RESUMO
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
A common cause of hereditary thrombophilia is activated protein C resistance (APCR), and most cases result from factor V Leiden mutation. An APCR phenotype without association with factor V Leiden has been described. This transversal, observational, nonrandomized study evaluated these 2 phenomena in healthy indigenous and mestizo Mexican subjects (n = 4345), including 600 Mexican natives. No indigenous subjects had APCR, but 82 mestizo subjects did. After retesting, 50 subjects had a negative test. The remaining 32 subjects had factor V Leiden, giving a 0.85% prevalence of factor V Leiden in the mestizo Mexican population. Only 31% of APCR carriers had factor V Leiden. These results show a very low prevalence of APCR and factor V Leiden in Mexico. Except for factor V Leiden, there are no other mutations in the factor V gene responsible for the APCR phenotype. Acquired APCR is nearly twice as prevalent as the inherited variant.
Assuntos
Resistência à Proteína C Ativada/epidemiologia , Fator V/análise , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , PrevalênciaRESUMO
OBJECTIVE: Over a 70-month period, 100 consecutive Mexican mestizo individuals with a clinical marker associated with a primary hypercoagulable state were studied. METHODS: We prospectively assessed: the sticky platelet syndrome (SPS), the activated protein C resistance (aPCR) phenotype, coagulation protein C activity and antigen, coagulation protein S, antithrombin III, plasminogen, IgG and IgM isotypes of antiphospholipid antibodies, homocysteine levels, the factor V gene Leiden, Cambridge, Hong Kong, and Liverpool mutations, the 677 C-->T mutation in the 5,10-methylenetetrahydrofolatereductase (MTHFR), and the G20210A polymorphism in the 3'-untranslated region of the prothrombin gene. RESULTS: Of the 100 consecutive patients prospectively accrued in the study, only 29% were males. In only 6 individuals could we not record any abnormality, whereas in most individuals (81%), two to five co-existing abnormalities were identified. In a multivariate analysis of the association of all these assesments, the only significant association was found between the factor V Leiden mutation and the aPCR phenotype (r = .495; p < 0.001). CONCLUSIONS: These results confirm previous observations on thrombophilia in Mexico underlining that it is a multifactorial disease. They also suggest that the abnormalities detected are not associated to each other.
Assuntos
Indígenas Norte-Americanos/genética , Trombofilia/epidemiologia , Trombofilia/genética , Resistência à Proteína C Ativada/epidemiologia , Resistência à Proteína C Ativada/genética , Adolescente , Adulto , Idoso , Transtornos Plaquetários/epidemiologia , Transtornos Plaquetários/genética , Criança , Fator V , Feminino , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Fenótipo , Polimorfismo Genético , Estudos Prospectivos , Fatores Sexuais , Trombose/epidemiologia , Trombose/genéticaRESUMO
Objetivo: En un periodo de 70 meses estudiamos de manera prospectiva a 100 pacientes mestizos mexicanos con algún marcador clínico de trombofilia: a) Trombosis antes de los 40 años, b) Historia familiar de trombosis, c) Trombosis recurrente sin la presencia de un factor precipitante aparente, d) Trombosis en sitios anatómicos inusuales, o e) Resistencia a la terapia antitrombótica convencional. Métodos: En estos pacientes, investigamos el síndrome de las plaquetas pegajosas, la mutación 677 C >T del gen de la 5,10-metilentetrahidrofolato reductasa (MTHFR), el fenotipo de resistencia a la proteína C activada (RPCa), la presencia de anticuerpos antifosfolípidos, las mutaciones Leiden, Cambridge, Liverpool y Hong Kong del gen del factor V, el haplotipo HR2 del mismo gen del factor V, el polimorfismo G20210A de la región 3´-no traducida del gen de la protrombina y las deficiencias de proteínas C y S y de antitrombina III. Resultados: En el 94 % de los casos encontramos por lo menos alguna alteración; de estos casos con alteración, la mayoría (81 %) tuvo dos o más condiciones trombofílicas asociadas. El análisis multivariado de todas estas variables sólo mostró asociación estadística entre la mutación tipo Leiden del gen del factor V y el fenotipo de RPCa (r = .495; p < 0.001). Conclusiones: Se concluye que, realizando este grupo de estudios, es posible identificar alguna alteración trombofílica en la mayoría de los pacientes mestizos mexicanos con algún marcador clínico de trombofilia y que las alteraciones no se asocian entre sí.
OBJECTIVE: Over a 70-month period, 100 consecutive Mexican mestizo individuals with a clinical marker associated with a primary hypercoagulable state were studied. METHODS: We prospectively assessed: the sticky platelet syndrome (SPS), the activated protein C resistance (aPCR) phenotype, coagulation protein C activity and antigen, coagulation protein S, antithrombin III, plasminogen, IgG and IgM isotypes of antiphospholipid antibodies, homocysteine levels, the factor V gene Leiden, Cambridge, Hong Kong, and Liverpool mutations, the 677 C-->T mutation in the 5,10-methylenetetrahydrofolatereductase (MTHFR), and the G20210A polymorphism in the 3'-untranslated region of the prothrombin gene. RESULTS: Of the 100 consecutive patients prospectively accrued in the study, only 29% were males. In only 6 individuals could we not record any abnormality, whereas in most individuals (81%), two to five co-existing abnormalities were identified. In a multivariate analysis of the association of all these assesments, the only significant association was found between the factor V Leiden mutation and the aPCR phenotype (r = .495; p < 0.001). CONCLUSIONS: These results confirm previous observations on thrombophilia in Mexico underlining that it is a multifactorial disease. They also suggest that the abnormalities detected are not associated to each other.
Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Indígenas Norte-Americanos/genética , Trombofilia/epidemiologia , Trombofilia/genética , Fator V , Análise Multivariada , Mutação , México/epidemiologia , Fenótipo , Polimorfismo Genético , Estudos Prospectivos , Resistência à Proteína C Ativada/epidemiologia , Resistência à Proteína C Ativada/genética , Fatores Sexuais , Transtornos Plaquetários/epidemiologia , Transtornos Plaquetários/genética , Trombose/epidemiologia , Trombose/genéticaRESUMO
Primary deep venous thrombosis of the upper extremity (UEDVT) is an unusual disorder. Limited data are available on the contribution of hypercoagulable status in the pathogenesis of this disease. This study aims to report the prevalence of inherited and acquired thrombophilic risk factors (TF) in patients with primary (effort-related and spontaneous) UEDVT. From 1993 to 2002, 31 patients (17 females, median age 38.8 years, range 16-60 years; and 14 males, median age 31.4 years, range 20-56 years) with primary UEDVT (n = 15 effort-related and n = 16 spontaneous) were referred for screening of hypercoagulable status. Nineteen (61.3%) patients had at least one coagulation abnormality. The most common acquired TF were antiphospholipid antibodies (31% lupus anticoagulant and 12.9% anticardiolipin antibodies). Factor V Leiden (12.9%) and prothrombin G20210A mutation (20%) were the most prevalent genetic risk factors. Five patients (16.1%) had high plasma homocysteine levels, and one patient (4.7%) had protein S deficiency. Effort-related UEDVT was associated with male gender (P = 0.04) and younger age (P = 0.02). There was no significant difference in the prevalence of acquired or inherited TF between patients with effort-related or spontaneous UEDVT. A local anatomic abnormality was detected in seven patients (22.5%), and the prevalence of TF was significantly lower within this group (P = 0.006). The incidence of TF in patients without an anatomic abnormality was 75% (RR 5.25). This study found a high prevalence of an underlying thrombophilic status in spontaneous and effort-related UEDVT. Hypercoagulable status may play a significant role in both groups. Screening for local anatomical abnormalities and thrombophilia should be included in the evaluation of primary UEDVT.
Assuntos
Trombofilia/epidemiologia , Trombose Venosa/etiologia , Regiões 3' não Traduzidas , Resistência à Proteína C Ativada/complicações , Resistência à Proteína C Ativada/epidemiologia , Resistência à Proteína C Ativada/genética , Adolescente , Adulto , Anticorpos Anticardiolipina/sangue , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/epidemiologia , Argentina/epidemiologia , Braço , Vértebras Cervicais/anormalidades , Fator V/genética , Feminino , Humanos , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/epidemiologia , Inibidor de Coagulação do Lúpus/sangue , Masculino , Pessoa de Meia-Idade , Esforço Físico , Prevalência , Deficiência de Proteína S/complicações , Deficiência de Proteína S/epidemiologia , Protrombina/genética , Estudos Retrospectivos , Fatores de Risco , Artéria Subclávia/anormalidades , Trombofilia/complicações , Trombofilia/genética , Trombose Venosa/sangue , Trombose Venosa/epidemiologia , Trombose Venosa/patologiaRESUMO
Thrombophilia or prothrombotic state appears when activation of blood hemostatic mechanisms overcomes the physiological anticoagulant capacity allowing a thrombotic event. Thrombosis is the leading worldwide mortality cause and due to its high associated morbidity and mortality, it should be insisted in the opportune identification of a thrombophilic state. The study of thrombophilia identifies individuals at high risk for thrombosis. This meeting was conceived first to analyze the current status of the diagnosis of thrombophilia in Mexico and second to create the base for a national consensus for thrombophilia screening and for the establishment of a national center for laboratory reference and quality control for thrombophilia. Since searching of activated protein C resistance (APCR) and FV Leiden seem to have priority either in the clinical setting and in public health services, it was decided to start with these two abnormalities as a model to analyze the current status of thrombophilia diagnosis in the clinical laboratory. At this time, several thrombophilic abnormalities have been described however, APCR remains the most important cause of thrombophilia, accounting for as much as 20% to 60% of all venous thrombosis. APCR is a consequence of the resistance of activated FV to be inactivated by activated protein C. Procoagulant activity of activated FV increases the risk of thrombosis. Hereditary APCR is almost always due to a point mutation at the nucleotide 1691 of the FV gen inducing an Arg506Glu substitution in FV molecule. This mutation is better known as FV Leiden. Heterocygous carriers of FV Leiden have a thrombotic risk 5 to 10 times higher than general population while the risk for the homocygote state is increased 50 to 100-fold. When activated PC is added to plasma from patients with FV Leiden, this last resists the anticoagulant effect of activated PC. Therefore, thrombin production is not inhibited. This phenomenon is called APCR. The functional test evaluates the partially activated thromboplastin time (aPTT) in a plasma sample before and after adding activated PC. The result is reported as a standardized sensibility index: aPTT post-activated PC/aPTT pre-activated PC. The conclusions of this national reunion pretend to optimize the available resources in our country in order to allow a wide and less-expensive diagnosis of patients with thrombosis.
Assuntos
Resistência à Proteína C Ativada/diagnóstico , Resistência à Proteína C Ativada/complicações , Resistência à Proteína C Ativada/epidemiologia , Resistência à Proteína C Ativada/genética , Análise Mutacional de DNA , Fator V/genética , Genótipo , Laboratórios/normas , Laboratórios/provisão & distribuição , Programas de Rastreamento , México/epidemiologia , Reação em Cadeia da Polimerase , Controle de Qualidade , Trombofilia/epidemiologia , Trombofilia/etiologiaRESUMO
We have shown that in Mexican mestizo patients with clinical features of primary thrombophilia, 39% have activated protein C resistance phenotype, 5% protein C deficiency, and 2% protein S deficiency. In the present study, in a group of 37 thrombophilic Mexicans and 50 normal controls, we assessed the factor V G1691A (Leiden), the prothrombin G20210A, and the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphisms. Four patients were found to be heterozygous for factor V Leiden, 5 heterozygous for the prothrombin 20210, 16 heterozygous, and 6 homozygous for the MTHFR 677. There were four individuals with co-segregation of alleles: two heterozygotes for the factor V Leiden/prothrombin 20210, one heterozygote for prothrombin 20210/MTHFR 677, and one heterozygote for prothrombin 20210/homozygote for MTHFR 677. For factor V Leiden, prothrombin 20210, and MTHFR 677 mutations, the allele frequencies were respectively 1% (+/-0.2%, alpha = 0.05), <1% and 51% (+/-5%, alpha = 0.05), with calculated relative risks for thrombosis of 5.94 (P = 0.08), >7.66 (P < 0.05), and 0.44 (P NS), respectively. In Mexican mestizo thrombophilic patients, the low prevalence of the factor V Leiden mutation (10.8%) and the high prevalence of the prothrombin 20210 mutation (13.5%) contrast with those identified in Caucasian thrombophilic patients (21% and 6%, respectively; P < 0.01). On the other hand, the high prevalence of the MTHFR 677 mutation gene both in normal controls (78%) and thrombophilic patients (61%) does not support a role of this mutation in the thrombogenesis of Mexican mestizo patients.
Assuntos
Resistência à Proteína C Ativada/epidemiologia , Fator V/análise , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Protrombina/genética , Trombofilia/epidemiologia , Regiões 3' não Traduzidas/genética , Resistência à Proteína C Ativada/etnologia , Resistência à Proteína C Ativada/genética , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , População Negra/genética , Criança , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Indígenas Norte-Americanos/genética , Masculino , Casamento , Metilenotetra-Hidrofolato Redutase (NADPH2) , México/epidemiologia , Pessoa de Meia-Idade , Mutação Puntual , Prevalência , Estudos Prospectivos , Trombofilia/etnologia , Trombofilia/genética , População Branca/genéticaRESUMO
The Activated Protein C Resistance (APCR) is the common phenotype of Factor V Leiden (arg506gln), which is considered as a thrombotic risk factor. The aim of this study was to determine the prevalence of APCR and its association with Factor V Leiden in indian and black populations from Zulia State in western Venezuela. Blood samples were taken from 80 Yukpa indians from Sierra de Perijá and 91 black individuals from the southeast of Lago de Maracaibo. APCR was determined by the Dahlback's method with the modifications of Jorquera et al. and Trossaert et al. The results were expressed as n-APC-SR (positive value < or = 0.75). Factor V Leiden genotype was identified by PCR and restriction analysis standard methods at the Institute of Human Genetics (Greifswald, Germany). No significative difference was found between n-APC-SR from indians (mean +/- SEM 1.13 +/- 0.02, CI 95% = 1.07-1.19) and black people (1.07 +/- 0.02, CI 95% = 1.03-1.12). APCR prevalence from indians was 1.25% (1 out of 80) who was heterozygote case for F V Leiden and 4.4% (4 out of 91) from blacks (one case was heterozygous for F V Leiden). No thrombotic event personal or familial was demonstrate. Our data represent the first report related to the association between APCR and F V Leiden in venezuelan indian and black individuals. APCR without the Factor V Leiden expression suggest a different type of mutation in the Factor V molecule. In spite of high endogamy in the indian group, we can not discard the role of foreign genes in both populations. The determination of the prevalence of this phenotype and its molecular marker in various ethnic groups is important for the interpretation of their role as risk factors for thrombotic disease.
Assuntos
Resistência à Proteína C Ativada/genética , População Negra/genética , Indígenas Sul-Americanos/genética , Resistência à Proteína C Ativada/epidemiologia , Fator V/genética , Humanos , Mutação , Fenótipo , Prevalência , Trombose/epidemiologia , Trombose/genética , Venezuela/epidemiologiaRESUMO
A group of 102 Mexican Mestizo patients with appropriate clinical features suggestive of primary thrombophilia was prospectively studied. Thirty-nine percent of them had activated protein C resistance, but only four patients displayed the factor V Leiden mutation. Five percent of the individuals were found to be protein C deficient, whereas 2% had protein S deficiency. No cases of abnormalities in antithrombin III, plasminogen, tissue-type plasminogen activator or plasminogen activator inhibitor were found. The low prevalence of the activated protein C resistance genotype, probably stemming from the genetic admixture of the Mexican Mestizo group is noteworthy.