA releases profiles for SD/BSA NPs loaded into SDH films were similar to those profiles for the films carried with SD/curcumin NPs but release periods of BSA were short. Degrees of PTR effects with irradiation of near infrared on the releases of two drugs loaded films were different. Blood clot at wound areas of rats with SDH films implantations was not found for 24 h study.


Assuntos
Albuminas/química , Antioxidantes/farmacologia , Curcumina/administração & dosagem , Dopamina/química , Fibroínas/química , Trombose/terapia , Animais , Antioxidantes/química , Linhagem Celular , Curcumina/química , Curcumina/farmacologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Peróxido de Hidrogênio/metabolismo , Masculino , Camundongos , Nanopartículas , Terapia Fototérmica , Ratos , Trombose/metabolismo
16.
Curr Opin Hematol ; 28(5): 285-291, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34183535

RESUMO

PURPOSE OF REVIEW: This review summarizes high-impact research in myeloproliferative neoplasms (MPN) from the last 18 months, with a particular focus on basic science findings. RECENT FINDINGS: A pseudo-hypoxia state with stabilization of hypoxia-inducible factor (HIFα exists that is central to cell growth, cell renewal, inflammation, and thrombotic potential in MPN hematopoietic cells. SUMMARY: HIFα and inflammatory pathways are new therapeutic targets in MPN, with the potential to ameliorate thrombotic risk and perhaps eradicate mutant progenitor cells.


Assuntos
Neoplasias Hematológicas , Células-Tronco Hematopoéticas/metabolismo , Transtornos Mieloproliferativos , Trombose , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/genética , Inflamação/metabolismo , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Proteínas de Neoplasias/metabolismo , Trombose/etiologia , Trombose/genética , Trombose/metabolismo
17.
Angiogenesis ; 24(4): 755-788, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34184164

RESUMO

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 ß [IL-1ß] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy.


Assuntos
COVID-19/metabolismo , Mielopoese , Neovascularização Patológica/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , SARS-CoV-2/metabolismo , Trombose/metabolismo , COVID-19/patologia , COVID-19/terapia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Endoteliais/virologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Proteínas de Membrana/metabolismo , Neovascularização Patológica/patologia , Neovascularização Patológica/terapia , Neovascularização Patológica/virologia , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/terapia , Síndrome do Desconforto Respiratório/virologia , Trombose/patologia , Trombose/terapia , Trombose/virologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator de von Willebrand/metabolismo
19.
Vasc Health Risk Manag ; 17: 273-298, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34103921

RESUMO

COVID-19 sepsis is characterized by acute respiratory distress syndrome (ARDS) as a consequence of pulmonary tropism of the virus and endothelial heterogeneity of the host. ARDS is a phenotype among patients with multiorgan dysfunction syndrome (MODS) due to disseminated vascular microthrombotic disease (VMTD). In response to the viral septicemia, the host activates the complement system which produces terminal complement complex C5b-9 to neutralize pathogen. C5b-9 causes pore formation on the membrane of host endothelial cells (ECs) if CD59 is underexpressed. Also, viral S protein attraction to endothelial ACE2 receptor damages ECs. Both affect ECs and provoke endotheliopathy. Disseminated endotheliopathy activates two molecular pathways: inflammatory and microthrombotic. The former releases inflammatory cytokines from ECs, which lead to inflammation. The latter initiates endothelial exocytosis of unusually large von Willebrand factor (ULVWF) multimers and FVIII from Weibel-Palade bodies. If ADAMTS13 is insufficient, ULVWF multimers activate intravascular hemostasis of ULVWF path. In activated ULVWF path, ULVWF multimers anchored to damaged endothelial cells recruit circulating platelets and trigger microthrombogenesis. This process produces "microthrombi strings" composed of platelet-ULVWF complexes, leading to endotheliopathy-associated VMTD (EA-VMTD). In COVID-19, microthrombosis initially affects the lungs per tropism causing ARDS, but EA-VMTD may orchestrate more complex clinical phenotypes, including thrombotic thrombocytopenic purpura (TTP)-like syndrome, hepatic coagulopathy, MODS and combined micro-macrothrombotic syndrome. In this pandemic, ARDS and pulmonary thromboembolism (PTE) have often coexisted. The analysis based on two hemostatic theories supports ARDS caused by activated ULVWF path is EA-VMTD and PTE caused by activated ULVWF and TF paths is macrothrombosis. The thrombotic disorder of COVID-19 sepsis is consistent with the notion that ARDS is virus-induced disseminated EA-VMTD and PTE is in-hospital vascular injury-related macrothrombosis which is not directly  related to viral pathogenesis. The pathogenesis-based therapeutic approach is discussed for the treatment of EA-VMTD with antimicrothrombotic regimen and the potential need of anticoagulation therapy for coinciding macrothrombosis in comprehensive COVID-19 care.


Assuntos
COVID-19/epidemiologia , Células Endoteliais/metabolismo , Fibrinolíticos/uso terapêutico , Hemostasia/fisiologia , SARS-CoV-2 , Sepse/complicações , Trombose/etiologia , COVID-19/complicações , Humanos , Pandemias , Fenótipo , Sepse/metabolismo , Trombose/tratamento farmacológico , Trombose/metabolismo
20.
Biomolecules ; 11(5)2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066385

RESUMO

SARS-CoV-2 is a member of the family of coronaviruses associated with severe outbreaks of respiratory diseases in recent decades and is the causative agent of the COVID-19 pandemic. The recognition by and activation of the innate immune response recruits neutrophils, which, through their different mechanisms of action, form extracellular neutrophil traps, playing a role in infection control and trapping viral, bacterial, and fungal etiological agents. However, in patients with COVID-19, activation at the vascular level, combined with other cells and inflammatory mediators, leads to thrombotic events and disseminated intravascular coagulation, thus leading to a series of clinical manifestations in cerebrovascular, cardiac, pulmonary, and kidney disease while promoting severe disease and mortality. Previous studies of hospitalized patients with COVID-19 have shown that elevated levels of markers specific for NETs, such as free DNA, MPO, and H3Cit, are strongly associated with the total neutrophil count; with acute phase reactants that include CRP, D-dimer, lactate dehydrogenase, and interleukin secretion; and with an increased risk of severe COVID-19. This study analyzed the interactions between NETs and the activation pathways involved in immunothrombotic processes in patients with COVID-19.


Assuntos
COVID-19/patologia , Armadilhas Extracelulares/metabolismo , Trombose/imunologia , Trombose/patologia , Biomarcadores/metabolismo , COVID-19/imunologia , COVID-19/virologia , Proteínas do Sistema Complemento/metabolismo , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/patologia , Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/patologia , Humanos , Neutrófilos/citologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , SARS-CoV-2/isolamento & purificação , Trombose/metabolismo
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