Additional markers for genetic diagnosis of type 3 von Willebrand disease in Indian population.
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ABSTRACT:
SUBMITTER: Kasatkar P
PROVIDER: S-EPMC4774073 | biostudies-literature | 2015 Dec
REPOSITORIES: biostudies-literature
Publications
Additional markers for genetic diagnosis of type 3 von Willebrand disease in Indian population.
Kasatkar Priyanka P Ghosh Kanjaksha K Shetty Shrimati S
The Indian journal of medical research 20151201 6
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Project description:BackgroundThough von Willebrand disease (VWD) is a common coagulation disorder, due to the complexity of the molecular analysis of von Willebrand factor gene (VWF), not many reports are available from this country. Large size of the gene, heterogeneous nature of mutations and presence of a highly homologous pseudogene region are the major impediments in the genetic diagnosis of VWD. The study is aimed at unravelling the molecular pathology in a large series of VWD patients from India using an effective strategy.MethodWe evaluated 85 unrelated Indian type 3 VWD families to identify the molecular defects using a combination of techniques i.e. PCR-RFLP, direct DNA sequencing and multiple ligation probe amplification (MLPA).ResultsMutations could be characterized in 77 unrelated index cases (ICs). 59 different mutations i.e. nonsense 20 (33.9%), missense 13 (22%), splice site 4 (6.8%), gene conversions 6 (10.2%), insertions 2 (3.4%), duplication 1 (1.7%), small deletions 10 (17%) and large deletions 3 (5.1%) were identified, of which 34 were novel. Two common mutations i.e. p.R1779* and p.L970del were identified in our population with founder effect. Development of alloantibodies to VWF was seen in two patients, one with nonsense mutation (p.R2434*) and the other had a large deletion spanning exons 16-52.ConclusionThe molecular pathology of a large cohort of Indian VWD patients could be identified using a combination of techniques. A wide heterogeneity was observed in the nature of mutations in Indian VWD patients.
| S-EPMC3967998 | biostudies-literature
Project description:BackgroundPhenotypic von Willebrand disease (VWD) classification requires multiple tests including analysis of multimeric distributions von Willebrand factor (VWF) and evaluation of its structure. VWF multimer analysis is labor intensive, nonstandardized, and limited to specialized laboratories. A commercial semiautomatic assay, HYDRAGEL VW multimer assay (H5/11VWM, Sebia), has become available.ObjectivesEstablishment of reference ranges for H5/11VWM to improve VWD classification.MethodsImplementation validation, establishment and validation of normal and pathological reference intervals (NRIs/PRIs), comparison with in-house method using 40 healthy volunteers and 231 VWD patients.ResultsQualitative and quantitative validation of NRI obtained sensitivity of 88% and 79%, respectively, for type 2. Comparison of the two methods showed an overall concordance of 86% with major conflicting results in all atypical 2B (n = 7) and 50% 2M-GPIb (n = 41) showing quantitative and qualitative multimeric loss, that was not detected with in-house method. We were able to use established PRIs, with 73% validity in type 2 cases, to distinguish individual type 2A subtypes (IIA, IIC, IID, IIE) from 2M and 2B.ConclusionH5/11VWM could be used for all clinical purposes because its reliability and its rapid and accurate diagnostic ability and reduced observer bias. Although H5/11VWM cannot evaluate triplet structures, we were able to define 2A subtypes by stripping back to the percentage of intermediate/high-molecular-weight multimers. H5/11HWM could be an efficient and widely available alternative for the "gold standard" technique.
| S-EPMC7443431 | biostudies-literature
Project description:Progress in both basic and translational research into the molecular mechanisms of VWD can be seen in multiple fields.Genetics of vwdIn the past several decades, knowledge of the underlying pathogenesis of von Willebrand disease (VWD) has increased tremendously, thanks in no small part to detailed genetic mapping of the von Willebrand Factor (VWF) gene and advances in genetic and bioinformatic technology. However, these advances do not always easily translate into improved management for patients with VWD and low-VWF levels.Vwd and pregnancyFor example, the treatment of pregnant women with VWD both pre- and postpartum can be complicated. While knowledge of the VWF genotype at some amino acid positions can aid in knowledge of who may be at increased risk of thrombocytopenia or insufficient increase in VWF levels during pregnancy, in many cases, VWF levels and bleeding severity is highly heterogeneous, making monitoring recommended during pregnancy to optimize treatment strategies. VWF AND COVID-19: New challenges related to the consequences of dysregulation of hemostasis continue to be discovered. The ongoing COVID-19 pandemic has highlighted that VWF has additional biological roles in the regulation of inflammatory disorders and angiogenesis, disruption of which may contribute to COVID-19 induced vasculopathy. Increased endothelial cell activation and Weibel-Palade body exocytosis in severe COVID-19 lead to markedly increased plasma VWF levels. Coupled with impairment of normal ADAMTS13 multimer regulation, these data suggest a role for VWF in the pathogenesis underlying pulmonary microvascular angiopathy in severe COVID-19.ConclusionWith the increased affordability and availability of next-generation sequencing techniques, as well as a push towards a multi-omic approach and personalized medicine in human genetics, there is hope that translational research will improve VWD patient outcomes.
| S-EPMC9094051 | biostudies-literature
Project description:von Willebrand factor (VWF) level and function are influenced by genetic variation in VWF and several other genes in von Willebrand disease type 1 (VWD1) patients. This study comprehensively screened for VWF variants and investigated the presence of ABO genotypes and common and rare VWF variants in Swedish VWD1 patients. The VWF gene was resequenced using Ion Torrent and Sanger sequencing in 126 index cases historically diagnosed with VWD. Exon 7 of the ABO gene was resequenced using Sanger sequencing. Multiplex ligation-dependent probe amplification analysis was used to investigate for copy number variants. Genotyping of 98 single nucleotide variants allowed allele frequency comparisons with public databases. Seven VWD2 mutations and 36 candidate VWD1 mutations (5 deletions, 4 nonsense, 21 missense, 1 splice, and 5 synonymous mutations) were identified. Nine mutations were found in more than one family and nine VWD1 index cases carried more than one candidate mutation. The T-allele of rs1063857 (c.2385T > C, p.Y795 = ) and blood group O were both frequent findings and contributed to disease in the Swedish VWD1 population. VWD2 mutations were found in 20 and candidate VWD1 mutations in 51 index cases out of 106 (48%). VWF mutations, a VWF haplotype, and blood group O all contributed to explain disease in Swedish VWD1 patients.
| S-EPMC6524857 | biostudies-literature
Project description:von Willebrand disease (VWD) is associated with significant morbidity as a result of excessive mucocutaneous bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of diagnostic tests using different cutoff values of von Willebrand factor antigen (VWF:Ag) and platelet-dependent von Willebrand factor (VWF) activity assays in the diagnosis of VWD. We searched Cochrane Central Register for Controlled Trials, MEDLINE, and Embase databases for eligible studies. We pooled estimates of sensitivity and specificity and reported patient-important outcomes when relevant. This review included 21 studies that evaluated VWD diagnosis. The results showed low certainty in the evidence for a net health benefit from reconsidering the diagnosis of VWD vs removing the disease diagnosis in patients with VWF levels that have normalized with age. For the diagnosis of type 1 VWD, VWF sequence variants were detected in 75% to 82% of patients with VWF:Ag < 0.30 IU/mL and in 44% to 60% of patients with VWF:Ag between 0.30 and 0.50 IU/mL. A sensitivity of 0.90 (95% confidence interval [CI], 0.83-0.94) and a specificity of 0.91 (95% CI, 0.76-0.97) were observed for a platelet-dependent VWF activity/VWF:Ag ratio < 0.7 in detecting type 2 VWD (moderate certainty in the test accuracy results). VWF:Ag and platelet-dependent activity are continuous variables that are associated with an increase in bleeding risk with decreasing levels. This systematic review shows that using a VWF activity/VWF:Ag ratio < 0.7 vs lower cutoff levels in patients with an abnormal initial VWD screen is more accurate for the diagnosis of type 2 VWD.
| S-EPMC8753202 | biostudies-literature
Project description:BackgroundIn type 1 von Willebrand Disease (VWD) patients, von Willebrand Factor (VWF) levels and bleeding symptoms are highly variable. Recently, the association between genetic variations in STXBP5 and STX2 with VWF levels has been discovered in the general population. We assessed the relationship between genetic variations in STXBP5 and STX2, VWF levels, and bleeding phenotype in type 1 VWD patients.MethodsIn 158 patients diagnosed with type 1 VWD according to the current ISTH guidelines, we genotyped three tagging-SNPs in STXBP5 and STX2 and analyzed their relationship with VWF:Ag levels and the severity of the bleeding phenotype, as assessed by the Tosetto bleeding score.ResultsIn STX2, rs7978987 was significantly associated with VWF:Ag levels (bèta-coefficient (β) = -0.04 IU/mL per allele, [95%CI -0.07;-0.001], p = 0.04) and VWF:CB activity (β = -0.12 IU/mL per allele, [95%CI -0.17;-0.06], p<0.0001). For rs1039084 in STXBP5 a similar trend with VWF:Ag levels was observed: (β = -0.03 IU/mL per allele [95% CI -0.06;0.003], p = 0.07). In women, homozygous carriers of the minor alleles of both SNPs in STXBP5 had a significantly higher bleeding score than homozygous carriers of the major alleles. (Rs1039084 p = 0.01 and rs9399599 p = 0.02).ConclusionsGenetic variation in STX2 is associated with VWF:Ag levels in patients diagnosed with type 1 VWD. In addition, genetic variation in STXBP5 is associated with bleeding phenotype in female VWD patients. Our findings may partly explain the variable VWF levels and bleeding phenotype in type 1 VWD patients.
| S-EPMC3391281 | biostudies-literature
Project description:Recent studies have reported that patients with von Willebrand disease treated perioperatively with a von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a ratio of 2.4:1 (Humate P/Haemate P) often present with VWF and/or FVIII levels outside of prespecified target levels necessary to prevent bleeding. Pharmacokinetic (PK)-guided dosing may resolve this problem. As clinical guidelines increasingly recommend aiming for certain target levels of both VWF and FVIII, application of an integrated population PK model describing both VWF activity (VWF:Act) and FVIII levels may improve dosing and quality of care. In total, 695 VWF:Act and 894 FVIII level measurements from 118 patients (174 surgeries) who were treated perioperatively with the VWF/FVIII concentrate were used to develop this population PK model using nonlinear mixed-effects modeling. VWF:Act and FVIII levels were analyzed simultaneously using a turnover model. The protective effect of VWF:Act on FVIII clearance was described with an inhibitory maximum effect function. An average perioperative VWF:Act level of 1.23 IU/mL decreased FVIII clearance from 460 mL/h to 264 mL/h, and increased FVIII half-life from 6.6 to 11.4 hours. Clearly, in the presence of VWF, FVIII clearance decreased with a concomitant increase of FVIII half-life, clarifying the higher FVIII levels observed after repetitive dosing with this concentrate. VWF:Act and FVIII levels during perioperative treatment were described adequately by this newly developed integrated population PK model. Clinical application of this model may facilitate more accurate targeting of VWF:Act and FVIII levels during perioperative treatment with this specific VWF/FVIII concentrate (Humate P/Haemate P).
| S-EPMC7948283 | biostudies-literature
Project description: Not available
| S-EPMC5664402 | biostudies-literature
Project description:BackgroundPlatelet-type von Willebrand disease (PT-VWD) is a rare autosomal dominant disorder. It is caused by gain-of-function gene variants in the platelet GP1BA, which results in excessive binding between GPIbα and von Willebrand factor (VWF). The prevalence of PT-VWD is unknown.ObjectivesTo establish the worldwide and within distinct ethnic groups prevalence of PT-VWD.MethodsWe used available exome and genome sequencing data of 807,162 (730,947 exomes and 76,215 genomes) subjects from the Genome Aggregation Database (gnomAD-v4.1).ResultsAmong the 1,614,324 alleles analyzed in the gnomAD population, there were 1397 distinct GP1BA variants. Of them, 4 variants (p.Arg127Gln, p.Leu194Phe, p.Gly249Val, and p.Met255Ile) have been previously reported to cause PT-VWD. Considering these 4 known pathogenic variants, we estimated a global PT-VWD prevalence of 136 cases/106. The highest estimated prevalence of PT-VWD was found in Africans/African Americans (160/106), Finnish (156/106), Europeans (149/106), and South Asians (110/106), followed by Ashkenazi Jewish (68/106) and East Asian (45/106) ethnicities. In the population with no assigned ethnicity, a prevalence of 126/106 was estimated. Since no pathogenic GP1BA variants that were previously reported to cause PT-VWD were found in Admixed American and Middle Eastern ethnicities, we were unable to estimate the PT-VWD prevalence in these 2 populations. We found a global prevalence of 2.5/106 for severe PT-VWD and 134/106 for the mild form.ConclusionThis population-based genetic epidemiology analysis indicates a substantially higher than expected frequency of PT-VWD. This novel finding suggests that a large number of PT-VWD patients are still under- or misdiagnosed.
| S-EPMC11836505 | biostudies-literature
Project description:von Willebrand disease is a common inherited bleeding disorder characterized by excessive mucocutaneous bleeding. Characteristic bleeding symptoms include epistaxis, easy bruising, oral cavity bleeding, menorrhagia, bleeding after dental extraction, surgery, and/or childbirth, and in severe cases, bleeding into joints and soft tissues. There are three subtypes: types 1 and 3 represent quantitative variants and type 2 is a group of four qualitative variants: (1) type 2A-characterized by defective von Willebrand factor-dependent platelet adhesion because of decreased high-molecular-weight von Willebrand factor multimers, (2) type 2B-caused by pathologically increased von Willebrand factor-platelet interactions, (3) type 2M-caused by decreased von Willebrand factor-platelet interactions not based on the loss of high-molecular-weight multimers, and (4) type 2N-characterized by reduced binding of von Willebrand factor to factor VIII. The diagnosis of von Willebrand disease requires specialized assays of von Willebrand factor and/or molecular genetic testing of von Willebrand factor. Severe bleeding episodes can be prevented or controlled with intravenous infusions of virally inactivated plasma-derived clotting factor concentrates containing both von Willebrand factor and factor VIII. Depending on the von Willebrand disease type, mild bleeding episodes usually respond to intravenous or subcutaneous treatment with desmopressin, a vasopressin analog. Other treatments that can reduce symptoms include fibrinolytic inhibitors and hormones for menorrhagia.
| S-EPMC3832952 | biostudies-literature