RESUMO
Hereditary thrombophilias can impair vascular placental functions and predispose to the birth of small-for-gestational age (SGA) babies. The placental anticoagulant protein annexin A5 (ANXA5) may contribute to this process. A functional haplotype (M2) within the ANXA5 gene is associated with fetal loss and venous thrombosis. This study investigated the prevalence of the M2 haplotype in a group of women with idiopathic SGA newborn babies. Seventy-eight women with at least one previous unexplained SGA birth and 195 controls all from Southern Italy were investigated. Hereditary thrombophilia was found in 13 (16.5%) cases and 21 (11%) controls (P < 0.05.). The M2 haplotype was found in 29% of cases (n = 23) and 15% of controls [n = 30; P = 0.001; OR = 2.3, 95% CI (1.17-4.48)]. Within the case group, 82.5% of the M2 haplotype carriers gave birth to babies with a birthweight below the 3rd percentile [P = 0.01; OR = 2.4, 95% CI (1.26-4.73)]. A logistic regression, corrected for age, parity and gravity showed that the M2 haplotype was independently associated with the delivery of an SGA new born [P = 0.029; OR = 2.6, 95% CI (1.1-6.0)]. In conclusion, the M2 haplotype of the ANXA5 gene confers a risk of delivering SGA babies.
Assuntos
Anexina A2/genética , Haplótipos , Recém-Nascido Pequeno para a Idade Gestacional , Trombofilia/genética , Trombose Venosa/genética , Adolescente , Adulto , Peso ao Nascer/genética , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Gravidez , Complicações na Gravidez/genética , Fatores de Risco , Adulto JovemRESUMO
This study shows clinical efficacy and safety profile of an off-label use of caplacizumab for the treatment of immune-mediated thrombotic thrombocytopenic purpura in a middle-aged obese male patient manifesting aphasia, weakness and unconsciousness. Routine blood tests revealed haemolytic anaemia, severe thrombocytopenia (platelet count=20×109/L) and moderate creatinine increase. Diagnosis was based on the clinical judgement and laboratory determinations (undetectable ADAMTS13 activity and presence of anti-ADAMTS13 antibodies). The patient underwent plasma-exchange and an adjunctive treatment with prednisone (1mg/Kg/day), but the occurrence of a refractory and exacerbated form of disease suggested also using rituximab (375mg/m2 weekly for 4 weeks) and caplacizumab as salvage treatments. The caplacizumab was given at 10mg/day subcutaneously without the first intravenous bolus. Because von Willebrand factor inhibition, platelet count recovery and remission of symptoms were achieved, use of caplacizumab with this scheme appeared to be as effective as the approved one. Although this is an off-label use, this case highlights the potential of this new treatment, in terms of drug's efficacy and safety.
Assuntos
Uso Off-Label , Púrpura Trombocitopênica Trombótica , Anticorpos de Domínio Único , Proteína ADAMTS13 , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/tratamento farmacológico , Troca Plasmática , Púrpura Trombocitopênica Trombótica/tratamento farmacológico , Anticorpos de Domínio Único/uso terapêuticoRESUMO
SUMMARY: Factor XI (FXI) deficiency is a rare bleeding disorder, resulting in a wide range of bleeding manifestations, from asymptomatic bleeding to injury-related bleeding. To identify mutations in FXI-deficient patients and to establish a possible relationship between clinical phenotype and genotype, we studied two patients from Southern Italy with FXI deficiency. They were identified by presurgical or routine laboratory screening. None of them showed bleeding. Three different mutations were detected (Glu117Stop, Cys118Arg and Trp497Gly); two of them were novel (Cys118Arg and Trp497Gly). One patient (with severe FXI levels) showed a compound heterozygosity (Glu117Stop with Cys118Arg). Two novel missense mutations were highly conserved among different species. In our patients, bleeding tendency did not appear to be correlated with FXI levels or with a single mutation in heterozygosis. On the other hand, the compound heterozygosis might explain low FXI levels, but it is not associated with bleeding. Our data confirm that a severe FXI deficiency is not necessarily associated with bleeding.
Assuntos
Deficiência do Fator XI/genética , Mutação de Sentido Incorreto , Idoso , Análise Mutacional de DNA , Fator XI/análise , Feminino , Predisposição Genética para Doença , Humanos , Itália , Pessoa de Meia-Idade , Fenótipo , População Branca/genéticaRESUMO
Pregnancy is a condition of excessive clotting due to a decrease of some coagulation factors and a reduction of anticoagulant proteins, such as protein S. It is known that the causes of congenital or acquired thrombophilia may be associated with an increased risk of venous thromboembolism during pregnancy and/or obstetric complications, such early or late fetal loss, intrauterine fetal deaths, pre-eclampsia, fetal growth restriction. During pregnancy the use of a prophylaxis with antithrombotic drugs is considered at present a promising opportunity to significantly reduce the prevalence of thromboembolic complications, improving maternal and fetal outcomes. This article is a review to most recent evidence of pregnant anticoagulant prophylaxis in women with previous thromboembolic events.
Assuntos
Anticoagulantes/uso terapêutico , Complicações Hematológicas na Gravidez/prevenção & controle , Trombofilia/prevenção & controle , Feminino , Humanos , Gravidez , Complicações Hematológicas na Gravidez/fisiopatologia , Fatores de Risco , Trombofilia/fisiopatologiaRESUMO
BACKGROUND: Myeloproliferative disorders (MPDs) represent a risk factor for thrombosis in the portal, mesenteric, and hepatic districts. OBJECTIVE: We aimed to assess whether the Janus kinase 2 (JAK2) V617F mutation, an acquired mutation that occurs in MPD patients, is a risk factor for portal and mesenteric venous thrombosis (PMVT) independently of the presence of overt MPDs. PATIENTS AND METHODS: The medical histories of 99 patients presenting with PMVT were obtained. The presence of the JAK2 V617F and VHL 598C > T mutations was determined by polymerase chain reaction followed by restriction enzyme analysis and direct cycle sequence analysis. RESULTS: Over a 10-year period of observation, of the 99 patients presenting with PMVT, the JAK2 V617F mutation was detected in heterozygous state in 17 individuals [17.2%; 95% confidence interval (95% CI) 10.9-25.9]. None of the patients presenting with the JAK2 V617F mutation carried an inherited thrombophilic risk factor. Seven patients with (43.8%; 95% CI 19.8-70.1) and two without (2.4%; 95% CI 0.3-8.4) the JAK2 V617F mutation had a diagnosis of MPD at the occurrence of the venous thrombotic event. After a median follow-up of 41 months (range 3-114 months), three out of the 10 patients carrying the JAK2 V617F mutation were then diagnosed as having idiopathic myelofibrosis (n = 2) or polycythemia vera (n = 1), whereas in seven patients a MPD was not detected. Two of the 83 patients without the JAK2 V617F mutation went on to develop MPDs. CONCLUSIONS: Determination of the JAK2 V617F mutation may contribute to the search for genetic determinants of PMVT and may be useful to recognize patients who should be carefully observed for the subsequent development of overt MPDs.
Assuntos
Frequência do Gene , Janus Quinase 2/genética , Oclusão Vascular Mesentérica/genética , Mutação , Veia Porta , Trombose Venosa/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Itália , Masculino , Oclusão Vascular Mesentérica/etiologia , Oclusão Vascular Mesentérica/patologia , Veias Mesentéricas , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Razão de Chances , Fenilalanina , Veia Porta/patologia , Fatores de Risco , Fatores de Tempo , Valina , Trombose Venosa/etiologia , Trombose Venosa/patologia , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
BACKGROUND: Annexin A5 is a natural anticoagulant assumed to have thrombomodulary functions as it shields phospholipid layers from coagulation complexes. It was recently shown that the M2 haplotype within the annexin A5 gene (ANXA5) promoter reduces the transcriptional activity of the gene. In a previous report, the M2 haplotype was found to be associated with pregnancy-related venous thrombosis (VT). OBJECTIVES: To investigate whether the M1 or M2 haplotypes or other genetic variations in ANXA5 are associated with pregnancy-related VT. PATIENTS/METHODS: We investigated samples from 313 cases and 353 controls included in the VIP study, which is a case-control study of pregnancy-related VT. We analyzed tag single nucleotide polymorphisms (SNPs) selected from the CEU population (Utah Residents with Northern and Western European Ancestry) of HapMap and the M1 and the M2 haplotypes of the promoter. Odds ratios for VT were calculated for each haplotype with the wild type as the reference and for each tag SNP with the most common genotype as reference. RESULTS: We did not find any association between genetic variants in ANXA5 and the risk of pregnancy related VT, but some of the genetic variants were not in Hardy-Weinberg equilibrium. CONCLUSION: Neither the M1/M2 haplotypes nor the tag SNPs in ANXA5 were convincingly associated with pregnancy related VT, but other studies in this field are needed.
Assuntos
Anexina A5/genética , Polimorfismo de Nucleotídeo Único , Complicações Cardiovasculares na Gravidez/genética , Trombose Venosa/genética , Estudos de Casos e Controles , Bases de Dados Genéticas , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Heterozigoto , Homozigoto , Humanos , Modelos Logísticos , Noruega , Razão de Chances , Fenótipo , Gravidez , Complicações Cardiovasculares na Gravidez/diagnóstico , Complicações Cardiovasculares na Gravidez/etnologia , Regiões Promotoras Genéticas , Fatores de Risco , Utah , Trombose Venosa/diagnóstico , Trombose Venosa/etnologia , População Branca/genéticaRESUMO
INTRODUCTION: The role of thrombophilia screening and antithrombotic therapy in unselected women undergone Assisted Reproductive Technologies (ART) is largely unknown. Nonetheless, in many Countries infertile women undergo thrombophilia screening and/or antithrombotic therapy. MATERIALS AND METHODS: We carried out a follow-up study. The original sample (n=1107) consisted of infertile women observed in 13 years. A cohort of 157 women with at least 1 cycle before thrombophilia test and 1 after test was investigated. All underwent thrombophilia screening; an antithrombotic treatment was prescribed in 216 out of 801 cycles. Clinical pregnancy and live birth rates were the main clinical objectives. RESULTS: Overall, 15 (9.6%) women carried thrombophilia. The Cox regression showed that LMWH alone or combined with ASA was significantly associated with the outcome "live birth" "live births" (p: 0.015, HR: 2.8, 95%CI: 1.2-6.6 for combined therapy), independently of the carriership of thrombophilia. Women with a lower number of attempts had a higher likelihood of delivering a live-born child using the combined therapy (p<0.001, HR: 0.7, 95%CI: 0.7-0.8), independently of the presence of thrombophilia. CONCLUSIONS: A potential benefit of LMWH in improving number of live births, independently of the presence of thrombophilia, is suggested. Universal thrombophilia screening before ART is not useful to discriminate women with a worse pregnancy prognosis.
Assuntos
Anticoagulantes/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Técnicas de Reprodução Assistida , Trombofilia/diagnóstico , Trombofilia/tratamento farmacológico , Adulto , Feminino , Seguimentos , Humanos , Infertilidade Feminina/diagnóstico , Nascido Vivo , Pessoa de Meia-Idade , Gravidez , Resultado da Gravidez , Trombofilia/complicações , Adulto JovemRESUMO
INTRODUCTION: The utility of an antithrombotic prophylaxis in Assisted Reproductive Technologies (ART) is highly debated. It has been hypothesised that specific effects of heparin on the coagulation system during implantation can improve the number of clinical pregnancies and live births. MATERIALS AND METHODS: We studied a cohort of 327 women undergone at least 1 ART cycle before thrombophilia testing. Overall, a number of 751cycles was analysed. Low-Molecular-Weight Heparin (LMWH) and/or low-dose aspirin (ASA) were prescribed in 132 (17.6%) cycles. Furthermore, all the women underwent thrombophilia screening. RESULTS: The univariate analysis showed that LMWH with/without ASA was significantly associated with both the outcomes clinical pregnancy and live birth, while the use of ASA was not associated with live birth. The logistic regression showed that the use of LMWH was significantly associated with both the outcomes, clinical pregnancy (OR: 6.0, 95%CI: 2.8-15.6) and live birth (OR: 10.7, 95%CI: 3.2-36.1). The type of ART procedure significantly influenced the likelihood of achieving clinical pregnancy. CONCLUSIONS: Present findings suggest that LMWH alone or combined with ASA could have a role in fostering the implantation of embryos and improving the number of live births after ART.
Assuntos
Anticoagulantes/uso terapêutico , Aspirina/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Técnicas de Reprodução Assistida , Adulto , Implantação do Embrião , Feminino , Humanos , Nascido Vivo , Pessoa de Meia-Idade , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Trombofilia/diagnóstico , Adulto JovemRESUMO
The role of protein Z (PZ) in the etiology of human disorders is unclear. A number of PZ gene variants, sporadic or polymorphic and found exclusively in the serine protease domain, have been observed. Crystal structures of PZ in complex with the PZ-dependent inhibitor (PZI) have been recently obtained. The aim of this study was a structural investigation of the serine protease PZ domain, aiming at finding common traits across disease-linked mutations. We performed 10-20 ns molecular dynamics for each of the observed PZ mutants to investigate their structure in aqueous solution. Simulation data were processed by novel tools to analyse the residue-by-residue backbone flexibility. Results showed that sporadic mutations are associated with anomalous flexibility of residues belonging to specific regions. Among them, the most important is a loop region which is in contact with the longest helix of PZI. Other regions have been identified, which hold anomalous flexibility associated with potentially protective gene variants. In conclusion, a possible interpretation of effects associated with observed gene variants is provided. The exploration of PZ/PZI interactions seems essential in explaining these effects.
Assuntos
Aborto Espontâneo/sangue , Proteínas Sanguíneas/química , Proteínas Sanguíneas/genética , Adolescente , Adulto , Idoso , Sequência de Aminoácidos , Anticoagulantes/metabolismo , Coagulação Sanguínea , Estudos de Casos e Controles , Feminino , Variação Genética , Humanos , Pessoa de Meia-Idade , Modelos Moleculares , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Mutação , Polimorfismo Genético , Estrutura Terciária de Proteína , Adulto JovemRESUMO
BACKGROUND: Factor (F)V Leiden and the prothrombin 20210A mutation (PTm) are associated with the occurrence of obstetric complications, including pregnancy-related venous thromboembolism (VTE). It is not known whether family members of women with FV Leiden or PTm and previous obstetric complications have a higher risk of VTE or adverse obstetric outcomes. METHODS: A retrospective family study including 563 relatives of 177 women with previous adverse outcomes carrying FV Leiden or PTm, referred between April 1993 and June 2010. A history of obstetric complications and VTE was obtained. Prevalence of VTE and obstetric complications in relatives with and without inherited thrombophilias was compared. Adjusted odd ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression models that controlled for predictors (age, FV Leiden and PTm). RESULTS: Relatives carrying FV Leiden had a significant and independent risk for obstetric complications (OR: 1.98, 95% CI 1.03-3.83); this risk was not observed in the presence of PTm (OR: 1.03, 95% CI 0.46-2.32). The presence of FV Leiden or PTm in heterozygosis was significantly and independently associated with the occurrence of VTE (OR: 5.2, 95% CI: 1.70-15.91). Severe thrombophilias were strong risk factors for VTE (OR: 23.2, 95% CI: 6.0-89.85). Male gender was a significant and independent risk factor for VTE (OR: 3.49, 95% CI: 1.51-8.05). The risk did not change when relatives of women with a previous pregnancy-related VTE were excluded (OR: 3.49, 95% CI: 1.51-8.05). CONCLUSIONS: Knowledge of thrombophilia status may help to better define the obstetric and thromboembolic risks in asymptomatic family members of women who suffered from obstetric complications.
Assuntos
Fator V/genética , Mutação , Complicações na Gravidez/genética , Protrombina/genética , Tromboembolia/genética , Trombofilia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Feminino , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Homozigoto , Humanos , Itália/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/epidemiologia , Prevalência , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Tromboembolia/diagnóstico , Tromboembolia/epidemiologia , Trombofilia/diagnóstico , Trombofilia/epidemiologia , Adulto JovemAssuntos
Aborto Espontâneo/etiologia , Aborto Espontâneo/genética , Fator V/genética , Complicações Hematológicas na Gravidez/genética , Protrombina/genética , Trombofilia/genética , Estudos de Casos e Controles , Feminino , Humanos , Polimorfismo Genético , Gravidez , Fatores de Risco , Trombofilia/complicaçõesRESUMO
BACKGROUND: Although an association between thrombophilias and adverse pregnancy outcome has been shown, the influence of the most common inherited thrombophilias and the somatic mutation JAK2 V617F in determining an adverse outcome is questioned. OBJECTIVES: We examined the contribution of the factor V Leiden (FVL), the prothrombin G20210A (PTm) and the somatic JAK2 V617F mutations to adverse pregnancy outcome in an unselected cohort of pregnant women. PATIENTS/METHODS: During the study period, 5345 pregnant women were admitted to the 14 hospitals of the five provinces of the Campania region (Italy). Of these, 3097 samples were investigated and obstetric history collected. The presence of the FVL, PTm, and JAK2 V617F mutation was prospectively determined by polymerase chain reaction followed by TaqMan SNP genotyping assays. RESULTS AND CONCLUSIONS: We identified 119 (3.8%) women that carried FVL and 138 (4.4%) with the PTm. Only 4 (0.1%) women carried both mutations. Only one woman tested positive for the JAK2 V617F somatic mutation. The prevalence of a previous history of an adverse pregnancy outcome was similar in women with common thrombophilias as compared to those without. In the current pregnancy, there was no association of any of the genetic markers considered with any of the adverse outcomes investigated. Carriership of FVL or PTm showed a positive trend with delivery of a small for gestational age newborn (OR: 1.5, 95% CI: 0.9-2.5). Pregnancy outcomes in asymptomatic women with inherited thrombophilias are often uneventful. Therefore, in women at low-risk of an adverse pregnancy, neither screening for common thrombophilias nor administration of routine thromboprophylaxis are warranted.