Etiology and diagnostic approach of recurrent miscarriage at a reference center in Bucaramanga, Colombia.

OBJECTIVE: The purpose of this study was to determine the etiologies of recurrent miscarriage in our hospital and whether its diagnostic approach followed the recommendations of the American Society of Reproductive Medicine (ASRM) guidelines published in 2012 and the National Institute for Health and Care Excellence (NICE) guidelines published in 2011. METHODS: This was a retrospective study. The medical records of 158 patients diagnosed with recurrent miscarriage between 2013 and 2018 at Santander University Hospital were reviewed. The Institutional Review Board of HUS approved the study in May 2020. RESULTS: The most common etiologies identified were protein S deficiency, thrombophilia, and cervical insufficiency, with incidence rates of 25.9%, 10.7%, and 3.8%, respectively. Moreover, the most frequently requested diagnostic tests were for protein S, protein C, and anti-phospholipid IgG. Abnormal results for protein S were obtained in 49% of the patients, whereas lupus anticoagulant was abnormal in 12.8%, and Factor V Leiden gene mutations in 8.5% of the patients. Three substantial deviations from the recommended diagnostic approach for recurrent miscarriage by international guidelines were identified in our population: the lack of request for cytogenetic analysis of pregnancy tissue, request for cytogenetic analysis for the parents in only 0.6% of the study sample, and the request for imaging tests to assess uterine anatomy in only 6.3% of the studied population. Both the ASRM and NICE guidelines were only partially followed with a combined adherence rate of 66.5%. CONCLUSION: The diagnostic approach for recurrent miscarriage poses important clinical challenges when compared to the recommendations of international guidelines. Therefore, the development of a local recurrent miscarriage assessment protocol is proposed in our institution.

Paternal thrombophilia and recurrent implantation failure: an exploratory case-control study.

OBJECTIVE: Many pieces of literature have reported that inherited and acquired thrombophilia might be a risk factor for recurrent implantation failure (RIF), however, most studies have only focused on RIF patients and not their male partners. We studied the possible association of paternal thrombophilia with RIF risk. METHODS: Forty-two male partners aged 20-45 suffered from RIF compared with 42 males from couples with at least one successful pregnancy. All participants were investigated for thrombophilia markers. RESULTS: The prevalence of coagulation Factor V activity was significantly higher in the case group (42.9%) than in the control group (16.7%) (p=0.008) (OR=3.75; 95% CI, 1.38, 10.12). The prevalence of protein C and protein S deficiencies in RIF patients were 4.8% and 2.4%, respectively, and 0% in the controls. The prevalence of antithrombin III (ATIII) deficiency was significantly higher in the case group (19%) than in the control group (2.4%) (p=0.01). None of MTHFR C677T and MTHFR A1298C were statistically significant between the two groups. Combined thrombophilia was 45.2% in the men of the RIF group when compared with the control, 14.2% (p=0.001) (OR = 4.95; 95% CI, 1.75-13.86). CONCLUSIONS: Paternal thrombophilia may be related to recurrent implantation failure, so evaluation of this factor in RIF patients could be used to identify relevant risk groups and may help in the proper management of these cases to enhance the chance of implantation.

Trastornos de la coagulación: factor V Leiden, panorama biológico, clínico y epidemiológico / Coagulation Disorders: Factor V Leiden, Biological, Clinical, and Epidemiological Overview

Resumen El sistema de coagulación mantiene la sangre en estado fluido en todo momento y, por tanto, está incesantemente activa durante toda la vida. Sin embargo, en el momento en que ocurre una lesión del sistema vascular, el sistema de coagulación inmediatamente gira 180° y transforma la sangre en un cuerpo sólido perfectamente localizado, al que llamamos coágulo. Este proceso, mediante el cual se forma un coágulo, se conoce como hemostasia, que es uno de los componentes del sistema de coagulación. La importancia de la mutación Leiden del factor V se basa en lo siguiente: el factor V de la coagulación es una proteína que se sintetiza en el hígado y el gen que lo codifica está situado en la región 23 del brazo largo del cromosoma 1, este factor circula en sangre periférica de manera inactiva hasta que interactúa con el factor X activado, formando un complejo que convierte al factor II (protrombina) en trombina, que va a tener su acción sobre el fibrinógeno convirtiéndolo en fibrina. La regulación del factor V activado se da por la actividad de la proteína C activada, cuando el factor V tiene una mutación (nombrada Leiden) que es ocasionada por el cambio de una adenina por una guanina en el nucleótido 1691 del factor V (G1691A), que causa que se sustituya una arginina por una glutamina en el residuo 506 de la proteína factor V; la proteína resultante es un factor V anómalo, mismo que no puede inactivarse por la proteína C activada, por lo que el factor V continúa activado y no puede impedir que el proceso de coagulación se detenga. En nuestro país (considerando varias afecciones) se ha descrito en diversas publicaciones de investigadores mexicanos que las mutaciones Leiden del factor V y la G20210A de la protrombina no son frecuentes, como lo son en los países europeos.

Abstract The coagulation system always keeps the blood in a fluid state and is therefore incessantly active throughout life. However, the moment an injury to the vascular system occurs, the coagulation system immediately rotates 180° and transforms the blood into a perfectly localized solid body, which we call a clot. This process, by which a clot forms, is known as hemostasis, which is one of the components of the coagulation system. The importance of the Leiden mutation of factor V is based on the following: coagulation factor V is a protein that is synthesized in the liver and the gene that encodes it is located in region 23 of the long arm of chromosome 1, this factor circulates in peripheral blood inactively until it interacts with activated factor X forming a complex that converts factor II (prothrombin) into thrombin, which will have its action on fibrinogen turning it into fibrin. The regulation of activated factor V is given by the activity of activated protein C, when factor V has a mutation (named Leiden) that is caused by the exchange of an adenine for a guanine in the nucleotide 1691 of factor V (G1691A), which causes arginine to be replaced by a glutamine in the 506 residue of the factor V protein, the resulting protein is an abnormal factor V, which cannot be inactivated by activated protein C, so factor V remains activated and cannot prevent the clotting process from stopping. In our country (considering several conditions) it has been described in various publications of Mexican researchers that Leiden mutations of factor V and G20210A of prothrombin are not frequent, as they are in European countries.

Acute mesenteric thrombosis in a pregnant woman with Factor V Leiden mutation with a history of in vitro fertilization and embryo transfer: case report and literature review / Trombosis mesentérica aguda en gestante con mutación de Factor V Leiden y antecedentes de fertilización in vitro y transferencia de embriones: reporte de caso y revisión de la literature

Objectives: To report the case of a patient diagnosed with acute mesenteric vein thrombosis (AMVT) associated with Factor V Leiden mutation and a history of in vitro fertilization and embryo transfer and review the literature on risk factors and treatments performed for AMVT. Materials and methods: We reported the case of a 37-year-old pregnant woman. A bibliographic search was carried out in Medline/PubMed and LILACS, filtering by type of language (English and Spanish). Primary cohort studies, cases and controls, case reports and case series were included, which addressed the risk factors associated with the development of acute mesenteric thrombosis during pregnancy and treatments performed. Results: The search identified cases and control studies, case reports and case series related to mesenteric ischemia, pregnancy and in vitro fertilization. The literature reported that the main factors associated with mesenteric ischemia are pregnancy itself, genetic factors, drugs, protein C and protein S deficiency and idiopathic causes. Conclusions: SMV thrombosis is a life-threatening and very rarely seen condition that emerges in pregnancies. The literature suggests that, during gestation, the factors associated with the development of acute mesenteric thrombosis are hypercoagulability induced by pregnancy, the administration of oral estrogen during IVF-ET, and other precipitating factors. More studies are required to better understand the possible additional factors and build better optimal treatment algorithms.

Objetivos: presentar el caso de una paciente diagnosticada con trombosis aguda de la vena mesentérica (TAVM) asociada a mutación de Factor V Leiden y antecedente de fertilización in vitro y transferencia de embriones, y hacer una revisión de la literatura sobre los factores de riesgo y los tratamientos realizados en los casos de TAVM. Materiales y métodos: reporte de un caso de mujer gestante de 37 años. Se realizó una búsqueda bibliográfica en las bases de datos Medline/PubMed y LILACS, filtrando por idioma (inglés y español). Se incluyeron estudios de cohortes primarias, casos y controles, reportes de casos y series de casos que examinaran los factores de riesgo asociados con el desarrollo de trombosis mesentérica aguda durante el embarazo y los tratamientos realizados. Resultados: se identificaron estudios de casos y controles, reportes de casos y series relacionados con isquemia mesentérica, embarazo y fertilización in vitro, y se encontró que los principales factores asociados con isquemia mesentérica son el embarazo mismo, factores genéticos, medicamentos, la deficiencia de proteína C y S, y causas idiopáticas. Conclusiones: la trombosis de la vena mesentérica superior es una condición infrecuente que amenaza la vida y ocurre durante el embarazo. La literatura sugiere que, durante la gestación, los factores asociados con la trombosis mesentérica aguda son la hipercoagulabilidad inducida por el embarazo, la administración de estrógeno oral durante el proceso de fertilización in vitro y transferencia de embriones, y otros factores desencadenantes. Es necesario realizar más estudios para comprender mejor los posibles factores adicionales y desarrollar mejores algoritmos para un tratamiento óptimo.

Prevalence of thrombophilia-associated genetic risk factors in blood donors of a regional hospital in southern Brazil

ABSTRACT Introduction: Thromboembolic events occur due to an imbalance in the hemostasis and some factors associated with this condition can be inherited. In order to evaluate the frequency of genotypes considered to be common hereditary risk factors for thrombophilia associated with venous thrombosis (g.1691G>A and g.20210G>A) and hyperhomocysteinemia (g.677C>T and g.1298A>C), samples from voluntary healthy blood donors at the Hospital de Clínicas de Porto Alegre were tested. Methods: We examined 325 blood samples from blood donors collected from October 2017 to July 2018. Blood was collected on filter paper and the DNA was extracted for single nucleotide polymorphisms (SNPs) analysis using the qualitative real time polymerase chain reaction. Results: The calculated frequencies of each genetic variant in heterozygosity were 4% for the FV gene (g.1691G> A), 4% for the F2 gene (g.20210G> A) and 42% and 39% for methylenetetrahydrofolate reductase (MTHFR), g.677C>T and g.1298A>C, respectively. Only the genetic variants of MTHFR were found in homozygosity, with frequencies of 14% and 6% (g.677C>T and g.1298A>C), respectively. Discussion: Altogether, these results describe the frequencies of genetic variants associated with venous thrombosis and hyperhomocysteinemia in the analyzed group and are important to enhance our current knowledge about the genetic profiles of Brazilian blood donors.

Factores congénitos de los trastornos trombóticos arteriales en recién nacidos / Congenital factors of arterial thrombotic disorders in newborns

La trombosis arterial neonatal representa el 5,8% de todos los tipos de trombosis conocidos en recién nacidos, esto convierte a esta enfermedad en un punto de enfoque específico para su diagnóstico oportuno, y descifrar los factores congénitos de mayor recurrencia, se realizó una revisión sistemática PRISMA, donde se evaluaron 20 artículos de tipo observacional transversal, detallando los resultados obtenidos en cuanto al factor congénito más recurrente que en este caso es el sexo masculino, prematuridad y defectos genéticos se han mencionado además los marcadores bioquímicos y moleculares mayormente evaluados en esta muestra, demostrando que en estos casos los marcadores bioquímicos analizados con frecuencia son: antitrombina III, Proteína C y S, anticuerpos antifosfolípidos y homocisteína y como marcadores moleculares se evalúa con mayor recurrencia a: Factor V Leiden y el gen de la protrombina G20210A.

Factores congénitos de los trastornos trombóticos arteriales en recién nacidos / Congenital factors of arterial thrombotic disorders in newborns

La trombosis arterial neonatal representa el 5,8% de todos los tipos de trombosis conocidos en recién nacidos, esto convierte a esta enfermedad en un punto de enfoque específico para su diagnóstico oportuno, y descifrar los factores congénitos de mayor recurrencia, se realizó una revisión sistemática PRISMA, donde se evaluaron 20 artículos de tipo observacional transversal, detallando los resultados obtenidos en cuanto al factor congénito más recurrente que en este caso es el sexo masculino, prematuridad y defectos genéticos se han mencionado además los marcadores bioquímicos y moleculares mayormente evaluados en esta muestra, demostrando que en estos casos los marcadores bioquímicos analizados con frecuencia son: antitrombina III, Proteína C y S, anticuerpos antifosfolípidos y homocisteína y como marcadores moleculares se evalúa con mayor recurrencia a: Factor V Leiden y el gen de la protrombina G20210A.

Neonatal arterial thrombosis represents 5.8% of all known types of thrombosis in newborns, this makes this disease a specific point of focus for its timely diagnosis, and to decipher the congenital factors of greater recurrence, a systematic review PRISMA was performed, where 20 articles of cross-sectional observational type were evaluated, detailing the results obtained in terms of the most recurrent congenital factor which in this case is male sex, prematurity and genetic defects have also been mentioned biochemical and molecular markers mostly evaluated in this sample, showing that in these cases the biochemical markers frequently analyzed are: Antithrombin III, Protein C and S, antiphospholipid antibodies and homocysteine and as molecular markers are evaluated with greater recurrence to: Factor V Leiden and the prothrombin gene G20210A.

Acute mesenteric thrombosis in a pregnant woman with Factor V Leiden mutation with a history of in vitro fertilization and embryo transfer: case report and literature review / Trombosis mesentérica aguda en gestante con mutación de Factor V Leiden y antecedentes de fertilización in vitro y transferencia de embriones: reporte de caso y revisión de la literatura

Objectives: To report the case of a patient diagnosed with acute mesenteric vein thrombosis (AMVT) associated with Factor V Leiden mutation and a history of in vitro fertilization and embryo transfer and review the literature on risk factors and treatments performed for AMVT. Materials and methods: We reported the case of a 37-year-old pregnant woman. A bibliographic search was carried out in Medline/PubMed and LILACS, filtering by type of language (English and Spanish). Primary cohort studies, cases and controls, case reports and case series were included, which addressed the risk factors associated with the development of acute mesenteric thrombosis during pregnancy and treatments performed. Results: The search identified cases and control studies, case reports and case series related to mesenteric ischemia, pregnancy and in vitro fertilization. The literature reported that the main factors associated with mesenteric ischemia are pregnancy itself, genetic factors, drugs, protein C and protein S deficiency and idiopathic causes. Conclusions: SMV thrombosis is a life-threatening and very rarely seen condition that emerges in pregnancies. The literature suggests that, during gestation, the factors associated with the development of acute mesenteric thrombosis are hypercoagulability induced by pregnancy, the administration of oral estrogen during IVF-ET, and other precipitating factors. More studies are required to better understand the possible additional factors and build better optimal treatment algorithms.

Objetivos: presentar un caso de necrosis uterina tras técnica de sutura hemostática por hemorragia posparto y hacer una revisión de la literatura para determinar la técnica de sutura utilizada, los hallazgos clínicos, la técnica diagnóstica y el tratamiento realizado en los casos clínicos descritos. Materiales y métodos: se presenta el caso de una mujer de 34 años que consultó por dolor abdominal al octavo día tras cesárea por placenta previa, que precisó sutura de B-Lynch por atonía uterina y cuyo diagnóstico fue necrosis uterina. La paciente requirió histerectomía abdominal total, con evolución satisfactoria. Se realizó una búsqueda sistemática de la literatura en las bases de datos Medline vía Pubmed, Embase y Web of Science. Se buscaron series y reportes de casos y cohortes de mujeres con necrosis uterina posterior al uso de suturas de compresión uterina para control de hemorragia posparto. Se analizaron variables sociodemográficas y clínicas al diagnóstico, técnica de sutura, pruebas diagnósticas y tratamiento. Resultados: se incluyeron 23 estudios con 24 pacientes. El 83 % de las necrosis ocurrieron tras cesárea. La técnica más utilizada fue B-Lynch (66 %), seguida de Cho (25 %). Los síntomas más frecuentes fueron fiebre y dolor abdominal. La prueba diagnóstica más utilizada fue la tomografía computarizada (9 de 24 casos). En la mayoría de casos se realizó histerectomía (75 %). Conclusiones: la necrosis de la pared uterina es una complicación infrecuente pero grave. Sería recomendable el diseño de cohortes de seguimiento de mujeres sometidas a estos procedimientos para determinar la incidencia de complicaciones asociadas.

Prevalence of thrombophilia-associated genetic risk factors in blood donors of a regional hospital in southern Brazil.

INTRODUCTION: Thromboembolic events occur due to an imbalance in the hemostasis and some factors associated with this condition can be inherited. In order to evaluate the frequency of genotypes considered to be common hereditary risk factors for thrombophilia associated with venous thrombosis (g.1691G > A and g.20210G > A) and hyperhomocysteinemia (g.677C > T and g.1298A > C), samples from voluntary healthy blood donors at the Hospital de Clínicas de Porto Alegre were tested. METHODS: We examined 325 blood samples from blood donors collected from October 2017 to July 2018. Blood was collected on filter paper and the DNA was extracted for single nucleotide polymorphisms (SNPs) analysis using the qualitative real time polymerase chain reaction. RESULTS: The calculated frequencies of each genetic variant in heterozygosity were 4% for the FV gene (g.1691G > A), 4% for the F2 gene (g.20210G > A) and 42% and 39% for methylenetetrahydrofolate reductase (MTHFR), g.677C > T and g.1298A > C, respectively. Only the genetic variants of MTHFR were found in homozygosity, with frequencies of 14% and 6% (g.677C > T and g.1298A > C), respectively. DISCUSSION: Altogether, these results describe the frequencies of genetic variants associated with venous thrombosis and hyperhomocysteinemia in the analyzed group and are important to enhance our current knowledge about the genetic profiles of Brazilian blood donors.

Prevalencia de mutaciones metilentetrahidrofolato reductasa (MTHFR), protrombina (II G20210G/G20210A) y factor V Leyden en pacientes sometidos a estudio por perfil trombofílico en el Hospital San Vicente de Paúl, Costa Rica, 2017-2018 / Prevalence of mutations Methylentetrahydrofolate reductase (MTHFR), Prothrombin (II G20210G/G20210A) and Leyden V factor in patients undergoing studies by thrombophilic profile. Hospital San Vicente de Paul. Costa Rica, 2017 to 2018

Resumen Introducción: en los últimos años se han descrito alteraciones genéticas asociadas con un mayor o menor riesgo de padecer una enfermedad trombótica. El objetivo del presente estudio es conocer la prevalencia de las mutaciones para la metilentetrahidrofolato reductasa (MTHFR), la protrombina (II G20210G/G20210A) y el factor V Leyden en las muestras de pacientes sometidas a estudio por perfil trombofílico en el Hospital San Vicente de Paúl. Metodología: con la base de datos de muestras referidas del Hospital San Vicente de Paúl, se estudiaron los marcadores de riesgo para trombofilia: MTHFR, Ac Lúpico, mutación del Factor II y Factor V Leyden correspondientes al periodo comprendido entre abril de 2017 a abril de 2018. Resultados: se observó que la frecuencia de la solicitud de estudio por trombofilia era mayor para el sexo femenino, con un 83,7 % del total de análisis, mientras que, para el sexo masculino fue de un 16,3 %. La mutación más prevalente fue la MTHFR, seguida del factor V Leyden, además, ambas se presentaron superiormente en las mujeres. Conclusión: se ha demostrado en varios estudios la asociación de las alteraciones genéticas estudiadas con los eventos trombóticos, por lo tanto, conocer su prevalencia en determinada población es de gran importancia para ayudar al clínico a llegar a un diagnóstico adecuado.

Abstract Introduction: Genetic alterations associated with a higher or lower risk of thrombotic disease have been reported in recent years, the objective of this study is to understand the prevalence of mutations for methylentetrahydrofolate reductase (MTHFR), Mutation for prothrombin (II G20210G/G20210A) and Mutation for factor V Leyden, in the samples of patients undergoing studies by thrombophilic profile, at the Hospital San Vicente de Paul. Methodology: To carry out this study, we use the database of reference samples of the Hospital San Vicente de Paúl for the study of risk markers for thrombophilia: MTHFR, Ac Lúpico, Mutation of Factor II, Factor V Leyden in the period from April 2017 to April 2018. Results: From the analyses requested for thrombophilia study, the frequency in the thrombophilia study request was observed to be higher for female sex, with a frequency of 83.7% of total testing and 16.3% for the male sex. The most prevalent mutation is MTHFR, followed by the Mutation for factor V Leyden, and both mutations occur in greater numbers in women. Conclusion: The association of genetic alterations studied with thrombotic events has been shown in several studies so knowing their prevalence in a given population is of great importance to help the clinic arrive at an appropriate diagnosis.

High risk of venous thromboembolism after orthopedic surgery in patients with thrombophilia.

OBJECTIVE: This study aimed at evaluating the effect of thrombophilia on the risk of venous thromboembolism (VTE) in patients undergoing any type of orthopedic surgery. BACKGROUND: Patients undergoing orthopedic surgery are at high risk for VTE. Although patients with thrombophilia have an increased risk of VTE, it is currently unclear whether there is a synergetic effect in patients with thrombophilia who undergo orthopedic surgery. METHODS: Data from a large population-based case-control study (the Multiple Environmental and Genetic Assessment [MEGA] of risk factors for venous thrombosis study) were used. Odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for age, sex, and body mass index (BMI) (ORadj) were calculated for patients undergoing any orthopedic intervention. RESULTS: Of 4721 cases and 5638 controls, 263 cases and 94 controls underwent orthopedic surgery. Patients who had any orthopedic intervention in the year before the index date were at higher risk of VTE (ORadj 3.7; 95% CI, 2.9-4.8) than those who did not undergo any orthopedic surgery. There was an additionally increased risk in patients with factor V Leiden (OR 17.5, 95% CI, 4.1-73.6), non-O blood group (OR 11.2; 95% CI, 3.4-34.0), or elevated plasma levels of factor VIII (OR 18.6; 95% CI, 7.4-46.9) all relative to patients without these defects, not undergoing orthopedic surgery. CONCLUSIONS: Patients with factor V Leiden, high levels of factor VIII, or blood group non-O were found to have a high risk of VTE after orthopedic surgery. Identification of these patients may enable individualized thromboprophylactic treatment to efficiently reduce VTE risk.

Prevalence of Factor V Leiden in a healthy population in Santa Catarina, Southern Brazil.

Thrombophilic disorders are found in 50% of patients with venous thromboembolism, and factor V Leiden (FVL) is the most common genetic risk factor for the development of these conditions. FVL prevalence varies according to population group. In Europe, many countries have a high prevalence of the mutation, including Portugal, Germany, and Italy. Santa Catarina State, southern Brazil, was colonized by different European nations; most inhabitants are descendants of Portuguese, Italian, and German immigrants. There are, however, no data on the prevalence of FVL in the state. This study aimed to determine FVL prevalence in a healthy population in Santa Catarina and assess whether there is an association between the mutation and demographic characteristics, thereby contributing to the understanding of the heterogeneity of prevalence of this important VTE risk factor and racial or geographical differences in the incidence of thrombotic diseases. Analysis of the FVL mutation was performed on 400 blood donors using the PCR technique followed by enzymatic digestion. The findings show that 2.5% of the participants were heterozygous for FVL, and none were homozygous. No association was found between the presence of FVL in heterozygosis and individual characteristics. In conclusion, this study found a prevalence of FVL in heterozygosis of 2.5% among healthy individuals in Santa Catarina, Brazil. Further studies are needed to assess the prevalence of FVL in other regions of the country, determine the distribution of the mutation among population groups, and evaluate how these factors affect the incidence of thrombotic diseases.

Inherited thrombophilia and pregnancy loss. Study of an Argentinian cohort. / Trombofilia hereditaria y pérdidas de embarazo. Estudio de una cohorte de Argentina.

BACKGROUND AND OBJECTIVES: Thrombophilia might increase the risk of suffering from obstetric complications by adversely affecting the normal placental vascular function. Our aim was to study the distributions of five thrombosis-associated genetic variants: factor V Leiden, prothrombin G20210A, -675 4G/5G PAI-1, 10034C/T gamma fibrinogen and 7872C/T factor XI and the frequencies of the deficiencies of protein C, S and antithrombin in Argentinian patients with recurrent pregnancy loss (RPL) and, therefore, to analyse their association with the risk and timing of RPL and the risk of suffering other vascular obstetric pathologies. PATIENTS AND METHODS: We performed a case-control study that included 247 patients with idiopathic RPL (cases), 107 fertile controls and 224 subjects from general population (reference group). Cases were stratified according to the gestational time of the losses (early RPL, n = 89; late losses, n = 158; foetal losses, n = 107) and according to the type of vascular obstetric pathologies. RESULTS: No differences were found in the distribution of the genetic variants among RPL group vs. control/reference group (p >.05). Similarly, no differences were observed in their distributions when analysing RPL patients stratified according to gestational times or vascular obstetric pathologies (p >.05), except for the factor V Leiden carriage in patients with foetal growth retardation vs. controls (11.8%, 4/34 vs. 1.9%, 2/107; p = .04) (OR = 7.11 [1.24-40.93], p = .03). CONCLUSIONS: Factor V Leiden might have a significant impact on certain obstetric pathologies such as foetal growth retardation. The genetic variants, 10034C/T gamma fibrinogen and 7872C/T factor XI, associated with thromboembolic disease, would not have an impact on PRE.

Lipase and factor V (but not viral load) are prognostic factors for the evolution of severe yellow fever cases

BACKGROUND Despite a highly efficacious vaccine, yellow fever (YF) is still a major threat in developing countries and a cause of outbreaks. In 2018, the Brazilian state of São Paulo witnessed a new YF outbreak in areas where the virus has not been detected before. OBJECTIVE The aim is to describe the clinical and laboratorial characteristics of severe cases of YF, evaluate viral to determine markers associated with fatal outcome. METHODS Acute severe YF cases (n = 62) were admitted to the Intensive Care Unit of a reference hospital and submitted to routine laboratorial evaluation on admission. YFV-RNA was detected in serum and urine by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and then sequenced. Patients were classified in two groups: survival or death. FINDINGS In the univariate analysis the following variables were associated with outcome: alanin aminotransferase (ALT), aspartat aminotransferase (AST), AST/ALT ratio, total bilirubin (TB), chronic kidney disease epidemiology collaboration (CKD-EPI), ammonia, lipase, factor V, international normalised ratio (INR), lactate and bicarbonate. Logistic regression model showed two independent variables associated with death: lipase [odds ratio (OR) 1.018, 95% confidence interval (CI) 1.007 to 1.030, p = 0.002], and factor V (OR -0.955, 95% CI 0.929 to 0.982, p = 0.001). The estimated lipase and factor V cut-off values that maximised sensitivity and specificity for death prediction were 147.5 U/L [area under the curve (AUC) = 0.879], and 56.5% (AUC = 0.913). MAIN CONCLUSIONS YF acute severe cases show a generalised involvement of different organs (liver, spleen, heart, kidneys, intestines and pancreas), and different parameters were related to outcome. Factor V and lipase are independent variables associated with death, reinforcing the importance of hemorrhagic events due to fulminant liver failure and pointing to pancreatitis as a relevant event in the outcome of the disease.

Anti-phospholipid syndrome in seven leprosy patients with thrombotic events on corticosteroid and/or thalidomide regimen: insights on genetic and laboratory profiles

Abstract INTRODUCTION Corticosteroids and/or thalidomides have been associated with thromboembolism events (TBE) in multibacillary (MB) leprosy. This report aimed to determine genetic and laboratory profiles associated with leprosy and TBE. METHODS Antiphospholipid antibodies (aPL), coagulation-related exams, prothrombin and Leiden's factor V mutations, and ß2-glycoprotein-I (ß2GPI) Val247Leu polymorphism were assessed. RESULTS Six out of seven patients with leprosy were treated with prednisone and/or thalidomide during TBE and presented at least one positive aPL. All patients presented ß2GPI polymorphism, and one showed prothrombin mutation. CONCLUSIONS Corticosteroid or thalidomide adverse effects and aPL and ß2GPI polymorphisms may cause TBE in patients with MB leprosy.

Three novel variants in the coagulation factor V gene associated with deep venous thrombosis in Chilean patients with Amerindian ethnic background.

BACKGROUND: The activated protein C (APC) resistance is the most common prothrombotic defect in thrombosis patients, mainly related with alterations in the F5 gene. In this work, we evaluated the presence of variants in the FV gene in Amerindian patients with deep venous thrombosis and APC resistance. METHODS: A total of 87 patients with deep venous thrombosis (DVT) confirmed by Doppler ultrasonography, and Amerindian genetic background, were included in this study. APC resistance was assayed by clotting methods and polymorphism F51691G>A was genotyped by molecular methods. In Amerindian patients with APC resistance, the promoter region, exon 7 and exon 10 of the F5 gene were screened by PCR-SSCP and DNA sequencing. The prediction of functional effect of novel mutations was analyzed using Polyphen-2 software. RESULTS: In DVT patients, 14.9% showed functional APC resistance in the absence of F51691G>A polymorphism. Interestingly, three novel missense mutations in exon 10 of F5 gene (M443L, E461Q and G493E) were identified. These genetic variants were absent in 100 healthy subjects. According to in silico analysis, the sequence variants G493E and E461Q are potentially deleterious. CONCLUSIONS: Our data shows that the APC resistance phenotype is not associated with the presence of the F51691G>A variant. We described, for the first time, the presence of three novel variants in F5 gene in Chilean patients with APC resistance. Further studies are required to investigate the real contribution of these novel mutations to the APC resistance phenotype.

Trombofilias hereditarias / Hereditary Thrombophilia

Las trombofilias hereditarias suponen un grupo de enfermedades que predisponen al desarrollo de enfermedad tromboembólica arterial y venosa, debido a déficit o ganancia de función de factores anticoagulantes o procoagulantes incrementando de manera significativa la morbilidad y mortalidad en la población adulta y pediátrica. La expresión y penetrancia genética de este grupo de enfermedades es diversa, y las formas de presentación clínica varía desde la purpura fulminans neonatal hasta episodios tromboembólicos recurrentes a edades tempranas y efectos adversos en el embarazo. El screening no es rutinario en pacientes con cuadros tromboembólicos y sus indicaciones son precisas, en especial personas menores a los 45 años, con cuadros recurrentes, y abortos o muertes fetales a repetición sin causa específica. El tratamiento es basado de acuerdo a la presentación del cuadro clínico, sin embargo la anticoagulación convencional es ampliamente utilizada en el manejo de este grupo de pacientes.

Inherited thrombophilia represent a group of diseases that predispose to the development of arterial and venous thromboembolic disease due to deficiency or gain of function of anticoagulant or procoagulant factors, increasing significantly the morbidity and mortality in the adult and pediatric population. Expression and genetic penetrance to this group of diseases is diverse, and the form of clinical presentation varies from the neonatal purple fulminans to recurrent thromboembolic events at a young age and pregnancy with side effects. The screening is not routine in patients with thromboembolic condition and its indications are accurate, especially in younger people than 45, with recurrent episodes of abortions or fetal deaths without specific cause. Treatment is based according to the clinical presentation of the condition; however conventional anticoagulation is widely used in the treatment of this patient group.

Deficiencia congénita del factor V / Congenital deficiency of factor V

El factor V de la coagulación es encontrado en el plasma y en las plaquetas y tiene un profundo impacto sobre la generación de la trombina. La deficiencia de este factor puede ser congénita o adquirida y se caracteriza por un amplio espectro de signos, que van desde sangrado mucocutáneo hasta compromiso del sistema nervioso central. A continuación se presenta el caso de una paciente de 33 años de edad con hemorragia uterina anormal de varios años de evolución, sin evidenciar mejoría en el manejo instaurado en consultas previas, realizándose paraclínicos que concluyen deficiencia congénita del factor V.

Blood coagulation factor V (FV) plays a pivotal role in blood coagulation. It is found in both plasma and in platelets and has a profound impact on thrombin generation. Deficiency of this clotting factor due to inherited or acquired conditions results in a broad spectrum of bleeding symptoms. ranging from mucocutaneous bleeding to central nervous system bleeding. We present a case of a 33-year-old woman with abnormal uterine bleeding for several years, not improvement with the management in previous consultations, concluding after several tests a congenital Leiden V factor deficiency.

Síndrome de Budd Chiari: Reporte de tres casos y revisión de la literatura / Budd Chiari Syndrome: Three Case Reports and a Literature Review

Se describen los casos de tres pacientes de sexo femenino a quienes se les hizo diagnóstico de síndrome de Budd Chiari. En una paciente la presentación del síndrome fue subaguda, pudiendo ser manejada exitosamente con la colocación de TIPS. Otra con mutación del factor V Leyden asociada desarrolló disfunción hepática progresiva y requirió de trasplante hepático. En dos de los tres casos se identificó una enfermedad hematológica como trastorno de base, y en uno el uso de anticonceptivos orales como factor de riesgo. Las tres pacientes fueron sometidas a terapia anticoagulante y el manejo quirúrgico fue definido de acuerdo a su condición clínica. Sin embargo, en un caso la presentación fue aguda con falla hepática y muerte.

This article describes the cases of three female patients who were diagnosed with Budd-Chiari syndrome. One patient was subacute and could be successfully managed by placement of a transjugular intrahepatic portosystemic stent (TIPS). Another patient who had the Factor V Leiden mutation developed associated progressive liver dysfunction and required liver transplantation. A hematologic disease was identified as the underlying disorder in two of the three cases. For one patient, the use of oral contraceptives was a risk factor. Since all three patients were undergoing anticoagulant therapy, surgical management was determined according to each patient’s clinical condition. Nevertheless, the one patient who that presented acute hepatic failure did not survive.

Fatores de risco hereditários e adquiridos na coagulação: impacto no desenvolvimento de eventos tromboembólicos em pacientes com lesão medular causada por trauma raquimedular / Hereditary and acquired clinical risk factors in the coagulation: impact in the development of thromboembolic events in patients with spinal injury caused by spinal cord injury

Objetivo: Avaliar o impacto de fatores de risco no desenvolvimento de eventos tromboembólicos em pacientes com lesão medular. Métodos: Estudo observacional, prospectivo e cruzado. Pacientes elegíveis (n=100) tinham lesão medular por trauma raquimedular e mais de 18 anos. O grau de lesão sensorial e motora foi avaliado com base na escala ASIA (ASIA Impairment Scale - AIS). Amostras de sangue foram coletadas para exames de coagulação, hemogramas, análises bioquímicas e laboratoriais. Exames de ultrassonografia foram realizados nos sistemas venosos superficial e profundo dos membros inferiores. Experimentos de PCR em tempo real foram realizados com o intuito de investigar mutações nos genes da protrombina (G20210A) e do fator V de Leiden (G1691A). Resultados: O principal achado deste estudo foi a maior ocorrência de Trombose Venosa Profunda (TVP) em pacientes com fator V de Leiden e hiperhomocisteinemia. Não houve associação entre Lesão Medular por TVP, Tromboembolismo Venoso (TEV) e trombofilia. Não houve também relação com lúpus anticoagulante e anti-cardiolipina. Conclusões: Houve importante diferença na incidência de TVP em pacientes com Lesão Medular, tanto aguda quanto crônica (após um ano da lesão). A investigação de trombofilia deve ter como base os fatores clínicos, fatores de risco para TVP e história familiar de trombose

Objective: Evaluate the impact of risk factors in the development of thromboembolic events in patients with spinal cord injury. Design: Observational, prospective and cross study. Eligible patients (n=100) had spinal injury (SI) by spinal cord injury (SCI), older than 18 years of age. The degree of motor and sensory lesion was evaluated based on ASIA Impairment Scale (AIS). Blood samples were collected for coagulation exams, hemogram, laboratory and biochemical analyses. Ultrasonography analyzes were performed from deep and superficial venous systems of lower limbs. Quantitative real-time PCR experiments were performed in order to investigate mutations in the prothrombin (G20210A) and Leiden factor V (G1691A) genes. Results: The main finding of this study was the higher occurrence of Deep Venous Thromboembolism (DVT) in patients with Leiden factor V and hyper homocysteinemia. There was no association between SI for DVT, venous thromboembolism (VT) and thrombophilia. Also, there was no relation between lupus anticoagulant and anti-cardiolipin. Conclusions: There is an important difference in the incidence of DVT in patients with SI by acute SCI and after 1 year. The conduct of the investigation for thrombophilia should be based on clinical factors, risk factors for DVT and family history of thrombosis