Edad y mutación de la protrombina G20210A en los pacientes con trombosis venosa espontánea
The influence of the age in the risk of the prothrombin G20210A mutation for spontaneous venous thrombosis
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"etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 2 => array:3 [ "nombre" => "Gloria" "apellidos" => "García-Donas Gabaldón" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 3 => array:3 [ "nombre" => "María del Mar" "apellidos" => "Viloria Peñas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 4 => array:3 [ "nombre" => "Isabel" "apellidos" => "Simón Pilo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 5 => array:3 [ "nombre" => "Carmen" "apellidos" => "Almeida González" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Department of Hematology. The Valme University Hospital. Seville. Spain." "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Department of Research and Biostatistics. The Valme University Hospital. Seville. Spain." "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "The influence of the age in the risk of the prothrombin G20210A mutation for spontaneous venous thrombosis" ] ] "textoCompleto" => "<p class="elsevierStylePara">Factor V Leiden (FVL) mutation and the prothrombin G20210A mutation (PT G20210A) are recognized thrombophilic risk factors for venous thrombosis<span class="elsevierStyleSup">1,2</span>. Both polymorphisms are considered to be a smaller risk than the deficiencies of natural anticoagulants (antithrombin III, protein C and S deficiencies)<span class="elsevierStyleSup">3</span> and the risk is weaker with PT G20210A than FVL<span class="elsevierStyleSup">1,3,4</span>. In carriers of these mutations with an age of less than 40-45 years, the first thrombotic episode is usually related to an associated risk factor (surgery, immobilization, trauma, gestation/puerperium, oral contraceptives, obesity, chronic obstructive pulmonary disease, varicose veins)<span class="elsevierStyleSup">4,5</span>. In older carriers the thrombosis can be spontaneous, and in them, age is a risk factor<span class="elsevierStyleSup">4</span>. In our series, we analyzed the effect of age on the probability of spontaneous venous thrombosis in relation to thrombophilic mutations.</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Patients and method</span></p><p class="elsevierStylePara">During 2 year (2001-2003) a prospective case-control study was made at the University Hospital of Valme in Seville, consisting of 735 individuals, of which 407 were healthy volunteers with no history of thromboembolic disease (TED) and 328 were patients with venous thrombosis. The controls were blood donors, and at the time of donation were informed by a doctor about the SAS 100/01 Project and asked for permission to include them in the study. If the response was affirmative, a blood sample was taken and the clinical data noted.</p><p class="elsevierStylePara">In all the patients the TED had been confirmed by image's techniques: pulmonary gammagraphy, helicoidal scanner and Doppler sonography; all were recruited consecutively from thrombophilia screening in our hospital, after at least 4 months since an acute thrombotic event.</p><p class="elsevierStylePara">The detection of PT G20210A and FVL was made by method of protein chain reaction (PCR), in liquid phase, in real time, in a LightCycler<span class="elsevierStyleSup">®</span> (Roche Diagnostics) thermal cycler. The DNA for the molecular determinations was extracted by a manual technique from citrate anticoagulated blood by using the High Pure PCR Template Preparation Kit (Roche Diagnostics).</p><p class="elsevierStylePara">In each patient, in addition to the polymorphisms, we measured the natural anticoagulants: antithrombin III and protein C by chromogenic substrate, and protein S (free and total) by immunology techniques; activated protein C resistance by coagulative methods, all in an STA clinical analyzer (Roche Diagnostics). Antiphospholipid antibody was assayed according to recommendations published from the 1998 Sapporo workshop<span class="elsevierStyleSup">6</span>. Evaluations of homocystein were made by ELISA technique.</p><p class="elsevierStylePara">Statistical method<span class="elsevierStyleSup">7,8</span></p><p class="elsevierStylePara">In order to calculate sample size we used the program Epi-Info™ 2000, the program nQuery Advisor<span class="elsevierStyleSup">®</span> Release 4.0 and the results of a pilot study. Thus, with an expected prevalence for PT G20210A of 5% in the controls and 13.4% in patients, we considered that for a 1:1 case-control study with an error a = 5% and 1-b = 80%, we needed a sample of 208 cases and 208 controls. This sample size was applicable to the similar study for FVL as well as the binary logistic regression analysis.</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Statistical analysis</span></p><p class="elsevierStylePara">Means and standard deviations or medians (P<span class="elsevierStyleInf">25</span>, P<span class="elsevierStyleInf">75</span>) were determined for the quantitative variables. Percentages were used for qualitative variables. For the determination of the prevalence of the thrombophilic polymorphisms, in controls and patients, we obtained precise estimators and intervals of confidence to 95%.</p><p class="elsevierStylePara">We analyzed the relationship between pairs of qualitative variables by x<span class="elsevierStyleSup">2</span> test, x<span class="elsevierStyleSup">2</span> with Yates's continuity correction and Fisher's exact test. To study the relationship between qualitative and quantitative variables we used the Student t test and non-parametric Mann-Whitney U test. We used logistic regression analysis to forecast the risk of venous TED. For those variables that entered the statistical model, logistic regression coefficients were estimated and used to calculate the odds ratio (OR) of each independent variable in the model and its confidence intervals (IC) to 95%. The dates were analyzed with statistical program SPSS v.14.0</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Results</span></p><p class="elsevierStylePara">Epidemiology data</p><p class="elsevierStylePara">The median of the age of the patients, at the time of study, was 57 years (P<span class="elsevierStyleInf">25</span>: 42; P<span class="elsevierStyleInf">75</span>: 68; 156 (47.6%) patients were men and 172 (52.4%) were women. In the control group the median of the age was 36 years (P<span class="elsevierStyleInf">25</span>: 29; P<span class="elsevierStyleInf">75</span>: 45); 271 subjects (66.6%) were men and 136 (33.4%) were women. The median of the age of the patients during the first thrombosis was 49 years (P<span class="elsevierStyleInf">25</span>: 35; P<span class="elsevierStyleInf">75</span>: 62).</p><p class="elsevierStylePara">The venous thrombosis had been spontaneous in 144 patients (46.2%), and in the rest there were very diverse risk factors associated with the thrombotic episode (surgery, immobilization, trauma, gestation/puerperium, oral contraceptives, obesity, chronic obstructive pulmonary disease, varicose veins and others), which were present in isolated or associated form. In 16 patients, it has not been possible to find dates in relation to circumstances of first thrombotic event. In 92 patients (28%) a second episode of thrombosis took place.</p><p class="elsevierStylePara">Most of patients (79%) had a deep venous thrombosis and least (21%) pulmonary embolism, alone or with deep venous thrombosis (table 1).</p><p class="elsevierStylePara"><img src="2v128n17-13102051tab01.gif"></img></p><p class="elsevierStylePara">Analyzing the patients with venous TED that had FVL, the thrombotic episode in all of them was deep vein thrombosis, sometimes accompanied by pulmonary thromboembolism, but there was no isolated case of pulmonary thromboembolism; in relation to carriers of PT G20210A, the distribution was as in the total group.</p><p class="elsevierStylePara">Spontaneous venous thrombosis</p><p class="elsevierStylePara">We analyzed the factor dichotomized «age» (< 40, > 40) in this group of patients with spontaneous venous thrombosis with and without mutation of the PT G20210A, by x<span class="elsevierStyleSup">2</span> test, a value of p = 0.051 we were detected; taking in count this fact, a logistic regression model with interactions can be defined.</p><p class="elsevierStylePara">In the logistic regression model with interactions, we can see that those carrier patients of PT G20210A who are more 40 years old have a risk factor for spontaneous venous thrombosis OR = 9.28 (95% CI, 3.01-28,60; p < 0.0005) times more that carriers of PT 20210 who are 40 years old or younger.</p><p class="elsevierStylePara">When we were studied in this group the FVL in relation to age factor, by similar method to PT G20210A, the results are not outstanding. The FVL and age are risk factors for spontaneous venous thrombosis, but they have not interactions in the logistic regression model.</p><p class="elsevierStylePara">The risk factor for spontaneous venous thrombosis of FVL is OR = 4.91 (95% CI, 2.28-10.57; p < 0.0005) times more in carriers in relation to non carriers. The risk factor of dichotomized age is OR = 2.99 (95% CI, 1.95;4.62; p < 0.0005) times more the subjects who are more 40 years old in relation to who are 40 years old or younger.</p><p class="elsevierStylePara">The male sex means a risk factor for venous spontaneous thrombosis (p = 0.021; OR = 1.64; 95% CI, 1.08;2.51 times more for men in relation to women).</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Discussion</span></p><p class="elsevierStylePara">Every day we watch, in our clinical labor, that the younger carriers of PT G20210A «need» a risk factor in relation to thrombotic event (surgery, immobilization, trauma, gestation/puerperium, oral contraceptives, obesity), and, on the other hand, the older carrier patients have spontaneous venous thrombosis often; we wanted to analyze this clinical observation using a right statistical method.</p><p class="elsevierStylePara">We have made the dichotomize of the age, similarly to others authors<span class="elsevierStyleSup">4</span>; it has been realized by a clinical viewpoint and also to be the median between the patients and the controls.</p><p class="elsevierStylePara">In patients whose first venous thrombotic episode was unrelated to predisposing risk factors, we analyzed diverse circumstances or factors implicated by different statistical models. In all of them, we saw that the thrombophilic mutation PT G20210A combined with age presents a risk factor for spontaneous thrombosis, as do other authors<span class="elsevierStyleSup">4</span>, that increased age potentates the probability of spontaneous thrombosis in carriers of PT G20210A; therefore the age in these patients could be considered a predisposing risk factor for spontaneous venous thrombosis. In order to evaluate the epidemiological importance of this finding, it would be necessary to show that PT G20210A is currently the more prevalent hereditary thrombophilic anomaly of our population<span class="elsevierStyleSup">9,10</span>.</p><p class="elsevierStylePara">We think that it's important to have been able to demonstrate in our study this clinical hypothesis, because we shall can make same recommendations to the carrier of PT G20210A patients older in relation to prevent a spontaneous thrombotic event.</p><p class="elsevierStylePara">Age and FVL are risk factors for spontaneous venous thrombosis, but do not exhibit any interaction. Similarly, other authors<span class="elsevierStyleSup">11,12</span> define it also.</p><p class="elsevierStylePara">We suggest to do the study of thrombophilia with FVL and PT G20210A included, in all cases spontaneous venous thrombosis. In case of unprovoked venous thromboembolism, the screening of thrombophilia is recommended whatever the age of the patients<span class="elsevierStyleSup">13,14</span>.</p><p class="elsevierStylePara">The male sex means a risk factor for venous spontaneous thrombosis. On the other hand, the female sex can be considered «protective» in relation to venous spontaneous thrombosis. We don't find other similar dates in the revised bibliography.</p><p class="elsevierStylePara">As is unanimously accepted, venous TED is a multifactorial phenomenon where genetic and other factors interact, and an example of this can be the potentiation of the thrombotic risk represented by increased age in carriers of PT G20210A in relation to spontaneous venous thrombosis.</p>" "pdfFichero" => "2v128n17a13102051pdf001.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec690757" "palabras" => array:4 [ 0 => "Factor V Leiden" 1 => "Prothrombin G20210A" 2 => "Risk factor" 3 => "Thromboembolism disease" ] ] ] "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec690758" "palabras" => array:4 [ 0 => "Factor V Leiden" 1 => "Protrombina G20210A" 2 => "Factor de riesgo" 3 => "Enfermedad tromoboembólica" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "Fundamento y objetivo: El factor V Leiden (FVL) y la mutación de la protrombina G20210A (PT G20210A) son unos polimorfismos que suponen un débil factor de riesgo para presentar enfermedad tromboembólica venosa. Hemos analizado la probabilidad de tener una trombosis venosa espontánea en los portadores de las mutaciones trombofílicas (FVL y PT G20210A). Pacientes y método: Hemos estudiado a 735 personas (407 controles sanos y 328 pacientes con trombosis venosa) con relación al FVL y a la PT G20210A, determinados por reacción en cadena de la polimerasa en fase líquida, en tiempo real. Para evaluar los resultados utilizamos el test de la x2 y el análisis de regresión logística. Los datos se analizaron con el programa estadístico SPSS versión 14.0. Resultados: Los pacientes con la mutación PT G20210A que eran mayores de 40 años tuvieron un factor de riesgo para trombosis venosa espontánea con una odds ratio (OR) 9,28 (intervalo de confianza (IC) del 95%, 3,01-28,60; p < 0,0005) veces mayor que los portadores de la mutación PT G20210A que tenían 40 años o menos. En nuestra serie el sexo masculino representó un factor de riesgo débil para trombosis venosa espontánea (p = 0,021; OR = 1,64; IC del 95%, 1,08-2,51). Conclusiones: Nuestros resultados demuestran una potenciación del riesgo trombótico por el incremento de la edad en los individuos portadores de la mutación PT G20210A." ] "en" => array:1 [ "resumen" => "Background and objective: Factor V Leiden mutation (FVL), and the prothrombin G20210A mutation (PT G20210A) are polymorphisms with a weak risk factor for venous thromboembolic disease. The probability of spontaneous venous thrombosis in carriers of thrombophilic mutations (FVL and PT G20210A) was analyzed. Patients and method: We studied 735 individuals (407 were healthy controls and 328 patients with venous thrombosis) with respect to FVL and PT G20210A, determined by polimerase chain reaction in liquid phase, real time. x2 test and logistic regression analysis were used to evaluate the results. The dates were analyzed with the statistical program SPSS v. 14.0. Results: The carrier patients of PT G20210A mutation whose age was over 40 years had a risk factor for spontaneous venous thrombosis which was 9.28 (odds ratio [OR]) (95% confidence interval [CI], 3.01-28.60; p < 0.0005) times greater than carriers of the PT G20210A mutation who were 40 year-old or younger. In our patients, being male meant a weak risk factor for venous spontaneous thrombosis (p = 0.021; OR = 1.64; 95% CI, 1.08-2.51) . Conclusions: Our results demonstrate a potentiation of the thrombotic risk by an increase of age in the carriers of the PT G20210A mutation." ] ] "multimedia" => array:2 [ 0 => array:6 [ "identificador" => "tbl1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "2v128n17-13102051tab01.gif" "imagenAlto" => 523 "imagenAncho" => 768 "imagenTamanyo" => 24822 ] ] ] ] ] ] 1 => array:5 [ "identificador" => "tbl2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:14 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation. 1999;99:999-1004." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Ridker PM" 1 => "Hennekens CH" 2 => "Miletich JP." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Circulation" "fecha" => "1999" "volumen" => "99" "paginaInicial" => "999" "paginaFinal" => "1004" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10051291" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "The venous thrombosis risk factor 20210 allele of the prothrombin gene is not a major risk factor for arterial thrombotic disease. Br J Haematol. 1997;99:304-7." 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Article information
ISSN: 00257753Original language: English
DOI:10.1157/13102051
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