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Resumen Introducción. En mujeres, el riesgo de desarrollar enfermedad tromboembólica venosa (ETV) es 5 a 6 veces mayor durante el embarazo, riesgo que puede aumentar considerablemente si existen antecedentes personales o familiares de otros estados protrombóticos. La ETV es una de las principales causas de morbimortalidad en esta población, por lo que para evaluar la pertinencia de usar tromboprofilaxis, ya sea farmacológica o no farmacológica, es necesario reconocer oportunamente los factores de riesgo clínico asociados a esta condición. Objetivo. Describir el uso de pruebas de tamizaje de estados protrombóticos y de la tromboprofilaxis farmacológica y no farmacológica para prevenir la ETV durante la gestación, durante el parto y durante el puerperio. Materiales y métodos. Se realizó una revisión de la literatura en Embase, ClinicalKey, ScienceDirect, Access Medicine, Scopus, ProQuest, PubMed y LILACS. Se buscaron estudios sobre trombofilia y tromboprofilaxis en el embarazo publicados entre enero de 2004 y marzo de 2018 en inglés y en español. Resultados. En la búsqueda inicial se identificaron 126 artículos, de los cuales 52 cumplieron los criterios de inclusión. La mayoría de estudios correspondió a revisiones narrativas (n = 15), revisiones sistemáticas (n=8) y guías de práctica clínica (n=6). Conclusión. Se recomienda el uso de pruebas de tamizaje de estados protrombóticos durante la gestación, el parto y el puerperio, ya que la identificación oportuna de la ETV permite disminuir las tasas de morbimortalidad en esta población mediante la implementación de medidas tromboprofilácticas, sean o no farmacológicas.
Abstract Introduction: The risk of developing venous thromboembolism (VTE) in women is 5 to 6 times higher during pregnancy. In addition, this risk can be significantly higher if the patient has a history or family history of hypercoagulate states. VTE is a leading cause of morbidity and mortality in this population, so in order to assess if it is appropriate to use thromboprophylaxis during pregnancy, whether pharmacological or non-pharmacological, it is necessary to timely recognize the clinical risk factors associated with this condition. Objective: To describe the use, on the one hand, of screening tests for hypercoagulate states and, on the other, of pharmacological and non-pharmacological thromboprophylaxis to prevent the development of VTE during pregnancy, labor and the puerperium Materials and methods: A literature review was conducted in the Embase, ClinicalKey, ScienceDirect, Acces Medicine, Scopus, ProQuest, PubMed and LILACS databases. The search included studies on thrombophilia and thrombophylaxis during pregnancy published in English or Spanish between January 2004 and March 2018. Results: After completing the initial search, 126 studies were identified, of which 52 met the inclusion criteria. Most studies were narrative reviews (n = 15), systematic reviews (n = 8) and clinical practice guidelines (n=6). Conclusion: The use of screening tests for hypercoagulate states during pregnancy, labor and the puerperium is recommended, since the timely identification of VTE will allow the reduction of morbidity and mortality rates in this population through the implementation of thromboprophylactic measures, whether they are pharmacological or non-pharmacological.
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Fucoidan-loaded nanoparticles emerge as great candidates to oral anticoagulant therapy, due to increasing of bioavailability and circulation time of this natural anticoagulant. Crosslink between chitosan chains are performed using glutaraldehyde to confer higher gastric pH resistance to nanoparticle matrices. In this work, chitosan-fucoidan nanoparticles, without (NpCF) and with glutaraldehyde crosslink (NpCF 1% and NpCF 2%), were prepared to evaluate their anticoagulant, antithrombotic and hemorrhagic profile. Nanoparticles were characterized by average diameter, polydispersity index, zeta potential, Fourier transform infrared spectroscopy and fucoidan in vitro release. Anticoagulant and antithrombotic activities were determined by in vitro and in vivo models, respectively. Hemorrhagic profile was in vivo evaluated by tail bleeding assay. Preparations showed nanometric and homogeneous average diameters. Zeta potentials of NpCF and NpCF 1% were stable over gastrointestinal pH range, which was confirmed by low fucoidan release in gastric and enteric media. In pH 7.4, NpCF and NpCF 1% demonstrated fucoidan release of 65.5% and 60.6%, respectively, within the first 24 hours. In comparison to fucoidan, NpCF and NpCF 1% showed increased in vitro anticoagulant activity. A significant difference on oral antithrombotic profile of NpCF 1% was found in comparison to fucoidan. Bleeding profile of NpCF and NpCF 1% showed no differences to control group, indicating the safety of these systems. Surprisingly, oral antithrombotic profile of commercially available fucoidan, from Fucus vesiculosus, has not been previously determined, which reveals new possibilities. In this work, significant advances were observed in anticoagulant and antithrombotic profiles of fucoidan through the preparation of NpCF 1%.
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Essentials Inhibitors of protein disulfide isomerase (PDI) have been considered a new antithrombotic class. CxxC is a PDI-targeted peptide that has been previously shown to inhibit its reductase activity. CxxC binds to surface PDI and inhibits ADP- and thrombin-evoked platelet activation and aggregation. CxxC binds to Cys400 on CGHC redox motif of PDI a' domain, a site for PDI prothrombotic activity. SUMMARY: Background Protein disulfide isomerase (PDI) plays a major role in platelet aggregation, and its inhibitors have emerged as novel antithrombotic drugs. In previous work, we designed a peptide based on a PDI redox motif (CGHC) that inhibited both PDI reductase activity and PDI-modulated superoxide generation by neutrophil Nox2. Thus, we hypothesized that this peptide would also inhibit platelet aggregation by association with surface PDI. Methods Three peptides were used: CxxC, containing the PDI redox motif; Scr, presenting a scrambled sequence of the same residues and AxxA, with cysteines replaced by alanine. These peptides were tested under platelet aggregation and flow cytometry protocols to identify their possible antiplatelet activity. We labeled membrane free thiol and electrospray ionization liquid chromatography tandem mass spectrometry to test for an interaction. Results CxxC decreased platelet aggregation in a dose-dependent manner, being more potent at lower agonist concentrations, whereas neither AxxA nor Scr peptides exerted any effect. CxxC decreased aIIbb3 activation, but had no effect on the other markers. CxxC also decreased cell surface PDI pulldown without interfering with the total thiol protein content. Finally, we detected the addition of one CxxC molecule to reduced PDI through binding to Cys400 through mass spectrometry. Interestingly, CxxC did not react with oxidized PDI. Discussion CxxC has consistently shown its antiplatelet effects, both in PRP and washed platelets, corroborated by decreased aIIbb3 activation. The probable mechanism of action is through a mixed dissulphide bond with Cys400 of PDI, which has been shown to be essential for PDI's actions. Conclusion In summary, our data support antiplatelet activity for CxxC through binding to Cys400 in the PDI a0 domain, which can be further exploited as a model for sitedriven antithrombotic agent development.
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Inibidores da Agregação Plaquetária/química , Pró-Colágeno-Prolina Dioxigenase/química , Isomerases de Dissulfetos de Proteínas/química , Alanina/química , Motivos de Aminoácidos , Plaquetas/metabolismo , Domínio Catalítico , Cisteína/química , Dissulfetos , Humanos , Oxirredução , Peptídeos/química , Ativação Plaquetária , Agregação Plaquetária , Ligação Proteica , Domínios Proteicos , Dobramento de ProteínaRESUMO
Objetivo: a intensão deste estudo foi identificar, através da literatura pertinente, a conduta mais ponderada no tratamento odontológico dos indivíduos que fazem uso de anticoagulantes e ou antiagregantes plaquetários. Material e Métodos: a pesquisa, realizada em julho 2016, incluiu as bases eletrônicas de dados bibliográficos MEDLINE/ PubMed e BVS entre os anos de 2000 a 2016. A busca inicial identificou 141 artigos indexados, sendo que 25 foram selecionados conforme metodologia. Resultados: os artigos avaliados indicaram contextos variados no atendimento deste grupo de pacientes que faz uso de medicações anticoagulante e ou antiagregantes plaquetários. As ocorrências de hemorragias foram tratadas de forma satisfatória na totalidade. Conclusão: os pacientes podem seguramente submeter a procedimentos cirúrgicos odontológicos desde que seja avaliada a via extrínseca da coagulação para determinação da tendência de coagulação do sangue, isto é, a INR. Além disso, considerar o risco cirúrgico de acordo com o tipo de intervenção, procurar minimizar o trauma cirúrgico, fazer uso de métodos locais de hemostasia e prestar orientações pós-operatórias detalhadas.
Objective: the aim of this study was to identify, through literature, the most appropriate strategy for the dental treatment of patients taking anticoagulants or antiplatelet agents. Materials and Methods: the survey, conducted in July 2016, included the electronic bibliographic databases MEDLINE/ PubMed and BVS, between the years 2000 and 2016. The initial search identified 141 articles indexed, and 25 were selected according to the methodology. Results: the articles were analyzed and various contexts in the care of this group of patients taking anticoagulant and/or antiplatelet agents were pointed out. The bleeding events were all handled satisfactorily. Conclusion: patients can safely undergo dental surgical procedures provided that the extrinsic pathway of coagulation to determine the blood clotting tendency is assessed, i.e., the INR. Furthermore, it is advisable to assess the surgical risk according to the type of procedure, approaches to minimize surgical trauma, the use of local hemostasis agents, and provide detailed postoperative instructions.
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INTRODUCTION: Brazil is among the first countries approving the commercialization and clinical use of biosimilar enoxaparins. Our research group has performed quality control assessments of these drugs over the last decade. Areas covered: We have not found noticeable differences between Brazilian biosimilar enoxaparins and the original product regarding their physicochemical properties, disaccharide composition, anticoagulant activity, bioavailability and safety. Expert commentary: In spite of clinical and pharmacological advantages of enoxaparin, subcutaneous formulations of unfractionated heparin are employed by the Brazilian public health system for prevention and treatment of thromboembolism. The underuse of both original and biosimilar enoxaparins in Brazil directly correlates with their high cost.
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Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Medicamentos Biossimilares , Enoxaparina/farmacologia , Enoxaparina/uso terapêutico , Tromboembolia/tratamento farmacológico , Anticoagulantes/química , Brasil , Análise Custo-Benefício , Enoxaparina/química , HumanosRESUMO
Plant serine proteases have been widely used in food science and technology as well as in medicine. In this sense, several plant serine proteases have been proposed as potential anti-coagulants and anti-platelet agents. Previously, we have reported the purification and identification of a plant serine protease from Solanum tuberosum leaves. This potato enzyme, named as StSBTc-3, has a molecular weight of 72 kDa and it was characterized as a subtilisin like protease. In this work we determine and characterize the biochemical and medicinal properties of StSBTc-3. Results obtained show that, like the reported to other plant serine proteases, StSBTc-3 is able to degrade all chains of human fibrinogen and to produces fibrin clot lysis in a dose dependent manner. The enzyme efficiently hydrolyzes ß subunit followed by partially hydrolyzed α and γ subunits of human fibrinogen. Assays performed to determine StSBTc-3 substrate specificity using oxidized insulin ß-chain as substrate, show seven cleavage sites: Asn3-Gln4; Cys7-Gly8; Glu13-Ala14; Leu15-Tyr16; Tyr16-Leu17; Arg22-Gly23 and Phe25-Tyr26, all of them were previously reported for other serine proteases with fibrinogenolytic activity. The maximum StSBTc-3 fibrinogenolytic activity was determined at pH 8.0 and at 37 C. Additionally, we demonstrate that StSBTc-3 is able to inhibit platelet aggregation and is unable to exert cytotoxic activity on human erythrocytes in vitro at all concentrations assayed. These results suggest that StSBTc-3 could be evaluated as a new agent to be used in the treatment of thromboembolic disorders such as strokes, pulmonary embolism and deep vein thrombosis.
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Fibrinolíticos , Proteínas de Plantas , Inibidores da Agregação Plaquetária , Solanum tuberosum/enzimologia , Subtilisinas , Plaquetas/metabolismo , Eritrócitos/metabolismo , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Humanos , Proteínas de Plantas/química , Proteínas de Plantas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Embolia Pulmonar/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Subtilisinas/química , Subtilisinas/farmacologia , Trombose Venosa/tratamento farmacológicoRESUMO
INTRODUCTION: Antiphospholipid syndrome (APS) is a pro-thrombotic autoimmune disease that affects different vascular beds, with potential risk for recurrence. Systemic lupus erythematosus (SLE), specific autoantibodies profile and atherogenic disorders have been described as risk factors for the occurrence of first thrombosis in patients with antiphospholipid antibodies (aPL). However, factors associated with recurrent thrombosis have not yet been completely elucidated in APS. The aim of this study was to evaluate the association of recurrent thrombosis with markers of inflammation, autoimmunity and the presence of atherogenic disorders in APS patients. MATERIALS AND METHODS: We performed a retrospective evaluation of a cohort of APS patients in order to determine if markers of inflammation, autoimmunity and cardiovascular risk were associated with recurrence of thrombosis. RESULTS: One hundred fifteen patients with APS were included, 60% had primary APS. History of recurrent thrombosis was positive in 38.3% of patients, and 40% of them were on oral anticoagulants at the time of recurrence. Independent risk factors associated with recurrent thrombosis were arterial hypertension (OR = 3.7, 95% CI = 1.68.5, P = 0.002) and monocytosis above 500 u/mm(3) (OR = 2.4, 95% CI = 1.25.3, P = 0.02). These factors were particularly relevant in cases of venous index event. CONCLUSION: The results suggest that arterial hypertension and monocyte counts may be independent factors for thrombosis recurrence in APS. Given the morbidity of recurrent cases, the results may support the evaluation of therapeutic measures to a rigid control of blood pressures and modulation of inflammatory response in APS, as additional prophylaxis against the recurrence of vascular events.
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Síndrome Antifosfolipídica/complicações , Doenças Cardiovasculares/etiologia , Inflamação/complicações , Trombose/etiologia , Adulto , Autoimunidade , Estudos de Coortes , Feminino , Humanos , Masculino , Recidiva , Estudos Retrospectivos , Fatores de RiscoRESUMO
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.
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Amiodarona/administração & dosagem , Anticoagulantes/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Idoso , Antiarrítmicos/administração & dosagem , Fibrilação Atrial/fisiopatologia , Brasil/epidemiologia , Causas de Morte/tendências , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Eletrocardiografia , Europa (Continente)/epidemiologia , Inibidores do Fator Xa/administração & dosagem , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Ontário/epidemiologia , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Taxa de Sobrevida/tendências , Tromboembolia/complicações , Tromboembolia/epidemiologia , Tromboembolia/prevenção & controle , Resultado do Tratamento , Estados Unidos/epidemiologia , Varfarina/administração & dosagemRESUMO
BACKGROUND: Sulfated galactans are polysaccharides with heterogeneous structures that frequently show anticoagulant activity. Their anticoagulant mechanisms are complex and distinct from those observed for heparin. Sulfated galactans act through a combination of effects involving serpin-dependent and serpin-independent mechanisms. Interestingly, these polymers can also induce blood coagulation due to activation of factor XII (FXII). OBJECTIVES: The structure of a complex sulfated galactan from the red alga Acanthophora muscoides was characterized by solution nuclear magnetic resonance. This polysaccharide and another previously characterized algal sulfated galactan from Botryocladia occidentalis were each used in in vitro and in vivo anticoagulant and antithrombotic assays to understand the possible structural determinants of their functional effects. RESULTS AND CONCLUSIONS: The serpin-dependent anticoagulant effects and FXII-related procoagulant effects of the sulfated galactans decreased in parallel with the molecular size. The serpin-independent anticoagulation also correlated with the chemical structure of the sulfated galactans. The sulfated galactan from A. muscoides, which showed mostly serpin-independent anticoagulant activity and reduced activation of FXII, drastically reduced arterial thrombus formation. However, the sulfated galactans produced opposite effects on venous thrombosis; this difference appears to result from the tenuous balance between the various effects on coagulation, including serpin-dependent and serpin-independent anticoagulation and FXIIa-dependent procoagulation. This study of novel sulfated polysaccharides with distinct effects on coagulation and thrombosis helps to establish the minimal structural-function relationship required for the development of antithrombotic drugs.