As trombofilias na perda gestacional de repetição: uma revisão de prevalência e condutas / Thrombophilias in recurrent pregnancy loss: a review of prevalence and conduct

Objetivo: Discutir o papel das trombofilias na perda gestacional de repetição, com foco em prevalência/associação dessas patologias com perdas de repetição e seu tratamento, por meio de resultados de ensaios clínicos, revisões sistemáticas e metanálises. Métodos: Trata-se de uma revisão não sistemática de artigos publi- cados nas bases eletrônicas PubMed, Cochrane e SciELO nos últimos cinco anos, utilizando os seguintes descritores: "recurrent pregnancy loss", "recurrent abortion", "habitual abortion", "thrombophilia", "antiphospholipid syndrome" e "treatment". Resultados: A maioria dos estudos relatou forte associação entre os anticorpos antifosfolípides específicos e a síndrome do anticorpo antifosfolípide com perda gestacional de repetição. Mulheres portadoras da mutação do fator V de Leiden, mutação do gene da protrombina e deficiência de proteína S apresentaram alto risco de perda gestacional de repetição em uma grande revisão sistemática. Estudos recentes demonstraram taxas de prevalência das trombofilias hereditárias e da síndrome do anticorpo antifosfolípide, em mulheres com perda gestacional de repetição, semelhantes às da população em geral. Os estudos atuais endossam o uso da heparina associada à aspirina em mulheres com síndrome do anticorpo antifosfolípide, com aumento da taxa de nascidos vivos, mas sem diferença em re- lação às complicações obstétricas. Conclusão: Apesar de novos estudos demons- trarem que a prevalência das trombofilias hereditárias e adquiridas em mulheres com perda gestacional de repetição é semelhante à da população em geral, reco- menda-se a pesquisa rotineira de síndrome do anticorpo antifosfolípide nessas pacientes. O uso de aspirina em baixas doses associada à heparina é a intervenção farmacológica de primeira linha para a prevenção de perda gestacional de repeti- ção em pacientes com síndrome do anticorpo antifosfolípide.

Objective: To discuss the role of thrombophilias in recurrent pregnancy loss, focu- sing on the prevalence/association of these pathologies with recurrent abortion and treatment, through results of clinical trials, systematic reviews and meta-analyses. Methods: This is a non-systematic review of articles published in electronic databa- ses PubMed, Cochrane, SciELO in the last five years, using the following descriptors: "recurrent pregnancy loss", "recurrent abortion", "habitual abortion", "thrombophilia", "antiphospholipid syndrome", and "treatment". Results: Most studies have reported a strong association between specific antiphospholipid antibodies and antiphospho- lipid antibody syndrome with recurrent pregnancy loss. Women carrying the factor V Leiden mutation, prothrombin gene mutation, and protein S deficiency were shown to be at high risk of recurrent pregnancy loss in a large systematic review. Recent studies have shown prevalence rates of hereditary thrombophilias and antiphospholipid antibody syndrome, in women with re- current pregnancy loss, similar to those of the general po- pulation. Current studies endorse the use of heparin plus aspirin in women with antiphospholipid antibody syndrome, with an increase in live birth rate, but with no difference in obstetric complications. Conclusion: Although new studies demonstrate that the prevalence of hereditary and acquired thrombophilias in women with recurrent pregnancy loss is si- milar to that of the general population, routine investigation of antiphospholipid antibody syndrome in these patients is recommended. The use of low-dose aspirin plus heparin is the first-line pharmacological intervention for the prevention of recurrent pregnancy loss in patients with antiphospholipid antibody syndrome.

The role of methylation of placental glucocorticoid response gene in the association between pregnancy-related anxiety in the third trimester and birth outcomes / 中华预防医学杂志

Objective: To investigate the role of methylation of placental glucocorticoid response gene in the association between pregnancy-related anxiety in the third trimester and birth outcomes. Methods: Based on a prospective cohort study, singleton live births and their mothers from the Ma'anshan Birth Cohort Study (MABC) were included as participants in this study. The maternal pregnancy-related anxiety symptoms in the third trimester of pregnancy were evaluated by using the Pregnancy-related Anxiety Questionnaire. The neonatal birth outcomes were collected from medical records. The placental tissues from 300 pregnant women with pregnancy-related anxiety and 300 without pregnancy-related anxiety were collected to detect the methylation of FKBP5, NR3C1 and HSD11B2 genes using the Methyl Target approach. The methylation factors were extracted by exploratory factor analysis. Linear regression or logistic regression models were used to analyze the association between pregnancy-related anxiety in the third trimester, methylation factor scores, and birth outcomes. The mediating role of methylation factors in the association between pregnancy-related anxiety in the third trimester and birth outcomes was analyzed by using the Process procedure. Results: The mean age of 2 833 pregnant women was (26.60±3.60) years old. After adjusting for confounding factors, pregnancy-related anxiety in the third trimester increased the risk of small-for-gestational-age (OR=1.32, 95%CI:1.00-1.74). A total of 5 methylation factors were extracted, and the factor 5 was loaded with FKBP5 CpGs 18-21. Pregnancy-related anxiety in the third trimester was negatively correlated with the factor 5 (β=-0.24,95%CI:-0.44--0.05). The factor 5 was positively correlated with the gestational age (β=0.17, 95%CI:0.06-0.27). In addition, the factor 2 (β=0.02,95%CI:0.00-0.04) and factor 3 (β=0.03,95%CI:0.01-0.05) were positively correlated with 5-min Apgar score after delivery. However, this study did not found the mediating role of the scores of the factor characterized by FKBP5 in the relationship between pregnancy-related anxiety and birth outcomes. Conclusion: Pregnancy-related anxiety in the third trimester may reduce the methylation level of FKBP5 CpGs 18-21 in placental tissues and is associated with the risk of small-for-gestational-age.

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.

Analysis of Phenotype and Genotype of A Family with Hereditary Coagulation Factor Ⅴ Deficiency Caused by A Compound Heterozygous Mutation / 中国实验血液学杂志

OBJECTIVE@#To analyze the molecular pathogenesis by analysis of phenotype and gene mutation in families with hereditary coagulation factor V (FⅤ) defect caused by complex heterozygous mutation.@*METHODS@#Plasma pro-thrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), FⅤ procoagulant activity (FⅤ∶C), FⅤ antigen (FⅤ∶Ag), and other related coagulation indexes were detected in the proband and his family members (3 generations 10 people). Using DNA direct sequencing to analyze all exons, flanks, 5' and 3' untranslated regions of F5 genes and the corresponding mutation site regions of family members, the mutation site was confirmed by reverse sequencing．The conservation of mutant amino acids was analyzed by ClustalX-2.1-win software. The PROVEAN and MutationTaster online bioinformatics software were used to predict the effect of mutation on protein function. Protein model and amino acid interaction at mutation sites was analyzed by Swiss-pdbviewer software.@*RESULTS@#The PT and APTT of the proband were significantly prolonged compared with healthy controls (34.2 vs 13.2 s and 119.3 vs 36.0 s), while FⅤ∶C and FⅤ∶Ag extremely reduced (3% and 6%). The PT and APTT of the second-born, the third son, daughter, and grandson of the proband were slightly prolonged, and the FⅤ∶C and FⅤ∶Ag decreased to varying degrees. The related coagulant parameters of other family members were within normal range. Genetic analysis revealed that the proband had a c.911G>A heterozygous missense mutation on the exon 6 lead to p.Gly276Glu, and a c.5343C>G heterozygous missense mutation on the exon 16 lead to p.Ser1781Arg of the proband. The second-born, the third son, and grandson of the proband carry p.Gly276Glu heterozygotes, and the daughter carries p.Ser1781Arg heterozygotes, while the other family members were wild-type. The results of conservative analysis indicated that p.Gly276 and p.Ser1781 were highly conserved in homologous species. The two bioinformatics software predicted the same results, PROVEAN (score -6.214 and -12.79) indicated that the compound heterozygous mutation was a harmful mutation; MutationTaster (score 0.976 and 0.999) suggested that these mutations might cause corresponding disease. p.Gly276Glu protein model analysis showed that, the Glu side chain was prolonged and the molecular weight became larger, which would increase the steric hindrance between it and the surrounding amino acids, affect the normal local folding of the FⅤ protein, and eventually lead to the decrease of protein activity and content. This paper can not provide analysis of the spatial structure of p.Ser1781Arg mutant protein because of the lack of X ray 3 D structure file of FⅤ exon 16.@*CONCLUSION@#The new compound heterozygous mutations (p.Gly276Glu and p.Ser1781Arg) identified in this study are the main reasons for the decrease in the FⅤ level of the family, among which p.Ser1781Arg is rarely reported at home and abroad.

Clinical phenotype and variantal analysis of a pedigree affected with hereditary coagulation factor V deficiency / 中华医学遗传学杂志

OBJECTIVE@#To explore the molecular basis for a pedigree affected with coagulation factor V (FV) deficiency.@*METHODS@#Clinical data of the patient and his family members was analyzed. Targeted capture and next-generation sequencing (NGS) and Sanger sequencing were carried out to detect potential variant of the FV gene.@*RESULTS@#The patient presented with jaundice and prolonged prothrombin time (PT) and activated partial thromboplastic time (APTT). V factor activity measured only 0.1% of the normal level, though the patient had no sign of bleeding. A paternal heterozygous variant c.653T>C (p.F218S) and a maternal heterozygous variant c.3642_3643del (p.P1215Rfs*175) were identified in the FV gene of the patient. His elder brother was a heterozygous carrier of the c.653T>C (p.F218S) variant. c.653T>C(p.F218S) was a known pathogenic variant, while the c.3642_3643del (p.P1215Rfs*175) variant was unreported previously.@*CONCLUSION@#Mutations of the FV gene probably underlie the hereditary coagulation factor V deficiency in this patient. NGS combined with Sanger sequencing has detected potential variant with efficiency and provided a reliable basis for clinical and prenatal diagnosis for this family.

Identification of a novel variant of F5 gene in a consanguineous pedigree affected with inherited coagulation factor V deficiency / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a consanguineous pedigree affected with inherited coagulation factor V deficiency.@*METHODS@#Genomic DNA was extracted from peripheral blood samples from the pedigree and subjected to next generation sequencing for screening variants of the F5 gene. Suspected pathogenic variant was verified by using Sanger sequencing. Pathogenicity of the variant was evaluated according to ACMG guidelines.@*RESULTS@#A homozygous frameshifting variant, c.4096delC (p.Leu1366Phefs*3), was identified in the F5 gene in the proband, which was confirmed to be derived from her consanguineous parents. This variant was absent in all databases including 10 000 in-house Chinese exome sequences. Based on the ACMG guidelines, the c.4096delC was predicted to be a pathogenic variant.@*CONCLUSION@#A novel pathogenic variant has been identified in the F5 gene in a consanguineous pedigree with inherited coagulation factor V deficiency, which has enriched the spectrum of F5 gene variants.

First Korean case of factor V Leiden mutation in pregnant woman with a history of recurrent pregnancy loss

Thrombophilia refers to inherited or acquired hemostatic disorders that result in a predisposition to blood clot formation. When combined with the hypercoagulable state that is characteristic of pregnancy, there is an increased risk of severe and recurrent pregnancy complications. Activated protein C resistance caused by factor V Leiden (FVL) mutation is known to be the most common cause of inherited thrombophilia in Caucasian population. FVL mutation has been related to pregnancy complications associated with hypercoagulation, e.g. miscarriage, intrauterine fetal demise, placental abruption, and intrauterine growth retardation. Although the FVL mutation is easily detected using molecular DNA techniques, patients who are heterozygous for this disorder often remain asymptomatic until they develop a concurrent prothrombotic condition. Because there are potentially serious effects of FVL mutation for pregnancy, and because effective treatment strategies exist, early detection and treatment of this condition might be considered.

Phenotypic and genetic analysis of a pedigree affected with hereditary FV deficiency due to a novel deletional variant of F5 gene / 中华医学遗传学杂志

OBJECTIVE@#To analyze the phenotype and F5 gene variant in a pedigree affected with hereditary coagulation factor V (FV) deficiency.@*METHODS@#All of the exons, flanking sequences, and 5' and 3' untranslated regions of the F5 gene were subjected to PCR and direct sequencing. Suspected variant sites were confirmed by clone sequencing. Influence of the variants was predicted by using software including ClustalX and Mutation Taster.@*RESULTS@#The prothrombin time (PT) and activated partial thromboplastin time (APTT) of the proband were prolonged to 20.3 s and 59.2 s, respectively, while FV activity (FV:C) and FV antigen (FV:Ag) were reduced by 13% and 17%, respectively. The FV:C and FV:Ag of his father, sister and daughter were decreased to 35%, 37%, 29% and 42%, 46%, 35%, respectively. The proband was found to carry a heterozygous c.2851delT variant in exon 13 of the F5 gene, which caused a frameshift and resulted in a truncated protein (p.Ser923LeufsX8). In addition, a heterozygous c.1538G to A (p.Arg485Lys) variant was found in exon 10. The father, sister and daughter of the proband all carried the p.Ser923LeufsX8 variant, while his mother and son carried the heterozygous p.Arg485Lys polymorphism. His younger brother and wife were of the wild type. Bioinformatic analysis showed that p.Ser923 was highly conserved across various species. Mutation Taster scored 1.00 for the p.Ser923LeufsX8 variant, and the result has predicted a corresponding disease.@*CONCLUSION@#A heterozygous deletional mutation c.2851delT in exon 13 of the F5 gene and a heterozygous c.1538G to A polymorphism harbored by the proband may be associated with the decreased FV level in this pedigree.

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.

Phenotypic and mutational analysis of a pedigree affected with hereditary coagulation factor Ⅴ deficiency / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the molecular pathogenesis for a pedigree affected with coagulation factor Ⅴ (FⅤ) deficiency.</p><p><b>METHODS</b>Prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), coagulation factor Ⅱ activity (FⅡ: C), FⅤ activity (FⅤ: C), coagulation factor Ⅶ activity (FⅦ: C), and coagulation factor Ⅹ activity (FⅩ: C) were determined with a STAGO automatic coagulometer. FⅤ antigen (FⅤ: Ag) was detected with enzyme linked immunosorbent assay (ELISA). All exons and their flanking regions, and 5' and 3' untranslated regions of the F5 gene were analyzed by direct sequencing. Suspected mutation was verified by reverse sequencing as well as testing of family members. ClustalX software was used to analyze the conservative property of the mutation sites. PROVEAN and MutationTaster online software was used to predict the effect of the mutation on the protein function. Swiss-pdbViewer was used to analyze the protein model and interaction of amino acids.</p><p><b>RESULTS</b>The PT and APTT of the proband were slightly prolonged to 15.2 s and 41.8 s, respectively. And the FⅤ: C and FⅤ: Ag measured 55% and 62%, respectively. The FⅤ: C and FⅤ: Ag of his father and son were decreased to various extent (60%, 65% and 31%, 40%, respectively). A c.911G>A heterozygous mutation (Gly276Glu) was detected in exon 6 of the proband, for which her father and son were heterozygotes. The same mutation was not found in her mother, brother and husband. Conservation analysis showed that the Gly276 is highly conserved across various species. By bioinformatic analysis, the PROVEAN (scored -6.214) indicated Gly276Glu was harmful, and MutationTaster (scored 0.976) suggested that it is pathogenic. Model analysis suggested there are two hydrogen bonds between Gly276 and Ile298 in the wild type protein. When Gly276 was replaced by Glu276, the original hydrogen bond did not change, but the side chain of Glu was extended, which added steric hindrance with the surrounding amino acids, which resulted in decreased protein stability.</p><p><b>CONCLUSION</b>The heterozygous c.911G>A (Gly276Glu) mutation of the F5 gene probably underlies the decreased level of FⅤin the proband.</p>

Paciente con trombosis venosa profunda recidivante por factor V Leiden y respuesta al tratamiento homeopático / Patient with recurrent deep venous thrombosis by factor V Leiden and response to homeopathic treatment

El tromboembolismo venoso (TEV) es un problema de salud significativo, con morbimortalidad cercana al 30%. El factor V Leiden (FVL) es una forma "mutada" del factor V normal que se inactiva 10 veces más lentamente, produciendo estados de hipercoagulación y trombosis. En este artículo se presenta el caso de una mujer de 23 años de edad en quien, a raíz de un episodio de TVP se diagnosticó su condición de portadora de enfermedad por FVL de carácter homocigota. Transcurridos 8 años del primer episodio y estando aún bajo tratamiento convencional, el alto nivel de dímeroD (DD) señalaba alto riesgo de sufrir nuevos episodios de TVP. En ese momento se inició tratamiento con medicación homeopática unicista constitucional, en baja dinamización y dosis diarias, observándose una rápida caída en las cifras de DD cambiando así el pronóstico de futuras recidivas y llevando a los hematólogos a suspender el tratamiento convencional. No hubo recidivas hasta el presente y el Doppler venoso muestra rehabilitación del lecho venoso. (AU)

Venous thromboembolism (VTE) is a significant health problem with morbidity and mortality around 30%. Factor V Leiden (FVL) is a "mutated" form of the normal factor V which is inactivated 10 times slower causing hypercoagulation states and thrombosis. The present articles describes the case of a 23-year-old women in whom that status of homozygous was diagnosed on the occasion of a VTE episode. High dimer-D (DD) levels 8 years later and still under conventional treatment high pointed to high risk for recurrence of VTE. Homeopathic treatment was started (constitutional unicast) in low potency and daily doses. DD fell rapidly, and thus the prognosis changed, leading hematologists to withdraw conventional treatment. Disease did not relapse to this day and venous Doppler sonography evidenced rehabilitated vein system. (AU)

Paciente con trombosis venosa profunda recidivante por factor V Leiden y respuesta al tratamiento homeopático / Patient with recurrent deep venous thrombosis by factor V Leiden and response to homeopathic treatment

El tromboembolismo venoso (TEV) es un problema de salud significativo, con morbimortalidad cercana al 30%. El factor V Leiden (FVL) es una forma "mutada" del factor V normal que se inactiva 10 veces más lentamente, produciendo estados de hipercoagulación y trombosis. En este artículo se presenta el caso de una mujer de 23 años de edad en quien, a raíz de un episodio de TVP se diagnosticó su condición de portadora de enfermedad por FVL de carácter homocigota. Transcurridos 8 años del primer episodio y estando aún bajo tratamiento convencional, el alto nivel de dímeroD (DD) señalaba alto riesgo de sufrir nuevos episodios de TVP. En ese momento se inició tratamiento con medicación homeopática unicista constitucional, en baja dinamización y dosis diarias, observándose una rápida caída en las cifras de DD cambiando así el pronóstico de futuras recidivas y llevando a los hematólogos a suspender el tratamiento convencional. No hubo recidivas hasta el presente y el Doppler venoso muestra rehabilitación del lecho venoso. (AU)

Venous thromboembolism (VTE) is a significant health problem with morbidity and mortality around 30%. Factor V Leiden (FVL) is a "mutated" form of the normal factor V which is inactivated 10 times slower causing hypercoagulation states and thrombosis. The present articles describes the case of a 23-year-old women in whom that status of homozygous was diagnosed on the occasion of a VTE episode. High dimer-D (DD) levels 8 years later and still under conventional treatment high pointed to high risk for recurrence of VTE. Homeopathic treatment was started (constitutional unicast) in low potency and daily doses. DD fell rapidly, and thus the prognosis changed, leading hematologists to withdraw conventional treatment. Disease did not relapse to this day and venous Doppler sonography evidenced rehabilitated vein system. (AU)

Venous Thromboembolism in Children / 임상소아혈액종양

Although the incidence of venous thromboembolism (VTE) is significantly lower than in adults, recognition of VTE in children is increasing as advanced medical care enhances treatment intensity in pediatric patients. VTE in children usually develops as a secondary complication of underlying clinical conditions such as venous catheterization, malignancy, infections, trauma, surgery, and inherited or acquired thrombophilia, of which venous catheterization poses the highest risk. Neonates are at the greatest risk for VTE with a second peak in incidence during adolescence. There is some debate regarding which patients should have testing for inherited risk factors such as factor V Leiden, prothrombin G20210A, protein C-, protein S- and antithrombin deficiency. Guidelines for diagnosis and treatment of VTE in children are mostly extrapolated from adult data, despite the uniqueness of pediatric hemostatic system. The most common treatment is unfractionated heparin or low molecular weight heparin with vitamin K antagonist, whereas newly developed direct oral anticoagulants are under discussion and have been evaluated in only a small number of clinical trials in pediatric patients. Prospective multicenter collaborative research is necessary to develop validated guidelines for the diagnosis, antithrombotic therapy, prevention and follow-up monitoring of pediatric VTE.

A Case of Acquired Factor V Deficiency after Percutaneous Coronary Intervention / 대한내과학회지

Acquired factor V deficiency is extremely rare. Here we report the case of an 88-year-old female patient who presented with hematochezia 1 month after undergoing percutaneous coronary intervention. Her laboratory results showed an extremely prolonged prothrombin time and an activated partial thromboplastin time, but neither improved after fresh frozen plasma transfusion. She was finally diagnosed with acquired factor V deficiency and successfully treated with an immunosuppressant.

Venous Thromboembolism in Children / 임상소아혈액종양

Although the incidence of venous thromboembolism (VTE) is significantly lower than in adults, recognition of VTE in children is increasing as advanced medical care enhances treatment intensity in pediatric patients. VTE in children usually develops as a secondary complication of underlying clinical conditions such as venous catheterization, malignancy, infections, trauma, surgery, and inherited or acquired thrombophilia, of which venous catheterization poses the highest risk. Neonates are at the greatest risk for VTE with a second peak in incidence during adolescence. There is some debate regarding which patients should have testing for inherited risk factors such as factor V Leiden, prothrombin G20210A, protein C-, protein S- and antithrombin deficiency. Guidelines for diagnosis and treatment of VTE in children are mostly extrapolated from adult data, despite the uniqueness of pediatric hemostatic system. The most common treatment is unfractionated heparin or low molecular weight heparin with vitamin K antagonist, whereas newly developed direct oral anticoagulants are under discussion and have been evaluated in only a small number of clinical trials in pediatric patients. Prospective multicenter collaborative research is necessary to develop validated guidelines for the diagnosis, antithrombotic therapy, prevention and follow-up monitoring of pediatric VTE.

Thrombophilia in Korean patients with arterial or venous thromboembolisms

PURPOSE: To determine the prevalence of thrombophilia in Korean patients with an arterial thromboembolism (ATE) or a venous thromboembolism (VTE), and to evaluate the characteristic of VTE in patients with thrombophilia. METHODS: Hospital records of 294 patients (228 with VTE, 66 with ATE) including two foreign ones (mean age, 51.4 years) who underwent thrombophilia testing between August 2006 and March 2015 were reviewed retrospectively. In general, such screening was performed according to the guidelines of the international consensus statement for VTE. Thrombophilia testing included evaluations of the factor V Leiden and prothrombin G20210A mutations, levels of proteins C and S and antithrombin, and antiphospholipid antibody syndrome (APLS). RESULTS: A factor V Leiden mutation was not found in the 292 Korean patients. A prothrombin G21210A mutation was investigated in 33 patients but none was found. Among 226 Korean patients with VTE, 130 demonstrated no thrombophilia and 55 patients did after exclusion of 41 patients without confirmatory test. The most common form was protein S deficiency (31 of 55, 56%) followed by protein C deficiency, antithrombin deficiency, and APLS. When comparing patients with a VTE or deep vein thrombosis (DVT) according to the presence of thrombophilia, thrombophilia was associated with younger age (P = 0.001 for VTE; P < 0.001 for DVT) and a family history (P < 0.001 for VTE and DVT). CONCLUSION: We did not find any factor V Leiden mutation in Korean subjects at high risk for thrombophilia. Therefore, this testing is not warranted. Thrombophilia was associated with VTE in younger age and a family history.

Combined factor V and VIII deficiency in a young woman with abundant bleeding after tooth extraction

No abstract available.

Potential Risk Factors Associated With Vascular Diseases in Patients Receiving Treatment for Hypertension

BACKGROUND: Currently, the hypertension (HTN) patients undergo appropriate medical treatment, and traditional risk factors are highly controlled. Therefore, potential risk factors of atherosclerotic vascular diseases (AVD) and venous thromboembolisms (VTE) in HTN should be reconsidered. We investigated thrombophilic genetic mutations and existing biomarkers for AVD or VTE in HTN patients receiving treatment. METHODS: A total of 183 patients were enrolled: AVD with HTN (group A, n=45), VTE with HTN (group B, n=62), and HTN patients without any vascular diseases (group C, n=76). The lipid profile, homocysteine (Hcy) levels, D-dimers, fibrinogen, antithrombin, lupus anticoagulant, and anti-cardiolipin antibody (aCL) were evaluated. Prothrombin G20210A, Factor V G1691A, and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C were analyzed. RESULTS: All patients revealed wild type prothrombin G20210A and Factor V G1691A polymorphisms. The frequency of MTHFR polymorphisms was 677CT (n=84, 45.9%); 677TT (n=46, 25.1%); 1298AC (n=46, 25.1%); and 1298CC (n=2, 1.1%). The MTHFR 677TT genotype tended to increase the odds ratio (OR) to AVD events in HTN patients (OR 2.648, confidence interval 0.982-7.143, P=0.05). The group A demonstrated significantly higher Hcy levels (P=0.009), fibrinogen (P=0.004), and platelet counts (P=0.04) than group C. Group B had significantly higher levels of D-dimers (P=0.0001), platelet count (P=0.0002), and aCL (P=0.02) frequency than group C. CONCLUSIONS: The MTHFR 677TT genotype and Hcy level could be potential risk factors associated with development of AVD in HTN patients receiving treatment. D-dimer and aCL might be useful to estimate the occurrence of VTE in them.

Genetic Confirmation of Congenital Factor V Deficiency in Korean Patients

No abstract available.