RESUMO
INTRODUCTION: There is a high incidence of venous thromboembolism (VTE) in patients with Multiple Myeloma (MM), however; until now, the exact mechanisms behind VTE in MM are unknown, and some of the elements that may play a significant role are the treatment with an immunomodulator (IMiD) and acquired resistance to activated protein C (APC). OBJECTIVE: The study aims to reveal the possible mechanisms linked to the reduced antithrombotic activity of APC associated with thalidomide. METHODS: The molecular docking approach was used to ascertain the in silico inhibitory potential of thalidomide on the APC protease domain in the architecture of the catalytic triad and its interaction with major substrate binding sites. RESULTS: The coupling showed that the inhibitory activity of thalidomide depends on the induction of structural changes in the protease domain of APC, at the level of the Ser/His/Asp catalytic triad, as a result of a significant increase between the distances of CαAsp102 and Cα Ser195 (11.175 angstroms, increase 14.83%) and between CαSer195 and CαHis57 (9.478 angstroms, increase 13.78 %). This can result in an inefficient transfer of the proton between these residues, the other possible mechanism of inhibition, is a potential reduced binding of the substrate as a result of a direct interaction through a carbon-hydrogen bond on His57, an H-bond on Arg306, and a carbon hydrogen bond on Arg506. CONCLUSION: We demonstrate the in silico inhibitory potential of thalidomide on APC, through two possible inhibition mechanisms, a pathophysiologically relevant finding to understand the factors that can affect the stability and functions of APC in vivo.
Assuntos
Resistência à Proteína C Ativada , Mieloma Múltiplo , Tromboembolia Venosa , Humanos , Talidomida/efeitos adversos , Resistência à Proteína C Ativada/induzido quimicamente , Resistência à Proteína C Ativada/complicações , Tromboembolia Venosa/complicações , Simulação de Dinâmica Molecular , Simulação de Acoplamento Molecular , Peptídeo HidrolasesRESUMO
El evento tromboembólico (ET) es un problema de salud pública asociado a una significativa morbimortalidad, cuyo manejo incluye la evaluación del estado hipercoagulable del paciente, especialmente en individuos jóvenes. Las trombofilias hereditarias más frecuentes son el polimorfismo del Factor V Leiden (FVL) y de la Protrombina 20210 (PT20210). En la población general caucásica europea la prevalencia del FVL es del 3 al 7% y del 1-4% para PT20210 y en pacientes con un primer ET es del 20-50% para FVL y del 5-10% para PT20210. Estudios realizados en nuestro país revelaron un 2.9% de portadores heterocigotas para FVL y 2.6% para PT20210 en población general, similares a lo descripto para el sur de Europa, mientras que otros autores reportaron un 10% y 6.3% para FVL y PT20210 respectivamente en individuos con un primer ET. El objetivo de este estudio fue investigar FVL y PT20210 en mujeres jóvenes, en edad fértil, que sufrieron un ET sin factores de riesgo aparentes y fueron derivadas al Laboratorio de Salud Pública de Tucumán entre 2015 y 2016. Se efectuó un estudio observacional descriptivo de corte transversal en 39 mujeres. Se detectó que el 2.5% (1/39) fueron heterocigotas para FVL mientras que el 5.7% (2/39) para PT20210. Nuestro estudio contempla pacientes pertenecientes a la provincia de Tucumán, donde observamos que la prevalencia de las mutaciones es menor que la descripta en otras regiones del país, reflejando posiblemente, la diferente composición étnica; no obstante, estas alteraciones genéticas están presentes en nuestra provincia y las sociedades científicas recomiendan de primera línea el estudio de éstas en pacientes seleccionados. Estas mujeres podrían afrontar factores de riesgo circunstanciales protrombóticos como gestas, traumas, inmovilización prolongada, tratamientos hormonales que predispondrían a un nuevo ET, por lo cual la investigación de éstas variantes genéticas resulta necesaria para la prevención de los mismos
Assuntos
Fatores de Risco , Trombofilia , Resistência à Proteína C Ativada , Tromboembolia Venosa , Biologia MolecularRESUMO
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.
Assuntos
Infarto do Miocárdio/sangue , Acidente Vascular Cerebral/sangue , Trombofilia/sangue , Trombose/sangue , Resistência à Proteína C Ativada/sangue , Adolescente , Adulto , Fatores Etários , Antitrombinas/sangue , Biomarcadores/sangue , Proteínas Sanguíneas/análise , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Índia , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Valores de Referência , Estudos Retrospectivos , Fatores de Risco , Fumar/sangue , Acidente Vascular Cerebral/complicações , Centros de Atenção Terciária , Trombofilia/etiologia , Trombose/complicações , Adulto JovemRESUMO
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, ...
Assuntos
Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Infarto do Miocárdio/sangue , Acidente Vascular Cerebral/sangue , Trombofilia/sangue , Trombose/sangue , Resistência à Proteína C Ativada/sangue , Fatores Etários , Antitrombinas/sangue , Biomarcadores/sangue , Proteínas Sanguíneas/análise , Estudos de Casos e Controles , Índia , Lipoproteínas/sangue , Infarto do Miocárdio/complicações , Valores de Referência , Estudos Retrospectivos , Fatores de Risco , Fumar/sangue , Acidente Vascular Cerebral/complicações , Centros de Atenção Terciária , Trombofilia/etiologia , Trombose/complicaçõesRESUMO
CONTEXT AND OBJECTIVE: venous thrombosis occurs as a result of interaction of genetic and acquired factors including activated protein C resistance (APC-R), fibrinogen levels, antithrombin, protein C, protein S, lupus anticoagulants and anticardiolipin antibodies. This study was aimed at determining the prevalence of these common thrombophilia markers in Asian Indians with primary venous thrombosis. DESIGN AND SETTING: this was a cross-sectional study carried out in Mumbai. METHODS: samples from 78 patients with a confirmed diagnosis of venous thrombosis and 50 controls were tested. Semi-quantitative estimation (functional assays) of protein C, protein S and antithrombin was performed. Quantitative estimation of fibrinogen was done using the Clauss method. Lupus anticoagulants were screened using lupus-sensitive activated partial thromboplastin time and ß2-glycoprotein-I dependent anticardiolipin antibodies were estimated by ELISA. APC-R was measured using a clotting-based method with factor V deficient plasma and Crotalus viridis venom. Statistical analysis was performed using Epi-info (version 6). RESULTS: the popliteal vein was the most commonly involved site. Forty-four samples (56%) gave abnormal results. The commonest were elevated fibrinogen and APC-R (17.9% each), followed by low protein S (16.6%). CONCLUSIONS: this study confirms the literature findings that fibrinogen level estimation and screening for APC-R are important for the work-up on venous thrombosis patients since these, singly or in combination, may lead to a primary thrombotic episode. The frequency of the other thrombophilia markers was higher among the patients than among the controls, but without statistically significant difference.
Assuntos
Resistência à Proteína C Ativada/sangue , Fibrinogênio/análise , Veia Poplítea/patologia , Proteína S/análise , Trombofilia/diagnóstico , Trombose Venosa/complicações , Adulto , Biomarcadores/sangue , Métodos Epidemiológicos , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto JovemRESUMO
In this work, we evaluated the frequency of prothrombotic defects associated with deep venous thrombosis (DVT) in southern Chilean subjects. A total of 261 individuals, 87 patients with DVT confirmed by Doppler ultrasonography and 174 controls, were included in this study. Factor V and factor VIII levels, activated protein C (APC) resistance, and lupus anticoagulant detection were assayed by clotting methods. Basal homocysteine was quantified by immunoassay, and the polymorphisms in factor V (F5), methylenetetrahydrofolate reductase (MTHFR), and cystathionine ß-synthase (CBS) genes were genotyped by molecular methods. The most frequent defects were APC resistance, hyperhomocysteinemia, and increased levels of factor VIII. We observed a complete absence of the F5 G1691A variant in the studied population, and the frequency of MTHFR C677T polymorphism was significantly different between patients and controls (odds ratio = 3.2; 95% confidence interval, 1.513-6.735; p = 0.016). In addition, subjects carrying the homozygous MTHFR 677TT genotype exhibited higher levels of plasma homocysteine. Our data suggest that the APC resistance is the most important defect in Chilean patients with DVT. However, this phenotype is not associated with the presence of the F5 G1691A variant. In addition, only MTHFR C677T polymorphism constituted a molecular biomarker of DVT in Chilean population.
Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Protrombina/genética , Trombofilia/genética , Trombose Venosa/epidemiologia , Resistência à Proteína C Ativada/epidemiologia , Resistência à Proteína C Ativada/genética , Adolescente , Adulto , Idoso , Chile/epidemiologia , Cistationina beta-Sintase/genética , Fator V/genética , Fator VIII/análise , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Hiper-Homocisteinemia/epidemiologia , Hiper-Homocisteinemia/genética , Inibidor de Coagulação do Lúpus/análise , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Fenótipo , Fatores de Risco , Trombofilia/diagnóstico , Trombofilia/epidemiologia , Ultrassonografia , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/genética , Adulto JovemRESUMO
The assessment of activated protein C resistance (APCR) caused by mutations in factor V (factor V Leiden) is an important risk factor for venous thromboembolism, of which role as the originator of arterial obstructions in situ is still a controversial subject. The clinical case of a young patient with history of coronariopathy, multiple cerebrovascular lesions and peripheral artery disease is reported. The diagnostic investigation showed APCR as the possible etiology.
Assuntos
Resistência à Proteína C Ativada/complicações , Isquemia Encefálica/etiologia , Doença das Coronárias/etiologia , Doença Arterial Periférica/etiologia , Tromboembolia Venosa/etiologia , Adulto , Arteriopatias Oclusivas/etiologia , Fator V/genética , Humanos , Masculino , Fatores de RiscoRESUMO
BACKGROUND: Leiden and Cambridge factor V coagulation mutations and activated protein C resistance (RaPC) are alterations related with vein and artery thrombosis. In this study we aimed to determine whether RaPC is associated with the presence of Leiden and Cambridge mutation and the frequency of these mutations in the racially mestizo Mexican population. METHODS: We included 150 Mexican patients with primary thrombophilia and 100 healthy subjects in this study. RaPC was determined using commercial methods and genotypes FV Leiden and FV Cambridge with PCR-RFLPs. RESULTS: RaPC was positive in four patients and in one control individual; however, there was no presence of Leiden or Cambridge mutation in the studied group; thus, RaPC was not correlated with the presence of any of the studied mutations. CONCLUSIONS: These results indicate that there are other primary or secondary causes different from those studied, which condition the presence of RaPC. Furthermore, the frequency obtained for RaPC in our thrombophilic population of racially mixed Mexicans is lower compared to that obtained in the Caucasian population, most probably because they are genetically different populations.
Assuntos
Resistência à Proteína C Ativada/genética , Fator V/genética , Mutação , Trombofilia/genética , Adulto , Feminino , Humanos , Masculino , México , Estudos ProspectivosRESUMO
Introducción: Las mutaciones Leiden y Cambridge del factor V de la coagulación y la resistencia a la proteína C activada (RPCA) son alteraciones que se relacionan con trombosis venosa y arterial. En este trabajo se analizó si la RPCA está asociada con las mutaciones Leiden y Cambridge, y la frecuencia de éstas en población mestiza mexicana. Material y métodos: Se incluyeron 150 pacientes mexicanos con trombofilia primaria y 100 sujetos sanos. Se determinó la RPCA empleando método comercial y los genotipos factor V Leiden y factor V Cambridge mediante PCR-RFLPs. Resultados: La RPCA fue positiva en cuatro pacientes y en un individuo control; sin embargo, no se encontró la mutación Leiden o Cambridge en la población estudiada, por lo que la RPCA no se correlacionó con ninguna de las mutaciones investigadas. Conclusiones: Los resultados indican que existen otras causas primarias o secundarias diferentes a las analizadas, que condicionan la RPCA. Además, la frecuencia obtenida para la RPCA en nuestra población trombofílica mestiza mexicana fue menor comparada con la obtenida en población caucásica, quizá por tratarse de poblaciones genéticamente diferentes.
BACKGROUND: Leiden and Cambridge factor V coagulation mutations and activated protein C resistance (RaPC) are alterations related with vein and artery thrombosis. In this study we aimed to determine whether RaPC is associated with the presence of Leiden and Cambridge mutation and the frequency of these mutations in the racially mestizo Mexican population. METHODS: We included 150 Mexican patients with primary thrombophilia and 100 healthy subjects in this study. RaPC was determined using commercial methods and genotypes FV Leiden and FV Cambridge with PCR-RFLPs. RESULTS: RaPC was positive in four patients and in one control individual; however, there was no presence of Leiden or Cambridge mutation in the studied group; thus, RaPC was not correlated with the presence of any of the studied mutations. CONCLUSIONS: These results indicate that there are other primary or secondary causes different from those studied, which condition the presence of RaPC. Furthermore, the frequency obtained for RaPC in our thrombophilic population of racially mixed Mexicans is lower compared to that obtained in the Caucasian population, most probably because they are genetically different populations.
Assuntos
Humanos , Masculino , Feminino , Adulto , Fator V/genética , Mutação , Resistência à Proteína C Ativada/genética , Trombofilia/genética , México , Estudos ProspectivosRESUMO
A avaliação da resistência à ação da proteína C ativada (rPCA), causada por mutação no fator V (fator V de Leiden), é fator de risco importante para tromboembolia venosa, cujo papel como geradora de obstruções arteriais in situ é um tema ainda controverso. O caso clínico de um jovem com história de coronariopatia, múltiplas lesões cerebrovasculares e doença arterial periférica é relatado. A investigação diagnóstica apontou a rPCA como possível etiologia.
The assessment of activated protein C resistance (APCR) caused by mutations in factor V (factor V Leiden) is an important risk factor for venous thromboembolism, of which role as the originator of arterial obstructions in situ is still a controversial subject. The clinical case of a young patient with history of coronariopathy, multiple cerebrovascular lesions and peripheral artery disease is reported. The diagnostic investigation showed APCR as the possible etiology.