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1.
Pediatr Emerg Care ; 38(2): e475-e481, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33848094

RESUMO

OBJECTIVES: To review the presentation, management, and outcomes of pediatric pulmonary embolism (PE) patients treated at a single institution over 10 years to determine whether laboratory findings and clinical presentation predict disease severity. METHODS: We performed a retrospective chart review of patients treated for PE in a 14-bed pediatric intensive care unit from January 1, 2008, to December 31, 2018. Associations between clot burden and disease severity, clinical risk factors (body mass index, recent hospitalization, estrogen use), clinical presentation (heart rate, oxygen saturation), and laboratory values (white blood cell count, D-Dimer, troponin, proBNP) were performed using Student t test, χ2 tests, and 1-way analysis of variance. Patients were risk stratified by American Heart Association guidelines. RESULTS: Eighteen (72%) patients (girls) were treated for PE. Common risk factors included recent hospitalization (67%) and oral contraceptives (62%). Risk factors, clinical presentation (including hypoxemia and tachypnea), and laboratory studies did not correlate with disease severity or clot burden. Electrocardiogram and radiographic findings were non-specific. Computer tomography pulmonary angiography (CTPA) was required to diagnose 94%. Sixteen received unfractionated heparin, and 5 required additional intervention. Risk factors, clinical features, and laboratory studies did not predict who required intervention. CONCLUSIONS: Of 18 pediatric patients treated for PE at a single institution over 10 years, vital signs and laboratory data did not predict disease severity or clot burden, and CTPA was required for diagnosis in all but 1. Emergency room providers must have a high index of suspicion for diagnosis and cannot be reassured by normal electrocardiogram or plain film findings. At a time when pediatric providers are under pressure to minimize unnecessary radiation exposure, this lack of correlation of clinical presentation and laboratory findings highlights the importance of considering CTPA when PE is suspected.


Assuntos
Heparina , Embolia Pulmonar , Angiografia , Criança , Angiografia por Tomografia Computadorizada , Feminino , Humanos , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/tratamento farmacológico , Estudos Retrospectivos
2.
Stroke ; 51(2): 542-548, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31842706

RESUMO

Background and Purpose- Data regarding the safety and efficacy of intravenous tPA (tissue-type plasminogen activator) in childhood acute arterial ischemic stroke are inadequate. The TIPS trial (Thrombolysis in Pediatric Stroke; National Institutes of Health grant R01NS065848)-a prospective safety and dose-finding trial of intravenous tPA in acute childhood stroke-was closed for lack of accrual. TIPS sites have subsequently treated children with acute stroke in accordance with established institutional protocols supporting data collection on outcomes. Methods- Data on children treated with intravenous tPA for neuroimaging-confirmed arterial ischemic stroke were collected retrospectively from 16 former TIPS sites to establish preliminary safety data. Participating sites were required to report all children who were treated with intravenous tPA to minimize reporting bias. Symptomatic intracranial hemorrhage (SICH) was defined as ECASS (European Cooperative Acute Stroke Study) II parenchymal hematoma type 2 or any intracranial hemorrhage associated with neurological deterioration within 36 following tPA administration. A Bayesian beta-binomial model for risk of SICH following intravenous tPA was fit using a prior distribution based on the risk level in young adults (1.7%); to test for robustness, the model was also fit with uninformative and conservative priors. Results- Twenty-six children (age range, 1.1-17 years; median, 14 years; 12 boys) with stroke and a median pediatric National Institutes of Health Stroke Scale score of 14 were treated with intravenous tPA within 2 to 4.5 hours (median, 3.0 hours) after stroke onset. No patient had SICH. Two children developed epistaxis. Conclusions- The estimated risk of SICH after tPA in children is 2.1% (95% highest posterior density interval, 0.0%-6.7%; mode, 0.9%). Regardless of prior assumption, there is at least a 98% chance that the risk is <15% and at least a 93% chance that the risk is <10%. These results suggest that the overall risk of SICH after intravenous tPA in children with acute arterial ischemic stroke, when given within 4.5 hours after symptom onset, is low.


Assuntos
Hemorragias Intracranianas/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/uso terapêutico , Adolescente , Isquemia Encefálica/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Lactente , Masculino , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/sangue
3.
Semin Thromb Hemost ; 45(3): 297-301, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30912102

RESUMO

Platelet function testing, which began more than a hundred years ago, is a time-consuming and uncertain process. Simulating hemostasis and the blood vessel microenvironment in vitro is challenging, which poses a difficulty for diagnosing platelet dysfunction and mild von Willebrand disease (VWD). In an effort to simulate the rheological microenvironment within blood vessels, several blood flow devices have been introduced since the 1980s. These devices are capable of reproducing the shear rates found in arterioles and venules, and of incorporating endothelial cell monolayers and surfaces with adsorbed platelet-adhesive proteins. The authors will describe and review here the presently most well-known blood flow devices. The technologies inherent in these devices offer a combination of physiologic accuracy and small blood volume requirements in the evaluation of platelet disorders and mild VWD (or "symptomatic low von Willebrand factor") in flowing whole blood, with the potential to individualize therapeutic options for and to achieve greater diagnostic accuracy in mild platelet disorders and VWD.


Assuntos
Plaquetas/metabolismo , Microfluídica/métodos , Testes de Função Plaquetária/métodos , Humanos
4.
J Org Chem ; 83(19): 11825-11838, 2018 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-30168327

RESUMO

Acid-catalyzed condensation of a benzo[ f]indane dialdehyde with a tripyrrane, followed by an oxidation step, afforded the first example of a naphtho[2,3- b]-21-carbaporphyrin. This π-extended porphyrinoid system is strongly aromatic and gave a porphyrin-like UV-vis spectrum with a Soret band at 432 nm. Protonation with TFA gave a monocation, but under highly acidic conditions a C-protonated dication was generated. Reaction of the naphthoporphyrin with ferric chloride produced a 21-chloro derivative. Alkylation with methyl iodide and potassium carbonate gave a 22-methyl derivative, and this reacted with palladium(II) acetate to afford a palladium(II) complex in which the internal methyl group had migrated from a nitrogen to a carbon atom. Treatment of the naphthocarbaporphyrin with silver(I) acetate generated the corresponding silver(III) complex. In naphtho[2,3- b]-21-carbaporphyrin and many of its derivatives, the aromatic conjugation pathways appear to bypass the naphthalene unit, and for this reason the UV-vis spectra were little affected. However, the diprotonated dication and the palladium(II) complex have aromatic pathways that pass through the naphthalene moiety, and this leads to large bathochromic shifts for these species. The results provide insights on the influence of fused aromatic units on the reactivity, spectroscopic properties, and aromatic characteristics of carbaporphyrinoid systems.

6.
Kidney Int ; 90(4): 774-82, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27378476

RESUMO

Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli (STEC HUS) is a worldwide endemic problem, and its pathophysiology is not fully elucidated. Here we tested whether the mannose-binding lectin (MBL2), an initiating factor of lectin complement pathway activation, plays a crucial role in STEC HUS. Using novel human MBL2-expressing mice (MBL2 KI) that lack murine Mbls (MBL2(+/+)Mbl1(-/-)Mbl2(-/-)), a novel STEC HUS model consisted of an intraperitoneal injection with Shiga toxin-2 (Stx-2) with or without anti-MBL2 antibody (3F8, intraperitoneal). Stx-2 induced weight loss, anemia, and thrombocytopenia and increased serum creatinine, free serum hemoglobin, and cystatin C levels, but a significantly decreased glomerular filtration rate compared with control/sham mice. Immunohistochemical staining revealed renal C3d deposition and fibrin deposition in glomeruli in Stx-2-injected mice. Treatment with 3F8 completely inhibited serum MBL2 levels and significantly attenuated Stx-2 induced-renal injury, free serum hemoglobin levels, renal C3d, and fibrin deposition and preserved the glomerular filtration rate. Thus, MBL2 inhibition significantly protected against complement activation and renal injury induced by Stx-2. This novel mouse model can be used to study the role of complement, particularly lectin pathway-mediated complement activation, in Stx-2-induced renal injury.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Complemento C3d/metabolismo , Infecções por Escherichia coli/tratamento farmacológico , Síndrome Hemolítico-Urêmica/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Lectina de Ligação a Manose/imunologia , Toxina Shiga II/toxicidade , Animais , Anticorpos Monoclonais Murinos , Ativação do Complemento/efeitos dos fármacos , Modelos Animais de Doenças , Infecções por Escherichia coli/sangue , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Técnicas de Introdução de Genes , Taxa de Filtração Glomerular , Síndrome Hemolítico-Urêmica/sangue , Síndrome Hemolítico-Urêmica/imunologia , Síndrome Hemolítico-Urêmica/microbiologia , Humanos , Imuno-Histoquímica , Rim/imunologia , Masculino , Lectina de Ligação a Manose/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Toxina Shiga II/imunologia , Escherichia coli Shiga Toxigênica/metabolismo
7.
Brain ; 138(Pt 11): 3206-20, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26377633

RESUMO

See Aubourg (doi:10.1093/awv271) for a scientific commentary on this article.X-linked adrenoleukodystrophy is caused by mutations in the ABCD1 gene leading to accumulation of very long chain fatty acids. Its most severe neurological manifestation is cerebral adrenoleukodystrophy. Here we demonstrate that progressive inflammatory demyelination in cerebral adrenoleukodystrophy coincides with blood-brain barrier dysfunction, increased MMP9 expression, and changes in endothelial tight junction proteins as well as adhesion molecules. ABCD1, but not its closest homologue ABCD2, is highly expressed in human brain microvascular endothelial cells, far exceeding its expression in the systemic vasculature. Silencing of ABCD1 in human brain microvascular endothelial cells causes accumulation of very long chain fatty acids, but much later than the immediate upregulation of adhesion molecules and decrease in tight junction proteins. This results in greater adhesion and transmigration of monocytes across the endothelium. PCR-array screening of human brain microvascular endothelial cells after ABCD1 silencing revealed downregulation of both mRNA and protein levels of the transcription factor c-MYC (encoded by MYC). Interestingly, MYC silencing mimicked the effects of ABCD1 silencing on CLDN5 and ICAM1 without decreasing the levels of ABCD1 protein itself. Together, these data demonstrate that ABCD1 deficiency induces significant alterations in brain endothelium via c-MYC and may thereby contribute to the increased trafficking of leucocytes across the blood-brain barrier as seen in cerebral adrenouleukodystrophy.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Adrenoleucodistrofia/genética , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Doenças Desmielinizantes/metabolismo , Endotélio Vascular/metabolismo , Microvasos/metabolismo , RNA Mensageiro/metabolismo , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP , Adolescente , Adrenoleucodistrofia/metabolismo , Adrenoleucodistrofia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas de Ligação ao Cálcio , Estudos de Casos e Controles , Células Cultivadas , Criança , Claudina-5/genética , Claudina-5/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Doenças Desmielinizantes/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio Vascular/patologia , Ácidos Graxos/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Heterozigoto , Homozigoto , Células Endoteliais da Veia Umbilical Humana , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Proteínas dos Microfilamentos , Microscopia Confocal , Microvasos/citologia , Microvasos/patologia , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/metabolismo , Esclerose Múltipla Recidivante-Remitente/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo , Adulto Jovem , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
8.
Stroke ; 45(7): 2018-23, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24916908

RESUMO

BACKGROUND AND PURPOSE: In adult stroke, the advent of thrombolytic therapy led to the development of primary stroke centers capable to diagnose and treat patients with acute stroke rapidly. We describe the development of primary pediatric stroke centers through preparation of participating centers in the Thrombolysis in Pediatric Stroke (TIPS) trial. METHODS: We collected data from the 17 enrolling TIPS centers regarding the process of becoming an acute pediatric stroke center with capability to diagnose, evaluate, and treat pediatric stroke rapidly, including use of thrombolytic therapy. RESULTS: Before 2004, <25% of TIPS sites had continuous 24-hour availability of acute stroke teams, MRI capability, or stroke order sets, despite significant pediatric stroke expertise. After TIPS preparation, >80% of sites now have these systems in place, and all sites reported increased readiness to treat a child with acute stroke. Use of a 1- to 10-Likert scale on which 10 represented complete readiness, median center readiness increased from 6.2 before site preparation to 8.7 at the time of site activation (P≤0.001). CONCLUSIONS: Before preparing for TIPS, centers interested in pediatric stroke had not developed systematic strategies to diagnose and treat acute pediatric stroke. TIPS trial preparation has resulted in establishment of pediatric acute stroke centers with clinical and system preparedness for evaluation and care of children with acute stroke, including use of a standardized protocol for evaluation and treatment of acute arterial stroke in children that includes use of intravenous tissue-type plasminogen activator. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01591096.


Assuntos
Ensaios Clínicos como Assunto/normas , Fibrinolíticos/administração & dosagem , Hospitais Pediátricos/normas , Qualidade da Assistência à Saúde/normas , Acidente Vascular Cerebral/terapia , Centros de Atenção Terciária/normas , Terapia Trombolítica/normas , Ativador de Plasminogênio Tecidual/administração & dosagem , Adolescente , Criança , Pré-Escolar , Feminino , Fibrinolíticos/efeitos adversos , Hospitais Pediátricos/organização & administração , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Masculino , Estudos Multicêntricos como Assunto , Qualidade da Assistência à Saúde/estatística & dados numéricos , Acidente Vascular Cerebral/tratamento farmacológico , Centros de Atenção Terciária/organização & administração , Centros de Atenção Terciária/estatística & dados numéricos , Terapia Trombolítica/efeitos adversos , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/efeitos adversos
9.
Cancer ; 120(1): 126-33, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24122173

RESUMO

BACKGROUND: The leading cause of death among patients with hereditary retinoblastoma is second malignancy. Despite its high rate of efficacy, radiotherapy (RT) is often avoided due to fear of inducing a secondary tumor. Proton RT allows for significant sparing of nontarget tissue. The current study compared the risk of second malignancy in patients with retinoblastoma who were treated with photon and proton RT. METHODS: A retrospective review was performed of patients with retinoblastoma who were treated with proton RT at the Massachusetts General Hospital or photon RT at Boston Children's Hospital between 1986 and 2011. RESULTS: A total of 86 patients were identified, 55 of whom received proton RT and 31 of whom received photon RT. Patients were followed for a median of 6.9 years (range, 1.0 years-24.4 years) in the proton cohort and 13.1 years (range, 1.4 years-23.9 years) in the photon cohort. The 10-year cumulative incidence of RT-induced or in-field second malignancies was significantly different between radiation modalities (proton vs photon: 0% vs 14%; P = .015). The 10-year cumulative incidence of all second malignancies was also different, although with borderline significance (5% vs 14%; P = .120). CONCLUSIONS: Retinoblastoma is highly responsive to radiation. The central objection to the use of RT, the risk of second malignancy, is based on studies of patients treated with antiquated, relatively nonconformal techniques. The current study is, to the authors' knowledge, the first to present a series of patients treated with the most conformal of the currently available external-beam RT modalities. Although longer follow-up is necessary, the preliminary data from the current study suggest that proton RT significantly lowers the risk of RT-induced malignancy.


Assuntos
Neoplasias Induzidas por Radiação/etiologia , Segunda Neoplasia Primária/etiologia , Terapia com Prótons/métodos , Retinoblastoma/patologia , Retinoblastoma/radioterapia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Incidência , Lactente , Masculino , Neoplasias Induzidas por Radiação/patologia , Neoplasias Induzidas por Radiação/prevenção & controle , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/prevenção & controle , Estudos Retrospectivos , Adulto Jovem
11.
Blood ; 120(4): 748-60, 2012 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-22538854

RESUMO

Age-group analyses were conducted of patients in the prophylactic platelet dose trial (PLADO), which evaluated the relation between platelet dose per transfusion and bleeding. Hospitalized patients with treatment-induced hypoproliferative thrombocytopenia were randomly assigned to 1 of 3 platelet doses: 1.1 × 10(11), 2.2 × 10(11), or 4.4 × 10(11) platelets/m(2) per transfusion, given for morning counts of ≤ 10 000 platelets/µL. Daily hemostatic assessments were performed. The primary end point (percentage of patients who developed grade 2 or higher World Health Organization bleeding) was evaluated in 198 children (0-18 years) and 1044 adults. Although platelet dose did not predict bleeding for any age group, children overall had a significantly higher risk of grade 2 or higher bleeding than adults (86%, 88%, 77% vs 67% of patients aged 0-5 years, 6-12 years, 13-18 years, vs adults, respectively) and more days with grade 2 or higher bleeding (median, 3 days in each pediatric group vs 1 day in adults; P < .001). The effect of age on bleeding differed by disease treatment category and was most pronounced among autologous transplant recipients. Pediatric subjects were at higher risk of bleeding over a wide range of platelet counts, indicating that their excess bleeding risk may be because of factors other than platelet counts.


Assuntos
Hemorragia/etiologia , Transfusão de Plaquetas/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Feminino , Hemorragia/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Contagem de Plaquetas , Prognóstico , Estudos Prospectivos , Adulto Jovem
12.
Thromb Res ; 240: 109038, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38850807

RESUMO

BACKGROUND: Shiga toxin (Stx) can activate inflammatory signaling, leading to vascular dysfunction and promotion of a pro-thrombotic tissue microenvironment. Stx can trigger the development of the enterohemorrhagic (childhood) hemolytic uremic syndrome (eHUS), a triad of thrombocytopenia, hemolytic anemia, and acute kidney injury, often requiring dialysis. Additional features may include damage to other organs, including the gastrointestinal tract, pancreas, brain and cardiovascular system; death occurs in 2-5 %. eHUS is a thrombotic microangiopathy; thus, endothelial cell (EC) injury and platelet fibrin thrombus formation in glomerular arterioles and in the arterioles of other affected organs are likely. To elucidate mechanisms of this microangiopathy, we examined in human ECs the regulation of the platelet adhesion proteins P-selectin and von Willebrand factor (VWF), along with the downregulation of erythroblast-transformation-specific transcription factor (ERG) a key regulator of angiogenesis and megakaryocyte development. METHODS: VWF, P-selectin, and ERG levels were determined using immunofluorescence and Western blot in human umbilical endothelial cells (HUVECs). HUVECs were treated with tumor necrosis factor-alpha (TNF-α), Stx-1 or both, versus normal controls. Capillary morphogenesis on Matrigel was performed using HUVECs treated, for 22 h with TNF-α, Stx-1, or both, or treated 4 h with Stx-1 alone or in combination with TNF-α for 22 h. RESULTS: Stx-1 significantly reduced ERG and VWF expression on HUVECs, but upregulated P-selectin expression. ERG levels decreased with Stx-1 alone or in combination with TNF-α, in the nuclear, perinuclear and cytoplasmatic regions. Stx-1 reduced capillary morphogenesis, while Stx-1-TNF-α combined treatment reduced capillary morphogenesis still further. CONCLUSIONS: In the presence of Stx-1 or TNF-α or both treatments, ECs were activated, expressing higher levels of P-selectin and lower levels of VWF. Our findings, further, provide evidence that Stx-1 downregulates ERG, repressing angiogenesis in vitro.


Assuntos
Regulação para Baixo , Células Endoteliais da Veia Umbilical Humana , Humanos , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Regulador Transcricional ERG/metabolismo , Toxina Shiga/metabolismo , Toxina Shiga/farmacologia , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Fator de von Willebrand/metabolismo , Angiogênese
13.
J Thromb Haemost ; 21(1): 26-36, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36695393

RESUMO

BACKGROUND: Antithrombotic therapy (anticoagulation and antiplatelet therapy) is frequently needed in patients with hereditary hemorrhagic telangiectasia (HHT); however, data describing and guiding its use are very limited. OBJECTIVES: To investigate the safety, tolerability, and effectiveness of antithrombotic therapy in HHT in a cohort large enough to compare agents, evaluate for baseline predictors of premature discontinuation, and evaluate hematologic support requirements and healthcare utilization before and after antithrombitc therapy initiation. METHODS: We performed a multicenter observational cohort study characterizing the outcomes of antithrombic therapy in adults with HHT. RESULTS: A total of 119 patients with HHT with 187 discrete antithrombotic therapy episodes were included. Of these, 59 patients (50%) dose-reduced and/or prematurely discontinued therapy (including 52 patients [44%] who discontinued) due to worsened bleeding complications. Initiation at reduced dose intensity had a similar premature discontinuation rate (49%) as initiation at standard dose intensity (43%). In a multivariable logistic model, a history of gastrointestinal bleeding was associated with 3.25-fold odds of discontinuation (p = .001). Hemoglobin was significantly lower (10.8 g/dL vs 12.2 g/dL, p < .001), and the need for hematologic support (intravenous iron and/or red blood cell transfusion) was significantly higher (29 patients vs 12 patients, p = .004) in the 3 months after antithrombotic therapy initiation vs the 3 months before; emergency department visits and hospital admissions due to bleeding also increased. The rates of dose-reduction and/or premature discontinuation were similar regardless of the anticoagulant class (warfarin, 46%; heparin-based, 48%; direct oral anticoagulants, 44%) or with multiple simultaneous agents (44%) but were slightly lower with single-agent antiplatelet therapy (37%). Thromboembolism despite receiving antithrombotic therapy was common (18 patients, 15%) with varying outcomes. CONCLUSION: Antithrombotic therapy is challenging in HHT, resulting in objectively higher morbidity and health care utilization from worsened bleeding. Discontinuation rates approached 50% regardless of the dose intensity at initiation or type of antithrombotic agent used and were higher in patients with a gastrointestinal bleeding history.


Assuntos
Telangiectasia Hemorrágica Hereditária , Adulto , Humanos , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/diagnóstico , Telangiectasia Hemorrágica Hereditária/tratamento farmacológico , Inibidores da Agregação Plaquetária/efeitos adversos , Fibrinolíticos/uso terapêutico , Anticoagulantes/efeitos adversos , Hemorragia Gastrointestinal/induzido quimicamente
16.
Am J Hematol ; 87 Suppl 1: S51-5, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22495911

RESUMO

Hemostasis and thrombosis are now increasingly recognized as integrally related to blood rheology and blood flow. Platelets, for example, are known to access the vessel wall in ways which depend upon the small-scale motions of neighboring erythrocytes, and access one another via collisions driven by gradients in blood flow velocity. In this context, flow devices have become a subject of great interest in the clinical assessment of bleeding disorders, especially platelet function defects and von Willebrand disease. While these devices currently lack standardization and outcomes measures which establish clear clinical utility, their promise remains great, particularly in the potential to simulate the microenvironment of arteries vs. veins and in their ability to incorporate such intrinsically flow-dependent phenomena as co-localization of tissue-factor-bearing microparticles with platelets, the weakness of the GPIb-vWF bond at very high shear stresses, and even the hemostatic and antithrombotic function of vascular endothelium. In contrast, currently utilized assays are often performed under static conditions that do not involve flow and therefore are not able to simulate the microenvironment of arteries and veins.


Assuntos
Hemorreologia , Hemorragia , Hemostasia , Trombose , Doenças de von Willebrand/sangue , Doenças de von Willebrand/fisiopatologia , Animais , Velocidade do Fluxo Sanguíneo , Plaquetas/metabolismo , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiopatologia , Micropartículas Derivadas de Células/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Eritrócitos/metabolismo , Hemorragia/sangue , Hemorragia/fisiopatologia , Humanos , Glicoproteínas de Membrana/sangue , Complexo Glicoproteico GPIb-IX de Plaquetas , Tromboplastina/metabolismo , Trombose/sangue , Trombose/fisiopatologia , Fator de von Willebrand
17.
Circulation ; 121(16): 1838-47, 2010 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-20385928

RESUMO

BACKGROUND: The aim of this study was to estimate the impact of thrombophilia on risk of first childhood stroke through a meta-analysis of published observational studies. METHODS AND RESULTS: A systematic search of electronic databases (Medline via PubMed, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2009 was conducted. Data on year of publication, study design, country of origin, number of patients/control subjects, ethnicity, stroke type (arterial ischemic stroke [AIS], cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Twenty-two of 185 references met inclusion criteria. Thus, 1764 patients (arterial ischemic stroke [AIS], 1526; cerebral sinus venous thrombosis [CSVT], 238) and 2799 control subjects (neonate to 18 years of age) were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with first stroke was demonstrated for each thrombophilia trait evaluated, with no difference found between AIS and CSVT. Summary ORs (fixed-effects model) were as follows: antithrombin deficiency, 7.06 (95% CI, 2.44 to 22.42); protein C deficiency, 8.76 (95% CI, 4.53 to 16.96); protein S deficiency, 3.20 (95% CI, 1.22 to 8.40), factor V G1691A, 3.26 (95% CI, 2.59 to 4.10); factor II G20210A, 2.43 (95% CI, 1.67 to 3.51); MTHFR C677T (AIS), 1.58 (95% CI, 1.20 to 2.08); antiphospholipid antibodies (AIS), 6.95 (95% CI, 3.67 to 13.14); elevated lipoprotein(a), 6.27 (95% CI, 4.52 to 8.69), and combined thrombophilias, 11.86 (95% CI, 5.93 to 23.73). In the 6 exclusively perinatal AIS studies, summary ORs were as follows: factor V, 3.56 (95% CI, 2.29 to 5.53); and factor II, 2.02 (95% CI, 1.02 to 3.99). CONCLUSIONS: The present meta-analysis indicates that thrombophilias serve as risk factors for incident stroke. However, the impact of thrombophilias on outcome and recurrence risk needs to be further investigated.


Assuntos
Isquemia Encefálica/epidemiologia , Trombose dos Seios Intracranianos/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Trombofilia/epidemiologia , Criança , Humanos , Recém-Nascido , Fatores de Risco
18.
Thromb Haemost ; 120(5): 793-804, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32369850

RESUMO

BACKGROUND: Accurate diagnosis of symptomatic low von Willebrand factor (VWF) remains a major challenge in von Willebrand disease (VWD). However, present tests do not adequately take into account flow forces that, at very high shear rates, reveal a weakness in the VWF-platelet glycoprotein glycoprotein Ib bond in normal subjects. The degree of this weakness is greater in symptomatic, but not asymptomatic, low VWF. OBJECTIVE: The aim of this study is to distinguish patients with symptomatic low VWF (levels in the 30-50 IU/dL range) from those with asymptomatic low VWF and normal subjects. METHODS: We measured platelet adhesion (PA)/aggregation in our novel microfluidic flow system that permits real-time assessment of PA (surface coverage) and PA/aggregation (V, aggregate volume) using epifluorescence digital videomicroscopy in flowing noncitrated whole blood at 4,000 second-1. Blood samples from 24 low VWF patients and 15 normal subjects were collected into plastic tubes containing 4 U/mL enoxaparin. MetaMorph software was used to quantify rates of PA and V increase. RESULTS: Rates of PA increase showed a bimodal distribution, with values for 16/24 patients (Group I) all below the 2.5th percentile of normal, and values for 8/24 patients (Group II) similar to controls. Bleeding scores (mean ± standard error) were 5.50 ± 0.45 versus 2.75 ± 0.45 (p = 0.00077), and 10 clinically significant bleeding events were observed in seven versus zero (p = 0.0295) Group I and Group II subjects, respectively. CONCLUSION: The present approach may offer a definitive means to distinguish symptomatic low VWF from either asymptomatic low VWF or normal controls.


Assuntos
Adesividade Plaquetária , Agregação Plaquetária , Testes de Função Plaquetária , Doenças de von Willebrand/diagnóstico , Fator de von Willebrand/metabolismo , Adolescente , Adulto , Doenças Assintomáticas , Biomarcadores/sangue , Velocidade do Fluxo Sanguíneo , Estudos de Casos e Controles , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Técnicas Analíticas Microfluídicas , Microscopia de Vídeo , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estresse Mecânico , Fatores de Tempo , Adulto Jovem , Doenças de von Willebrand/sangue , Doenças de von Willebrand/complicações
19.
Circulation ; 118(13): 1373-82, 2008 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-18779442

RESUMO

BACKGROUND: The aim of the present study was to estimate the impact of inherited thrombophilia (IT) on the risk of venous thromboembolism (VTE) onset and recurrence in children by a meta-analysis of published observational studies. METHODS AND RESULTS: A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2007 was conducted using key words in combination as both MeSH terms and text words. Citations were independently screened by 2 authors, and those meeting the inclusion criteria defined a priori were retained. Data on year of publication, study design, country of origin, number of patients/controls, ethnicity, VTE type, and frequency of recurrence were abstracted. Heterogeneity across studies was evaluated, and summary odds ratios and 95% CIs were calculated with both fixed-effects and random-effects models. Thirty-five of 50 studies met inclusion criteria. No significant heterogeneity was discerned across studies. Although >70% of patients had at least 1 clinical risk factor for VTE, a statistically significant association with VTE onset was demonstrated for each IT trait evaluated (and for combined IT traits), with summary odds ratios ranging from 2.63 (95% CI, 1.61 to 4.29) for the factor II variant to 9.44 (95% CI, 3.34 to 26.66) for antithrombin deficiency. Furthermore, a significant association with recurrent VTE was found for all IT traits except the factor V variant and elevated lipoprotein(a). CONCLUSIONS: The present meta-analysis indicates that detection of IT is clinically meaningful in children with, or at risk for, VTE and underscores the importance of pediatric thrombophilia screening programs.


Assuntos
Trombofilia/epidemiologia , Trombofilia/genética , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/genética , Criança , Predisposição Genética para Doença/epidemiologia , Humanos , Fatores de Risco
20.
Nat Commun ; 10(1): 1895, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028256

RESUMO

The major biogeochemical cycles of marine ecosystems are driven by solar energy. Energy that is initially captured through photosynthesis is transformed and transported to great ocean depths via complex, yet poorly understood, energy flow networks. Herein we show that the chemical composition and specific energy (Joules per unit mass or organic carbon) of sinking particulate matter collected in the North Pacific Subtropical Gyre reveal dramatic changes in the upper 500 m of the water column as particles sink and age. In contrast to these upper water column processes, particles reaching the deep sea (4000 m) are energy-replete with organic carbon-specific energy values similar to surface phytoplankton. These enigmatic results suggest that the particles collected in the abyssal zone must be transported by rapid sinking processes. These fast-sinking particles control the pace of deep-sea benthic communities that live a feast-or-famine existence in an otherwise energy-depleted habitat.

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