Eficácia e segurança de anticoagulantes orais diretos comparados à anticoagulação tradicional com heparina e varfarina para tratamento de tromboembolismo pulmonar e trombose venosa profunda / Effectiveness and safety of direct oral anticoagulants compared to traditional anticoagulation with heparin and varfarine to treat pulmonary thromboembolism and deep venous thrombosis

Tecnologia: Inibidores Diretos do Fator Xa (IDFXa) ­ Rivaroxabana, Apixabana, Edoxabana ­ e Inibidores Diretos da Trombina (IDT) ­ Dabigatrana ­ todos são anticoagulantes orais diretos (DOAC). Indicação: tratamento e prevenção de fenômenos tromboembólicos. Pergunta: Para tratamento de tromboembolismo pulmonar (TEP) e trombose venosa profunda (TVP), os DOAC são mais eficazes e seguros que a anticoagulação tradicional com heparina e varfarina? Métodos: Levantamento bibliográfico na base de dados Pubmed seguindo estratégias de buscas predefinidas. Avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta Assessing the Methodological Quality of Systematic Reviews (AMSTAR). Resultados: Foram selecionadas e incluídas 4 revisões sistemáticas. Conclusão: Na maioria dos estudos incluídos, os DOAC demonstraram eficácia e segurança similar à anticoagulação tradicional com heparina e varfarina para tratamento de TEP e TVP. Em um estudo, o risco de TVP recorrente foi menor no tratamento de IDFXa (por menos 3 meses de tratamento) e de episódios de sangramento maior foi menor no tratamento de IDT e IDFXa (por mais 3 meses de tratamento)

Technology: Direct Factor Xa Inhibitors (DFXaI) - Rivaroxaban, Apixaban, Edoxaban ­ and Direct Thrombin Inhibitors (DTI) - Dabigatran - all are direct oral anticoagulants (DOAC). Indication: treatment and prevention of thromboembolic phenomena. Question: For treatment of pulmonary thromboembolism (PTE) and deep vein thrombosis (DVT), are DOACs more effective and safer than traditional anticoagulation with heparin and warfarin? Methods: Bibliographic survey in the Pubmed database following predefined search strategies. Evaluation of the methodological quality of systematic reviews with the tool Assessing the Methodological Quality of Systematic Reviews (AMSTAR). Results: 4 systematic reviews were selected and included. Conclusion: In most of the included studies, DOAC demonstrated similar efficacy and safety to traditional anticoagulation with heparina and warfarin for the treatment of PTE and DVT. In one study, the risk of recurrent DVT was lower in the treatment of DFXaI (for at least 3 months of treatment) and of major bleeding episodes was lower in the treatment of DTI and DFXaI (for another 3 months of treatment)

Manejo de hemorragia asociada a anticoagulantes orales directos: estado actual de las estrategias de reversión / Management of bleeding associated with direct oral anticoagulants: update on reversal strategies

Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban have at least comparable efficacy as vitamin K antagonists along with a better safety profile, reflected by a lower incidence of intracranial hemorrhage. Specific reversal agents have been developed in recent years. Namely, idarucizumab, a specific antidote for dabigatran, is currently approved in most countries. Andexanet, which reverses factor Xa inhibitors, has been recently approved by the FDA, and ciraparantag, a universal antidote targeted to reverse all DOACs, is still under investigation. In this review we provide an update on the pharmacology of DOACs, the risk of hemorrhagic complications associated with their use, the measurement of their anticoagulant effect and the reversal strategies in case of DOAC-associated bleeding.

The effect of hirudin on antagonisting thrombin induced apoptosis of human microvascular endothelial cells

Abstract Purpose: To investigate whether hirudin exerts its antithrombin action to decrease the ratio of Human Microvascular Endothelial Cells (HMVECs) apoptosis. Methods: Human microvascular endothelial cells (HMVECs) cultured in the third and fifth generations were used. HMVECs were divided into normal group, thrombin group (T group), natrual hirudin group (H group), thrombin + natrual hirudin group (T + H group), AG490 group, thrombin + AG490 group (T + AG490 group), natrual hirudin + AG490 group (H + AG490 group), thrombin + natural hirudin + AG490 (T + H + AG490 group).Apart from the normal group, the other groups were exposed to the relevant drugs for 24 hours.HMVEC apoptosis was assessed by flow cytometric and double Immunofluorescence of phosphorylation of JAK (P-JAK2) and TUNEL assay. Results: Compared with the normal group, in thrombin group the HMVECs apoptosis rate were significantly increased (P<0.05).The results indicated that the index of apoptosis and the apoptosis rate were improved in cultures treated by natural hirudin (T + H group), relative to cultures with thrombin only (T group). We found that the index of apoptosis and the apoptosis rate in the AG490 + thrombin group were higher than that in the hirudin + thrombin group (P<0.05). Double Immunofluorescence of p-JAK2 and TUNEL assays showed that cells were double positive for P-JAK2 uptake and TUNEL detection liquid binding. Conclusion: The natural hirudin and JAK2/STATs signal inhibitor AG490 could block the effects of thrombin. Natural hirudin could attenuate HMVECs apoptosis via antagonizing thrombin and it is suggested that this effect may occur by blocking the JAK2/STATs signaling pathway and this signaling pathways appears to be not the only pathway.

Use of direct oral anticoagulants for chronic thromboembolic pulmonary hypertension

OBJECTIVES: Chronic thromboembolic pulmonary hypertension is one of the most prevalent forms of pulmonary hypertension and is a major complication of acute pulmonary embolism. One mainstay of chronic thromboembolic pulmonary hypertension treatment is lifelong anticoagulation. The recent advent of direct oral anticoagulants for acute pulmonary embolism treatment has provided a viable and effective alternative for treating this condition. However, little is known about the efficacy of this new class of drugs for treating chronic thromboembolic pulmonary hypertension. We aimed to evaluate the safety and efficacy of direct oral anticoagulants in the treatment of chronic thromboembolic pulmonary hypertension. METHODS: A cohort of chronic thromboembolic pulmonary hypertension patients who initiated treatment with direct oral anticoagulants between June 2015 and November 2016 were enrolled in this study. RESULTS: Sixteen patients used rivaroxaban, three used dabigatran and one used apixaban for a mean follow-up of 20.9 months. The mean age was 51 years, and eighteen patients were classified as functional class II/III. Eight patients underwent a pulmonary endarterectomy and exhibited clinical, hemodynamic and functional improvement and currently continue to use direct oral anticoagulants. No episode of venous thromboembolism recurrence was identified during the follow-up period, but there was one episode of major bleeding after a traumatic fall. CONCLUSIONS: Although direct oral anticoagulants appear to be a safe and effective alternative for treating chronic thromboembolic pulmonary hypertension, larger studies are needed to support their routine use.

Nuevos anticoagulantes orales: actualización / New oral anticoagulants: a review

Resumen: Los anticoagulantes orales clásicos del tipo cumarinas han estado disponibles para uso clínico por más de medio siglo. Tienen gran eficacia para tratar o prevenir trombosis y tromboembolias, y son drogas cuyo uso ha aumentado con el mejor conocimiento clínico, el aumento de los factores de riesgo y el envejecimiento de la población. Entre sus desventajas se incluyen la alta variabilidad de su efecto en cada sujeto y entre individuos, la influencia del nivel de ingesta de vitamina K, la necesidad de control periódico del nivel de anticoagulación, su interacción con múltiples drogas. Si bien, el rango terapéutico está estandarizado, es estrecho, haciendo que el tiempo en rango terapéutico sea de ≈ 60%. Por estas limitaciones, se han creado nuevos anticoagulantes orales (NACOs), siendo progresivamente aprobados para uso clínico por agencias internacionales. Genéricamente, son de 2 tipos: inhibidores selectivos de trombina (dabigatrán) o de FXa (rivaroxabán, apixabán, edoxabán y betrixabán). Los NACOs se caracterizan por su dosificación una o dos veces al día, rapidez de acción, corta vida media en la circulación, predictibilidad de su efecto, dosis preestablecidas, sin necesidad de control periódico y con escasa o nula interacción con otras drogas. Estas ventajas no se han traducido en la mayoría de los ensayos en un superior efecto antitrombótico o menor riesgo de sangrado, y en su mayoría (salvo dabigatrán) carecen de antídoto específico demostrado.

Abstracts: Vitamin K inhibitors, coumarins, have been used for more than 50 years with no dispute by other drugs. Coumarins have demonstrated great efficacy in the treatment and prophylaxis of thrombotic and thromboembolic disorders, and their use has increased progressively with the advance of clinical knowledge as well as the increase of risk factors and aging of the population. Limitations of coumarins include great variability intra and inter-individuals, the influence of foods rich in vitamin K, the need for periodical assessment of the anticoagulant level and drug interactions. The therapeutic range is standardized using the INR (International Normalized Ratio). However, the therapeutic window is narrow, with frequent periods of either over or under-dosing, with the concomitant increase of bleeding and thrombotic risks, respectively. Long-term accredited anticoagulant clinics and clinical trials report that, at best, only ≈60% of time in treatment the patients are within the therapeutic range. These limitations have created the need for new oral anticoagulants (NOACs), and several of them have been approved for clinical use by international agencies after exhaustive and specific clinical trials. Generically, NACOs are belong in two types: selective inhibitors of thrombin (dabigatran) or FXa (rivaroxaban, apixaban, edoxaban and betrixaban). NOACs are prescribed once or twice daily, the onset of action is very fast, have a low T1/2 in the circulation, their effects are highly predictable, doses are pre-established, do not need laboratory control and have a low rate of interaction with other drugs. Despite these advantages most clinical trials have shown NOACs to be not inferior with respect to coumarin. However, NOACs have no clear advantages over warfarin in antithrombotic effect or bleeding reduction. Furthermore, most of them (except dabigatran) have no specific antidotes yet.

Características basales, manejo de terapias antitrombóticas y pronóstico de pacientes chilenos con FA no valvular. Lecciones del Registro GARFIELD AF en Chile / Features, management and prognosis of Chilean patients with non valvular atrial fibrillation: GARFIELD AF registry

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with high rates of death, ischemic stroke and systemic embolism (SE). There is scarce information about clinical characteristics and use of anti-thrombotic therapies in Chilean patients with non-valvular AF. Aim: To describe the characteristics and 1-year outcomes of patients with recently diagnosed AF recruited in Chile into the prospective global GARFIELD-AF registry. Material and Methods: Between 2011-2016, we prospectively registered information of 971 patients recruited at 15 centers, 85% of them from the public system and 15% from the private sector. Demographics, clinical characteristics and use of antithrombotic therapies were recorded for all patients. Adverse clinical outcomes were analyzed in 711 patients with 1-year follow-up. Results: The mean age was 71.5 years (66-79), 50% were men. Mean CHAD2S2 Vasc and HAS BLED scores for stroke risk were 3.3 (2.0-4.0) and 1.5 (1.0-2.0) respectively. Oral anticoagulants were prescribed in 82% of patients. Seventy percent received Vitamin K antagonists, 10% novel direct anticoagulants or antiplatelet therapy and only 8% did not receive any antithrombotic therapy. Mean time in optimal therapeutic range (an international normalized ratio of 2 to 3), was achieved in only 40.7% (23.0-54.8) of patients receiving Vitamin K antagonists. One year rates of death, stroke/systemic embolism and bleeding were 4.75 (3.36-6.71), 2.40 (1.47-3.92) and 1.64% (0.91-2.97) per 100 person-years. Ischemic stroke occurred in 1.8% and hemorrhagic stroke in 0.8% of patients at 1-year of follow up. Conclusions: Although the use of vitamin K antagonists at baseline was high, the mean time in optimal therapeutic range was low. Mortality and stroke rates are higher than those reported in other contemporary registries.

Función renal y nivel plasmático de dabigatrán en el valle, medido por un ensayo de trombina diluida / Renal function and plasma dabigatran level measured at trough by diluted thrombin time assay

El dabigatrán etexilato (inhibidor directo de trombina) es eficaz en la prevención tromboembólica en pacientes con fibrilación auricular. No requiere control rutinario de laboratorio, pero dada su eliminación renal, sería importante medirlo ante el deterioro de la función renal. Los objetivos del trabajo fueron verificar la calidad analítica del ensayo tiempo de trombina diluido para medición de la concentración plasmática (cc) de dabigatrán, correlacionar las cc con las pruebas básicas de coagulación tiempo de protrombina (TP) y tiempo de tromboplastina parcial activada (APTT) y evaluarlas de acuerdo al clearance de creatinina (CLCr). Se utilizaron muestras de plasma de 40 pacientes que recibían dabigatrán 150 (n = 19) o 110 (n = 21) mg/12 horas, colectadas 10-14 horas después de la última toma. Los ensayos de trombina diluida HemosIL DTI para la medición de dabigatrán, TP y APTT (IL), fueron realizados en coagulómetros fotoópticos ACL TOP 300 y 500 (IL). El DTI presentó coeficiente de variación intraensayo < 5.4% e interensayo < 6.0%, rango de linealidad 0-493 ng/ml; cc medidas en pacientes: mediana 83 (4-945) ng/ml. Individuos con CLCr en tercil inferior (< 46.1 ml/min) presentaron cc significativamente más elevadas, 308 (49-945), que los de tercilos medio, 72 (12-190), y superior, 60 (4-118) ng/ml. Las correlaciones cc vs. APTT o TP fueron moderadas, r2 = 0.59, -0.66, p < 0.0001, respectivamente. La prueba ensayada permitió cuantificar el nivel de dabigatrán plasmático tanto en pacientes con función renal normal como deteriorada, representando una herramienta útil en situaciones clínicas como deterioro de la función renal, pre cirugía o emergencias.

Dabigatran etexilate (direct thrombin inhibitor) is effective in preventing embolic stroke in patients with atrial fibrillation. It does not require laboratory control, but given the high renal elimination, its measurement in plasma is important in renal failure. The objectives of the study were to verify the analytical quality of the diluted thrombin time assay for measurement of dabigatran plasma concentration (cc), correlate cc with classic coagulation assays, prothrombin time (PT) and activated partial thromboplastin time (APTT), and evaluate them according to the creatinine clearance (CLCr). Forty plasma samples of patients (34 consecutive and 6 suspected of drug accumulation) receiving dabigatran at 150 (n = 19) or 110 (n = 21) mg/12 hours were collected. Blood samples were drawn at 10-14 hours of the last intake. Dabigatran concentration was determined by diluted thrombin time (HemosIl DTI, Instrumentation Laboratory (IL). PT and APTT (IL) were performed on two fotooptical coagulometers, ACL TOP 300 and 500 (IL). DTI presented intra-assay coefficient of variation < 5.4% and inter-assay < 6%, linearity range 0-493 ng/ml. Patients´ cc: median 83 (4-945) ng/ml. Individuals with CLCr in the lowest tertile (22.6-46.1 ml/min) showed significantly higher median cc: 308 (49-945), compared to the average 72 (12-190) and highest tertile, 60 (4-118) ng/ml. Correlation between cc and APTT or PT were moderate, r2 = 0.59 and -0.66, p < 0.0001, respectively. DTI test allowed us to quantify plasma dabigatran levels, both in patients with normal or altered renal function, representing a useful tool in clinical situations such as renal failure, pre surgery or emergencies.

Trombocitopenia inducida por heparina: Nuevas opciones terapéuticas / Heparin-induced thrombocytopenia. New therapeutical options

La trombocitopenia inducida por heparina (TIH) es una reacción adversa inmunológica mediada por la formación de anticuerpos contra el complejo heparina-factor plaquetario 4 (FP4), caracterizada por la presencia de trombocitopenia y la asociación paradojal de trombosis arterial o venosa. Es una complicación poco frecuente pero grave del uso de cualquier tipo de heparina. En tratados con procedimientos cardiovasculares como intervención coronaria percutánea y cirugía de revascularización cardiaca, la prevalencia de anticuerpos es significativamente mayor que en otros escenarios clínicos. El reconocimiento de las características clínicas y de laboratorio permite la suspensión inmediata de la heparina y la instauración de tratamiento anticoagulante alternativo, para evitar la progresión y formación de nuevos trombos y sus complicaciones. En la presente revisión se resumen las diferentes alternativas terapéuticas para la TIH, en particular los anticoagulantes orales directos (DOACS) como el dabigatran, rivaroxaban y apixaban que pueden proporcionar una nueva opción para el tratamiento de TIH.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse reaction due to antibodies to a multimolecular complex of heparin and platelet factor 4 (PF4) characterized by moderate thrombocytopenia and paradoxical arterial or venous thrombosis. It is a relatively infrequent complication related to the administration of any type of heparin. In patients undergoing percutaneous coronary revascularization or coronary artery by-pass graft the prevalence of HIT is higher than in other clinical settings. Recognizing clinical and laboratory features of HIT allow immediate discontinuation of heparin and the use of alternative anticoagulants to avoid serious thrombotic complications. In this review, we summarize different therapeutic options for the treatment of HIT with special emphasis on direct oral anticoagulants (DOACS) such as dabigatran, rivaroxaban and apixaban. DOACS might represent a therapeutic alternative for HIT treatment.

Readability of medicinal package leaflets: a systematic review / Legibilidade das bulas dos medicamentos: revisão sistemática

OBJECTIVE To review studies on the readability of package leaflets of medicinal products for human use. METHODS We conducted a systematic literature review between 2008 and 2013 using the keywords “Readability and Package Leaflet” and “Readability and Package Insert” in the academic search engine Biblioteca do Conhecimento Online, comprising different bibliographic resources/databases. The preferred reporting items for systematic reviews and meta-analyses criteria were applied to prepare the draft of the report. Quantitative and qualitative original studies were included. Opinion or review studies not written in English, Portuguese, Italian, French, or Spanish were excluded. RESULTS We identified 202 studies, of which 180 were excluded and 22 were enrolled [two enrolling healthcare professionals, 10 enrolling other type of participants (including patients), three focused on adverse reactions, and 7 descriptive studies]. The package leaflets presented various readability problems, such as complex and difficult to understand texts, small font size, or few illustrations. The main methods to assess the readability of the package leaflet were usability tests or legibility formulae. Limitations with these methods included reduced number of participants; lack of readability formulas specifically validated for specific languages (e.g., Portuguese); and absence of an assessment on patients literacy, health knowledge, cognitive skills, levels of satisfaction, and opinions. CONCLUSIONS Overall, the package leaflets presented various readability problems. In this review, some methodological limitations were identified, including the participation of a limited number of patients and healthcare professionals, the absence of prior assessments of participant literacy, humor or sense of satisfaction, or the predominance of studies not based on role-plays about the use of medicines. These limitations should be avoided in future ...

OBJECTIVO Analisar a literatura sobre legibilidade das bulas dos medicamentos para uso humano. MÉTODOS Estudo de revisão sistemática, utilizando as palavras-chave “Readability and Package Leaflet” e “Readability and Package Insert”e a ferramenta de busca académica b-on, que contém diferentes bases bibliográficas. O período analisado foi entre 2008 e 2013. Foram aplicados os critérios PRISMA para redigir o relatório da revisão. Foram incluídos artigos originais de pesquisa quantitativa ou qualitativa. Os critérios de exclusão foram: artigos de opinião ou de revisão, ou escritos numa língua diferente do inglês, português, italiano, francês ou espanhol. RESULTADOS Foram identificados 202 trabalhos, dos quais 180 foram excluídos e 22 selecionados para análise: dois com profissionais de saúde, 10 com pacientes, três sobre reações adversas e sete descritivos. As bulas apresentaram diversos problemas de legibilidade, entre os quais: textos insuficientemente claros e simples, utilização de tamanhos de letra pequenos e número reduzido de ilustrações. Os principais métodos utilizados para avaliar a legibilidade das bulas foram as fórmulas e os testes de legibilidade/usabilidade. Entre as limitações metodológicas, foram identificados aspetos como o recurso a amostras pequenas, a inexistência de fórmulas de legibilidade específicas para a língua em causa, e.g., português, e a realização de testes de compreensão em grupos de pacientes sem avaliação prévia da literacia, dos conhecimentos específicos na área da saúde, das capacidades cognitivas, ou do grau de satisfação dos participantes. CONCLUSÕES Em geral, as bulas apresentaram diversos problemas de legibilidade. Adicionalmente, nesta revisão foram identificadas algumas limitações metodológicas nos estudos revistos (e.g. a participação de um número reduzido de pacientes e profissionais de saúde, a ausência da avaliação prévia da literacia, do humor ou satisfação dos participantes ...

Nuevos anticoagulantes y anestesia regional / New anticoagulants and regional anesthesia

En los últimos años se ha producido un incremento de la práctica de la anestesia regional en pacientes que reciben fármacos que afectan el sistema fisiológico de la coagulación. La posibilidad de producirse un hematoma espinal, luego de una punción neuroaxial, en este tipo de pacientes, intranquiliza al médico anestesista. Por lo tanto, es indispensable que el médico anestesista conozca los mecanismos de acción de los diferentes anticoagulantes, sus propiedades farmacológicas y farmacocinéticas para poder así definir el intervalo entre la administración de los fármacos anticoagulantes y el bloqueo neuroaxial, la retirada del catéter y el reinicio de la anticoagulación permitiendo asociar la anestesia regional y la anticoagulación de forma segura para el paciente¹. Este trabajo tiene como objetivo principal realizar una revisión de los nuevos fármacos anticoagulantes y analizar las recomendaciones existentes como para poder hacer un uso racional y seguro en nuestra práctica diaria.

New anticoagulants and regional anesthesia In recent years there has been an increase in the practice of regional anesthesia in patients receiving drugs affecting the physiological coagulation system. The possibility of a spinal hematoma occurs after neuraxial puncture in these patients, uneasy the anesthesiologist. Therefore, it is essential that the anesthesiologist know the mechanism of action of different anticoagulants, their pharmacological and pharmacokinetic properties to well define the interval between administration of anticoagulants and neuraxial blockade, catheter removal and resetting anticoagulation allowing associate regional anesthesia and anticoagulation safely for patient1. This work has as main objective to carry out a review of the new anticoagulant drugs and analyze existing recommendations as to make rational and safe use in our daily practice.

Hemodiálisis para remover el anticoagulante dabigatrán en situaciones de urgencia / Hemodialysis to remove anticoagulant dabigatran during emergencies

El dabigatrán es un nuevo inhibidor directo de la trombina, de administración oral, empleado para la prevención de eventos tromboembólicos en pacientes con fibrilación auricular no valvular. A diferencia de la warfarina, no se dispone de un antídoto conocido. La hemodiálisis ha sido sugerida como un método para remover el dabigatrán y reducir el efecto anticoagulante. Se presenta el caso de un paciente con antecedente de fibrilación auricular y medicado con dabigatrán, que fue admitido en el hospital para una cirugía abdominal de urgencia. A las seis horas de la última dosis recibida, los estudios de coagulación mostraban alteración. Ante la falta de antídoto para revertir los efectos, se decidió realizar hemodiálisis. Luego de tres horas de diálisis los parámetros de coagulación tendieron a normalizarse y el paciente fue operado sin presentar hemorragias anormales durante la cirugía o en el postoperatorio.

Dabigatran is an oral anticoagulant from the class of the direct thrombin inhibitors, indicated for prevention of thromboembolic events in patients with non valvular atrial fibrillation. Unlike warfarin, dabigatran has no known antidote. Hemodialysis has been suggested as a method for removing dabigatran and thereby reducing its anticoagulant effect. We report the case of a patient with a known history of atrial fibrillation, treated with dabigatran, who was admitted for emergency abdominal surgery. At six hours after the last dose received, coagulation studies were altered. In absence of an antidote to reverse its effects, it was decided to perform hemodialysis. After three hours of dialysis coagulation parameters were improved and the patient underwent surgery without showing abnormal bleeding during surgery or in the postoperative period.

Tromboembolismo pulmonar: terapia pós-crise / Pulmonary embolism: therapy post-crisis

O principal objetivo do tratamento pós-fase aguda do tromboembolismo pulmonar é a prevenção de recorrência. Os pacientes devem ser estratificados quanto ao risco de recorrência da doença. Há mais de 50 anos os antagonistas da vitamina K são utilizados nessa fase do tratamento. Recentemente surgiram novos anticoagulantes orais que não necessitam de monitorização laboratorial, sendo uma promessa para o manejo mais fácil do tratamento.

The main objective of treatment post-acute phase of pulmonary thromboembolism is prevention of recurrence. Patients should be stratified by risk of disease recurrence. For over fifty years, vitamin K antagonists are used in this phase of treatment. Recently, a new anticoagulants which do not require laboratory monitoring with a promise for an easier handling of the treatment.

Clinical profile, common thrombophilia markers and risk factors in 85 young Indian patients with arterial thrombosis / Perfil clinico, marcadores comuns de trombofilia e fatores de risco em 85 pacientes indianos jovens com trombose arterial

CONTEXT AND OBJECTIVE: Arterial thrombosis may occur consequent to hereditary thrombophilia and increased lipoprotein(a) [Lp(a)] and fibrinogen. Our aim was to study the prevalence of common thrombophilia markers in 85 consecutive cases of arterial thrombosis. DESIGN AND SETTING: A retrospective study was conducted from 85 consecutive young patients treated as outpatients or admitted due to stroke or myocardial infarction at a tertiary care hospital. METHODS: Eighty-five Indian patients (age < 45 years) presenting ischemic stroke (n = 48) or myocardial infarction (n = 37) and 50 controls were studied for seven thrombophilia markers including antithrombin (AT), factor V, protein C, protein S, activated protein C resistance (APC-R), fibrinogen and Lp(a). Functional assays for protein C, protein S, factor V and APC-R were performed using clotting-based methods. Semi-quantitative estimation of fibrinogen was done using Clauss's method and Lp(a) using immunoturbidimetry. Statistical analysis was done using the Epi Info 6 software. RESULTS: Thirty-three samples (38.8%) tested positive for one or more thrombophilia markers. The three commonest abnormalities were elevated Lp(a) (20%), fibrinogen (17.6%) and low APC-R (14.2%). Low levels of protein C, protein S and AT were present in 4.7, 9.4 and 7% of the patients, respectively. Overall, the risk factor profile was: smoking (33%), positive family history (15.3%), hyperlipidemia (7%), hypertension, diabetes mellitus and obesity (2.3% each). CONCLUSIONS: An association was found between low levels of protein C, protein S and AT and arterial thrombosis, but only elevated fibrinogen levels, smoking, positive family history and hyperlipidemia showed statistical significance. .

CONTEXTO E OBJETIVO: Trombose arterial pode ocorrer em consequência de trombofilias hereditárias e de lipoproteína (a) [Lp (a)] e fibrinogênio aumentados. Nosso objetivo foi estudar a predominância de marcadores comuns da trombofilia em 85 casos consecutivos de trombose arterial. TIPO DE ESTUDO E LOCAL: Um estudo retrospectivo foi realizado sobre 85 pacientes jovens tratados consecutivamente no ambulatório ou admitidos por infarto do miocárdio ou acidente vascular cerebral (AVC) num hospital de cuidado terciário. MÉTODOS: Oitenta e cinco pacientes indianos (idade < 45 anos) que se apresentaram com AVC isquêmico (n = 48) ou infarto do miocárdio (n = 37) e 50 controles foram estudados para sete marcadores de trombofilia que incluíram antitrombina (AT), fator V, proteína C, proteína S, resistência ativada da proteína C (APC-R), fibrinogênio e Lp (a). Os ensaios funcionais da proteína C, proteína S, fator V e APC-R foram executados por métodos baseados em coagulação. A avaliação semiquantitativa do fibrinogênio foi feita pelo método de Clauss e a Lp(a) por imunoturbimetria. A análise estatística foi feita pelo software Epi Info 6. RESULTADOS: Trinta e três amostras (38.8%) foram positivas para um ou vários marcadores do trombofilia. As anomalias mais comuns foram Lp (a) (20%), fibrinogênio (17.6%) e APC-R (14.2%) elevados. Baixos níveis da proteína C, proteína S e AT foram detectados em 4.7%, 9.4% e 7% dos pacientes, respectivamente. Globalmente, os perfis dos fatores de risco foram: fumo (33%), antecedentes familiares positivos (15.3%), hiperlipidemia (7%), hipertensão, diabetes mellitus e obesidade (2.3% cada). CONCLUSÕES: Uma associação foi encontrada entre baixos níveis de proteína C, proteína S, AT e trombose arterial, ...

Anti-Xa e antitrombínicos específicos nas síndromes isquêmicas miocárdicas instáveis com e sem supradesnível do segmento ST / Factor Xa inhibitors and selective antithrombin agents in acute coronary syndromes

As síndromes isquêmicas miocárdicas instáveis incluem um amplo espectro de manifestações da doença coronária, variando de angina instável e infarto do miocárdio sem supradesnível do segmento ST até infarto do miocárdio com dupradesnível do seguimento ST. O mecanismo fisiopatológico subjacente envolve a combinação de aterosclerose e um evento trombótico. O tratamento com heparina não fracionada ou de baixo peso molecular tem demonstrado ser eficaz e seguro nesses pacientes. Entretanto, uma limitação inerente a essas medicações é a ausência de efeito na trombina ligada ao coágulo. Novos anticoagulantes foram desenvolvidos, tendo como alvo as duas formas de trombina - livre e aquela aderida ao coágulo (inibidores diretos da trombina) - bem como outros componentes individuais da cascata de coagulação (inibidores diretos ou indiretos do fator Xa). Esses agentes anticoagulantes demonstraram resultados promissores em estudos pré-clínicos e foram avaliados em ensaios de síndromes isquêmicas agudas em grande escala. Esta revisão discute a eficácia e a segurança desses novos agentes quando comparados com os regimes que utilizam heparina como anticoagulantes de escolha.

Acute coronary syndromes include a broad spectrum of coronary artery disease ranging from unstable angina, non-ST-segment elevation myocardial infarction to ST-segment elevation myocardial infarction. The underlying pathophysiological mechanism involves a combination of atherosclerosis and a thrombotic event. Treatment with unfractionated heparin or low-molecular-weight heparin has shown to be effective and safe in these patients. However, a common limitation of these medications is the lack of effect on clot-bound thrombin. Novel anticoagulants targeted for both the free and clot-bound forms of thrombin (direct thrombin inhibitors), or other individual components of the coagulation cascade (direct or indirect factor Xa inhibitors). These anticoagulants have shown promising results in preclinical testing and have been evaluated in large-scale clinical acute coronary syndrome trials. This review discusses the efficacy and safety of these novel agents compared with heparin-based anticoagulants.

O novo modelo da cascata de coagulação baseado nas superfícies celulares e suas implicações / A cell-based model of coagulation and its implications

O conceito da cascata da coagulação descreve as interações bioquímicas dos fatores da coagulação, entretanto, tem falhado como um modelo do processo hemostático in vivo. A hemostasia requer a formação de um tampão de plaquetas e fibrina no local da lesão vascular, bem como a permanência de substâncias procoagulantes ativadas nesse processo no sítio da lesão. O controle da coagulação sanguínea é realizado por meio de reações procoagulantes em superfícies celulares específicas e localizadas, evitando a propagação da coagulação no sistema vascular. Uma análise crítica do papel das células no processo hemostático permite a construção de um modelo da coagulação que melhor explica hemorragias e tromboses in vivo. O modelo da coagulação baseado em superfícies celulares substitui a tradicional hipótese da "cascata" e propõe a ativação do processo de coagulação sobre diferentes superfícies celulares em quatro fases que se sobrepõem: iniciação, amplificação, propagação e finalização. O modelo baseado em superfícies celulares permite um maior entendimento de como a hemostasia funciona in vivo e esclarece o mecanismo fisiopatológico de certos distúrbios da coagulação.

The concept of a coagulation cascade describes the biochemical interactions of the coagulation factors, but it is flawed as a model of the in vivo hemostatic process. Hemostasis requires both platelet and fibrin plug formation at the site of vessel injury and that the procoagulant substances activated in this process remain at the site of injury. This control of blood coagulation is accomplished as the procoagulant reactions only exist on specific cell surfaces to keep coagulation from spreading throughout the vascular system. A model of coagulation that better explains bleeding and thrombosis in vivo created after considering the critical role of cells. The cellbased model of hemostasis replaces the traditional "cascade" hypothesis, and proposes that coagulation takes place on different cell surfaces in four overlapping steps: initiation, amplification, propagation and termination. The cell-based model allows a more thorough understanding of how hemostasis works in vivo, and sheds light on the pathophysiological mechanism for certain coagulation disorder.

The role of autolysis loop in determining the specificity of coagulation proteases

We recently demonstrated that the substitution of the autolysis loop (residues 143 to 154 in the chymotrypsin numbering system) of activated protein C (APC) with the corresponding loop of factor Xa (fXa) renders the APC mutant (APC/fX143-154) susceptible to inhibition by antithrombin (AT) in the presence of pentasaccharide. Our recent results further indicated, that in addition to an improvement in the reactivity of APC/fX143-154 with AT, both the amidolytic and anti-factor Va activities of the mutant APC have also been significantly increased. Since the autolysis loop of APC is five residues longer than the autolysis loop of fXa, it could not be ascertained whether this loop in the mutant APC specifically interacts with the activated conformation of AT or if a shorter autolysis loop is responsible for a global improvement in the catalytic activity of the mutant protease. To answer this question, we prepared another APC mutant in which the autolysis loop of the protease was replaced with the corresponding loop of trypsin (APC/Tryp143-154). Unlike an ~500-fold improvement in the reactivity of APC/fX143-154 with AT in the presence of pentasaccharide, the reactivity of APC/Tryp143-154 with the serpin was improved ~10-fold. These results suggest that both the length and structure of residues of the autolysis loop are critical for the specificity of the coagulation protease interaction with AT. Further factor Va inactivation studies with the APC mutants revealed a similar role for the autolysis loop of APC in the interaction with its natural substrate.

Effect of estrogen-progestin hormonal replacement therapy on blood coagulation and fibrinolysis in postmenopausal women

OBJECTIVE: To evaluate antithrombin III (AT), thrombin (Fragment 1+2 [F1+2] and thrombin-antithrombin [TAT]) generation markers, as well as other coagulation parameters, such as prothrombin time, partial activated thromboplastin time, thrombin time, fibrinogen, euglobulin lysis time, and platelet count, in postmenopausal women after hormonal therapy. STUDY DESIGN: Forty-five patients who received either 0.625 mg/day unopposed oral conjugated equine estrogen (CEE), 0.625 mg/day oral CEE plus medroxyprogesterone acetate (MP), or 50 µg/day transdermal 17beta-estradiol plus MP, were included. Tests were performed before (T0) and after 3 (T3), 6 (T6) and 12 (T12) months of treatment. AT was determined by an amidolytic method, whereas F1+2 and TAT complex were measured by ELISA. RESULTS: There was a significant reduction in the AT level of patients who received oral CEE plus MP at T3. There was no AT reduction in patients taking either oral CEE alone or transdermal 17beta-estradiol plus MP. F1+2 increased in all patients, but it reached statistical significance only in patients receiving transdermal 17beta-estradiol MP at T3. CONCLUSIONS: The CEE associated with MP treatment may reduce AT levels, whereas unopposed CEE or transdermal 17beta-estradiol plus MP does not change AT. These changes might not be clinically relevant in the general population; however, hormonal replacement therapy may increase the risk of thrombosis in women with congenital or acquired thrombophilia.

OBJETIVO: Avaliar os marcadores antitrombina III (AT), fragmento 1 + 2 da trombina (F1+2) e complexo trombina-antitrombina (TAT), bem como outros parâmetros da coagulação, como tempo de pró-trombina, tempo parcial de tromboplastina ativado, tempo de trombina, fibrinogênio e tempo de lise da euglobulina em mulheres na pós-menopausa após terapia hormonal. DESENHO DO ESTUDO: Foram incluídas 45 voluntárias que receberam estrogênios conjugados eqüinos (ECE) 0,625 mg/dia, isoladamente ou associado ao acetato de medroxiprogesterona (AMP) ou usaram o 17beta-estradiol (50 µg/dia) transdérmico com AMP. Os exames foram realizados antes do tratamento (T0) e após três (T3), seis (T6) e doze (T12) meses após o início do tratamento. AT foi avaliada pelo método amidolítico, enquanto que o F1+2 e o complexo TAT por ELISA. RESULTADOS: Houve redução significante nos níveis de AT em pacientes que receberam ECE associado ao AMP no T3. Não houve redução na AT em mulheres que usaram ECE isoladamente ou aquelas com 17beta-estradiol transdérmico e AMP. O F1+2 aumentou em todos os grupos, mas apenas o grupo com 17beta-estradiol transdérmico e AMP apresentou diferença significante durante o T3. CONCLUSÕES: A associação de ECE e AMP pode reduzir os níveis de AT, enquanto ECE isoladamente ou 17beta-estradiol transdérmico com AMP não modificam-o acentuadamente. Essas alterações poderiam ser mais relevantes clinicamente na análise populacional. Todavia, a terapia de reposição hormonal aumentaria o risco de trombose em mulheres com trombofilia prévia congênita ou adquirida.

In vivo antithrombotic properties of a heparin from the oocyte test cells of the sea squirt Styela plicata(Chordata-Tunicata)

In the ascidian Styela plicata, the oocytes are surrounded by two types of accessory cells named follicle cells and test cells. A heparin-like substance with an anticoagulant activity equivalent to 10 percent of mammalian heparin and about 5 percent as potent as the mammalian counterpart for the inhibition of thrombin by antithrombin was isolated from the oocyte test cells. In the present study, we compared the antithrombotic and hemorrhagic effects of sea squirt oocyte test cell heparin with those of porcine heparin in rat models of venous thrombosis and blood loss. Intravenous administration of the oocyte test cell heparin to Wistar rats (both sexes, weighing ~300 g, N = 4 in each group) at a dose of 5.0 mg/kg body weight, which produced a 1.8-fold increase in plasma activated partial thromboplastin time, inhibited thrombosis by 45 ± 13.5 percent (mean ± SD) without any bleeding effect. The same dose of porcine heparin inhibited thrombosis by 100 ± 1.4 percent, but produced a blood loss three times greater than that of the saline-treated control. However, 10-fold reduction of the dose of porcine heparin to 0.5 mg/kg body weight, which produced a 5-fold increase in plasma-activated partial thromboplastin time, inhibited thrombosis by 70 ± 13 percent without any bleeding effect. The antithrombotic properties of a new heparin isolated from test cells of the sea squirt S. plicata, reported here for the first time, indicate that, although sea squirt oocyte test cell heparin was a poor anticoagulant compared to porcine heparin, it had a significant antithrombotic effect without causing bleeding.

The specificity of interactions between proteins and sulfated polysaccharides

Os polissacarídeos sulfatados são capazes de se ligar às proteínas com diferentes níveis de especificidade. São macromoléculas altamente ácidas que podem se ligar de forma inespecífica a qualquer domínio básico da superfície de uma proteína em soluções com baixa força iônica, contudo tais interações não parecem ser fisiologicamente significativas. Por outro lado, foram identificados vários sistemas nos quais componentes estruturais muito específicos dos polissacarídeos sulfatados conferem alta afinidade para algumas proteínas. O exemplo mais conhecido é o pentassacarídeo da heparina com alta afinidade pela antitrombina. Outros exemplos podem ser observados no estudo de invertebrados marinhos, tais como a importância da estrutura fina do dermatam sulfato para sua interação com o cofator II da heparina e o envolvimento defucanas sulfatadas encontradas no gel que envolve osóvulos dos ouriços-do-mar na espécie especificidade da fertilização. Um terceiro exemplo de interação específica é aquele descrito para o glicosaminoglicano heparam sulfato encontrado na superfície celular. Neste caso, o padrão de sulfatação pode determinar diferentes afinidades do carboidrato por citoquinas, fatores de crescimento e outras proteínas encontradas na superfície celular e na matriz extracelular. Estas interações complexas entre proteínas e carboidratos são capazes de influenciar a difusão das proteínas através dos tecidos, assim como modelar a resposta celular a estas moléculas.