RESUMO
Essentials Inherited factor XIII deficiency is a very rare bleeding disorder. We used recombinant factor XIII-A in a pregnant patient with factor XIII-A subunit deficiency. The patient had a successful pregnancy outcome with no pregnancy related complications. The dose of recombinant factor XIII-A was minimized by using frequent trough level monitoring. SUMMARY: Inherited factor XIII deficiency is a very rare bleeding disorder, and is one of the causes of recurrent pregnancy loss. The use of plasma-derived FXIII to improve pregnancy outcomes has been reported. We report a 26-year-old woman with FXIII A-subunit (FXIII-A) deficiency who was treated with recombinant FXIII-A and had a successful pregnancy outcome with no pregnancy-related complications. Our case illustrates that the dose of recombinant FXIII-A can be minimized and adjusted on the basis of frequent trough level monitoring.
Assuntos
Aborto Espontâneo/prevenção & controle , Coagulantes/administração & dosagem , Deficiência do Fator XIII/tratamento farmacológico , Fator XIII/administração & dosagem , Hemostasia/efeitos dos fármacos , Aborto Espontâneo/etiologia , Adulto , Monitoramento de Medicamentos , Deficiência do Fator XIII/sangue , Deficiência do Fator XIII/complicações , Deficiência do Fator XIII/diagnóstico , Feminino , Humanos , Nascido Vivo , Gravidez , Proteínas Recombinantes/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: Despite the lack of evidence that assessing the global cardiovascular risk leads to a decreased incidence of cardiovascular events, accurate patient profiling is paramount in preventive medicine. An excess of visceral fat (VF) is associated with an enhanced cardiovascular risk; importantly, VF is quantifiable rapidly, cheaply and safely by ultrasound, which makes it suitable for use in clinical practice. In the present study, we aimed to evaluate if US-measured VF (USVF) could be a better predictor of glucose homeostasis and cardiovascular risk than simple anthropometric measures. METHODS AND RESULTS: One-hundred sixty-two patients attending a Metabolic Disorders Clinic underwent a cross-sectional study for which USVF, anthropometric measures, a standard oral glucose tolerance test (OGTT), and calculation of cardiovascular Framingham score and vascular age were obtained. USVF was directly correlated with fasting and 2-h plasma glucose (respectively: r = 0.26, p < 0.001; r = 0.28, p < 0.0001), fasting and 2-h plasma insulin (for both: r = 0.41, p < 0.0001), homeostatic model assessment of insulin resistance (HOMA-IR; r = 0.42, p < 0.0001), cardiovascular Framingham score (r = 0.44 p < 0.0001) and vascular age (r = 0.30 p < 0.001). In receiver operator characteristic curves USVF had good diagnostic abilities for type 2 diabetes mellitus, fatty liver and metabolic syndrome, in both genders. At multivariate analysis, body mass index (BMI) outperformed USVF in the prediction of HOMA-IR; neverthless, USVF, not BMI, was an independent predictor of cardiovascular risk. Finally, models including USVF were the most parssimonious to predict Framingham score, vascular age and HOMA-IR. CONCLUSION: In overweight and obese subjects, USVF could usefully complement other parameters for cardiovascular risk stratification.
Assuntos
Glicemia/metabolismo , Doenças Cardiovasculares/etiologia , Transtornos do Metabolismo de Glucose/sangue , Gordura Intra-Abdominal/diagnóstico por imagem , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico por imagem , Obesidade/diagnóstico por imagem , Ultrassonografia , Adiposidade , Idoso , Antropometria , Biomarcadores/sangue , Índice de Massa Corporal , Doenças Cardiovasculares/diagnóstico , Estudos Transversais , Feminino , Transtornos do Metabolismo de Glucose/complicações , Transtornos do Metabolismo de Glucose/diagnóstico , Teste de Tolerância a Glucose , Homeostase , Humanos , Gordura Intra-Abdominal/fisiopatologia , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de RiscoAssuntos
Coagulação Sanguínea/genética , Deficiência do Fator XI/sangue , Deficiência do Fator XI/genética , Fator XI/genética , Alelos , Substituição de Aminoácidos , Análise Mutacional de DNA , Éxons , Fator XI/química , Fator XI/metabolismo , Deficiência do Fator XI/diagnóstico , Estudos de Associação Genética , Genótipo , Humanos , Íntrons , Mutação , FenótipoAssuntos
Testes de Coagulação Sanguínea , Deficiência do Fator XIII , Fator XIII , Hemorragia , HumanosRESUMO
INTRODUCTION: Mutations in fibrinogen (Fgn) genes, causing dysfibrinogenaemia, can result in either a bleeding or thrombophilic diathesis. Dysfibrinogenaemia is infrequently encountered in hospital laboratories, and the utility of different assays in the diagnosis of dysfibrinogenaemia has not previously been explored in a multicentre study. We describe here an exercise in which PRO-RBDD project (prospective data collection on patients with fibrinogen and Factor XIII deficiencies) centres, and UK NEQAS centres, performed investigations for dysfibrinogenaemia. METHODS: Samples from donors with dysfibrinogenaemia (sample 1: gamma p.Arg301Cys, sample 2: Bbeta166Arg3Cys-Fgn Longmont, sample 3: Aalpha p.Arg35His) and a normal donor were sent to laboratories for investigation for possible dysfibrinogenaemia. Median, coefficient of variation and range were determined for each assay method. RESULTS: Results were returned from 62 UK NEQAS and 24 PRO-RBDD centres. PT, APTT, Clauss fibrinogen and thrombin times were performed by >90% of centres, with 51% performing reptilase times, and 31% fibrinogen antigen. All centres identified samples 1 and 3 as abnormal. However, 39% of centres reported a normal or raised fibrinogen for the Fgn Longmont sample, and marked differences in Clauss fibrinogen results with different reagents were noted for this sample (median 1.01 g/L vs 5.10 g/L for the two mostly widely used reagents). CONCLUSION: In-house studies suggest that the method of detection of fibrin clot formation may result in different Clauss fibrinogen measurements with FgnLongmont plasma. It is possible that some widely used methodologies, both using optical and mechanical end-point detection systems, will fail to detect this rare fibrinogen variant.
Assuntos
Afibrinogenemia/diagnóstico , Afibrinogenemia/genética , Erros de Diagnóstico , Fibrinogênio , Testes de Coagulação Sanguínea/métodos , Feminino , Fibrinogênio/genética , Fibrinogênio/metabolismo , Humanos , Masculino , Mutação , Reino UnidoRESUMO
Essentials A strong association between bleeding severity and FXIII activity level (FXIII:C) was shown. The range 5-30 IU dL-1 of FXIII:C was associated with a high variability of bleeding severity. The PROspective study confirmed the association between FXIII:C activity and bleeding severity. A FXIII: C of 15 IU dL-1 is a proposed target to start prophylaxis for prevention of major bleeding. SUMMARY: Background Congenital factor XIII (FXIII) deficiency is a rare bleeding disorder associated with significant bleeding manifestations. The European Network of Rare Bleeding Disorders (EN-RBD) study, performed from 2007 to 2010, showed a strong association between bleeding severity and FXIII activity in plasma of patients with FXIII deficiency. Among these patients, variable levels of FXIII activity, from undetectable to 30%, were associated with a wide range of bleeding severity. Objectives and patients The present cross-sectional study, in the frame of the PRO-RBDD project, a prospective cohort study, analyzed data of 64 patients with FXIII deficiency and different types of clinical and laboratory severity. Results The results of this analysis confirmed that FXIII coagulant activity in plasma is well associated with clinical severity of patients. In addition, 15 IU dL-1 of FXIII activity was identified to be the level under which the probability of spontaneous major bleeding sharply increases (from 50% for levels of 15 IU dL-1 to more than 90% for levels of 5 IU dL-1 or lower). Conclusion The PRO-RBDD study suggests a FXIII coagulant activity level of 15 IU dL-1 as a target to start prophylaxis in order to prevent major bleedings, such as central nervous system or gastrointestinal tract hemorrhages.
Assuntos
Anticoagulantes/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Deficiência do Fator XIII/tratamento farmacológico , Fator XIII/análise , Fator XIII/uso terapêutico , Hemorragia/prevenção & controle , Adolescente , Adulto , Idade de Início , Área Sob a Curva , Biomarcadores/sangue , Testes de Coagulação Sanguínea , Tomada de Decisão Clínica , Estudos Transversais , Bases de Dados Factuais , Europa (Continente) , Deficiência do Fator XIII/sangue , Deficiência do Fator XIII/complicações , Deficiência do Fator XIII/diagnóstico , Feminino , Hemorragia/sangue , Hemorragia/etiologia , Humanos , Masculino , Paquistão , Fenótipo , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de Doença , Estados Unidos , Adulto JovemRESUMO
INTRODUCTION: FXIII deficiency is a rare bleeding disorders, and specific FXIII assays are recommended to detect this deficiency. We investigated the performance and accuracy of FXIII investigations in two exercises, comparing centres enrolled in the PRO-RBDD project (prospective data collection on patients with fibrinogen and Factor XIII deficiencies), and UK NEQAS BC centres. METHODS: Samples from a FXIII deficient subject and a normal donor were sent to participating centres, to investigate for FXIII deficiency, and interpret their results. Median, coefficient of variation and range were determined. RESULTS: Results were returned from 98 UK NEQAS BC and 28 PRO-RBDD centres. Up to 40% of UK NEQAS BC and 52% of PRO-RBDD centres reported clot solubility results - with diagnostic errors by two NEQAS BC centres (false negatives for the FXIII deficient sample) and one PRO-RBDD centre (false positive for the normal sample). Over 70% of UK NEQAS BC centres and PRO-RBDD centres performed FXIII assays. Median results were similar between the two groups, with the exception of sample 3 in survey 2 (5.5 vs. 14.0 µ/dl for UK NEQAS BC and PRO-RBDD centres respectively, P < 0.001). Diagnostic errors were made by 2 UK NEQAS BC centres. CONCLUSION: Approximately 70% of centres now employ FXIII assays, complying with international recommendations. However, solubility tests continue to be used. Our data show this can be successful, depending on the sensitivity of the method in use. Diagnostic errors are made by centres using both solubility screens and FXIII assays, and laboratories should ensure good quality assurance procedures to improve diagnostic accuracy.
Assuntos
Deficiência do Fator XIII/diagnóstico , Coagulação Sanguínea , Testes de Coagulação Sanguínea/métodos , Testes de Coagulação Sanguínea/normas , Serviços de Laboratório Clínico/normas , Fator XIII , Deficiência do Fator XIII/sangue , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Laboratórios , Masculino , Garantia da Qualidade dos Cuidados de Saúde , Reprodutibilidade dos Testes , Reino UnidoRESUMO
UNLABELLED: Essentials Plasma of factor XI-deficient patients (FXI-dp) displays enhanced fibrinolysis. We investigated the role of thrombin activatable fibrinolysis inhibitor (TAFI) in 18 FXI-dp. FXI-dp generated less activated TAFI (TAFIa) on clotting challenge and were resistant to TAFIa. TAFI activation and TAFIa resistance correlated with bleeding score and bleeding phenotype. SUMMARY: Background Factor XI (FXI) deficiency, a rare disorder with unpredictable bleeding, has been associated with reduced fibrinolytic resistance as a result of abnormal fibrin density. Objective We investigated the involvement of thrombin-activatable fibrinolysis inhibitor (TAFI) in the increased lysability of FXI-deficient (FXI-def) clots and the role of thrombin. Patients/Methods Eighteen patients with FXI deficiency (1-58%) and 17 matched controls were investigated for fibrinolytic resistance to t-PA, thrombin generation, TAFI activation and response to TAFIa. Results When clotting was induced by 0.5 pm tissue factor (TF), FXI-def plasmas displayed less thrombin and TAFIa generation and shorter lysis time than controls. A 100-fold higher TF concentration (to bypass FXI) abolished the difference in thrombin generation but not in lysis time between patients and controls. Normalization of FXI levels by a FXI concentrate increased thrombin generation but had no effect on the lysis time of FXI-def plasma. Moreover, when clots were induced by purified thrombin and high concentrations of FXa inhibitor, FXI-def plasma still generated less TAFIa and displayed a shorter lysis time than controls. Finally, upon TAFIa addition, the lysis time of FXI-def plasma was prolonged significantly less than that of control plasma, suggesting a TAFIa resistance. TAFIa generation and TAFIa resistance were correlated with the bleeding score, displaying a considerable capacity to discriminate between patients with and without bleeding. Conclusions TAFI pathway impairment, largely caused by a hitherto unknown TAFIa resistance, appears to be one main cause of decreased fibrinolytic resistance in FXI deficiency and might be clinically useful for assessing the bleeding risk of FXI-def patients.
Assuntos
Deficiência do Fator XI/sangue , Fibrinólise/genética , Trombina/química , Adolescente , Adulto , Idoso , Coagulação Sanguínea , Estudos de Casos e Controles , Criança , Pré-Escolar , Fator XI , Feminino , Fibrina/química , Seguimentos , Hemorragia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Terapia Trombolítica/métodos , Trombomodulina/metabolismo , Trombose , Ativador de Plasminogênio Tecidual/química , Adulto JovemRESUMO
Rare bleeding disorders (RBDs) are a heterogeneous group of diseases with varying bleeding tendency, only partially explained by their laboratory phenotype. We analysed the separate groups of RBD abnormalities, and we investigated retrospectively whether the novel haemostasis assay (NHA) was able to differentiate between bleeding tendency. We have performed simultaneous thrombin generation (TG) and plasmin generation (PG) measurements in 41 patients affected with deficiencies in prothrombin, factor (F) V, FVII, FX, FXIII and fibrinogen. Parameters of the NHA were classified based on (major or minor) bleeding tendency. Patients with deficiencies in coagulation propagation (FII, FV and FX) and major type of bleedings had diminished TG (expressed as AUC) below 20% of control. FVII deficient patients only had prolonged thrombin lag-time ratio of 1.6 ± 0.2 (P < 0.05) and normal AUC (92-125%). Afibrinogenemic patients demonstrated PG of 2-29% of normal and appeared to correlate with the type of mutation. Thrombin peak-height (57 ± 16%) was reduced (not significant) in these patients and AUC was comparable to the reference (102 ± 27%). FXIII-deficient plasmas resulted in a reduced thrombin peak-height of 59 ± 13% (P < 0.05) and normal AUC (90 ± 14%). Thrombin peak-height (P < 0.01) and plasmin potential (P < 0.05) were lower in the major bleeders compared with the minor bleeders. These results provided distinct TG and PG curves for each individual abnormality and differentiation of bleeding tendency was observed for thrombin and PG parameters. Prospective studies are warranted to confirm these retrospective results.
Assuntos
Transtornos da Coagulação Sanguínea/metabolismo , Fibrinolisina/metabolismo , Hemorragia/etiologia , Trombina/metabolismo , Adolescente , Adulto , Idoso , Transtornos da Coagulação Sanguínea/complicações , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: The European Network of Rare Bleeding Disorders (EN-RBD) was established to bridge the gap between knowledge and practise in the care of patients with RBDs. OBJECTIVES: To explore the relationship between coagulation factor activity level and bleeding severity in patients with RBDs. PATIENTS/METHODS: Cross-sectional study using data from 489 patients registered in the EN-RBD. Coagulation factor activity levels were retrieved. Clinical bleeding episodes were classified into four categories according to severity. RESULTS: The mean age of patients at data collection was 31 years (range, 7 months to 95 years), with an equal sex distribution. On linear regression analysis, there was a strong association between coagulation factor activity level and clinical bleeding severity for fibrinogen, factor (F) X, FXIII, and combined FV and FVIII deficiencies. A weaker association was present for FV and FVII deficiencies. There was no association between coagulation factor activity level and clinical bleeding severity for FXI. The coagulation factor activity levels that were necessary for patients to remain asymptomatic were: fibrinogen, > 100 mg dL(-1); FV, 12 U dL(-1); combined FV + VIII, 43 U dL(-1); FVII, 25 U dL(-1); FX, 56 U dL(-1) ; FXI, 26 U dL(-1); FXIII, 31 U dL(-1). Moreover, coagulation factor activity levels that corresponded with Grade III bleeding were: undetectable levels for fibrinogen, FV and FXIII, < 15 U dL(-1) for combined FV + VIII; < 8 U dL(-1) for FVI; < 10 U dL(-1) for FX; and < 25 U dL(-1) for FXI. CONCLUSIONS: There is a heterogeneous association between coagulation factor activity level and clinical bleeding severity in different RBDs. A strong association is only observed in fibrinogen, FX and FXIII deficiencies.
Assuntos
Transtornos da Coagulação Sanguínea/diagnóstico , Fatores de Coagulação Sanguínea/análise , Coagulação Sanguínea , Hemorragia/diagnóstico , Doenças Raras/diagnóstico , Adolescente , Adulto , Afibrinogenemia/sangue , Afibrinogenemia/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Transtornos da Coagulação Sanguínea/sangue , Testes de Coagulação Sanguínea , Criança , Pré-Escolar , Estudos Transversais , Europa (Continente) , Deficiência do Fator X/sangue , Deficiência do Fator X/diagnóstico , Deficiência do Fator XIII/sangue , Deficiência do Fator XIII/diagnóstico , Feminino , Hemorragia/sangue , Humanos , Lactente , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Doenças Raras/sangue , Sistema de Registros , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Turquia , Adulto JovemRESUMO
We aimed to evaluate the effect of regular prophylaxis with a Factor X (FX) concentrate for patients with severe FXD in Iran and to assess the correlation of the genotype and phenotype in these patients. Ten patients with severe FXD (FX activity <1%) were enrolled and characterized during 2010-2011. Prophylaxis with 20 IU FX P Behring per kg body weight was administered once a week. FX levels, were monitored at baseline, 15 and 30 min, 1, 3, 6, 12, 24, 48, 72 and 96 h after starting prophylaxis. All patients were followed for 1 year. The mean age of the patients was 15 ± 7.8 years (age range of: 6-27 years). One patient had anaphylactic reaction after the first infusion, and the treatment was stopped. During one-year follow-up after starting prophylaxis, no bleeding symptoms occurred in any patient who tolerated and remained on the prophylaxis programme and all of them had a FX level of 1% or above. The maximum level of FX activity has been observed at 15 min after starting prophylaxis. A level of 1.5-3.5% was detected after 96 h. Homozygous mutations p.Arg40Thr (Arg-1Thr), p.Gly51Arg and p.Glu69Lys were detected in patients with intracranial haemorrhage. In our patients, significant decrease in symptoms without any complication after administration of FX, was demonstrated in all except one patient who had an anaphylactic reaction. It seems that the dose of 20 IU kg(-1) could be probably the best choice for patients with severe FXD, who require regular prophylaxis.
Assuntos
Deficiência do Fator X/tratamento farmacológico , Deficiência do Fator X/genética , Fator X/administração & dosagem , Fator X/genética , Adolescente , Adulto , Criança , Fator X/efeitos adversos , Fator X/análise , Feminino , Estudos de Associação Genética , Humanos , Irã (Geográfico) , Masculino , Adulto JovemRESUMO
Patients affected by bleeding disorders present a wide spectrum of clinical symptoms that vary from a mild or moderate bleeding tendency to significant episodes. Women with inherited bleeding disorders are particularly disadvantaged since, in addition to suffering from general bleeding symptoms, they are also at risk of bleeding complications from regular haemostatic challenges during menstruation, pregnancy and childbirth. Moreover, such disorders pose important problems for affected women due to their reduced quality of life caused by limitations in activities and work, and alteration of their reproductive life. These latter problems include excessive menstrual bleeding or menorrhagia, miscarriage, bleeding complications during pregnancy and after delivery and their related complications such as acute or chronic anaemia. The management of these women is difficult because of considerable inter-individual variation. Moreover, reliable information on clinical management is scarce, only a few available long term prospective studies of large cohorts provide evidence-based guideline about diagnosis and treatment.
Assuntos
Transtornos da Coagulação Sanguínea/complicações , Complicações Hematológicas na Gravidez , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/fisiopatologia , Parto Obstétrico , Diagnóstico Diferencial , Feminino , Aconselhamento Genético , Humanos , Gravidez , Complicações Hematológicas na Gravidez/diagnóstico , Complicações Hematológicas na Gravidez/fisiopatologia , Diagnóstico Pré-Natal , Hemorragia Uterina/complicações , Hemorragia Uterina/fisiopatologiaRESUMO
BACKGROUND AND PURPOSE: The A>G polymorphism at position 19911 of the prothrombin gene is associated with a mildly increased risk of venous thromboembolism, alone or in association with such common thrombophilia mutations as factor V Leiden and prothrombin 20210 GA. Its role in cerebral sinus-venous thrombosis (CSVT) is not known. METHODS: The presence of prothrombin 19911 A>G was investigated in a casecontrol study of 107 patients with cerebral thrombosis and factor V Leiden (n = 25), prothrombin 20210 GA (n = 47), without known thrombophilia (n = 35) and 842 healthy individuals with the corresponding coagulation profile. RESULTS: Prothrombin 19911 A>G did not increase the risk of CSVT in carriers of factor V Leiden (adjusted odds ratio 1.6, 95%CI 0.64.7), prothrombin 20210 GA (odds ratio 1.1, 95%CI 0.62.2), nor in patients without known thrombophilia (odds ratio 1.3, 95%CI 0.53.1). CONCLUSIONS: Prothrombin 19911 A>G polymorphism does not appear to be a risk factor for CSVT, alone or in association with factor V Leiden or prothrombin 20210GA.
Assuntos
Polimorfismo Genético , Protrombina/genética , Trombose dos Seios Intracranianos/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Fator V/genética , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Trombofilia/genéticaRESUMO
Inherited deficiencies of plasma proteins involved in blood coagulation generally lead to lifelong bleeding disorders, whose severity is inversely proportional to the degree of factor deficiency. Haemophilia A and B, inherited as X-linked recessive traits, are the most common hereditary hemorrhagic disorders caused by a deficiency or dysfunction of blood coagulation factor VIII (FVIII) and factor IX (FIX). Together with von Willebrand's disease, a defect of primary haemostasis, these X-linked disorders include 95% to 97% of all the inherited deficiencies of coagulation factors. The remaining defects, generally transmitted as autosomal recessive traits, are rare with prevalence of the presumably homozygous forms in the general population of 1:500,000 for FVII deficiency and 1 in 2 million for prothrombin (FII) and factor XIII (FXIII) deficiency. Molecular characterization, carrier detection and prenatal diagnosis remain the key steps for the prevention of the birth of children affected by coagulation disorders in developing countries, where patients with these deficiencies rarely live beyond childhood and where management is still largely inadequate. These characterizations are possible by direct or indirect genetic analysis of genes involved in these diseases, and the choice of the strategy depends on the effective available budget and facilities to achieve a large benefit. In countries with more advanced molecular facilities and higher budget resources, the most appropriate choice in general is a direct strategy for mutation detection. However, in countries with limited facilities and low budget resources, carrier detection and prenatal diagnosis are usually performed by linkage analysis with genetic markers. This article reviews the genetic diagnosis of haemophilia, genetics and inhibitor development, genetics of von Willebrand's disease and of rare bleeding disorders.
Assuntos
Transtornos Herdados da Coagulação Sanguínea/diagnóstico , Transtornos Herdados da Coagulação Sanguínea/genética , Inibidores dos Fatores de Coagulação Sanguínea/biossíntese , Fator VIII/antagonistas & inibidores , Técnicas Genéticas , Hemofilia A/diagnóstico , Hemofilia A/genética , Hemofilia B/diagnóstico , Hemofilia B/genética , Humanos , Isoanticorpos/biossíntese , Doenças de von Willebrand/diagnóstico , Doenças de von Willebrand/genéticaRESUMO
Deficiencies of coagulation factors other than factor VIII and factor IX (afibrinogenemia, FII, FV, FV+FVIII, FVII, FX, FXI, FXIII) that cause bleeding disorders (RBDs) are inherited as autosomal recessive traits and are rare, with prevalences in the general population varying between 1 in 500,000 and 1 in 2 million for the homozygous forms. As a consequence of the rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects, and the actual management of bleeding episodes are not as well established as for hemophilia A and B. The study of the genetic basis of these disorders could represent an important tool for prevention through prenatal diagnosis. Treatment of patients with RBDs during bleeding episodes or surgery is a challenge because of the lack of experience and the paucity of data. For some deficiency factor concentrates are still non available and severe complications can occur. These complications can be minimized by assessment of risks of bleeding and thrombosis, use of haemostatic means other than blood components or no therapy at all. The RBDs pose a problem for guideline writers because there are no suitable clinical trials to supply good evidence for how these people are best treated. The lack of adequate information on clinical manifestations, treatment and genetic basis of RBDs could be improved by the collection of data in an International Database (http://www.rbdd.org), linkable to others previously published. This could be a useful tool to fill the gap between clinical data and clinical practice. This article reviews the genetic basis of RBDs, problems and complications of treatment, problems in the preparation of suitable guidelines for treatment and the future perspectives of the International Registry on RBDs.
Assuntos
Transtornos Herdados da Coagulação Sanguínea/terapia , Transtornos Herdados da Coagulação Sanguínea/genética , Humanos , Guias de Prática Clínica como Assunto , Sistema de RegistrosRESUMO
The human immunodeficiency virus type 1 (HIV-1) Tat protein stimulates cell proliferation, inhibits apoptosis, displays angiogenic functions and is believed to be involved in the pathogenesis of Kaposi's sarcoma (KS) and other tumours arising in AIDS patients. Tat-transgenic (TT) mice, which constitutively express Tat in all tissues and organs, may therefore be predisposed to tumorigenesis. To test this hypothesis, we treated TT mice with urethane, a general carcinogen inducing tumours of various organs. The results indicate that, after injection of urethane, the incidence of lung tumours and lymphomas is not significantly different in the TT and control (CC) mice, whereas liver preneoplastic lesions and tumours show a significantly greater incidence in TT than in CC mice. This remarkable carcinogenic effect of urethane for the liver may be due to a tat-induced predisposition, manifested as a liver cell dysplasia (LCD), spontaneously affecting most of the TT mice. LCD may exert a promoting effect by stimulating proliferation of cell clones initiated by the mutagenic effect of urethane. In addition, LCD, which is associated with aneuploidy and chromosome instability, may enhance the progression to malignancy of the preneoplastic lesions induced by urethane. Interestingly, a significantly greater incidence of vascular ectasias and haemangiomas was detected in the liver of urethane-treated TT mice, most likely due to the marked angiogenic properties of Tat. This study suggests a role for Tat in the promotion and progression of tumours initiated by exogenous and endogenous carcinogens in HIV-1-infected patients, thereby contributing to the tumorigenesis in the course of AIDS.
Assuntos
Carcinógenos/toxicidade , Infecções por HIV , HIV-1 , Neoplasias Hepáticas/induzido quimicamente , Uretana/toxicidade , Animais , Divisão Celular , DNA Complementar/análise , Feminino , Produtos do Gene tat , Humanos , Imuno-Histoquímica , Fígado/química , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/induzido quimicamente , Linfoma/induzido quimicamente , Masculino , Camundongos , Camundongos Transgênicos , Hibridização de Ácido Nucleico , Reação em Cadeia da Polimerase/métodos , Produtos do Gene tat do Vírus da Imunodeficiência HumanaRESUMO
BACKGROUND: The 'test and treat' strategy for Helicobacter pylori is recommended in dyspeptic patients under 55 years of age with no alarm symptoms. Reliable non-invasive tests are therefore needed. The aim of this study was to assess the pre- and post-treatment accuracy of a low dose (1 microCi [37kBq]), short collecting time [14C]-UBT (urea breath test) in diagnosing H pylori infection, examining different methods to analyse the best cut-off points. METHODS: The study included 119 patients. Endoscopy and [14C]-UBT were performed in the pre- and post-treatment setting. [14C]-UBT results were expressed in three different ways: 1) the measured disintegrations per minute (dpm) at sample time, 2) the difference (D) in dpm between sample time and the dpm at T0, 3) the ratio of dpm at sample time to dpm at T0. RESULTS: Seventy-six out of the 119 patients (63.9%; 95% CI: 54.9 to 71.9) were infected. Seventy-three (96%) patients completed the follow-up. The most accurate results in both pre- (sensitivity 95.9%; specificity 97.7%) and post-treatment (sensitivity 90.9%; specificity 100%) were obtained using the difference (D) in dpm between sample time at T0 and at T12.5. CONCLUSION: A low dose [14C]-UBT, with a short collecting time, is a reliable method to evaluate H. pylori infection in both the pre- and post-treatment setting.
Assuntos
Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/microbiologia , Helicobacter pylori , Ureia/análise , Adulto , Idoso , Área Sob a Curva , Testes Respiratórios , Radioisótopos de Carbono , Dispepsia/diagnóstico , Dispepsia/microbiologia , Endoscopia Gastrointestinal , Reações Falso-Positivas , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Úlcera Péptica/diagnóstico , Úlcera Péptica/microbiologia , Estudos Prospectivos , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
BACKGROUND AND AIM: There are few data on the course of Helicobacter pylori infection in asymptomatic subjects. The aim of this study was to assess the effect of eradication therapy on the development of dyspeptic and gastro-oesophageal reflux disease in a cohort of asymptomatic individuals observed over a prolonged period. METHODS: A total of 169 blood donors infected with H pylori who had volunteered for studies on eradication in 1990 formed the cohort. To be included in this cohort subjects had to have no symptoms, as determined by a validated symptom questionnaire at the baseline visit. Eighty eight subjects were infected with H pylori while 81 had successfully undergone eradication therapy. Subjects were followed up (annually) using the same symptom questionnaire and in 2000 they underwent repeat endoscopy. RESULTS: Thirteen subjects developed symptoms during follow up. The incidence of symptoms in H pylori positive subjects was 1.893/100 person-years of follow up and in H pylori negative individuals 0.163/100 person-years of follow up. H pylori infected subjects were significantly more likely to develop symptoms (log rank test, p=0.003) as well as those infected with CagA positive strains (log rank test, p=0.017). The development of symptomatic gastro-oesophageal reflux disease was no different in individuals with and without eradication (odds ratio 0.57 (95% confidence interval 0.26-1.24); p=0.163). CONCLUSIONS: H pylori eradication prevents the development of dyspeptic symptoms and peptic ulcer disease in healthy asymptomatic blood donors and is not associated with an increase in the incidence of symptomatic gastro-oesophageal reflux disease.
Assuntos
Dispepsia/microbiologia , Refluxo Gastroesofágico/microbiologia , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Anticorpos Antibacterianos/análise , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Úlcera Duodenal/microbiologia , Duodenite/microbiologia , Endoscopia Gastrointestinal , Esofagite/microbiologia , Feminino , Gastrite/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Úlcera Péptica/microbiologia , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Eradication rates of Helicobacter pylori with standard triple therapy are disappointing, and studies from several countries confirm this poor performance. AIM: To assess the eradication rate of a new sequential treatment regimen compared with conventional triple therapy for the eradication of H. pylori infection. METHODS: One thousand and forty-nine dyspeptic patients were studied prospectively. H. pylori-infected patients were randomized to receive 10-day sequential therapy [rabeprazole (40 mg daily) plus amoxicillin (1 g twice daily) for the first 5 days, followed by rabeprazole (20 mg), clarithromycin (500 mg) and tinidazole (500 mg) twice daily for the remaining 5 days] or standard 7-day therapy [corrected] [rabeprazole (20 mg), clarithromycin (500 mg) and amoxicillin (1 g) twice daily]. H. pylori status was assessed by histology, rapid urease test and 13C-urea breath test at baseline and 6 weeks or more after completion of treatment. RESULTS: Higher eradication rates were found with the sequential regimen compared to the standard regimen (intention-to-treat: 92% vs. 74%, P < 0.0001; per protocol: 95% vs. 77%, P < 0.0001). Higher eradication rates were also seen in patients with peptic ulcer disease and non-ulcer dyspepsia. In both treatments, compliance was similar (> 90%), as was the rate of side-effects, which were mild. CONCLUSIONS: This 10-day sequential treatment regimen achieves high eradication rates in peptic ulcer disease and non-ulcer dyspepsia.
Assuntos
Amoxicilina/uso terapêutico , Benzimidazóis/uso terapêutico , Claritromicina/uso terapêutico , Quimioterapia Combinada/uso terapêutico , Dispepsia/microbiologia , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Tinidazol/uso terapêutico , 2-Piridinilmetilsulfinilbenzimidazóis , Feminino , Infecções por Helicobacter/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Omeprazol/análogos & derivados , Cooperação do Paciente , Rabeprazol , Resultado do TratamentoRESUMO
AIM: To evaluate the association between infection with specific strains of Helicobacter pylori and peptic ulcer in patients referred for upper gastrointestinal endoscopy. METHODS: One thousand, six hundred and twenty-six consecutive dyspeptic patients, referred to one Endoscopy Unit in Bologna, Italy, were enrolled. For each participant, a blood sample was obtained for the measurement of distinct immunoglobulin G antibodies against H. pylori lysate and cytotoxin associated gene A (cagA). A case-control study included the whole series: patients diagnosed with duodenal (n=275) or gastric (n=71) ulcer were identified and independently compared with controls with non-ulcer dyspepsia (n=1280). RESULTS: H. pylori seroprevalence (at least one positive marker) was associated with increasing age, male sex and a diagnosis of peptic ulcer. This association was stronger with duodenal ulcer (multivariate odds ratio (OR), 5.2; 95% confidence interval (CI), 3.5-7.9) than with gastric ulcer (OR, 2.3; 95% CI, 1.2-4.4). Further analyses showed that H. pylori lysate+/cagA- subjects had a moderately increased risk of duodenal (OR, 3.2), but not gastric (OR, 1.1), ulcer. When cagA+ subjects were separately compared with seronegative patients, there was a six-fold increased risk for duodenal ulcer and a three-fold increased risk for gastric ulcer. CONCLUSIONS: A strong positive association between infection with a cagA+ H. pylori strain and the presence of peptic disease was found. The seroprevalence of anti-cagA antibodies among patients with non-ulcer dyspepsia is so high (41%) to preclude its use as a pre-endoscopic screening test.