RESUMEN
Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.
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Estudio de Asociación del Genoma Completo , Homeostasis del Telómero , Telómero , Humanos , Telómero/genética , Telómero/metabolismo , Células K562 , Homeostasis del Telómero/genética , Polimorfismo de Nucleótido Simple , Regulación de la Expresión Génica , Sistemas CRISPR-CasRESUMEN
Raising awareness and improving recognition, accurate classification, and enhanced access to new treatments represent current key challenges for carriers of haemophilia. Women and girls carrying genes for haemophilia often experience significant bleeding and/or low factor levels. The bleeding associated with female haemophilia is frequently overlooked, has a weak correlation with factor levels, and manifests differently than in males, with heavy menstrual bleeding being a predominant symptom. Recent changes in terminology now allow the diagnosis of haemophilia in females with low factor levels and differentiate between symptomatic and asymptomatic carriers of the gene. Observations from real-world experiences and limited clinical trial data have highlighted the positive impact of various new haemophilia treatments for women and girls with clotting factor deficiencies. There is an urgent need for initiatives that increase their access to these treatments and encourage well-designed clinical trials focusing on female-specific outcomes. In women with inherited bleeding disorders, early recognition and optimal management of heavy menstrual bleeding are crucial. However, treatment options and guidance from high-quality clinical trials are currently insufficient. Menstrual health assessment should be a regular part of monitoring women and girls with inherited bleeding disorders throughout their lives, emphasizing the importance of gathering data to improve future management.
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Hemofilia A , Menorragia , Masculino , Femenino , Humanos , Hemofilia A/complicaciones , Hemofilia A/diagnóstico , Hemofilia A/genética , Menorragia/etiología , Menorragia/genética , Hemorragia/genéticaRESUMEN
BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1, Serpine1) is an important circulating fibrinolysis inhibitor. PAI-1 exists in 2 pools, packaged within platelet α-granules and freely circulating in plasma. Elevated plasma PAI-1 levels are associated with cardiovascular disease. However, little is known about the regulation of platelet PAI-1 (pPAI-1). OBJECTIVES: We investigated the genetic control of pPAI-1 levels in mice and humans. METHODS: We measured pPAI-1 antigen levels via enzyme-linked immunosorbent assay in platelets isolated from 10 inbred mouse strains, including LEWES/EiJ (LEWES) and C57BL/6J (B6). LEWES and B6 were crossed to produce the F1 generation, B6LEWESF1. B6LEWESF1 mice were intercrossed to produce B6LEWESF2 mice. These mice were subjected to genome-wide genetic marker genotyping followed by quantitative trait locus analysis to identify pPAI-1 regulatory loci. RESULTS: We identified differences in pPAI-1 between several laboratory strains, with LEWES having pPAI-1 levels more than 10-fold higher than those in B6. Quantitative trait locus analysis of B6LEWESF2 offspring identified a major pPAI-1 regulatory locus on chromosome 5 from 136.1 to 137.6 Mb (logarithm of the odds score, 16.2). Significant pPAI-1 modifier loci on chromosomes 6 and 13 were also identified. CONCLUSION: Identification of pPAI-1 genomic regulatory elements provides insights into platelet/megakaryocyte-specific and cell type-specific gene expression. This information can be used to design more precise therapeutic targets for diseases where PAI-1 plays a role.
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Plaquetas , Inhibidor 1 de Activador Plasminogénico , Animales , Ratones , Plaquetas/metabolismo , Fibrinólisis , Genómica , Ratones Endogámicos C57BL , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , Sitios de Carácter Cuantitativo , HumanosRESUMEN
BACKGROUND: Decades of research have transformed hemophilia from severely limiting children's lives to a manageable disorder compatible with a full, active life, for many in high-income countries. The direction of future research will determine whether exciting developments truly advance health equity for all people with hemophilia (PWH). National Hemophilia Foundation (NHF) and American Thrombosis and Hemostasis Network conducted extensive inclusive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them. RESEARCH DESIGN AND METHODS: Working group (WG) 1 of the NHF State of the Science Research Summit distilled the community-identified priorities for hemophilia A and B into concrete research questions and scored their feasibility, impact, and risk. RESULTS: WG1 defined 63 top priority research questions concerning arthropathy/pain/bone health, inhibitors, diagnostics, gene therapy, the pediatric to adult transition of care, disparities faced by the community, and cardiovascular disease. This research has the potential to empower PWH to thrive despite lifelong comorbidities and achieve new standards of wellbeing, including psychosocial. CONCLUSIONS: Collaborative research and care delivery will be key to capitalizing on current and horizon treatments and harnessing technical advances to improve diagnostics and testing, to advance health equity for all PWH.
Hemophilia is the best known of the inherited bleeding disorders (BD). This is a rare condition that causes disproportionate bleeding, often into joints and vital organs. Factor replacement, injecting recombinant or plasma-based clotting factor products directly into the vein, became commonplace to control the disorder in the 1990s and 2000s. Prophylaxis, or injecting replacement factor every few days into people with hemophilia (PWH), has revolutionized patients' lives. In the last few years, other advances in new therapies have entered this space, such as non-factor replacement therapies and gene therapy. With many more research advances on the horizon, the National Hemophilia Foundation (NHF) initiated a State of the Science Research Summit in 2020. This event was attended by over 880 interested parties to help design an agenda of research priorities for inherited BDs for the next decade, based on community consultations. NHF formed multiple Working Groups (WG), each exploring a theme resulting from the community consultations, and presenting their results at the Summit. Led by 2 hematologists who manage and treat PWH daily, the 21-community member WG1 assigned to hemophilia A and B divided into 7 subgroups to identify and organize research priorities for different topic areas. The outcomes focused on prioritizing patients' needs, technological advances, and research in the areas of greatest potential for PWH and those who care for them. The results are a roadmap for the future execution of a research plan that truly serves the community.
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Hemofilia A , Medicina , Adulto , Humanos , Niño , Estados Unidos , Hemofilia A/diagnóstico , Hemofilia A/terapia , Atención a la Salud , InvestigaciónRESUMEN
BACKGROUND: Although most plasma FVIII (Factor VIII) circulates in complex with VWF (von Willebrand factor), a minority (3%-5%) circulates as free-FVIII, which is rapidly cleared. Consequently, 20% of total FVIII may be cleared as free-FVIII. Critically, the mechanisms of free-FVIII clearance remain poorly understood. However, recent studies have implicated the MGL (macrophage galactose lectin) in modulating VWF clearance. METHODS: Since VWF and FVIII share similar glycosylation, we investigated the role of MGL in FVIII clearance. FVIII binding to MGL was assessed in immunosorbent and cell-based assays. In vivo, FVIII clearance was assessed in MGL1-/- and VWF-/-/FVIII-/- mice. RESULTS: In vitro-binding studies identified MGL as a novel macrophage receptor that binds free-FVIII in a glycan-dependent manner. MGL1-/- and MGL1-/- mice who received an anti-MGL1/2 blocking antibody both showed significantly increased endogenous FVIII activity compared with wild-type mice (P=0.036 and P<0.0001, respectively). MGL inhibition also prolonged the half-life of infused FVIII in FVIII-/- mice. To assess whether MGL plays a role in the clearance of free FVIII in a VWF-independent manner, in vivo clearance experiments were repeated in dual VWF-/-/FVIII-/- mice. Importantly, the rapid clearance of free FVIII in VWF-/-/FVIII-/- mice was significantly (P=0.012) prolonged in the presence of anti-MGL1/2 antibodies. Finally, endogenous plasma FVIII levels in VWF-/- mice were significantly increased following MGL inhibition (P=0.016). CONCLUSIONS: Cumulatively, these findings demonstrate that MGL plays an important role in regulating macrophage-mediated clearance of both VWF-bound FVIII and free-FVIII in vivo. We propose that this novel FVIII clearance pathway may be of particular clinical importance in patients with type 2N or type 3 Von Willebrand disease.
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Hemostáticos , Enfermedades de von Willebrand , Ratones , Animales , Factor VIII/genética , Factor VIII/metabolismo , Factor de von Willebrand/metabolismo , Galactosa/metabolismo , Lectinas/metabolismo , Macrófagos/metabolismoRESUMEN
BACKGROUND: Previous studies have reported marked interindividual variation in factor VIII (FVIII) clearance in patients with hemophilia (PWH) and proposed a number of factors that influence this heterogeneity. OBJECTIVES: To investigate the importance of the clearance rates of endogenous von Willebrand factor (VWF) compared with those of other FVIII half-life modifiers in adult PWH. METHODS: The half-life of recombinant FVIII was determined in a cohort of 61 adult PWH. A range of reported modifiers of FVIII clearance was assessed (including plasma VWF:antigen and VWF propeptide levels; VWF-FVIII binding capacity; ABO blood group; and nonneutralizing anti-FVIII antibodies). The FVIII-binding region of the VWF gene was sequenced. Finally, the effects of variation in FVIII half-life on clinical phenotype were investigated. RESULTS: We demonstrated that heterogeneity in the clearance of endogenous plasma VWF is a key determinant of variable FVIII half-life in PWH. Both ABO blood group and age significantly impact FVIII clearance. The effect of ABO blood group on FVIII half-life in PWH is modulated entirely through its effect on the clearance rates of endogenous VWF. In contrast, the age-related effect on FVIII clearance is, at least in part, VWF independent. In contrast to previous studies, no major effects of variation in VWF-FVIII binding affinity on FVIII clearance were observed. Although high-titer immunoglobulin G antibodies (≥1:80) were observed in 26% of PWH, these did not impact FVIII half-life. Importantly, the annual FVIII usage (IU/kg/y) was significantly (p = .0035) increased in patients with an FVIII half-life of <12 hours. CONCLUSION: Our data demonstrate that heterogeneity in the half-life of FVIII concentrates in patients with hemophilia A is primarily attributable to variability in the clearance of endogenous VWF.
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Hemofilia A , Hemostáticos , Enfermedades de von Willebrand , Humanos , Factor VIII/uso terapéutico , Factor VIII/metabolismo , Factor de von Willebrand/metabolismo , Hemofilia A/diagnóstico , Hemofilia A/tratamiento farmacológico , Semivida , Sistema del Grupo Sanguíneo ABORESUMEN
Infectious disease is widely considered to be a major driver of evolution. A preponderance of signatures of balancing selection at blood group-related genes is thought to be driven by inherent trade-offs in susceptibility to disease. B4galnt2 is subject to long-term balancing selection in house mice, where two divergent allele classes direct alternative tissue-specific expression of a glycosyltransferase in the intestine versus blood vessels. The blood vessel allele class leads to prolonged bleeding times similar to von Willebrand disease in humans, yet has been maintained for millions of years. Based on in vivo functional studies in inbred lab strains, it is hypothesized that the cost of prolonged bleeding times may be offset by an evolutionary trade-off involving susceptibility to a yet unknown pathogen(s). To identify candidate pathogens for which resistance could be mediated by B4galnt2 genotype, we here employed a novel "pathometagenomic" approach in a wild mouse population, which combines bacterial 16S rRNA gene-based community profiling with histopathology of gut tissue. Through subsequent isolation, genome sequencing and controlled experiments in lab mice, we show that the presence of the blood vessel allele is associated with resistance to a newly identified subspecies of Morganella morganii, a clinically important opportunistic pathogen. Given the increasing importance of zoonotic events, the approach outlined here may find useful application in the detection of emerging diseases in wild animal populations.
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Antígenos de Grupos Sanguíneos , Microbioma Gastrointestinal , Humanos , Ratones , Animales , Morganella , ARN Ribosómico 16S , GenotipoRESUMEN
Understanding the genetic basis of human diseases and traits is dependent on the identification and accurate genotyping of genetic variants. Deep whole-genome sequencing (WGS), the gold standard technology for SNP and indel identification and genotyping, remains very expensive for most large studies. Here, we quantify the extent to which array genotyping followed by genotype imputation can approximate WGS in studies of individuals of African, Hispanic/Latino, and European ancestry in the US and of Finnish ancestry in Finland (a population isolate). For each study, we performed genotype imputation by using the genetic variants present on the Illumina Core, OmniExpress, MEGA, and Omni 2.5M arrays with the 1000G, HRC, and TOPMed imputation reference panels. Using the Omni 2.5M array and the TOPMed panel, ≥90% of bi-allelic single-nucleotide variants (SNVs) are well imputed (r2 > 0.8) down to minor-allele frequencies (MAFs) of 0.14% in African, 0.11% in Hispanic/Latino, 0.35% in European, and 0.85% in Finnish ancestries. There was little difference in TOPMed-based imputation quality among the arrays with >700k variants. Individual-level imputation quality varied widely between and within the three US studies. Imputation quality also varied across genomic regions, producing regions where even common (MAF > 5%) variants were consistently not well imputed across ancestries. The extent to which array genotyping and imputation can approximate WGS therefore depends on reference panel, genotype array, sample ancestry, and genomic location. Imputation quality by variant or genomic region can be queried with our new tool, RsqBrowser, now deployed on the Michigan Imputation Server.
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Secuenciación de Nucleótidos de Alto Rendimiento , Polimorfismo de Nucleótido Simple , Frecuencia de los Genes/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Polimorfismo de Nucleótido Simple/genética , Secuenciación Completa del GenomaRESUMEN
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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Enfermedad de von Willebrand Tipo 3 , Enfermedades de von Willebrand , Niño , Congresos como Asunto , Femenino , Finlandia , Hemorragia , Humanos , Sistema de Registros , Enfermedades de von Willebrand/complicaciones , Enfermedades de von Willebrand/diagnóstico , Enfermedades de von Willebrand/tratamiento farmacológico , Factor de von Willebrand/uso terapéuticoRESUMEN
BACKGROUND: Hemophilia A (HA) and hemophilia B (HB) are rare inherited bleeding disorders. Although causative genetic variants are clinically relevant, in 2012 only 20% of US patients had been genotyped. OBJECTIVES: My Life, Our Future (MLOF) was a multisector cross-sectional US initiative to improve our understanding of hemophilia through widespread genotyping. METHODS: Subjects and potential genetic carriers were enrolled at US hemophilia treatment centers (HTCs). Bloodworks performed genotyping and returned results to providers. Clinical data were abstracted from the American Thrombosis and Hemostasis Network dataset. Community education was provided by the National Hemophilia Foundation. RESULTS: From 2013 to 2017, 107 HTCs enrolled 11 341 subjects (68.8% male, 31.2% female) for testing for HA (n = 8976), HB (n = 2358), HA/HB (n = 3), and hemophilia not otherwise specified (n = 4). Variants were detected in most male patients (98.2%% HA, 98.1% HB). 1914 unique variants were found (1482 F8, 431 F9); 744 were novel (610 F8, 134 F9). Inhibitor data were available for 6986 subjects (5583 HA; 1403 HB). In severe HA, genotypes with the highest inhibitor rates were large deletions (77/80), complex intron 22 inversions (9/17), and no variant found (7/14). In severe HB, the highest rates were large deletions (24/42). Inhibitors were reported in 27.3% of Black versus 16.2% of White patients. CONCLUSIONS: The findings of MLOF are reported, the largest hemophilia genotyping project performed to date. The results support the need for comprehensive genetic approaches in hemophilia. This effort has contributed significantly towards better understanding variation in the F8 and F9 genes in hemophilia and risks of inhibitor formation.
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Hemofilia A , Hemofilia B , Estudios Transversales , Factor VIII/genética , Femenino , Genotipo , Hemofilia A/diagnóstico , Hemofilia A/genética , Hemofilia B/diagnóstico , Hemofilia B/epidemiología , Hemofilia B/genética , Humanos , Masculino , Estados Unidos/epidemiologíaRESUMEN
Individuals with inherited bleeding disorders (IBDs) have higher bleeding risk during pregnancy, childbirth, and the postpartum period. Clinical management requires recognition of the IBD as high risk for postpartum hemorrhage and a personalized multidisciplinary approach that includes the patient in decision making. When the fetus is known or at risk to inherit a bleeding disorder, fetal and neonatal bleeding risk also need to be considered. In pregnant IBD patients, it is common for providers to need to make decisions in the absence of high level of certainty evidence. We here present the case of a pregnant von Willebrand disease patient that reached multiple decision points where there is currently clinical ambiguity due to a lack of high level of certainty evidence. For each stage of her care, from diagnosis to the postpartum period, we discuss current literature and describe our approach. This is followed by a brief overview of considerations in other IBDs and pregnancy.
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Trastornos de la Coagulación Sanguínea Heredados , Trastornos Hemorrágicos , Enfermedades Inflamatorias del Intestino , Hemorragia Posparto , Enfermedades de von Willebrand , Trastornos de la Coagulación Sanguínea Heredados/complicaciones , Trastornos de la Coagulación Sanguínea Heredados/diagnóstico , Trastornos de la Coagulación Sanguínea Heredados/genética , Femenino , Humanos , Recién Nacido , Hemorragia Posparto/diagnóstico , Hemorragia Posparto/etiología , Hemorragia Posparto/terapia , Embarazo , Enfermedades de von Willebrand/complicaciones , Enfermedades de von Willebrand/diagnóstico , Enfermedades de von Willebrand/terapiaRESUMEN
Plasma levels of fibrinogen, coagulation factors VII and VIII and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole-exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and the National Heart, Lung and Blood Institute's Exome Sequencing Project. Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in fibrinogen gamma chain (FGG) (with fibrinogen, P = 9.1 × 10-13), coagulation factor VII (F7) (with factor VII, P = 1.3 × 10-72; seven novel variants) and VWF (with factor VIII and vWF; P = 3.2 × 10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; P = 4.2 × 10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to AAs (rs3211938) in CD36 molecule (CD36). This variant has previously been linked to dyslipidemia but not with the levels of a hemostatic factor. These efforts represent the largest integration of whole-exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.
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Factor VIII , Hemostáticos , Factor VII/genética , Factor VIII/genética , Fibrinógeno/genética , Humanos , Polimorfismo de Nucleótido Simple/genética , Secuenciación del Exoma , Factor de von Willebrand/análisis , Factor de von Willebrand/genéticaRESUMEN
Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.
RESUMEN
Recent manufacturing problems and increased utilization has created a shortage of 3.2% sodium citrate blood collection tubes used for coagulation testing, causing stakeholders such as hospitals, clinics and laboratories, to find suitable alternatives. Considerations for in-house citrate blood collection tube preparations or purchasing commercial products from unknown manufacturing sources is of particular concern to laboratories that perform coagulation testing. It is well recognized that variability exists between citrate blood collection tube manufacturers, thereby making any transition to new blood collection methods more challenging than simply switching to a new source. This document provides provisional guidance for validating alternative sources of sodium citrate blood collection tubes (commercial or in-house preparations) prior to clinical implementation.
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Coagulación Sanguínea , Hemostasis , Anticoagulantes/farmacología , Pruebas de Coagulación Sanguínea , Recolección de Muestras de Sangre , Humanos , Citrato de Sodio/farmacologíaRESUMEN
von Willebrand disease (VWD) is the most common inherited bleeding disorder. VWD is caused by deficiencies in von Willebrand factor (VWF), a critical adhesive haemostatic protein. This review provides an overview of VWD diagnosis and treatment, special considerations in treating women with VWD, and current genomic approaches to VWD. For diagnosis and treatment in VWD, an accurate diagnosis is critical to providing effective treatments, determining appropriate laboratory monitoring and for counselling the patient and family. Diagnosis of VWD begins with the clinical assessment for the bleeding phenotype, which is usually characterized by mucocutaneous and provoked bleeding. The diagnosis of VWD is then made by laboratory investigation. Multiple assays are used to assess VWF levels and functions. The mainstays of VWD treatment are tailored by VWD type and symptoms, and can include antifibrinolytic treatment, desmopressin and VWF replacement treatment. Women with VWD are also at risk for excessive uterine bleeding, such as with menses and childbirth. In addition to standard VWD treatments, heavy menstrual bleeding can be treated with hormones. Interdisciplinary management of childbirth and prophylaxis in the postpartum period are needed to reduce the risk of postpartum haemorrhage. Genomic approaches to VWD can inform VWD diagnosis, treatment, test assay selection, reproductive planning and family counselling. Most VWD patients have an identifiable VWF gene DNA variant. Next-generation sequencing is rapidly being adopted to provide more comprehensive VWF sequence information for patients with known or suspected VWD.
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Hemorragia Posparto , Enfermedades de von Willebrand , Femenino , Genómica , Humanos , Fenotipo , Embarazo , Enfermedades de von Willebrand/diagnóstico , Enfermedades de von Willebrand/tratamiento farmacológico , Enfermedades de von Willebrand/genética , Factor de von Willebrand/genéticaRESUMEN
BACKGROUND: Genetic variants in the SLC14A1, ACKR1, and KEL genes, which encode Kidd, Duffy, and Kell red blood cell antigens, respectively, may result in weakened expression of antigens or a null phenotype. These variants are of particular interest to individuals with sickle cell disease (SCD), who frequently undergo chronic transfusion therapy with antigen-matched units. The goal was to describe the diversity and the frequency of variants in SLC14A1, ACKR1, and KEL genes among individuals with SCD using whole genome sequencing (WGS) data. STUDY DESIGN AND METHODS: Two large SCD cohorts were studied: the Recipient Epidemiology and Donor Evaluation Study III (REDS-III) (n = 2634) and the Outcome Modifying Gene in SCD (OMG) (n = 640). Most of the studied individuals were of mixed origin. WGS was performed as part of the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. RESULTS: In SLC14A1, variants included four encoding a weak Jka phenotype and five null alleles (JKnull ). JKA*01N.09 was the most common JKnull . One possible JKnull mutation was novel: c.812G>T. In ACKR1, identified variants included two that predicted Fyx (FY*X) and one corresponding to the c.-67T>C GATA mutation. The c.-67T>C mutation was associated with FY*A (FY*01N.01) in four participants. FY*X was identified in 49 individuals. In KEL, identified variants included three null alleles (KEL*02N.17, KEL*02N.26, and KEL*02N.04) and one allele predicting Kmod phenotype, all in heterozygosity. CONCLUSIONS: We described the diversity and distribution of SLC14A1, ACKR1, and KEL variants in two large SCD cohorts, comprising mostly individuals of mixed ancestry. This information may be useful for planning the transfusion support of patients with SCD.
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Anemia de Células Falciformes/genética , Sistema del Grupo Sanguíneo Duffy/genética , Variación Genética , Sistema del Grupo Sanguíneo de Kell/genética , Sistema del Grupo Sanguíneo de Kidd/genética , Glicoproteínas de Membrana/genética , Proteínas de Transporte de Membrana/genética , Metaloendopeptidasas/genética , Receptores de Superficie Celular/genética , Secuenciación Completa del Genoma , Alelos , Anemia de Células Falciformes/etnología , Brasil/epidemiología , Estudios de Cohortes , Etnicidad/genética , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Mutación INDEL , Anotación de Secuencia Molecular , Mutación Missense , National Heart, Lung, and Blood Institute (U.S.) , Polimorfismo de Nucleótido Simple , Grupos Raciales/genética , Estados Unidos , Transportadores de UreaRESUMEN
We report 2 patients with coinheritance of the X-linked bleeding disorders hemophilia A and hemophilia B. We describe the family pedigrees, clinical features, and genotyping. The case report addresses the key clinical questions of how to manage patients with both hemophilia A and B and how to counsel families regarding recurrence risk. The patients with coinherited hemophilia A and B require a combination of factor VIII and factor IX replacement to achieve hemostasis. We calculated the estimated genomic meiotic recombination frequency between F8 and F9 to be 38%. The findings in these cases are consistent with this calculation. These findings provide critical information for management of families with coinherited hemophilia A and B.
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Previous studies have highlighted marked inter-individual variations in factor VIII (FVIII) clearance between patients with haemophilia (PWH). The half-life of infused FVIII has been reported to vary from as little as 5.3 hours in some adult PWH, up to as long as 28.8 hours in other individuals. These differences in clearance kinetics have been consistently observed using a number of different plasma-derived and recombinant FVIII products. Furthermore, recent studies have demonstrated that half-life for extended half-life (EHL-) FVIII products also demonstrates significant inter-patient variation. Since time spent with FVIII trough levels <1% has been shown to be associated with increased bleeding risk in PWH on prophylaxis therapy, this variability in FVIII clearance clearly has major clinical significance. Recent studies have provided significant novel insights into the cellular basis underlying FVIII clearance pathways. In addition, accumulating data have shown that endogenous plasma VWF levels, ABO blood group and age, all play important roles in regulating FVIII half-life in PWH. Indeed, multiple regression analysis suggests that together these factors account for approximately 34% of the total inter-individual variation in FVIII clearance observed between subjects with severe haemophilia A. In this review, we consider these and other putative modulators of FVIII half-life, and discuss the biological mechanisms through which these factors impact upon FVIII clearance in vivo.
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Coagulantes/farmacocinética , Factor VIII/farmacocinética , Hemofilia A/tratamiento farmacológico , Tasa de Depuración Metabólica/fisiología , Factor de von Willebrand/metabolismo , Sistema del Grupo Sanguíneo ABO , Adolescente , Adulto , Anciano , Variación Biológica Poblacional , Niño , Preescolar , Coagulantes/administración & dosificación , Coagulantes/uso terapéutico , Factor VIII/administración & dosificación , Factor VIII/uso terapéutico , Semivida , Hemofilia A/complicaciones , Hemorragia/etiología , Hemorragia/prevención & control , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Adulto JovenAsunto(s)
Infecciones por Coronavirus/terapia , Neumonía Viral/terapia , Adulto , Anciano , Anciano de 80 o más Años , Betacoronavirus/aislamiento & purificación , Transfusión de Componentes Sanguíneos/métodos , COVID-19 , Infecciones por Coronavirus/diagnóstico , Femenino , Humanos , Inmunización Pasiva/métodos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/diagnóstico , SARS-CoV-2 , Resultado del Tratamiento , Sueroterapia para COVID-19RESUMEN
INTRODUCTION: Patients with haemophilia can develop inhibitors to exogenous coagulation factors. Some patients are tolerant to factor, while those who develop inhibitors do so early in life. Genetics and environmental factors are known to contribute to inhibitor risk. However, it is not yet possible to predict inhibitor formation or treatment responsiveness in individuals. We hypothesize that factors in the antenatal/neonatal period inform inhibitor risk development. AIM: To consider the design of longitudinal studies beginning in the antenatal/neonatal period and the use of new technologies to better understand haemophilia inhibitors. METHODS: A working group was formed for the NHLBI State of the Science Workshop: Factor VIII Inhibitors: Generating a National Blueprint for Future Research to solicit input from the US haemophilia community and international collaborators to consider design of pregnancy/birth longitudinal cohorts that leverage -omics, existing phenotypic data, and in silico modelling to study inhibitors. RESULTS: An antenatal/neonatal longitudinal cohort should begin with enrolment of pregnant genetic carriers of haemophilia and span the at-risk period for inhibitor development in the child. Data and samples from the mother, placenta, neonate and young child can be obtained that are amenable to existing assays, genomics and other -omics studies. Data can inform in silico prediction and mathematical models. CONCLUSION: A longitudinal study beginning before birth offers the unique opportunity to study factors that influence inhibitor development prior to exposure. Advances in -omics and computational biology can study complex phenotypes in this rare disease. This study could be accomplished through interdisciplinary efforts and patient community engagement.