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INTRODUCTION: Turoctocog alfa pegol (N8-GP) is a glycoPEGylated, extended half-life (EHL), human recombinant factor VIII (FVIII) approved for the treatment and prevention of bleeding episodes in patients with haemophilia A. Since its launch in August 2019, > 800 patients have been treated worldwide. AIM: To present data from identified post-marketing cases of less-than-expected FVIII activity in previously treated patients (PTPs) without inhibitors after switching to N8-GP. METHODS: The post-marketing safety database was searched using keywords such as 'coagulation FVIII level decreased'. Identified cases reported prior to 13 October 2021 were included in this report. Cases in which patients had FVIII inhibitors were excluded. RESULTS: Here we report 14 cases of less-than-expected FVIII activity. Details varied greatly amongst the cases. At presentation, FVIII activity ranged from 1% (15 min post-dose) to 51% (2 days post-dose). Seven patients experienced bleeding episodes after switching to N8-GP with heterogeneity in bleeding presentations. Six out of seven patients who were tested for anti-PEG IgG and/or IgM antibodies were positive. In all known cases, FVIII activity returned to the expected range when switched to an alternative FVIII replacement product. CONCLUSION: In conclusion, the 14 reported cases of less-than-expected FVIII activity, without presence of detectable FVIII inhibitors, presented with heterogenous characteristics, and wide variations in FVIII activity and anti-PEG antibody titre. FVIII activity returned to the expected range after switching to alternative FVIII products. In line with WFH guidelines, monitoring of FVIII activity can ensure FVIII activity in the expected range. The safety surveillance of N8-GP continues.
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Hemofilia A , Hemostáticos , Humanos , Fator VIII/uso terapêutico , Polietilenoglicóis/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemorragia/etiologia , Hemorragia/prevenção & controle , Hemostáticos/uso terapêutico , Meia-Vida , Vigilância de Produtos ComercializadosRESUMO
BACKGROUND: Guidelines recommend that patients with haemophilia should preferably receive vaccination subcutaneously. COVID-19 and other vaccines, however, are only licenced for intramuscular application. AIMS: To assess the safety of intramuscular COVID-19 vaccination in patients living with haemophilia. METHODS: Part A of this prospective observational study enrolled consecutive patients with haemophilia A (HA) and B (HB) of all ages and severities and assessed injection site bleeding and other complications within 30 days of vaccination. Part B enrolled patients providing informed consent for detailed data collection including medication and prophylaxis around the time of vaccination. Logistic regression was performed to assess potential risk factors for bleeding. RESULTS: Four hundred and sixty-one patients were enrolled into part A. The primary endpoint injection site bleeding occurred in seven patients (1.5%, 95% confidence interval .7-3.1%). Comprehensive analysis of 214 patients (404 vaccinations, part B) revealed that 97% of patients with severe haemophilia had prophylaxis before vaccination, either as part of their routine prophylaxis or using additional doses. 56% and 30% of patients with moderate and mild haemophilia, respectively, received prophylaxis before vaccination. Among the seven bleeds recorded, three occurred when intramuscular vaccination was done without prophylaxis (odds ratio 12). CONCLUSIONS: This is the first prospective study reporting on the safety of intramuscular vaccination in haemophilia. The rate of injection site bleeding was low in mild haemophilia, and in moderate and severe haemophilia if patients received factor prophylaxis.
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Vacinas contra COVID-19 , COVID-19 , Hemofilia A , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Fator VIII/uso terapêutico , Hemofilia A/complicações , Hemofilia A/tratamento farmacológico , Hemorragia/prevenção & controle , Humanos , Estudos Prospectivos , Vacinação/efeitos adversosRESUMO
INTRODUCTION: The sixth Åland Islands Conference on von Willebrand disease (VWD) on the Åland Islands, Finland, was held from 20 to 22 September 2018. AIM: The meeting brought together experts in the field of VWD from around the world to share the latest advances and knowledge in VWD. RESULTS AND DISCUSSION: The topics covered both clinical aspects of disease management, and biochemical and laboratory insights into the disease. The clinical topics discussed included epidemiology, diagnosis and treatment of VWD in different countries, management of children with VWD, bleeding control during surgery, specific considerations for the management of type 3 VWD and bleeding control in women with VWD. Current approaches to the management of acquired von Willebrand syndrome were also discussed. Despite significant advances in the understanding and therapeutic options for VWD, there remain many challenges to be overcome in order to optimise patient care. In comparison with haemophilia A, there are very few registries of VWD patients, which would be a valuable source of data on the condition and its management. VWD is still underdiagnosed, and many patients suffer recurrent or severe bleeding that could be prevented. Awareness of VWD among healthcare practitioners, including non-haematologists, should be improved to allow timely diagnosis and intervention. Diagnosis remains challenging, and the development of fast, simple assays may help to facilitate accurate and rapid diagnosis of VWD.
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Doença de von Willebrand Tipo 3 , Doenças de von Willebrand , Criança , Congressos como Assunto , Feminino , Finlândia , Hemorragia , Humanos , Sistema de Registros , Doenças de von Willebrand/complicações , Doenças de von Willebrand/diagnóstico , Doenças de von Willebrand/tratamento farmacológico , Fator de von Willebrand/uso terapêuticoRESUMO
BACKGROUND AND OBJECTIVES: Chronic diseases, such as inherited bleeding disorders (IBD) are often associated with high costs of medical care. COVID-19 containment measures, including isolation and triage, led to restrictions in the health care of chronically ill patients. The aim of the present study was to investigate the effects of the COVID-19 pandemic on the health care of IBD patients. METHODS: In this multicentre cross-sectional study to evaluate the effects of COVID-19 on the mental health and quality of care of patients with inherited bleeding disorder, an ad hoc questionnaire was sent to 586 patients/parents of children with haemophilia A, B or von Willebrand syndrome type 3. In addition to demographic and clinical data, patients/parents of patients with inherited bleeding disorders were asked about their thoughts, concerns and experiences regarding their medical care during the COVID-19 pandemic. Differences between clinical subgroups were calculated. RESULTS: Significant differences were found between subgroups (severity, type of therapy, product class, comorbidities) with regard to the transmission of COVID-19 through plasma products, the effects of COVID-19 positive test results, fear of getting COVID-19, delayed drug supply and physiotherapy treatment. DISCUSSION: The medical care of patients with inherited bleeding disorders, who need a continuous supply of essential drugs, is a particular challenge in times of pandemics. Therefore, worries and fears of IBD patients should be taken seriously and innovative communication channels established to maintain therapy standards and quality of care.
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COVID-19 , Pandemias , Criança , Estudos Transversais , Alemanha/epidemiologia , Humanos , SARS-CoV-2RESUMO
BACKGROUND: The worldwide pandemic spread of SARS-CoV-2 can lead to either respiratory infection or containment-associated isolation with possible higher impact on chronic diseases such as inherited bleeding disorders (IBD). The aim of the study was to evaluate the impact of COVID-19 on patients and caregivers of IBD patients regarding their concerns and worries related to own health, access to treatment and availability of factor concentrates and their experiences related to medical care. METHODS: Multicentre, cross-sectional study evaluating the impact of COVID-19 on mental health of IBD patients. An ad hoc questionnaire was developed and sent to 586 patients/caregivers with haemophilia A, haemophilia B and VWD type III. The survey included information on demographic and clinical data, needs, concerns and experiences regarding medical care during COVID-19 pandemic. RESULTS: In total, 355 of the IBD-Group (200 patients, 155 caregivers) completed the survey (61.7% response rate). Most patients suffered from haemophilia A (73.8%) and were severely affected (64.7%). Eleven patients were in quarantine due to suspected COVID-19; none had symptoms. One quarter worried (very) strongly about getting the coronavirus, 71.3% asked themselves what will happen to them when they will get COVID-19, 40.1% felt unchanged, and 18.9% worried about delivery difficulties of their IBD treatment product. In 52.8%, medical appointments were postponed. Significant differences between caregivers and patients were found in most aspects. DISCUSSION: The IBD patients affected by a chronic disorder have particular thoughts and worries regarding COVID-19. Haemophilia specialists should be committed to address these concerns and guarantee treatment despite containment strategies.
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Ansiedade/epidemiologia , COVID-19/epidemiologia , Hemofilia A/epidemiologia , Saúde Mental/estatística & dados numéricos , SARS-CoV-2/fisiologia , Adulto , Doenças Assintomáticas , Cuidadores , Estudos Transversais , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Inquéritos e Questionários , Adulto JovemRESUMO
INTRODUCTION: HaemoassistTM 2 is an electronic system designed for people with bleeding disorders and their physicians to record prophylactic infusions and treatment of bleeds. It aims to improve adherence by permitting reminders and accuracy of documentation by facilitating real-time reporting. AIM: To assess documentation quality and adherence to prophylactic regimens in patients with haemophilia A, haemophilia B or von Willebrand disease who are using HaemoassistTM 2. METHODS: Ten centres enrolled consecutive patients, who had been using HaemoassistTM 2 for ≥ 3 months (Cohort 1, 'quality of documentation'). Of these, patients who had a specified prophylactic regimen in HaemoassistTM 2 for ≥ 3 months were eligible for inclusion in Cohort 2 ('adherence to prophylaxis'). RESULTS: Cohort 1 comprised 796 patients (71% with severe haemophilia A; median 20.5 months of HaemoassistTM 2 use). The most common method of documentation for patients was using the mobile app; the median time between infusion and documentation was 4 hours using the app, compared with 85 hours using a web portal on a stationery device. The median total annualised number of infusions was consistent in the first and last 3 months of documentation (128; IQR: 70-184 and 120; IQR 64-176, respectively). Cohort 2 comprised 202 patients (79% severe haemophilia A; median of 13 months on prophylactic regimen in HaemoassistTM 2). The rate of adherence to prophylaxis was 83%; median deviation between planned and actual infusion time was ± 2 hours. CONCLUSION: HaemoassistTM 2 was used consistently over prolonged periods of time and allowed for precise analysis of adherence to prophylaxis.
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Eletrônica/instrumentação , Hemofilia A/terapia , Doenças de von Willebrand/terapia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Inquéritos e QuestionáriosRESUMO
The first Team Haemophilia Education (THE) Meeting was held on 7-8 May 2015 in Amsterdam, The Netherlands. It aimed to promote the optimal care of patients with haemophilia through education of the multidisciplinary treatment team. This was achieved by reviewing the latest developments in haemophilia management, considering how these can be implemented in the clinic to improve patient care and providing a platform for networking and debate for all haemophilia treatment team members. The second THE Meeting was held on 19-20 May in Frankfurt, Germany, and participants included doctors, nurses, physiotherapists, patient representatives and data management staff from 20 different countries. Topics covered the role of the multidisciplinary team in delivering the best haemophilia care, challenges in the management of haemophilia across Europe, available clotting factor treatments, future treatments and the use of genetics in advising carriers of haemophilia. This report is a summary of the key developments in haemophilia care presented by various investigators and healthcare professionals at THE Meeting 2016.
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Hemofilia A/terapia , Hemofilia B/terapia , Atenção à Saúde , Gerenciamento Clínico , Europa (Continente) , Alemanha , Instalações de Saúde , Humanos , Equipe de Assistência ao PacienteRESUMO
Venous thromboembolism (VTE) is a major cause of maternal morbidity during pregnancy and the postpartum period. However, because there is a lack of adequate study data, management strategies for pregnancy-associated VTE must be deduced from observational stu-dies and extrapolated from recommendations for non-pregnant patients. In this review, the members of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH) have summarised the evidence that is currently available in the literature to provide a practical approach for treating pregnancy-associated VTE. Because heparins do not cross the placenta, weight-adjusted therapeutic-dose low molecular weight heparin (LMWH) is the anticoagulant treatment of choice in cases of acute VTE during pregnancy. No differences between once and twice daily LMWH dosing regimens have been reported, but twice daily dosing seems to be advisable, at least peripartally. It remains unclear whether determining dose adjustments according to factor Xa activities during pregnancy provides any benefit. Management of delivery deserves attention and mainly depends on the time interval between the diagnosis of VTE and the expected delivery date. In particular, if VTE manifests at term, delivery should be attended by an experienced multidisciplinary team. In lactating women, an overlapping switch from LMWH to warfarin is possible. Anticoagulation should be continued for at least 6 weeks postpartum or for a minimum period of 3 months. Although recommendations are provided for the treatment of pregnancy-associated VTE, there is an urgent need for well-designed prospective studies that compare different management strategies and define the optimal duration and intensity of anticoagulant treatment.
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Anticoagulantes/administração & dosagem , Complicações Cardiovasculares na Gravidez/terapia , Embolia Pulmonar/terapia , Tromboembolia Venosa/terapia , Trombose Venosa/terapia , Administração Oral , Anticoagulantes/efeitos adversos , Esquema de Medicação , Monitoramento de Medicamentos , Feminino , Humanos , Gravidez , Complicações Cardiovasculares na Gravidez/sangue , Complicações Cardiovasculares na Gravidez/diagnóstico , Embolia Pulmonar/sangue , Embolia Pulmonar/diagnóstico , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Tromboembolia Venosa/sangue , Tromboembolia Venosa/diagnóstico , Trombose Venosa/sangue , Trombose Venosa/diagnósticoRESUMO
Pregnancy and the postpartum period are associated with an increased risk of venous thromboembolism (VTE). Over the past decade, new diagnostic algorithms have been established, combining clinical probability, laboratory testing and imaging studies for the diagnosis of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the non-pregnant population. However, there is no such generally accepted algorithm for the diagnosis of pregnancy-associated VTE. Studies establishing clinical prediction rules have excluded pregnant women, and prediction scores currently in use have not been prospectively validated in pregnancy or during the postpartum period. D-dimers physiologically increase throughout pregnancy and peak at delivery, so a negative D-dimer test result, based on the reference values of non-pregnant subjects, becomes unlikely in the second and third trimesters. Imaging studies therefore play a major role in confirming suspected DVT or PE in pregnant women. Major concerns have been raised against radiologic imaging because of foetal radiation exposure, and doubts about the diagnostic value of ultrasound techniques in attempting to exclude isolated iliac vein thrombosis grow stronger as pregnancy progresses. As members of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH), we summarise evidence from the available literature and aim to establish a more uniform strategy for diagnosing pregnancy-associated VTE.
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Diagnóstico por Imagem/normas , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Complicações Cardiovasculares na Gravidez/diagnóstico , Embolia Pulmonar/diagnóstico , Tromboembolia Venosa/diagnóstico , Trombose Venosa/diagnóstico , Biomarcadores/sangue , Consenso , Diagnóstico por Imagem/efeitos adversos , Diagnóstico por Imagem/métodos , Feminino , Humanos , Valor Preditivo dos Testes , Gravidez , Complicações Cardiovasculares na Gravidez/sangue , Complicações Cardiovasculares na Gravidez/etiologia , Embolia Pulmonar/sangue , Embolia Pulmonar/etiologia , Reprodutibilidade dos Testes , Fatores de Risco , Tromboembolia Venosa/sangue , Tromboembolia Venosa/etiologia , Trombose Venosa/sangue , Trombose Venosa/etiologiaRESUMO
Venous thromboembolism [TE] is a multifactorial disease and protein C deficiency [PCD] constitutes a major risk factor. In the present study the prevalence of PCD and the clinical presentation at TE onset, including neonatal purpura fulminans, in a cohort of children are reported. In 367 unselected children (0·1-19 years) recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. Twenty-five of 338 children (7·4%) had PCD. Mean age at first TE onset was 10 years (range 0·1-18). Leading thromboembolic manifestations were neonatal purpura fulminans (n = 5), TE of cerebral veins (n = 3), stroke (n = 2) deep veinthrombosis (DVT) of the leg (n = 10), DVT & pulmonary embolism (n = 2) and DVT & pelvic veins (n = 3). Concomitant risk factors for TE were identified in 12 patients, whereas 13 children spontaneously developed TE. A positive family history of DVT was found in 10 children. In this unselected cohort of paediatric patients with symptomatic TE the overall prevalence of PCD was 7·4%; 1·5% presented with neonatal purpura fulminans. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high-risk population.
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Deficiência de Proteína C/complicações , Trombofilia/genética , Trombose Venosa/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genótipo , Alemanha/epidemiologia , Humanos , Lactente , Recém-Nascido , Israel/epidemiologia , Masculino , Mutação de Sentido Incorreto , Prevalência , Proteína C/genética , Deficiência de Proteína C/sangue , Deficiência de Proteína C/diagnóstico , Deficiência de Proteína C/epidemiologia , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/etiologia , Púrpura Fulminante/epidemiologia , Púrpura Fulminante/etiologia , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Trombofilia/sangue , Trombofilia/diagnóstico , Trombofilia/epidemiologia , Tromboflebite/epidemiologia , Tromboflebite/etiologia , Trombose Venosa/sangue , Trombose Venosa/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Postpartum hemorrhage (PPH) remains one of the leading causes of maternal morbidity and mortality worldwide, although the lack of a precise definition precludes accurate data of the absolute prevalence of PPH. STUDY DESIGN AND METHODS: An international expert panel in obstetrics, gynecology, hematology, transfusion, and anesthesiology undertook a comprehensive review of the literature. At a meeting in November 2011, the panel agreed on a definition of severe PPH that would identify those women who were at a high risk of adverse clinical outcomes. RESULTS: The panel agreed on the following definition for severe persistent (ongoing) PPH: "Active bleeding >1000 mL within the 24 hours following birth that continues despite the use of initial measures including first-line uterotonic agents and uterine massage." A treatment algorithm for severe persistent PPH was subsequently developed. Initial evaluations include measurement of blood loss and clinical assessments of PPH severity. Coagulation screens should be performed as soon as persistent (ongoing) PPH is diagnosed, to guide subsequent therapy. If initial measures fail to stop bleeding and uterine atony persists, second- and third-line (if required) interventions should be instated. These include mechanical or surgical maneuvers, i.e., intrauterine balloon tamponade or hemostatic brace sutures with hysterectomy as the final surgical option for uncontrollable PPH. Pharmacologic options include hemostatic agents (tranexamic acid), with timely transfusion of blood and plasma products playing an important role in persistent and severe PPH. CONCLUSION: Early, aggressive, and coordinated intervention by health care professionals is critical in minimizing blood loss to ensure optimal clinical outcomes in management of women with severe, persistent PPH.
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Hemorragia Pós-Parto/diagnóstico , Hemorragia Pós-Parto/terapia , Prática Profissional , Transtornos Herdados da Coagulação Sanguínea/complicações , Transtornos Herdados da Coagulação Sanguínea/diagnóstico , Transtornos Herdados da Coagulação Sanguínea/terapia , Transfusão de Componentes Sanguíneos/estatística & dados numéricos , Prova Pericial , Feminino , Hemostáticos/uso terapêutico , Humanos , Trabalho de Parto , Hemorragia Pós-Parto/etiologia , Guias de Prática Clínica como Assunto , Gravidez , Prática Profissional/normas , Prática Profissional/estatística & dados numéricos , Fatores de RiscoRESUMO
Introduction: The disease burden and bleeding risk of patients with mild hemophilia may be underestimated. Their health-related quality of life (QoL) may be negatively impacted by insufficient treatment and bleed-related joint damage connected to a potentially delayed diagnosis. Aim: This study aims to gain information on the care reality and QoL of patients aged ≥12 years with mild hemophilia in Germany. Methods: An anonymous cross-sectional patient survey using standardized questionnaires was conducted in a validated electronic patient-reported outcome system. Medical specialists, hemophilia centers, patient organizations, and support groups across Germany invited the patients. Results: A total of 43 patients (35 patients with hemophilia A, 5 patients with hemophilia B, and 3 patients for whom the information was missing) with a median age of 33 years were analyzed. The median age at diagnosis was 6.0 years (interquartile range [IQR] 2.0-15.0), and the median factor activity was 14.0% (IQR 12.0-25.0). Nearly 85% of the patients received factor concentrates in the past, and the most common reasons for the treatment were surgery or joint bleeding (each 65.6%). Half of the patients who provided feedback experienced complications during bleeding episodes. Prophylactic treatment with factor concentrates was rare (10.3%). The patients had minor problems regarding their health status. Conclusion: Bleeding complications and joint bleeding, in particular, may be highly underestimated in patients with mild hemophilia, highlighting a medical need in this population. Patients with a potential benefit from prophylaxis need to be identified. Mild hemophilia has a negative impact on patients' QoL. Hemophilia centers satisfied the patients' needs. Further research is needed to address the current lack of awareness and improve adequate treatment in the future.
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BACKGROUND: Von Willebrand disease (VWD), the most prevalent hereditary bleeding disorder, results from deficiency of von Willebrand factor (VWF). OBJECTIVES: This large cohort study aims to offer a comprehensive exploration of mutation spectra and laboratory features in quantitative VWF deficiencies, shedding light on genetic underpinnings and genotype-phenotype associations. METHODS: Our cohort consisted of 221 Caucasian index patients with quantitative VWD, along with 47 individuals whose plasma VWF levels fell within the lower normal boundaries (50-70 IU/dL). We conducted comprehensive VWF assays and genetic analyses, encompassing VWF gene sequencing, copy number variation investigations, and bioinformatic assessments. RESULTS: Following International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee VWF guidelines, 77 index patients were characterized as having type 1 VWD (VWF antigen [VWF:Ag] < 30 IU/dL), 111 as having type 1 VWD (VWF:Ag, 30-50 IU/dL), and 33 as having type 3 VWD. Mutation detection rates were 88%, 65%, and 92%, respectively. Notably, blood group O overrepresentation was evident in type 1 with VWF:Ag of 30 to 50 IU/dL, particularly among mutation-negative patients, suggesting a potential causal role of blood group O. A total of 223 VWF variants, comprising 147 distinct variations, were identified in quantitative VWD patients, of which 57 were novel variants (39%). Additionally, approximately 70% of individuals with VWF levels within the lower normal boundaries (50-70 IU/dL) displayed VWF variants. CONCLUSION: Our data advance our understanding of the molecular mechanisms underlying quantitative VWD, offering valuable insights for future research and clinical management. Distinct mutation patterns were observed among subgroups, particularly the contrast between type 1 VWD (VWF:Ag < 30 IU/dL) and type 1 VWD (VWF:Ag, 30-50 IU/dL), an area with limited prior investigation.
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ABSTRACT: Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in FGA, FGB, and FGG. We sought to comprehensively characterize patients with CFD using PRO-RBDD (Prospective Rare Bleeding Disorders Database). Clinical phenotypes, laboratory, and genetic features were investigated using retrospective data from the PRO-RBDD. Patients were classified from asymptomatic to grade 3 based on their bleeding severity. In addition, FGA, FGB, and FGG were sequenced to find causative variants. A total of 166 CFD cases from 16 countries were included, of whom 123 (30 afibrinogenemia, 33 hypofibrinogenemia, 55 dysfibrinogenemia, and 5 hypodysfibrinogenemia) were well characterized. Considering the previously established factor activity and antigen level thresholds, bleeding severity was correctly identified in 58% of the cases. The rates of thrombotic events among afibrinogenemic and hypofibrinogenemic patients were relatively similar (11% and 10%, respectively) and surprisingly higher than in dysfibrinogenemic cases. The rate of spontaneous abortions among 68 pregnancies was 31%, including 86% in dysfibrinogenemic women and 14% with hypofibrinogenemia. Eighty-six patients received treatment (69 on-demand and/or 17 on prophylaxis), with fibrinogen concentrates being the most frequently used product. Genetic analysis was available for 91 cases and 41 distinct variants were identified. Hotspot variants (FGG, p.Arg301Cys/His and FGA, p.Arg35Cys/His) were present in 51% of dysfibrinogenemia. Obstetric complications were commonly observed in dysfibrinogenemia. This large multicenter study provided a comprehensive insight into the clinical, laboratory, and genetic history of patients with CFDs. We conclude that bleeding severity grades were in agreement with the established factor activity threshold in nearly half of the cases with quantitative defects.
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Afibrinogenemia , Hemostáticos , Humanos , Feminino , Fibrinogênio/genética , Afibrinogenemia/epidemiologia , Afibrinogenemia/genética , Afibrinogenemia/complicações , Estudos Prospectivos , Estudos Retrospectivos , Hemorragia/genéticaRESUMO
Mild factor XIII deficiency is an underdiagnosed coagulation disorder. Considering the large number of coding and non-coding polymorphisms identified in the F13A1 gene, there is a possibility that some of these might result in alterations of plasma FXIII levels and cause mild FXIII deficiency. Recently, a homozygous F13A1 gene intron 1 variant (IVS1+12C>A) was found in a patient with FXIII deficiency. In vitro expression studies for this variant demonstrated its lowering effect on FXIII levels. In order to determine the impact of this variant on a population level, we analysed the prevalence of this variant in three clinically and genetically defined population cohorts: an apparently healthy control cohort C1 (n = 102), a mild FXIII deficiency cohort C2 with no detectable F13A1 or F13B gene mutations (n = 183) and a mild FXIII-A deficiency cohort C3 exhibiting heterozygous F13A1 mutations (n = 37). FXIII activity was determined using photometric assay on plasma samples. The F13A1 gene intron 1 variant was analysed by direct sequencing. The C1 cohort showed a normal distribution of FXIII activity (mean 114.1 ± 20.86%). Mean FXIII activity levels for the C2 and C3 cohorts were 54.45 ± 11.12% and 44.21 ± 10.16%, respectively. The frequencies of minor allele (A) were 0.07 in C1 cohort, 0.19 in C2 cohort and 0.11 in C3 cohort. The difference in minor allele frequencies for the C1 and C2 cohorts were highly significant (p < 0.001). The greater frequency of the IVS1+12(A) variant among C2 cohort patients suggests that this polymorphism is associated with mild FXIII deficiency.
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Deficiência do Fator XIII/genética , Fator XIII/genética , Adolescente , Adulto , Idoso , Alelos , Criança , Pré-Escolar , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , População Branca/genética , Adulto JovemRESUMO
Background The efficacy, safety, and immunogenicity of each of Octapharma's factor VIII (FVIII) products, Nuwiq, octanate, and wilate, have been investigated in previously untreated patients (PUPs) with severe hemophilia A in prospective clinical trials. The aim of the Protect-NOW study is to evaluate the effectiveness, safety, and utilization patterns of Nuwiq, octanate, and wilate in PUPs and minimally treated patients (MTPs; <5 exposure days [EDs] to FVIII concentrates or other blood products containing FVIII) with severe hemophilia A in a real-world setting. Real-world data provide valuable information that complement data obtained from interventional clinical trials. Methods Protect-NOW (ClinicalTrials.gov identifier: NCT03695978; ISRCTN identifier: 11492145) is a real-world study in PUPs and MTPs treated with either the human cell line-derived recombinant FVIII Nuwiq (simoctocog alfa) or a plasma-derived FVIII concentrate containing von Willebrand factor (octanate or wilate). It is a prospective and (partly) retrospective, observational, international, noncontrolled, noninterventional study. A total of 140 PUPs and MTPs with severe hemophilia A will be enrolled across around 50 specialized centers worldwide and followed for either 100 EDs or a maximum period of 3 years from ED1. The primary objectives are to assess effectiveness in the prevention and treatment of bleeding episodes and overall safety, including inhibitor development. The secondary objectives are to assess utilization patterns (including dosage and frequency of administration) and the effectiveness in surgical prophylaxis. Conclusions The Protect-NOW study will provide information on the treatment of PUPs and MTPs in routine clinical practice, which will help guide clinical decision making for treating these patients in the future.
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BACKGROUND: Congenital factor VII (FVII) deficiency, a rare bleeding disorder resulting from mutations in the F7 gene with autosomal recessive inheritance, exhibits clinical heterogeneity that lacks a strong correlation with FVII:C levels. The objective of this study was to discern genetic defects and assess their associations with the clinical phenotype in a substantial cohort comprising 785 white women exhibiting FVII:C levels below the age-dependent cut-off percentage. PATIENTS AND METHODS: Individuals with verified inherited factor VII deficiency underwent i) genotyping using the Sanger method and multiplex ligation-dependent probe amplification (MLPA) to identify F7 mutations, including common polymorphic variants. Additionally, they were ii) categorized based on clinical bleeding scores (BS). Thrombophilic variants and blood groups were also determined in the study participants. RESULTS: The probands in this study encompassed both asymptomatic individuals (referred for a laboratory investigation due to recurrent prolonged prothrombin time; n = 221) and patients who manifested mild, moderate, or severe bleeding episodes (n = 564). The spectrum of bleeding symptoms included epistaxis, gum bleeding, gastrointestinal bleeding, hematuria, postoperative bleeding, and gynecologic hemorrhage. The median ISTH bleeding score (BS) recorded within a two-year period prior to the work-up was 2 (0-17). Notably, this score was significantly higher in symptomatic women compared to their asymptomatic counterparts (3 versus 0; p < 0.001). The corresponding PBAC score before hormonal treatment stood at 225 (5-1200), exhibiting a positive correlation with the ISTH BS (rho = 0.38; p = 0.001). Blood group O was more prevalent in symptomatic women compared to asymptomatic individuals (58 versus 42%; p = 0.01). Among the 329 women (42%), known and novel mutations in the F7 gene, encompassing coding regions, exon/intron boundaries, and the promoter region, were identified, while common polymorphisms were detected in 647 subjects (95%). Logistic regression analysis, adjusted for clinical and laboratory data (including blood group, FVII activity, the presence of F7 gene mutations and/or polymorphisms, thrombophilia status, and additional factor deficiencies) revealed that older age at referral (increase per year) (odds/95% CI: 1.02/1.007-1.03), the presence of blood group O (odds/95% CI: 1.9/1.2-3.3), and the coexistence of further bleeding defects (odds/95% CI: 1.8/1.03-3.1) partially account for the differences in the clinical bleeding phenotype associated with FVII deficiency. CONCLUSION: The clinical phenotype in individuals with FVII deficiency is impacted by factors such as age, blood group, and the concurrent presence of other bleeding defects.
RESUMO
Thrombotic events are an increasing challenge in pediatrics. Standard-of-care anticoagulants for pediatric thrombosis have several disadvantages which could be overcome by using direct oral anticoagulants (DOACs). Until recently, there was not enough evidence from clinical trials to recommend for or against the use of any of the four DOACs in children with thrombosis. In this literature review, we looked at the latest clinical trials in this field. On clinicaltrials.gov, we found 13 current studies with published results. For two of the four DOACs, namely dabigatran and rivaroxaban, we found successful phase III studies which led to the approval for the use in children. The results of these pivotal phase III studies allow to finally recommend rivaroxaban and dabigatran for the prophylaxis and treatment of thrombotic events in children.
Assuntos
Anticoagulantes , Trombose , Administração Oral , Adolescente , Anticoagulantes/uso terapêutico , Criança , Dabigatrana/uso terapêutico , Humanos , Recém-Nascido , Rivaroxabana/uso terapêutico , Trombose/tratamento farmacológico , Trombose/prevenção & controleRESUMO
This monocentric study conducted at the Pediatric and Adult Hemoglobinopathy Outpatient Units of the University Hospital of Essen summarizes the results of hemoglobinopathies diagnosed between August 2018 and September 2021, prior to the introduction of a general newborn screening (NBS) for SCD in Germany (October 2021). In total, 339 patients (pts.), 182 pediatric [50.5% males (92/182)] and 157 adult pts. [75.8% females (119/157)] were diagnosed by molecular analysis. The most common (parental) descent among affected pts. were the Middle Eastern and North African/Turkey (Turkey: 19.8%, Syria: 11.8%, and Iraq: 5.9%), and the sub-Saharan African region (21.3%). Median age at diagnosis in pediatric carriers [N = 157; 54.1% males (85/157)] was 6.2 yrs. (range 1 (months) mos.-17.8 yrs.) and 31 yrs. (range 18-65 yrs.) in adults [N = 53; 75.2% females (115/153)]. Median age at diagnosis of homozygous or compound-heterozygous disease in pediatric pts. (72% (18/25) females) was 3.7 yrs., range 4 mos.-17 yrs. (HbSS (N = 13): 2.5 yrs., range 5 mos.-7.8 yrs.; HbS/C disease (N = 5): 8 yrs., range 1-8 yrs.; homozygous/compound heterozygous ß-thalassemia (N = 5): 8 yrs., range 3-13 yrs.), in contrast to HbH disease (N = 5): 18 yrs. (median), range 12-40 yrs. Hemoglobinopathies represent a relevant health problem in Germany due to immigration and late diagnosis of second/third generation migrants. SCD-NBS will accelerate diagnosis and might result in reduction of disease-associated morbidity. However, diagnosis of carriers and/or disease-states (i.e. thalassemic syndromes) in newly immigrated and undiagnosed patients will further be delayed. A first major step has been taken, but further steps are required.