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BACKGROUND: While direct-acting oral anticoagulants (DOACs) have established efficacy in reducing the risk of ischemic stroke, they still leave a residual risk of stroke, which may be greater in practice (0.7-2.3%) than in controlled clinical trial settings. This meta-analysis examines four therapeutic approaches following a stroke in patients already on DOACs: continuing with the same DOAC, changing to a different DOAC, increasing the current DOAC dosage, or switching to a vitamin K antagonist (VKA), such as warfarin. METHODS: Systematic review of literature from the MEDLINE, Embase, and Cochrane databases, was conducted in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The analysis focused on six studies with varied patient demographics, examining as outcomes as recurrent ischemic stroke, intracranial hemorrhage, other bleeding events, and mortality. RESULTS: Six studies comprising 12,159 patients were included, all of them were observational. Patients who remained on their initial DOAC regimen had a lower risk of experiencing ischemic strokes (risk ratio (RR) 0.55; 95% confidence interval (CI) 0.43-0.70; p < 0.001; I2 = 0%), intracranial hemorrhage (RR 0.37; 95% CI 0.25-0.55; p < 0.001; I2 = 0%), and hemorrhagic events (RR 0.44; 95% CI 0.30-0.63; p < 0.001; I2 = 6%) compared to those who were switched to warfarin, with an increase in mortality rates (hazard ratio (HR) 1.85; 95% CI 1.06-3.24; p = 0.03; I2 = 84%). In contrast, neither changing to a different DOAC nor adjusting the dose proved to be more effective than the original regimen. CONCLUSION: Post-stroke adjustments to anticoagulation therapy-whether altering the drug or its dosage-do not yield additional benefits. In addition, the results suggest that warfarin may be less effective than DOACs for preventing stroke recurrence, bleeding complications, and death in this patient population.
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Background/Objectives: There are limited data on the risks and benefits of using Andexanet alfa (AA) compared with four-factor prothrombin complex concentrate (4F-PCC) for the reversal of factor Xa inhibitor-associated intracranial hemorrhage (ICH). Our aim was to describe a compilation of the information available in the literature to date. Methods: PubMed, Embase, Web of Science (Clarivate Analytics) and the Cochrane Central Register of Controlled Trials were searched until December 2023. Following the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)" guidelines, our systematic literature review included studies that were retrospective in design and evaluated both drugs to control bleeding and complications (death and thromboembolic events). Two researchers re-examined the studies for relevance, extracted the data and assessed the risk of bias. No meta-analyses were performed for the results. Results: In this limited patient sample, we found no differences between published articles in terms of neuroimaging stability or thrombotic events. However, some studies show significant differences in mortality, suggesting that one of the AAs may be superior to 4F-PCC. Conclusions: Our qualitative analysis shows that AA has a better efficacy profile compared with 4F-PCC. However, further studies monitoring these patients and a multicenter collaborative network dedicated to this topic are needed.
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Resumo Fundamento Os antagonistas da vitamina K (AVKs) são o tratamento de primeira linha recomendado para trombo ventricular esquerdo (TVE); entretanto, os anticoagulantes orais diretos (AODs) têm sido considerados uma terapia alternativa. Objetivos Avaliar a eficácia e a segurança dos AODs em comparação com a terapia com AVKs em pacientes com TVE. Métodos PubMed, Embase e Cochrane foram sistematicamente pesquisados em busca de ensaios clínicos randomizados ou estudos de coorte que comparassem AODs versus AVKs para TVE. As razões de risco (RR) foram calculadas para desfechos binários, com intervalos de confiança (IC) de 95%. A significância estatística foi definida como valor de p < 0,05. Resultados Foram incluídos um total de 4 ensaios clínicos randomizados e 29 estudos de coorte, com 4.450 pacientes designados para AODs ou AVKs. Não houve diferença significativa entre os grupos para acidente vascular cerebral ou eventos embólicos sistêmicos (AVC/EES) (RR 0,84; IC 95% 0,65 a 1,07; p = 0,157), acidente vascular cerebral (RR 0,73; IC 95% 0,48 a 1,11; p = 0,140), eventos embólicos sistêmicos (EES) (RR 0,69; IC 95% 0,40 a 1,17; p = 0,166), resolução do trombo (RR 1,05; IC 95% 0,99 a 1,11; p = 0,077), qualquer sangramento (RR 0,78; IC 95% 0,60 a 1,00; p = 0,054), sangramento clinicamente relevante (RR 0,69; IC 95% 0,46 a 1,03; p = 0,066), sangramento menor (RR 0,73; IC 95% 0,43 a 1,23; p = 0,234), sangramento maior (RR 0,87; IC 95% 0,42 a 1,80; p = 0,705) e mortalidade por todas as causas (RR 1,05; IC 95% 0,79 a 1,39; p = 0,752). Em comparação com AVKs, a rivaroxabana reduziu significativamente AVC/EES (RR 0,35; IC 95% 0,16 a 0,91; p = 0,029) e EES (RR 0,39; IC 95% 0,16 a 0,95; p = 0,037). Conclusões Os AODs tiveram uma taxa semelhante de eventos tromboembólicos e hemorrágicos, bem como de resolução do trombo, em comparação com os AVKs no tratamento de TVE. A terapia com rivaroxabana teve uma redução significativa nos eventos tromboembólicos, em comparação com os AVKs.
Abstract Background Vitamin K antagonists (VKAs) are the recommended first-line treatment for left ventricular thrombus (LVT); however, direct oral anticoagulants (DOACs) have been considered an alternative therapy. Objectives To evaluate the efficacy and safety of DOACs compared with VKAs therapy in patients with LVT. Methods PubMed, Embase, and Cochrane were systematically searched for randomized clinical trials or cohort studies that compared DOACs versus VKAs for LVT. Risk ratios (RRs) were computed for binary endpoints, with 95% confidence intervals (95% CIs). Statistical significance was defined as p value < 0.05. Results A total of 4 randomized clinical trials and 29 cohort studies were included, with 4,450 patients assigned to either DOACs or VKAs. There was no significant difference between groups for stroke or systemic embolic (SSE) events (RR 0.84; 95% CI 0.65 to 1.07; p = 0.157), stroke (RR 0.73; 95% CI 0.48 to 1.11; p = 0.140), systemic embolic (SE) events (RR 0.69; 95% CI 0.40 to 1.17; p = 0.166), thrombus resolution (RR 1.05; 95% CI 0.99 to 1.11; p = 0.077), any bleeding (RR 0.78; 95% CI 0.60 to 1.00; p = 0.054), clinically relevant bleeding (RR 0.69; 95% CI 0.46 to 1.03; p = 0.066), minor bleeding (RR 0.73; 95% CI 0.43 to 1.23; p = 0.234), major bleeding (RR 0.87; 95% CI 0.42 to 1.80; p = 0.705), and all-cause mortality (RR 1.05; 95% CI 0.79 to 1.39; p = 0.752). Compared with VKAs, rivaroxaban significantly reduced SSE events (RR 0.35; 95% CI 0.16 to 0.91; p = 0.029) and SE events (RR 0.39; 95% CI 0.16 to 0.95; p = 0.037). Conclusions DOACs had a similar rate of thromboembolic and hemorrhagic events, as well as thrombus resolution, compared to VKAs in the treatment of LVTs. Rivaroxaban therapy had a significant reduction in thromboembolic events, compared to VKAs.
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OBJECTIVE: This systematic review and network meta-analysis aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) in adults aged 75 and over undergoing acute venous thromboembolism (VTE) treatment. METHODS: PubMed, Embase and the CENTRAL were searched up to 25 December 2023. The incidence of VTE recurrence and bleeding events was assessed. Employing a frequentist network meta-analysis approach, interventions not directly compared could be indirectly assessed through the 95% confidence interval (CI), enhancing the interpretability of the search results. The surface under the cumulative ranking curves (SUCRA) was utilized to generate the relative ranking probabilities for each group. RESULTS: Our study, analysing 6 randomised controlled trials with 3665 patients, compares direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in adults aged 75 and over with acute venous thromboembolism. Edoxaban reduces VTE recurrence risk compared with VKAs (risk ratio [RR] .50, 95% CI 0.27 - .95), while apixaban significantly decreases bleeding risk compared with VKAs (RR .23, 95% CI 0.08 - .69), edoxaban (RR .28, 95% CI 0.09 - .86) and rivaroxaban (RR .28, 95% CI 0.09 - .86). Despite low overall evidence quality, apixaban consistently ranks highest for both efficacy and safety. Findings underscore the nuanced efficacy-safety balance in this population, emphasizing cautious interpretation due to evidence limitations. CONCLUSION: Apixaban emerges as a favourable choice for acute VTE treatment in the elderly, displaying reduced bleeding risk compared to other treatments while maintaining comparable efficacy. Future studies should explore diverse anticoagulants efficacy and safety in older populations. Additionally, clinical prediction models tailored to geriatric cohorts are crucial for guiding treatment duration decisions.
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Inibidores do Fator Xa , Hemorragia , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/sangue , Idoso , Hemorragia/induzido quimicamente , Administração Oral , Fatores de Risco , Resultado do Tratamento , Fatores Etários , Feminino , Masculino , Idoso de 80 Anos ou mais , Medição de Risco , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/administração & dosagem , Anticoagulantes/efeitos adversos , Anticoagulantes/administração & dosagem , Doença AgudaRESUMO
Resumo Fundamento: A doença por coronavírus 2019 (COVID-19) está associada à hipercoagulabilidade. Permanece incerto se a anticoagulação contínua para fibrilação atrial (FA) em pacientes que posteriormente contraem COVID-19 melhora os desfechos clínicos. Objetivos: Comparar a anticoagulação oral crônica com ausência de anticoagulação prévia em pacientes com FA que contraíram uma infecção por COVID-19 em relação aos desfechos de mortalidade por todas as causas, mortalidade por COVID-19, admissão em unidade de terapia intensiva (UTI) e hospitalização. Métodos: Buscamos sistematicamente no PubMed, Embase e Cochrane Library estudos elegíveis desde o início até dezembro de 2022. Incluímos estudos que compararam desfechos de COVID-19 em pacientes com e sem anticoagulação crônica prévia para FA. Foram agrupadas razões de risco (RR) com intervalos de confiança (IC) de 95% por meio de um modelo de efeitos aleatórios. O nível de significância foi estabelecido em p < 0,05. As avaliações da qualidade e do risco de viés foram realizadas de acordo com as recomendações da Cochrane. Resultados: Foram identificados 10 estudos abrangendo 1.177.858 pacientes com COVID-19 e FA, dos quais 893.772 (75,9%) estavam em anticoagulação crônica prévia para FA. Em pacientes com COVID-19, a anticoagulação crônica para FA reduziu significativamente a mortalidade por todas as causas (RR 0,75; IC 95% 0,57 a 0,99; p = 0,048; I2 = 89%) e a mortalidade relacionada à COVID-19 (RR 0,76; IC 95% 0,72 a 0,79; p < 0,001; I2 = 0%) quando comparada com a ausência de anticoagulação prévia. Em contrapartida, não houve diferença entre os grupos em relação à hospitalização (RR 1,08; IC 95% 0,82 a 1,41; p = 0,587; I2 = 95%) ou internação em UTI (RR 0,86; IC 95% 0,68 a 1,09; p = 0,216; I2 = 69%). Conclusões: Nesta metanálise, a anticoagulação crônica para pacientes com FA que contraíram COVID-19 foi associada a taxas significativamente mais baixas de mortalidade por todas as causas e mortalidade relacionada à COVID-19 em comparação com a ausência de anticoagulação anterior.
Abstract Background: Coronavirus disease 2019 (COVID-19) is associated with hypercoagulability. It remains uncertain whether ongoing anticoagulation for atrial fibrillation (AF) in patients who later contract COVID-19 improves clinical outcomes. Objectives: To compare chronic oral anticoagulation with no previous anticoagulation in patients with AF who contracted a COVID-19 infection concerning the outcomes of all-cause mortality, COVID-19 mortality, intensive care unit (ICU) admission, and hospitalization. Methods: We systematically searched PubMed, Embase, and Cochrane Library for eligible studies from inception to December 2022. We included studies comparing COVID-19 outcomes in patients with versus without prior chronic anticoagulation for AF. Risk ratios (RR) with 95% confidence intervals (CI) were pooled with a random-effects model. The level of significance was set at p < 0.05. Quality assessment and risk of bias were performed according to Cochrane recommendations. Results: Ten studies comprising 1,177,858 patients with COVID-19 and AF were identified, of whom 893,772 (75.9%) were on prior chronic anticoagulation for AF. In patients with COVID-19, being on chronic anticoagulation for AF significantly reduced all-cause mortality (RR 0.75; 95% CI 0.57 to 0.99; p = 0.048; I2 = 89%) and COVID-19-related mortality (RR 0.76; 95% CI 0.72 to 0.79; p < 0.001; I2 = 0%) when compared with no prior anticoagulation. In contrast, there was no difference between groups regarding hospitalization (RR 1.08; 95% CI 0.82 to 1.41; p = 0.587; I2 = 95%) or ICU admission (RR 0.86; 95% CI 0.68 to 1.09; p = 0.216; I2 = 69%). Conclusions: In this meta-analysis, chronic anticoagulation for patients with AF who contracted COVID-19 was associated with significantly lower rates of all-cause mortality and COVID-19-related mortality as compared with no previous anticoagulation.
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Introducción: el progresivo avance en la edad media de la población ha propiciado un incremento de la prescripción del tratamiento anticoagulante oral en la práctica clínica. Objetivo: caracterizar la preparación sobre el manejo de pacientes con anticoagulantes orales en médicos generales de los policlínicos universitarios "Capitán Roberto Fleites", "Chiqui Gómez-Lubián" y "Santa Clara". Métodos: se realizó un estudio descriptivo transversal en el período enero-diciembre de 2020, en tres policlínicos universitarios del municipio de Santa Clara, Villa Clara, Cuba. Se utilizaron métodos teóricos: análisis-síntesis e inducción-deducción para la fundamentación de la información; empíricos: cuestionario y análisis de documentos; y matemático estadísticos para el procesamientos de los datos. Resultados: el cuestionario permitió valorar los conocimientos sobre el tratamiento con anticoagulantes orales en la categoría Regular en la mayoría de los muestreados; mientras en el análisis del programa se detectaron pocas horas dedicadas al tema investigado y la necesidad sentida de capacitación manifestada por los encuestados. Conclusiones: el diagnóstico realizado confirmó las carencias de los médicos generales en el manejo del paciente en la prescripción del tratamiento con anticoagulantes orales.
Background: the progressive advance in the average age of the population has led to an increase in the prescription of oral anticoagulant treatment in clinical practice. Objective: to characterize the training on the management of patients with oral anticoagulants in general practitioners of the "Capitán Roberto Fleites", "Chiqui Gómez-Lubian" and "Santa Clara" university polyclinics. Methods: a cross-sectional descriptive study was carried out from January to December 2020. Theoretical methods were used: analysis-synthesis and induction-deduction to support the information; Empirical: questionnaire and analysis of documents and statistical mathematics for data processing. Results: the questionnaire allowed to assess knowledge about treatment with oral anticoagulants in the average category in the majority of those sampled; while in the analysis of the program, few hours dedicated to the subject investigated and the felt need for training expressed by the respondents were detected. Conclusions: the diagnosis made confirmed the shortcomings of general practitioners in the management of medicated patients for the prescription of treatment with oral anticoagulants.
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Educação Médica , Cursos de Capacitação , Inibidores do Fator XaRESUMO
El uso de Anticoagulantes Orales de Acción Directa (ACOD) ha aumentado considerablemente en el último tiempo. En procedimientos odontológicos, como la exodoncia, es crucial un manejo óptimo de la hemostasia de pacientes bajo tratamiento con ACOD, para equilibrar el riesgo de hemorragia y tromboembolismo. Aun no existe consenso sobre el protocolo a aplicar en pacientes con ACOD sometidos a exodoncias. El objetivo fue evaluar la necesidad de suspender o continuar el tratamiento con ACOD en pacientes sometidos a exodoncia en relación con la incidencia de episodios hemorrágicos y protocolos utilizados. Se realizó una revisión sistemática en base a los estamentos PRISMA, en las bases de datos Pubmed, Wiley, Scopus. La búsqueda incluyó estudios publicados entre 2010 - 2020 en inglés, realizados en humanos, en pacientes bajo terapia con ACOD sometidos a exodoncia y que evalúan la incidencia de hemorragia en este procedimiento. Se excluyeron estudios que involucran pacientes que reciben otros tratamientos antitrombótico concomitante, o procedimientos distintos a la exodoncia. La calidad de los estudios seleccionados fue evaluada de acuerdo con la clasificación del Centro Oxford de Medicina Basada en la Evidencia. Luego de la búsqueda, en base a criterios de inclusión/exclusión, 34 artículos fueron analizados a texto completo. Trece artículos relevantes fueron seleccionados. Once participaron en la revisión final, contando con ocho estudios de cohorte, dos casos-controles y uno serie de casos. Los estudios evidencian que no es necesario suspender la terapia con ACOD en pacientes sometidos a exodoncia, se sugiere que el momento de baja concentración farmacológica puede ser utilizado a favor del tratante. Sin embargo, existe una gran diversidad de protocolos y medidas aplicadas entre estudios, por lo que es necesario realizar estudios clínicos aleatorizados controlados, para determinar un protocolo estándar en el manejo odontológico de estos pacientes.
The use of Direct Acting Oral Anticoagulants (ACOD) has increased considerably in recent times. In dental procedures, such as tooth extraction, optimal management of hemostasis in patients treated with ACOD is crucial to balance the risk of bleeding and thromboembolism. There is still no consensus on the protocol to be applied in patients with ACOD in dental extraction. The aim was to evaluate the need to suspend or continue treatment with ACOD in patients submitted to dental extraction in relation to the incidence of bleeding episodes and the protocols used. A systematic review was carried out based on the PRISMA estates, in the Pubmed, Wiley, Scopus databases. The search included studies published between 2010-2020 in English conducted in humans, in patients under therapy with ACOD submitted to dental extraction and that evaluate the incidence of bleeding in this procedure. Studies involving patients receiving other concomitant antithrombotic treatments or procedures other than dental extraction were excluded. The quality of the selected studies was evaluated according to the Oxford Center for Evidence-based Medicine classification. After the search, based on inclusion/ exclusion criteria, 34 articles were analyzed in full text. 13 relevant articles were selected. 11 participated in the final review, including 8 cohort studies, 2 case-controls and 1 case series. Studies show that it is not necessary to suspend therapy with ACOD in patients who have undergone dental extraction, it is suggested that the moment of low pharmacological concentration can be used in favor of the treatment. However, there is a great diversity of protocols and measures applied between studies, so it is necessary to carry out randomized controlled clinical studies to determine a standard protocol in the dental management of these patients.
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Humanos , Extração Dentária/métodos , Anticoagulantes/administração & dosagem , Anticoagulantes/farmacologia , Pirazóis/administração & dosagem , Administração Oral , Hemorragia Pós-Operatória , Dabigatrana/administração & dosagemRESUMO
OBJECTIVE: Thrombotic events are potential complications in patients receiving extracorporeal membrane oxygenation (ECMO) necessitating the use of systemic anticoagulation with heparin. Heparin works by potentiating the effects of antithrombin (AT), which may be deficient in critically ill patients and can be replaced. The clinical benefits and risks of AT replacement in children on ECMO remain incompletely understood. METHODS: This single-center, retrospective study reviewed 28 neonatal and pediatric patients supported on ECMO at a tertiary care hospital between April 1, 2013, and October 31, 2014, who received at least 1 dose of AT during their ECMO course. The primary outcome of the study was the change in anti-factor Xa levels after pooled human AT supplementation. Secondary outcomes included the percentage of anti-factor Xa levels within the therapeutic range surrounding AT administration; survival to decannulation; 30 days after cannulation and discharge; time to first circuit change; and incidence of bleeding and thrombotic events. RESULTS: A total of 78 doses of AT were administered during the study period. The mean increase in anti-factor Xa level following AT administration in patients without a ≥10% concurrent change in heparin was 0.075 ± 0.13 international units/mL. A greater percentage of anti-factor Xa levels were therapeutic for the 48 hours following AT administration (64.2% vs 38.6%). Survival and adverse events were similar to Extracorporeal Life Support Organization averages, with the exception of a higher incidence of intracranial hemorrhage. CONCLUSIONS: Patients experienced a small but significant increase in anti-factor Xa level and a greater percentage of therapeutic anti-factor Xa levels following AT supplementation.
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BACKGROUND: The term Direct Oral Anticoagulants (DOACs) refers to a group of drugs that inhibit factor Xa or thrombin. Even though their use for treating different thrombotic or prothrombotic conditions is increasing recently, there is no compelling evidence indicating that those medications are safe in all antiphospholipid syndrome (APS) patients. METHODOLOGY: To address this issue, specialists from the Antiphospholipid Syndrome Committee of the Brazilian Society of Rheumatology performed a comprehensive review of the literature regarding DOACs use in APS to answer the three following questions: (1) potential mechanisms of action of these drugs that could be relevant to APS pathogenesis, (2) DOACs interference on lupus anticoagulant testing, and (3) the efficacy of DOACs in APS. POSITION STATEMENT: After critically reviewing the relevant evidence, the authors formulated 8 Position Statements about DOACs use in APS. CONCLUSION: DOACs should not be routinely used in APS patients, especially in those with a high-risk profile (triple positivity to aPL, arterial thrombosis, and recurrent thrombotic events). In addition, DOACs interferes with LA testing, leading to false-positive results in patients investigating APS.
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Comitês Consultivos , Síndrome Antifosfolipídica/tratamento farmacológico , Antitrombinas/uso terapêutico , Consenso , Administração Oral , Antitrombinas/efeitos adversos , Antitrombinas/farmacologia , Brasil , Contraindicações de Medicamentos , Interações Medicamentosas , Substituição de Medicamentos , Humanos , Inibidor de Coagulação do Lúpus/análise , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Reumatologia , Sociedades Médicas , Trombose/tratamento farmacológico , Resultado do TratamentoRESUMO
The coagulation cascade is the process of the conversion of soluble fibrinogen to insoluble fibrin that terminates in production of a clot. Factor Xa (FXa) is a serine protease involved in the blood coagulation cascade. Moreover, FXa plays a vital role in the enzymatic sequence which ends with the thrombus production. Thrombosis is a common causal pathology for three widespread cardiovascular syndromes: acute coronary syndrome (ACS), venous thromboembolism (VTE), and strokes. In this research a series of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives as a potential factor Xa (FXa) inhibitor were designed, synthesized, and evaluated for their FXa inhibitor activity, cytotoxicity activity and coagulation parameters. Rational design for the desired novel molecules was performed through protein-ligand complexes selection and ligand clustering. The microwave-assisted synthetic strategy of selected compounds was carried out by using Ullmann-Goldberg, N-propargylation, Mannich addition, Friedel-Crafts, and 1,3-dipolar cycloaddition type reactions under microwave irradiation. The microwave methodology proved to be an efficient way to obtain all novel compounds in high yields (73-93%). Furthermore, a thermochemical analysis, optimization and reactivity indexes such as electronic chemical potential (µ), chemical hardness (η), and electrophilicity (ω) were performed to understand the relationship between the structure and the energetic behavior of all the series. Then, in vitro analysis showed that compounds 27, 29-31, and 34 exhibited inhibitory activity against FXa and the corresponding half maximal inhibitory concentration (IC50) values were calculated. Next, a cell viability assay in HEK293 and HepG2 cell lines, and coagulation parameters (anti FXa, Prothrombin time (PT), activated Partial Thromboplastin Time (aPTT)) of the most active novel molecules were performed to determine the corresponding cytotoxicity and possible action on clotting pathways. The obtained results suggest that compounds 27 and 29 inhibited FXa targeting through coagulation factors in the intrinsic and extrinsic pathways. However, compound 34 may target coagulation FXa mainly by the extrinsic and common pathway. Interestingly, the most active compounds in relation to the inhibition activity against FXa and coagulation parameters did not show toxicity at the performed coagulation assay concentrations. Finally, docking studies confirmed the preferential binding mode of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives inside the active site of FXa.
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Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/síntese química , Inibidores do Fator Xa/farmacologia , Fator Xa/química , Quinolinas/química , Triazóis/química , Compostos de Anilina/síntese química , Compostos de Anilina/química , Azidas/síntese química , Azidas/química , Testes de Coagulação Sanguínea , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Fator Xa/metabolismo , Inibidores do Fator Xa/química , Humanos , Concentração Inibidora 50 , Ligantes , Micro-Ondas , Simulação de Acoplamento Molecular , Quinolinas/síntese química , Triazóis/síntese químicaRESUMO
OBJECTIVES: To assess clinical outcomes in children treated with unfractionated heparin and monitored using an anti-factor Xa (Anti-FXa)-based nomogram. We also sought to assess the correlation between activated partial thromboplastin time (APTT) and Anti-FXa. STUDY DESIGN: This was a single-center, observational cohort study conducted over a 20-month period that included all pediatric patients (<21 years) who received therapeutic unfractionated heparin and were monitored using an anti-FXa-based nomogram. RESULTS: In total, 95 patients met prespecified inclusion criteria, and 1098 pairs of APTT and Anti-FXa measurements were performed. The median unfractionated heparin dose required to reach therapeutic Anti-FXa goal was significantly greater in infants compared with older children (P <.0001). The median time to achieve therapeutic Anti-FXa was 10 hours (range 2-96 hours) and was significantly shorter in patients who received a bolus compared with those who did not (P = .03). Five (5.3%) major bleeding events were noted. Age, peak Anti-FXa, peak APTT, lowest platelet count, and fibrinogen were not predictive of major and clinically relevant nonmajor bleeds. Moderate correlation between the APTT and Anti-FXa (r = 0.75; 95% CI 0.72-0.77) assays was appreciated. CONCLUSIONS: Using an anti-FXa-based nomogram to monitor unfractionated heparin in children is feasible. Although moderate correlation was observed between the APTT and Anti-FXa assays, the APTT frequently overestimated heparin activity. Safety and efficacy of an Anti-FXa nomogram needs further validation.
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Anticoagulantes/uso terapêutico , Monitoramento de Medicamentos/métodos , Inibidores do Fator Xa/sangue , Heparina/uso terapêutico , Nomogramas , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Correlação de Dados , Feminino , Humanos , Lactente , Masculino , Tempo de Tromboplastina Parcial , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Ixolaris is a two-Kunitz tick salivary gland protein identified in Ixodes scapularis that presents sequence homology to TFPI (tissue factor pathway inhibitor). It binds to the coagulation enzyme factor Xa (FXa) or to its zymogen form, FX, and further inhibits tissue factor/FVIIa complex (extrinsic Xnase compex). Differently from TFPI, Ixolaris does not bind to the active site cleft of FXa. Instead, complex formation is mediated by the FXa heparin-binding exosite, which may also results in decreased FXa activity into the prothrombinase complex. The Ixolaris-FXa/FX complex formation has been characterized by using a combination of biophysical and biochemical technics although no structural data is currently available. In this study, we reported the NMR chemical shift assignment of Ixolaris, as a first step to further establishing the structure, dynamics and function relationship for this protein.
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Ressonância Magnética Nuclear Biomolecular , Glândulas Salivares/metabolismo , Proteínas e Peptídeos Salivares/química , Proteínas e Peptídeos Salivares/metabolismo , Carrapatos , Animais , Estrutura Secundária de ProteínaRESUMO
Factor Xa (FXa), a vitamin K-dependent serine protease plays a pivotal role in the coagulation cascade, one of the most interesting targets for the development of new anticoagulants. In the present work, we performed a virtual screening campaign based on ligand-based shape and electrostatic similarity search and protein-ligand docking to discover novel FXa-targeted scaffolds for further development of inhibitors. From an initial set of 260,000 compounds from the NCI Open database, 30 potential FXa inhibitors were identified and selected for in vitro biological evaluation. Compound 5 (NSC635393, 4-(3-methyl-4H-1,4-benzothiazin-2-yl)-2,4-dioxo-N-phenylbutanamide) displayed an IC50 value of 2.02 nM against human FXa. The identified compound may serve as starting point for the development of novel FXa inhibitors.
Assuntos
Inibidores do Fator Xa/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Bases de Dados Factuais , Inibidores Enzimáticos/farmacologia , Fator Xa/química , Fator Xa/metabolismo , Simulação de Acoplamento Molecular , Estrutura Secundária de Proteína , Relação Estrutura-AtividadeRESUMO
Ixolaris is an anticoagulant protein identified in the tick saliva of Ixodes scapularis. Ixolaris contains 2 Kunitz like domains and binds to Factor Xa or Factor X as a scaffold for inhibition of the Tissue Factor (TF)/Factor VIIa (FVIIa). In contrast to tissue factor pathway inhibitor (TFPI), however, Ixolaris does not bind to the active site cleft of FXa. Instead, complex formation is mediated by the FXa heparin-binding exosite. Due to its potent and long-lasting antithrombotic activity, Ixolaris is a promising agent for anticoagulant therapy. Although numerous functional studies of Ixolaris exist, three-dimensional structure of Ixolaris has not been obtained at atomic resolution. Using the pET32 vector, we successfully expressed a TRX-His6-Ixolaris fusion protein. By combining Ni-NTA chromatography, enterokinase protease cleavage, and reverse phase HPLC (RP-HPLC), we purified isotopically labeled Ixolaris for NMR studies. 1D 1H and 2D 15N-1H NMR analysis yielded high quality 2D 15N-1H HSQC spectra revealing that the recombinant protein is folded. These studies represent the first steps in obtaining high-resolution structural information by NMR for Ixolaris enabling the investigation of the molecular basis for Ixolaris-coagulation factors interactions.
Assuntos
Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Glândulas Salivares/química , Proteínas e Peptídeos Salivares/química , Proteínas e Peptídeos Salivares/genética , Anticoagulantes/química , Anticoagulantes/metabolismo , Clonagem Molecular , Escherichia coli/genética , Histidina/genética , Ressonância Magnética Nuclear Biomolecular , Oligopeptídeos/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas e Peptídeos Salivares/metabolismoRESUMO
BACKGROUND: Cancer has long been associated with thrombosis and many of the standard chemotherapeutics used to treat cancer are pro-thrombotic. Thus, the identification of novel selective anticancer drugs that also have antithrombotic properties is of enormous significance. Amblyomin-X is an anticancer protein derived from the salivary glands of the Amblyomma cajennense tick. METHODS: In this work, we determined the inhibition profile of Amblyomin-X and its effect on activated partial thromboplastin time (aPTT) and prothrombin time (PT), using various approaches such as, kinetic analyses, amidolytic assays, SDS-PAGE, and mass spectrometry. RESULTS: Amblyomin-X inhibited factor Xa, prothrombinase and tenase activities. It was hydrolyzed by trypsin and plasmin. MS/MS data of tryptic hydrolysate of Amblyomin-X suggested the presence of Cys(8)-Cys(59) and Cys(19)-Cys(42) but not Cys(34)-Cys(55) disulfide bond. Instead of Cys(34)-Cys(55), two noncanonical Cys(34)-Cys(74) and Cys(55)-Cys(74) disulfide bonds were identified. Furthermore, when Amblyomin-X (1mg/kg) injected in rabbits, it prolonged aPTT and PT. CONCLUSION: Amblyomin-X is a noncompetitive inhibitor (Ki=3.9µM) of factor Xa. It is a substrate for plasmin and trypsin, but not for factor Xa and thrombin. The disulfide Cys(34)-Cys(55) bond probably scrambles with interchain seventh free cysteine residues (Cys(74)) of Amblyomin-X. The prolongation of PT and aPTT is reversible. GENERAL SIGNIFICANCE: In term of anticoagulant property, this is structural and functional characterization of Amblyomin-X. All together, these results and previous findings suggest that Amblyomin-X has a potential to become an anticancer drug with antithrombotic property.
Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/farmacologia , Fator Xa/metabolismo , Proteínas e Peptídeos Salivares/farmacologia , Animais , Antineoplásicos/farmacologia , Proteínas de Artrópodes , Testes de Coagulação Sanguínea/métodos , Humanos , Masculino , Domínios Proteicos , Tempo de Protrombina/métodos , Coelhos , Glândulas Salivares/metabolismo , Proteínas e Peptídeos Salivares/metabolismo , Trombina/metabolismo , Tromboplastina/metabolismo , Trombose/dietoterapia , Carrapatos/metabolismoRESUMO
Bleeding disorders are commonly associated with hemato-oncologic diseases. We report a 68 years old male with a chronic myelomonocytic leukemia derived from a long lasting mielodysplastic syndrome that did not respond to treatment with Azacitidine. The patient was hospitalized due to tonic clonic seizures. A CAT scan showed a hematoma in the frontal lobe. A new assessment of hemostasis revealed an isolated deficiency of Factor X. We speculate that this deficit could be secondary to consumption due to the chronic Myelomonocytic Leukemia.
Assuntos
Idoso , Humanos , Masculino , Deficiência do Fator X/etiologia , Lobo Frontal/lesões , Leucemia Mielomonocítica Crônica/complicações , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Deficiência do Fator X/diagnóstico , Hematoma/diagnóstico , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucócitos , Monócitos , Convulsões/complicaçõesRESUMO
Background: The therapeutic range (TR) of activated partial thromboplastin time (aPTT) for unfractionated heparin (UFH) dosing was established in the 1970 decade. Since then aPTT determination has changed. Current TR may be sub or supra-therapeutic depending on the reagents of the test, and therefore, responsible for complications of therapy. Aim: To establish the TR for UFH dosing in our institution using antifactor Xa analysis as reference standard. Material and Methods: After obtaining an informed consent, 43 blood samples were obtained for aPTT determination and antifactor Xa assay in 23 patients treated with intravenous UFH. Samples were processed at Emergency and Hemostasis Labs. We excluded patients receiving other anticoagulants, with thrombophilia, pregnancy or liver disease. Results: Mean aPTT values in the Hemostasis and Emergency labs were 57.1 ± 18.9 and 56.6 ± 18.3 seconds, respectively (p = 0.77). The squared correlation coefficients between aPTT and antifactor Xa at hemostasis and emergency labs were R2 0.5 and 0.45 respectively, p < 0.001. Using a linear regression analysis, therapeutic aPTT range values in our laboratory were established between 50 and 80 seconds, corresponding to antifactor Xa values of 0.3 to 0.7 IU/mL. Conclusions: According to current recommendations, validation of aPTT determination with reference techniques should be done in every institution.
Assuntos
Humanos , Anticoagulantes/administração & dosagem , Inibidores do Fator Xa/sangue , Heparina/administração & dosagem , Tempo de Tromboplastina Parcial/métodos , Indicadores e Reagentes , Nomogramas , Padrões de Referência , Valores de Referência , Análise de Regressão , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
BACKGROUND: Amiodarone is an effective medication in preventing atrial fibrillation (AF), but it interferes with the metabolism of warfarin. OBJECTIVES: This study sought to examine the association of major thrombotic clinical events and bleeding with the use of amiodarone in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. METHODS: Baseline characteristics of patients who received amiodarone at randomization were compared with those who did not receive amiodarone. The interaction between randomized treatment and amiodarone was tested using a Cox model, with main effects for randomized treatment and amiodarone and their interaction. Matching on the basis of a propensity score was used to compare patients who received and who did not receive amiodarone at the time of randomization. RESULTS: In ARISTOTLE, 2,051 (11.4%) patients received amiodarone at randomization. Patients on warfarin and amiodarone had time in the therapeutic range that was lower than patients not on amiodarone (56.5% vs. 63.0%; p < 0.0001). More amiodarone-treated patients had a stroke or a systemic embolism (1.58%/year vs. 1.19%/year; adjusted hazard ratio [HR]: 1.47, 95% confidence interval [CI]: 1.03 to 2.10; p = 0.0322). Overall mortality and major bleeding rates were elevated, but were not significantly different in amiodarone-treated patients and patients not on amiodarone. When comparing apixaban with warfarin, patients who received amiodarone had a stroke or a systemic embolism rate of 1.24%/year versus 1.85%/year (HR: 0.68, 95% CI: 0.40 to 1.15), death of 4.15%/year versus 5.65%/year (HR: 0.74, 95% CI: 0.55 to 0.98), and major bleeding of 1.86%/year versus 3.06%/year (HR: 0.61, 95% CI: 0.39 to 0.96). In patients who did not receive amiodarone, the stroke or systemic embolism rate was 1.29%/year versus 1.57%/year (HR: 0.82, 95% CI: 0.68 to 1.00), death was 3.43%/year versus 3.68%/year (HR: 0.93, 95% CI: 0.83 to 1.05), and major bleeding was 2.18%/year versus 3.03%/year (HR: 0.72, 95% CI: 0.62 to 0.84). The interaction p values for amiodarone use by apixaban treatment effects were not significant. CONCLUSIONS: Amiodarone use was associated with significantly increased stroke and systemic embolism risk and a lower time in the therapeutic range when used with warfarin. Apixaban consistently reduced the rate of stroke and systemic embolism, death, and major bleeding compared with warfarin in amiodarone-treated patients and patients who were not on amiodarone.