Assuntos
Síndrome Coronariana Aguda/cirurgia , Cardiologia/normas , Intervenção Coronária Percutânea/métodos , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/tratamento farmacológico , Anticoagulantes/farmacologia , Aspirina/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Clopidogrel/farmacologia , Variação Genética , Humanos , Cooperação Internacional , Monitorização Fisiológica , Inibidores da Agregação Plaquetária/farmacologia , Sociedades Médicas , Ticlopidina/farmacologiaRESUMO
INTRODUCTION: Intracranial haemorrhage in children with inherited bleeding disorders is a potentially life-threatening complication and presents a significant therapeutic challenge. AIM: To define the characteristics, management and outcomes of intracranial haemorrhage presenting in UK children ≤16 years of age with inherited bleeding disorders from 2003 to 2015. METHOD: Retrospective analysis of children treated at UK haemophilia centres. RESULTS: Of 66 children presenting with Intracranial haemorrhage (ICH), 82% had haemophilia A or B, 3% VWD and 15% a rare IBD. The IBD was a severe phenotype in 91%. The rates of ICH were 6.4 and 4.2 per 1000 patient years for haemophilia A and B, respectively. Median age at presentation was 4 months (33% neonates; 91% children <2 years of age). In neonates, delivery was spontaneous vaginal (SV) in 11, instrumental in 6, caesarean in 4 and unknown in 1. In children with haemophilia, the risk of ICH after instrumental delivery was 10.6 times greater than after SV delivery. Trauma was more common in children >2 years (67%) than in children 1 month to 2 years (18%; P = .027). Prior to ICH, only 4.5% of children were on prophylaxis. 6% of haemophiliacs had an inhibitor. The median duration of initial replacement therapy was 15 days. Mortality was 13.5%. Neurological sequelae occurred in 39% of survivors, being more common following intracerebral bleeding. In haemophilia survivors, 52% subsequently developed a FVIII inhibitor. CONCLUSION: Intracranial haemorrhage occurs most frequently in children with severe IBDs, during the first 2 years of life and in children not receiving prophylaxis. Intracranial haemorrhage often occurs without documented trauma.
Assuntos
Hemofilia A/complicações , Hemofilia B/complicações , Hemorragias Intracranianas/complicações , Estudos de Coortes , Parto Obstétrico , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Recidiva , Fatores de Risco , Reino UnidoAssuntos
Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Idoso , Testes de Coagulação Sanguínea , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Wastewaters from oil and gas development pose largely unknown risks to environmental resources. In January 2015, 11.4ML (million liters) of wastewater (300g/L TDS) from oil production in the Williston Basin was reported to have leaked from a pipeline, spilling into Blacktail Creek, North Dakota. Geochemical and biological samples were collected in February and June 2015 to identify geochemical signatures of spilled wastewaters as well as biological responses along a 44-km river reach. February water samples had elevated chloride (1030mg/L) and bromide (7.8mg/L) downstream from the spill, compared to upstream levels (11mg/L and <0.4mg/L, respectively). Lithium (0.25mg/L), boron (1.75mg/L) and strontium (7.1mg/L) were present downstream at 5-10 times upstream concentrations. Light hydrocarbon measurements indicated a persistent thermogenic source of methane in the stream. Semi-volatile hydrocarbons indicative of oil were not detected in filtered samples but low levels, including tetramethylbenzenes and di-methylnaphthalenes, were detected in unfiltered water samples downstream from the spill. Labile sediment-bound barium and strontium concentrations (June 2015) were higher downstream from the Spill Site. Radium activities in sediment downstream from the Spill Site were up to 15 times the upstream activities and, combined with Sr isotope ratios, suggest contributions from the pipeline fluid and support the conclusion that elevated concentrations in Blacktail Creek water are from the leaking pipeline. Results from June 2015 demonstrate the persistence of wastewater effects in Blacktail Creek several months after remediation efforts started. Aquatic health effects were observed in June 2015; fish bioassays showed only 2.5% survival at 7.1km downstream from the spill compared to 89% at the upstream reference site. Additional potential biological impacts were indicated by estrogenic inhibition in downstream waters. Our findings demonstrate that environmental signatures from wastewater spills are persistent and create the potential for long-term environmental health effects.
Assuntos
Monitoramento Ambiental , Águas Residuárias/análise , Poluentes Químicos da Água/análise , North Dakota , Campos de Petróleo e Gás , Rios/químicaRESUMO
Genetic diagnosis in families with inherited platelet disorders (IPD) is not performed widely because of the genetic heterogeneity of this group of disorders and because in most cases, it is not possible to select single candidate genes for analysis using clinical and laboratory phenotypes. Next-generation sequencing (NGS) technology has revolutionized the scale and cost-effectiveness of genetic testing, and has emerged as a valuable tool for IPD. This review examines the potential utility of NGS as a diagnostic tool to streamline detection of causal variants in known IPD genes and as a vehicle for new gene discovery.
Assuntos
Transtornos Plaquetários/diagnóstico , Genômica , Transtornos Plaquetários/congênito , Transtornos Plaquetários/genética , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fenótipo , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Análise de Sequência de DNA , Trombocitopenia/congênito , Trombocitopenia/diagnósticoRESUMO
BACKGROUND: Inherited platelet function disorders (PFDs) are heterogeneous, and identification of the underlying genetic defects is difficult when based solely on phenotypic and clinical features of the patient. OBJECTIVE: To analyze 329 genes regulating platelet function, number, and size in order to identify candidate gene defects in patients with PFDs. PATIENTS/METHODS: Targeted analysis of candidate PFD genes was undertaken after next-generation sequencing of exomic DNA from 18 unrelated index cases with PFDs who were recruited into the UK Genotyping and Phenotyping of Platelets (GAPP) study and diagnosed with platelet abnormalities affecting either Gi signaling (n = 12) or secretion (n = 6). The potential pathogenicity of candidate gene defects was assessed using computational predictive algorithms. RESULTS: Analysis of the 329 candidate PFD genes identified 63 candidate defects, affecting 40 genes, among index cases with Gi signaling abnormalities, while 53 defects, within 49 genes, were identified among patients with secretion abnormalities. Homozygous gene defects were more commonly associated with secretion abnormalities. Functional annotation analysis identified distinct gene clusters in the two patient subgroups. Thirteen genes with significant annotation enrichment for 'intracellular signaling' harbored 16 of the candidate gene defects identified in nine index cases with Gi signaling abnormalities. Four gene clusters, representing 14 genes, with significantly associated gene ontology annotations were identified among the cases with secretion abnormalities, the most significant association being with 'establishment of protein localization.' CONCLUSION: Our findings demonstrate the genetic complexity of PFDs and highlight plausible candidate genes for targeted analysis in patients with platelet secretion and Gi signaling abnormalities.
Assuntos
Transtornos Plaquetários/genética , Análise Mutacional de DNA , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Transtornos Plaquetários/sangue , Transtornos Plaquetários/diagnóstico , Plaquetas/metabolismo , Criança , Análise por Conglomerados , Biologia Computacional , Exoma , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/sangue , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Transdução de Sinais/genética , Reino Unido , Adulto JovemRESUMO
Release of arsenic (As) from sedimentary rocks has resulted in contamination of groundwater in aquifers of the New Jersey Piedmont Physiographic Province, USA; the contamination also may affect the quality of the region's streamwater to which groundwater discharges. Biogeochemical mechanisms involved in the release process were investigated in the streambeds of Six Mile Run and Pike Run, tributaries to the Millstone River in the Piedmont. At Six Mile Run, streambed pore water and shallow groundwater were low or depleted in oxygen, and contained As at concentrations greater than 20 µg/L. At Pike Run, oxidizing conditions were present in the streambed, and the As concentration in pore water was 2.1 µg/L. The 16S rRNA gene and the As(V) respiratory reductase gene, arrA, were amplified from DNA extracted from streambed pore water at both sites and analyzed, revealing that distinct bacterial communities that corresponded to the redox conditions were present at each site. Anaerobic enrichment cultures were inoculated with pore water from gaining reaches of the streams with acetate and As(V). As(V) was reduced by microbes to As(III) in enrichments with Six Mile Run pore water and groundwater, whereas no reduction occurred in enrichments with Pike Run pore water. Cloning and sequencing of the arrA gene indicated 8 unique operational taxonomic units (OTUs) at Six Mile Run and 11 unique OTUs at Pike Run, which may be representative of the arsenite oxidase gene arxA. Low-oxygen conditions at Six Mile Run have favored microbial As reduction and release, whereas release was inhibited by oxidizing conditions at Pike Run.
Assuntos
Arsênio/análise , Monitoramento Ambiental , Rios/química , Poluentes Químicos da Água/análise , Sedimentos Geológicos , Água Subterrânea/química , Água Subterrânea/microbiologia , New Jersey , Rios/microbiologiaRESUMO
Platelet-expressed GPCRs are critical regulators of platelet function. Pharmacological blockade of these receptors forms a powerful therapeutic tool in the treatment and prevention of arterial thrombosis associated with coronary atherosclerosis and ischaemic stroke. However, anti-thrombotic drug therapy is associated with high inter-patient variability in therapeutic response and adverse bleeding side effects. In order to optimize the use of existing anti-platelet drugs and to develop new therapies, more detailed knowledge is required relating to the molecular mechanisms that regulate GPCR and therefore platelet function. One approach has been to identify rare, function-disrupting mutations within key platelet proteins in patients with bleeding disorders. In this review, we describe how an integrated functional genomics strategy has contributed important structure-function information about platelet GPCRs with specific emphasis upon purinergic and thromboxane A2 receptors. We also discuss the potential implications these findings have for pharmacotherapy and for understanding the molecular basis of mild bleeding disorders.
Assuntos
Receptores Acoplados a Proteínas G/genética , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Variação Genética , Humanos , Inibidores da Agregação Plaquetária/farmacologia , Receptores Acoplados a Proteínas G/metabolismoRESUMO
BACKGROUND: Diagnosis of inherited platelet function disorders (IPFDs) is important for appropriate management and to improve epidemiologic and clinical knowledge. However, there remains a lack of consensus on the diagnostic approach. OBJECTIVES: To gain knowledge on the current practices for the diagnosis of IPFD worldwide. METHODS: A 67-item questionnaire was distributed to the ISTH members and to the members of several national hemostasis and thrombosis societies. RESULTS: A total of 202 laboratories from 37 countries participated in the survey. The most frequent criterion to define patients with a suspected IPFD was a history of mucocutaneous bleeding and no acquired cause, but heterogeneity on the identification criteria was evident. Only 64.5% of respondents performed a direct clinical interview. On average, each laboratory studied 72 patients per year. The most commonly used laboratory equipment were the light-transmission aggregometer, the Platelet Function Analyzer-100, and the flow cytometer. Screening tests were platelet count, peripheral blood smear, light-transmission aggregometry, and Platelet Function Analyzer-100. Second-step tests were flow cytometry, molecular genetic analysis, and electron microscopy. Methodologies varied widely. In total, ~ 14,000 patients were investigated yearly and 60% turned out to not have a defect. Of the remaining 40%, only 8.7% received a diagnosis at a molecular level. CONCLUSIONS: Many laboratories worldwide are involved in the diagnosis of IPFD. A large fraction of the patients studied remain without a diagnosis. A high variability in the diagnostic approaches is evident.
Assuntos
Transtornos Plaquetários/diagnóstico , Agregação Plaquetária , Testes de Função Plaquetária/instrumentação , Plaquetas/citologia , Cardiologia/normas , Técnicas de Laboratório Clínico , Citometria de Fluxo , Humanos , Cooperação Internacional , Microscopia Eletrônica , Ativação Plaquetária , Contagem de Plaquetas , Sociedades Médicas , Inquéritos e QuestionáriosRESUMO
Heritable platelet function disorders (HPFD) are a heterogeneous group of bleeding disorders with diverse clinical and laboratory characteristics. In contrast to the severe phenotype disorders, Glanzmann thrombasthenia and Bernard-Soulier syndrome, most nonsevere HPFD are incompletely characterized. This is a consequence of the poor standardization of diagnostic tests and of the lack of consensus about diagnostic criteria for the different subgroups of nonsevere HPFD. Distinguishing patients who have a nonsevere HPFD from those who do not is an essential first step in diagnosis which may be aided by bleeding assessment tools and screening tests such as the Platelet Function Analyser-100. However, high diagnostic accuracy can only be achieved with both light transmission aggregation (LTA) and secretion tests, for which streamlined agonist panels may be of similar utility to extended panels. Standardization of the methodology of these tests and quality assurance are essential for robust diagnosis. Identification of which platelet pathway is defective in patients with nonsevere HPFD is also usually possible with LTA and secretion tests. This strategy also sometimes enables exact diagnosis by implicating a single candidate protein and gene. Next-generation sequencing may offer a rapid approach to diagnosis of nonsevere HPFD, although rigorous strategies must be adopted to distinguish causative gene defects from bystander variations.
Assuntos
Transtornos Plaquetários/diagnóstico , Transtornos Plaquetários/genética , Testes de Função Plaquetária , Transtornos Plaquetários/fisiopatologia , Plaquetas/metabolismo , Humanos , Testes de Função Plaquetária/métodos , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Genetic variations that affect the structure of the thromboxane A2 receptor (TP receptor) provide insights into the function of this key platelet and vascular receptor, but are very rare in unselected populations. OBJECTIVES: To determine the functional consequences of the TP receptor Trp29Cys (W29C) substitution. PATIENTS/METHODS: We performed a detailed phenotypic analysis of an index case (P1) with reduced platelet aggregation and secretion responses to TP receptor pathway activators, and a heterozygous TP receptor W29C substitution. An analysis of the variant W29C TP receptor expressed in heterologous cells was performed. RESULTS: Total TP receptor expression in platelets from P1 was similar to that of controls, but there was reduced maximum binding and reduced affinity of binding to the TP receptor antagonist [(3) H]SQ29548. HEK293 cells transfected with W29C TP receptor cDNA showed similar total TP receptor expression to wild-type (WT) controls. However, the TP receptor agonist U46619 was less potent at inducing rises in cytosolic free Ca(2+) in HEK293 cells expressing the W29C TP receptor than in WT controls, indicating reduced receptor function. Immunofluorescence microscopy and cell surface ELISA showed intracellular retention and reduced cell surface expression of the W29C TP receptor in HEK293 cells. Consistent with the platelet phenotype, both maximum binding and the affinity of binding of [(3) H]SQ29548 to the W29C TP receptor were reduced compared to WT controls. CONCLUSION: These findings extend the phenotypic description of the very rare disorder TP receptor deficiency, and show that the W29C substitution reduces TP receptor function by reducing surface receptor expression and by disrupting ligand binding.
Assuntos
Transtornos da Coagulação Sanguínea/sangue , Plaquetas/metabolismo , Variação Genética , Agregação Plaquetária , Receptores de Tromboxano A2 e Prostaglandina H2/sangue , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Transtornos da Coagulação Sanguínea/genética , Plaquetas/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes , Cálcio/sangue , Ensaio de Imunoadsorção Enzimática , Ácidos Graxos Insaturados , Predisposição Genética para Doença , Células HEK293 , Humanos , Hidrazinas/metabolismo , Ligantes , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Fenótipo , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/genética , Ensaio Radioligante , Receptores de Tromboxano A2 e Prostaglandina H2/agonistas , Receptores de Tromboxano A2 e Prostaglandina H2/deficiência , Receptores de Tromboxano A2 e Prostaglandina H2/genética , TransfecçãoAssuntos
Síndrome de Hermanski-Pudlak/diagnóstico , Síndrome de Hermanski-Pudlak/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Análise de Sequência de DNA/métodos , Adulto , Transtornos Herdados da Coagulação Sanguínea/diagnóstico , Transtornos Herdados da Coagulação Sanguínea/genética , Consanguinidade , Genótipo , Fatores de Troca do Nucleotídeo Guanina , Humanos , Masculino , Fenótipo , Projetos PilotoRESUMO
AIM: To characterize the microbial community structure and bamA gene diversity involved in anaerobic degradation of toluene and benzoate under denitrifying conditions. METHODS AND RESULTS: Nitrate-reducing enrichment cultures were established on either toluene, benzoate or without additional substrate. Bacterial community structures were characterized by 16S rRNA gene-based PCR-DGGE analysis. bamA gene diversity was analysed using DGGE and cloning methods. The results showed that bamA gene related to bamA of Thauera chlorobenzoica was dominant in toluene and benzoate cultures. However, a greater diversity of sequences was obtained in benzoate cultures. Low diversity of bamA gene was observed, and some similarities of bamA were also found between active cultures and backgrounds, suggesting that potential natural attenuation of aromatic compounds might occur. CONCLUSIONS: The combined analysis of 16S rRNA and bamA genes suggests that the species related to genera Thauera dominated toluene- and benzoate-degrading cultures. The combination of multiple methods (DGGE and cloning) provides a more complete picture of bamA gene diversity. SIGNIFICANCE AND IMPACT OF THE STUDY: To our knowledge, this is the first report of bamA gene in denitrifying enrichments using DGGE and cloning analysis.
Assuntos
Bactérias/genética , Bactérias/metabolismo , Proteínas da Membrana Bacteriana Externa/genética , Benzoatos/metabolismo , Desnitrificação , Variação Genética , Tolueno/metabolismo , Anaerobiose , Bactérias/classificação , Biodegradação Ambiental , Biodiversidade , Dados de Sequência Molecular , Filogenia , Thauera/metabolismo , Poluentes Químicos da Água/metabolismoRESUMO
On-demand therapy with recombinant activated factor VII (rFVIIa) can provide effective haemostasis for spontaneous bleeds in haemophilia patients with inhibitors. However, treatment approaches vary amongst physicians, positively or negatively affecting outcomes. A panel of physicians proposed recommendations for securing and maintaining predictable efficacy with rFVIIa, comparing these with 'real-life' patient management, using a questionnaire circulated to other expert physicians from haemophilia care centres in Europe and the United States. For rFVIIa treatment of spontaneous bleeds in inhibitor patients, early intervention with the highest appropriate dose is recommended. Home-based therapy can facilitate early intervention. If additional rFVIIa therapy is required after the initial dose, rFVIIa 90 µg kg(-1) may be administered at 2-3 h intervals. Treatment should be tailored to bleed site/severity, recognizing the advantages of appropriate adjunct therapy. Questionnaire results suggested that many respondents adopted strategies in line with the recommendations. Most (36/46) recommended initial therapy within 1 h of bleed onset. rFVIIa 270 µg kg(-1) was the most frequently prescribed/recommended initial dose for paediatric (aged ≤ 15 years; 22/44 respondents) and adult (aged > 15 years; 23/44 respondents) patients. However, there may be opportunity for improved bleed management on occasion, with regard, for instance, to dosing and dose interval. To secure and maintain predictable efficacy with rFVIIa, judicious dose selection and treatment timing are important, together with adjunct therapy where necessary. As inhibitor patients present with different bleeding scenarios, a tailored treatment approach should be adopted.
Assuntos
Fator VIIa/administração & dosagem , Hemofilia A/tratamento farmacológico , Adulto , Criança , Europa (Continente) , Hemofilia A/imunologia , Hemorragia/prevenção & controle , Humanos , Guias de Prática Clínica como Assunto , Proteínas Recombinantes/administração & dosagem , Inquéritos e Questionários , Fatores de Tempo , Estados UnidosRESUMO
Glanzmann Thrombasthenia (GT) is a rare autosomal recessive disorder which usually manifests as severe mucocutaneous bleeding and is caused by deficiency of the platelet glycoprotein IIb-IIIa. Pregnancy in women with GT presents particular challenges as there is increased risk of both maternal and foetal bleeding. To improve understanding and clarify the optimum management of pregnancy in this disorder, we performed a systematic review of the world literature of pregnancy and GT. This identified three single-centre case series of patients with GT that included brief descriptions of women in pregnancy and 31 detailed case reports of 40 pregnancies in 35 women that resulted in 38 live births. Among the detailed case reports, ante-natal bleeding was described in 50% of pregnancies but was usually mild and occurred at mucocutaneous sites. Primary postpartum haemorrhage (PPH) was reported in 34% of pregnancies and secondary PPH in 24%. PPH was frequently severe and occurred up to 20 days after delivery. There was a wide variation in approach to prevention and treatment of PPH but most women received platelet transfusion, sometimes with additional recombinant FVIIa and anti-fibrinolytics. Maternal alloimmunization against platelet antigens was reported in 73% of pregnancies and was associated with four neonatal deaths. These data emphasize the need for multidisciplinary management of pregnancy in women with GT. Delivery plans should recognize the need for prevention and aggressive treatment of PPH and should minimize foetal bleeding risk in pregnancies complicated by alloimmunization.
Assuntos
Hemorragia Pós-Parto/prevenção & controle , Complicações Hematológicas na Gravidez/prevenção & controle , Trombastenia/complicações , Antifibrinolíticos/uso terapêutico , Gerenciamento Clínico , Fator VIIa/uso terapêutico , Feminino , Humanos , Recém-Nascido , Doenças do Recém-Nascido/prevenção & controle , Complicações do Trabalho de Parto/prevenção & controle , Transfusão de Plaquetas , Hemorragia Pós-Parto/etiologia , Gravidez , Complicações Hematológicas na Gravidez/etiologia , Resultado da Gravidez , Proteínas Recombinantes/uso terapêuticoRESUMO
INTRODUCTION: Protein C (PC) Asn2Ile is a rare pro-thrombotic variant in which loss of anticoagulant function in vivo is likely to result from defective PC binding to the endothelial PC receptor and phospholipid. METHODS: To characterize the consequences of this functional defect on the diagnostic performance of commercial PC activity assays, we performed one antigen, three chromogenic and three coagulometric assays on plasma from a subject who was heterozygous for the PC Asn2Ile substitution. RESULTS: As anticipated, the PC antigen (96.2 IU/dl) and chromogenic PC activity assays (98.4 IU/dl) were insensitive to PC Asn2Ile, which has intact enzymatic activity and is secreted normally. There was a marked reduction in apparent PC activity by STACLOT coagulometric assay (50.4 IU/dl). However, there was only a small reduction in apparent PC activity by CRYOcheck Clot C assay (69.5 IU/dl) and by HemosIL ProClot assay, the PC activity was within the laboratory reference range (91 IU/dl). This discrepancy between coagulometric assays could not be explained by lupus anticoagulant, activated PC resistance or elevated plasma factor VIII activity. CONCLUSION: We demonstrate that coagulometric assays are not equally sensitive to clinically important functional defects of PC and that multiple assays may be required to identify all variants.
Assuntos
Testes de Coagulação Sanguínea , Deficiência de Proteína C/sangue , Deficiência de Proteína C/diagnóstico , Proteína C/metabolismo , Adulto , Substituição de Aminoácidos/genética , Feminino , Heterozigoto , Humanos , Proteína C/genética , Proteína C/imunologiaAssuntos
Retículo Endoplasmático/metabolismo , Oxigenases de Função Mista/genética , Varfarina/farmacologia , Administração Oral , Adolescente , Adulto , Idoso , Anticoagulantes/farmacologia , Fibrilação Atrial/sangue , Fibrilação Atrial/terapia , Carbono-Carbono Ligases/metabolismo , Feminino , Humanos , Masculino , Fenótipo , Vitamina D/metabolismo , Vitamina K Epóxido RedutasesRESUMO
Purpura fulminans (PF) is a haematological emergency in which there is skin necrosis and disseminated intravascular coagulation. This may progress rapidly to multi-organ failure caused by thrombotic occlusion of small and medium-sized blood vessels. PF may complicate severe sepsis or may occur as an autoimmune response to otherwise benign childhood infections. PF may also be the presenting symptom of severe heritable deficiency of the natural anticoagulants protein C or protein S. Early recognition and treatment of PF is essential to reduce mortality and to prevent major long-term health sequelae. However, management strategies require accurate identification of the underlying cause. This review focuses on the clinical features, differential diagnosis and laboratory features of the range of PF disorders and includes expert consensus opinion about immediate and on-going management.
Assuntos
Púrpura Fulminante/diagnóstico , Anticoagulantes/uso terapêutico , Criança , Pré-Escolar , Diagnóstico Diferencial , Humanos , Lactente , Recém-Nascido , Prognóstico , Proteína C/uso terapêutico , Deficiência de Proteína C/complicações , Deficiência de Proteína S/complicações , Púrpura Fulminante/etiologia , Púrpura Fulminante/terapia , Sepse/complicaçõesRESUMO
Haemophilia A and B in one individual may arise from co-incident inheritance of independent mutations in the F8 and F9 genes. However, this association is rare and has been studied poorly at a genetic level. We report a male patient with abnormal bleeding and reduced factor VIII:C (26 IU dL(-1)) and factor IX:C (35 IU dL(-1)). This index case harboured a F8 c.979C>G transversion (predictive of p.Leu327Val) and a F9 c.845A>G transition (predictive of p.His282Arg) which have been previously associated with mild haemophilia A and B, respectively. Identical F8 and F9 mutations were identified in the mother and maternal grandmother. However, an affected maternal uncle showed only the F8 c.979C>G mutation, indicating haemophilia A alone. The sister of the index case was heterozygous only for F9 c.845A>G, indicating carriership of haemophilia B alone. The non-Mendelian inheritance of F8 c.979C>G and F9 c.845A>G in this kindred is consistent with recombination between F8 and F9 and illustrates the large recombination distance between these loci. Recognition of this phenomenon was essential for accurate genetic counselling in this kindred.