Diagnóstico y tratamiento de las trombofilias en edad fértil / Diagnosis and treatment of thrombophilias of childbearing age

INTRODUCCIÓN: El embarazo se caracteriza por ser un estado protrombótico, con aumento del potencial procoagulante, disminución de la actividad anticoagulante y de la actividad fibrinolítica. A esto se le suma la estasis venosa de miembros inferiores por compresión del útero sobre los grandes vasos venosos pelvianos, aumento de la capacitancia venosa, aumento de la resistencia a la insulina y del perfil lipídico protrombótico. Existe asociación entre la trombofilia y la ocurrencia de trombosis venosa profunda. Adicionalmente, las trombofilias tanto hereditarias como adquiridas se han asociado a resultados adversos en los embarazos, tales como abortos espontáneos, muerte fetal tardía, preeclampsia, restricción en el crecimiento intrauterino (RCIU) y desprendimento placentario. ESTRATEGIA DE BÚSQUEDA: Se realizó una búsqueda no sistemática de la evidencia para responder a los interrogantes clínicos. Los sitios de búsqueda incluyeron bases de datos electrónicas (PUBMED, Cochrane library, TripDatabase, Epistemonikos), Agencias de Evaluación de Tecnologías Sanitarias, organismos elaboradores de Guías de Práctica Clínica y sumários electrónicos de alta calidad. Se recuperó adicionalmente información relevante proveniente de las citas de los trabajos encontrados mediante la estrategia inicial. Se utilizaron como criterios de inclusión estudios de investigación secundarios (Guías de Práctica Clínica y Consensos de Sociedades Científicas, Revisiones Sistemáticas, Informes de Evaluación de Tecnologías Sanitarias) que analizaran información sobre métodos diagnósticos y/o tratamiento de las trombofilias; complicaciones obstétricas y maternas tanto de la patología como de su tratamiento. RESULTADOS: Se seleccionaron 10 estudios considerados pertinentes. CONCLUSIONES: Existe evidencia escasa sobre cuatro puntos relevantes: si la presencia de trombofilias hereditarias y/o adquiridas se asocia con resultados adversos en los embarazos, qué subgrupo de pacientes es el que se puede beneficiar con la realización de pruebas de diagnóstico, si el tratamiento anticoagulante que se indica a partir de este diagnóstico mejora los resultados en salud de los embarazos; y si el tratamiento anticoagulante es razonablemente seguro para su indicación en las mujeres que reciban el diagnóstico de trombofilias. Estas preguntas no quedan respondidas con suficiente confianza a partir de este informe ultrarrápido, en donde no fue posible realizar una búsqueda exhaustiva ni sistemática de evidencia. Por otro lado, la calidad de la evidencia no fue evaluada de manera formal debido a la necesidad de una respuesta en un lapso breve de tiempo. Sin embargo se puede afirmar que, por el diseño de los estudios incluidos, es para la mayoría de los casos, baja. El punto en el que más coincidencia se encuentra es que las pruebas diagnósticas deben ser limitadas a un grupo seleccionado de pacientes (historia personal de aborto recurrente, de eventos tromboembólicos, o historia familiar de primer grado), y no deben ser solicitadas de rutina a mujeres en edad fértil, ni a mujeres con un antecedente de aborto, ni a mujeres que tengan hasta dos intentos de fertilización asistida fallidos. Y aún en estos grupos seleccionados el tratamiento posterior con anticoagulación se encuentra cuestionado. En caso de trombofilias hereditarias, el tratamiento con heparina de bajo peso molecular no mostró mejorar la tasa de nacidos vivos en comparación com pacientes que no recibieron HBPM. En cambio en el caso de Sindrome antifosfolipídico los estudios sí mostraron mejores resultados en cuanto a tasa de nacidos vivos em mujeres que recibieron HBPM en comparación con las que no lo recibieron. Todos los estudios en los que se basa este efecto fueron de bajo número de participantes, por los que estos datos deben interpretarse con cautela. Sobre cuáles son los estudios que deberían solicitarse, no se observa concordancia entre los hallados en las recomendaciones nacionales e internacionales y los propuestos en el artículo 6 del proyecto de ley recibido. Se efectuó una búsqueda sobre cada uno de los métodos mencionados en el artículo 6. Para ninguno de ellos se encontró recomendación a favor de incluirlos. La mayoría de los trabajos incluidos coincide en recomendar como pruebas diagnósticas al factor V de Leiden y a la mutación del gen de la protrombina em caso de trombofilias hereditarias; y a los anticuerpos antifosfolipídicos en el caso de trombofilias adquiridas. Debido a la relevancia de este tema en relación a su impacto en el sistema de salud, a que existen estudios heterogéneos con resultados contradictorios, y a que la evidencia es de calidad incierta, se recomienda complementar esta revisión rápida con la elaboración de Recomendaciones basadas en evidencia, a través de um Informe de Evaluación de Tecnología Sanitaria y/o una Guía de Práctica Clínica, que incluyan la valoración de la calidad de la evidencia existente y sínteses cuantitativa de los datos hallados.

Manejo obstétrico de la deficiencia hereditaria de antitrombina durante el embarazo y puerperio. Dos casos clínicos / Obstetric management of hereditary antithrombin deficiency in pregnancy and postpartum. Two case studies

La deficiencia de antitrombina III hereditaria es una rara enfermedad que afecta al 0.02-0.2 por cento de la población. Puede presentar mayor frecuencia de complicaciones y resultados adversos tanto en la madre como en el feto. Se presenta el manejo obstétrico de dos gestaciones consecutivas en una mujer con deficiencia de antitrombina III. Descripción: en ambos embarazos la madre realiza profilaxis de la enfermedad tromboembólica con heparina de bajo peso molecular para evitar la aparición de esta patología tanto en el embarazo como en el puerperio y mejorar el flujo útero-placen-tario. Con respecto a las complicaciones obstétricas, sólo existe un enlentecimiento del crecimiento fetal que obliga a un control obstétrico estricto. En ambas gestaciones los estudios eco-Doppler están dentro de la normalidad lo que permite una conducta expectante, consiguiendo llegar a término. Discusión: la profilaxis con heparina de bajo peso molecular en las gestantes con esta trombofilia y las intervenciones preventivas de factores de riesgo de enfermedad tromboembólica, junto con un control obstétrico adecuado, ha conseguido evitar la apari-ción de complicaciones derivadas de esta patología en el embarazo y en el puerperio. Por otra parte, el control del crecimiento fetal y el estudio Eco-Doppler han permitido asegurar el bienestar fetal no adelan-tando el parto, consiguiendo partos a término...

Hereditary antithrombin III deficiency is a rare disease that affects 0.02-0.2 percent of the population. It may be associated with a higher rate of complications and adverse outcomes in both mother and fetus. The present study describes the management of a woman with antithrombin III deficiency and two consecutive pregnancies. Description: in both pregnancies, the woman under went prophylaxis with low molecular weigh heparin, to prevent thromboembolic disease and improve the utero-placental flow during pregnancy and the postpartum period. The only obstetric compli-cation was fetal growth retardation requiring strict obstetric control. In these two cases the eco-Doppler studies offeto-placentalflow were normal, leading to the expectation of managing a term birth. Discussion: low molecular weigh heparin prophylaxis in pregnant women with thrombophilia and preventive interventions for risk factors for throm-boembolic disease, together with appropriate obstetric care managed to avoid the emergence of complications of this disease in pregnancy and puer-perium. Fetal growth control and a Doppler study also help to ensure the well-being of the fetus and avoid a preterm birth...

Anticoagulant proteins in a population of Mexican mestizo donors.

BACKGROUND: To determine the activity of antithrombin (AT), protein C (PC), and protein S (PS), as well as the frequency of deficiencies of these proteins in a population of healthy Mexican mestizo blood donors. METHODS: AT, PC, and PS were determined from 1,502 plasma samples of healthy blood donors by using commercial kits in a coagulometer 4 STA (Diagnostica Stago, Asnières, France). RESULTS: A total of 741 women and 761 men were under study. They were divided into age range groups (18-24, 25-34, 35-44, 45-54, and 55-64 years). Activity of AT, PC, and PS was determined. For AT, activity values were specific for each age group according to gender when it had to do with PS, as well as when PC was determined. Frequencies of AT, PC, PS, and activated PC resistance activity deficiencies were obtained from reference levels (RLs) and average levels of this study. Differences were found between both frequencies for AT, PC, and PS, and the average levels obtained were used in this study. The frequencies of the activity deficiencies obtained through the values gotten in this population were: AT, 0.6%; PC, 1.06% (which is higher than the one obtained using the RLs described by commercial kits 0.33% and 0.66%, respectively); and PS, 1% (which is less than 4.5%). CONCLUSIONS: It is necessary to know the characteristics and biological behavior of the coagulation proteins in the Mexican population because the RLs used have been established for populations that are genetically different.

Antithrombin.

Antithrombin (AT) is a heparin cofactor and a member of the serine protease inhibitor family (serpin). The mature AT molecule is composed of 432 amino acids and it is produced mainly in the liver. Initially, several different AT activities in plasma were reported, leading to the classification of antithrombin in a range from I to IV. It was subsequently shown that these various antithrombin activities were the function of one molecule, antithrombin III, whose name was reduced to antithrombin at the meeting of the International Society in Thrombosis and Haemostasis in 1993. AT is an important protease inhibitor of thrombin and factor Xa. However, AT is also able to inhibit factors IXa, XIa, XIIab, kallikrein, and plasmin. Given that AT is one of the major naturally occurring inhibitors of coagulation, acquired or hereditary deficiencies of this protein result in excessive thrombin generation. As a vast array of mutations are responsible for hereditary AT deficiencies, screening for their presence by DNA testing would require sequencing each entire gene involving numerous exons. Moreover, the knowledge of the gene mutation does not offer any benefit in the treatment of affected families, so the routine molecular characterization is not indicative. These defects are detected by functional or immunological assays. AT amidolytic assays are recommended for initial testing for AT deficiency. There is no need to routinely perform AT immunological assays. However, they are useful in order to distinguish type I from type II hereditary AT deficiency.

[Moyamoya disease in a girl with Down syndrome. Report of one case]. / Síndrome moyamoya en paciente con síndrome de Down y déficit de antitrombina III.

Moyamoya disease is a unique chronic progressive cerebrovascular disease characterized by bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation. It can be primary or secondary to genetic syndromes such as Down syndrome. We report a seven year-old girl with a Down syndrome that presented with a disturbance of consciousness, seizures and a right hemiparesia at the age of five. Magnetic resonance imaging showed old cortical ischemic lesions in both cerebral hemispheres and a recent infarction in the territory of the left middle cerebral artery. Brain angiography showed a proximal stenosis of both medial cerebral arteries and a net of collateral vessels, consistent with the diagnosis of moyamoya syndrome. The patient had also an antithrombin III deficiency. Aspirin was indicated and a surgical correction was recommended. However, prior to the procedure, the patient had a new infarction in the territory of the right middle cerebral artery, which caused a severe disability.

Síndrome moyamoya en paciente con síndrome de Down y déficit de antitrombina III / Moyamoya disease in a girl with Down syndrome. Report of one case

Moyamoya disease is a unique chronic progressive cerebrovascular disease characterized by bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation. It can be primary or secondary to genetic syndromes such as Down syndrome. We report a seven year-old girl with a Down syndrome that presented with a disturbance of consciousness, seizures and a right hemiparesia at the age of five. Magnetic resonance imaging showed old cortical ischemic lesions in both cerebral hemispheres and a recent infarction in the territory of the ¡eft middle cerebral artery. Brain angiography showed a proximal stenosis of both medial cerebral arteries and a net of collateral vessels, consistent with the diagnosis of moyamoya syndrome. The patient had also an antithrombin III deficiency. Aspirin was indicated and a surgical correction was recommended. However, prior to the procedure, the patient had a new infarction in the territory of the right middle cerebral artery, which caused a severe disability.

[Deep vein thrombosis associated with osteoarticular infection in two siblings with anti-thrombin III deficiency]. / Trombosis venosa profunda asociada a infección osteoarticular en dos hermanos con deficiencia de antitrombina III.

The development of deep vein thrombosis in an osteoarticular infection in children is rare. We report the case of two siblings with an osteoarticular infection in the hip and in the knee, respectively, who developed deep vein thrombosis and, in one sibling, pulmonary thromboembolism. The only hematological alteration found was reduction of anti-thrombin III in both patients. This reduction was acquired and secondary to sepsis due to Staphylococcus aureus. Anti-thrombin III levels recovered after 2 weeks of treatment. The association of deep vein thrombosis and osteoarticular infection with sepsis should lead to suspicion of hematological deficiencies, including acquired anti-thrombin III deficiency.

Trombofilias congénitas impacto reproductivo y perspectivas de tratamiento / Congenital thrombophilias reproductive impact and treatment

La intención de esta publicación ha sido revisar la relación existente entre las condiciones pro-trombóticas hereditarias conocidas como trombofilias congénitas y algunas de las patologías más severas que pueden ocurrir durante la gestación. Las trombofilias pueden afectar desde la implantación, formación y funcionamiento de la placenta, manifestándose como abortos a repetición, cuadros hipertensivos severos, restricción de crecimiento y hasta la muerte fetal. Estas enfermedades, al estar relacionadas a trombofilias, abren una ventana a la posibilidad de establecer nuevas estrategias de prevención, diagnóstico y tratamiento.

Trombofilia primaria: detección y manifestación clínica en 105 casos / Primary thombophilia: Report of 93 cases and 12 asymptomatic relatives

Background: Thrombophilia is defined as an altered hemostasis that predisposes to thrombosis. It can be primary when there is a family clustering of the disease or secondary, when it is associated to an acquired risk factor. Aim: To report clinical features in a series of patients with primary thrombophilia. Material and methods: Review of clinical records of patients with thrombotic episodes that lead to the suspicios of primary thrombophilia. Analysis of asymptomatic adult close relatives of these patients. Results: We report 93 subjects (56 females, age range 14-77 years) with repeated episodes of thrombosis and a family history of thrombosis and 12 asymptomatic close relatives. Seventy one percent had the first thrombotic episode before the age of 40 years, 62% had more than one thrombotic episode and 37% had a family history of thrombosis. Twenty four percent had protein C deficiency, 24% had antithrombin III deficiency, 18% had resistance to activated C protein by factor V Leiden, 10% had protein S deficiency, and 10% had the G20210 mutation of prothrombin gene. Among acquired defects studied simultaneously, 30% had lupus anticoagulant and 11% had hyperhomocysteinemia. Twenty four percent of cases had more than one thrombophilic risk factor. Among asymptomatic relatives, five had factor V Leiden, four had protein C deficiency and three had the G20210 mutation of prothrombin gene. Conclusions: Thrombophilia must be suspected in young subjects with thrombotic episodes and a family history. The type of coagulation defect will determine prognosis, and the type of treatment.

Portal vein thrombosis in children and adolescents: the low prevalence of hereditary thrombophilic disorders.

PURPOSE: The aim of this study was to determine the frequency of thrombophilic disorders in children and adolescents with portal vein thrombosis (PVT) as well as assessing the hereditary character of this disorder. METHODS: A 2-year prospective study was carried out in pediatric PVT patients (n = 14), their parents (n = 25), and an age-matched control group free of liver disease (n = 28). The presence of PVT was assessed by means of Doppler ultrasound scan or angiography. None of the PVT patients presented biochemical or histologic signs of liver disease. RESULTS: The frequency in PVT patients of protein C (PC), protein S (PS) and antithrombin (AT) deficiency was 42.9% (P <.05 v controls), 21.4% (P >.05) and 7.1% (P >.05), respectively. None of the controls or parents of PVT patients presented hereditary PC, PS, or AT deficiency. One PVT patient and one control (P =.999) presented prothrombin G20210A mutation. Homozygous methylenetetrahydrofolate reductase C677T genotype was observed in 3 of 14 (21.4%) PVT patients and in 5 of 28 (17.9%; P =.356) controls. None of these patients presented factor V G1691A mutation. CONCLUSIONS: PC deficiency was frequent in pediatric PVT patients and does not seem to be an inherited condition. The hereditary prothrombotic disorders do not seem to play a vital role in thrombosis in children and adolescents with PVT.

[Primary thrombophilia. Report of 93 cases and 12 asymptomatic relatives]. / Trombofilia primaria: detección y manifestación clínica en 105 casos.

BACKGROUND: Thrombophilia is defined as an altered hemostasis that predisposes to thrombosis. It can be primary when there is a family clustering of the disease or secondary, when it is associated to an acquired risk factor. AIM: To report clinical features in a series of patients with primary thrombophilia. MATERIAL AND METHODS: Review of clinical records of patients with thrombotic episodes that lead to the suspicions of primary thrombophilia. Analysis of asymptomatic adult close relatives of these patients. RESULTS: We report 93 subjects (56 females, age range 14-77 years) with repeated episodes of thrombosis and a family history of thrombosis and 12 asymptomatic close relatives. Seventy one percent had the first thrombotic episode before the age of 40 years, 62% had more than one thrombotic episode and 37% had a family history of thrombosis. Twenty four percent had protein C deficiency, 24% had antithrombin III deficiency, 18% had resistance to activated C protein by factor V Leiden, 10% had protein S deficiency, and 10% had the G20210 mutation of prothrombin gene. Among acquired defects studied simultaneously, 30% had lupus anticoagulant and 11% had hyperhomocysteinemia. Twenty four percent of cases had more than one thrombophilic risk factor. Among asymptomatic relatives, five had factor V Leiden, four had protein C deficiency and three had the G20210 mutation of prothrombin gene. CONCLUSIONS: Thrombophilia must be suspected in young subjects with thrombotic episodes and a family history. The type of coagulation defect will determine prognosis, and the type of treatment.

Estados de hipercoagulabilidad heredados y trombosis venosa cerebral: experiencia en 3 casos / Cerebral venous thrombosis in hereditary hypercoagulability: report of three cases

Hereditary hypercoagulability has been identified as risk factor in approximately 30 percent of cerebral venous thrombosis cases. We report three females with this association. A 38 years old female with a history of deep venous thrombosis of the lower limb, presented with headache, vomiting and a generalized seizure. Magnetic resonance angiography showed a partial thrombosis of the left lateral and superior longitudinal venous sinuses. Coagulation study showed a resistance to activated C protein and factor V Leyden. A 42 years old woman with a history of deep venous thrombosis, presented a right hemiplegia during a hospitalization. Magnetic resonance showed a left lateral hemorrhagic infarction. Magnetic resonance angiography showed an absence of signal in three venous sinuses. Coagulation study showed a protein C deficiency. A 17 years old woman presented a right hemiparesis in the sixth day of puerperium. CAT scan showed a left frontoparietal subcortical venous infarction. Coagulation study showed an antithrombin III deficiency

Thrombophilic factors in chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTE-PH) is an infrequent cause of pulmonary hypertension that develops in 0.1-0.2% of patients who survive after an acute venous thromboembolic event. According to the largest series so far reported, 15-30% of patients with diagnosis of CTE-PH have an underlying congenital or acquired hypercoagulable state. To determine the prevalence of thrombophilic factors in our population, we analyzed 24 patients admitted to our institution between November 1992 and March 2000 fulfilling criteria for CTE-PH. Eighteen patients disclosed abnormal results in the screening for thrombophilia. The presence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies) was the abnormality most frequently found (12 out of 24 patients). We found hyperhomocysteinaemia in 7/14, true protein S deficiency in 1/10, protein C deficiency in 1/13, activated protein C resistance in 1/22, antithrombin III deficiency in 1/24, and prothrombin gene G20210A mutation in 1/18 patients. Factor V Leiden was normal in all 18 patients studied. Five patients (20.8%) disclosed more than one thrombophilic abnormality. In conclusion, contrary to the largest series of patients with CTE-PH so far reported, we found that 75% of patients with CTE-PH presented at least one thrombophilic risk factor, being antiphospholipid antibodies in 50% of the cases. We recommend a thorough screening for thrombophilia in all patients with diagnosis of CTE-PH.

Acute fatty liver and HELLP syndrome: two distinct pregnancy disorders.

OBJECTIVE: to report the experience clinical, biochemical findings, complications and the maternal-perinatal outcome in patients with HELLP syndrome and acute fatty liver of pregnancy (AFLP) during the same period. MATERIALS AND METHODS: during the period between January 1996 and December 1999, medical records of patients with the discharge diagnosis of AFLP and HELLP syndrome were reviewed for presenting symptoms, laboratory findings, maternal and perinatal complications. Routine laboratory evaluation included serial measurement of liver function tests, complete blood cell count, coagulation profile and renal function tests. RESULTS: during the study period 10 patients had AFLP and 75 women had HELLP syndrome as the discharge diagnosis. Patients with HELLP syndrome had major parity than AFLP (P<0.006). The most common presenting symptom for patients with AFLP was malaise noted in all patients, nausea and/or vomiting, abdominal pain and jaundice were very common. Headache, abdominal or epigastric pain and hematuria were the most common symptoms of patients with HELLP syndrome. Women with AFLP had major hypoglycemia, hypocholesterolemia, hypotriglyceridemia, serum transaminase activity and low antithrombin III. Disseminated intravascular coagulation, acute renal insufficiency, ascites, seroma and encephalophaty were more common with AFLP. CONCLUSIONS: our opinion is that AFLP had clinical presentation, biochemical findings and complications clearly distinguished of HELLP syndrome.

Antithrombin deficiency in Brazilian patients with venous thrombosis: molecular characterization of a single splice site mutation, an insertion and a de novo point mutation.

The prevalence of antithrombin (AT) deficiency in 342 unselected Brazilian patients with venous thrombosis was 1.16%, which increased to 3% when only patients under the age of 50 or with a familial history of thrombosis were considered. In two patients, a clinical (contraceptive use) or genetic risk factor (factor V Leiden and C677T in the methylene tetrahydrofolate reductase gene [MTHFR]) was identified and corroborated the hypothesis that an interaction of factors accounted for the appearance of thrombosis. However, no risk factor other than AT deficiency was identified in one patient with an important clinical and family history of spontaneous thrombosis. Three mutations were identified in these patients: a G-->A transition in intron 5 at position +1 (5'-->3'), three base insertions corresponding to arginine at position 5383 in exon 3A, and a G-->A transition at 13328, corresponding to an Ala404Thr de novo mutation. The polymorphisms in the genes coding for coagulation factors XII and XIII and fibrinogen normally associated with an increased risk for venous thrombosis were not related to thrombosis in these patients. This is the first study in South America to assess the prevalence of AT deficiency and to report the molecular characterization of the mutations involved.

Trombofilia primaria: características de una enfermedad poligénica / Primary Thrombophilia: characteistics of a polygenic disease

Se presenta una panorámica sobre las causas hemostáticas de una trombofilia, fundamentalmente las hereditarias como los déficit de antitrombina III (AT III), proteína C (PC), proteína S (PS) y la hiperhomocisteinemia. Se describen sus características moleculares más sobresalientes y sus mecanismos de acción, así como el tipo de herencia que siguen y todos los detectados hasta el momento, los cambios genéticos que los producen, y se refieren en los defectos combinados más frecuentes(AU)

Deficiência de inibidores naturais: diagnóstico laboratorial / Deficiency of natural inhibitor: laboratory diagnosis

Neste relato são apresentados aspectos clínicos e a importância da deficiência dos inibidores da coagulação, antitrombina, proteina C e proteína S, ressaltando-se o diagnóstico laboratorial desta anomalia.

The clinical aspects and the importance of the deflciency of the three coagulation inhibitors, antithrombin, protein C and protein S, are discussed in this report.

Déficit congénito de antitrombina III: reporte de un caso clínico de una paciente sometida a cirugía oral / Congenital deficiency of antithrombine III: report of a patient submitted to oral surgery

El déficit congénico de antitrombina III (AT III) es una patología de escasa prevalencia que se manifiesta clínicamente por fenómenos tromboembólicos que ocurren principalmente en territorio venoso, especialmente de las extremidades inferiores. En estos pacientes la incidencia de trombosis venosa aumenta con la edad, al igual que al someter a los pacientes a factores disponibles como son cirugía, parto, trauma, reposo prolongado, etc. Por esta razón la terapia profiláctica-anticoagulante en estos enfermos es necesaria cuando debe someterse a una cirugía. La administración de AT III exógenal, sola o junto a heparina, aparece como el tratamiento profiláctico más efectivo en prevenir los eventos trombólicos. En el presente trabajo se describe la evolución y manejo terapéutico de una paciente portadora de un déficit congénito de AT III, en relación a su segundo parto y cirugía de terceros molares