67 research outputs found
The elusive and heterogeneous pattern of type 2M von Willebrand disease: A diagnostic challenge
No full textType 2M is a very heterogeneous form of von Willebrand disease (VWD) associated with impaired platelet and von Willebrand factor (VWF) interactions not due to a lack of large VWF multimers
Type 1 von Willebrand disease due to a vicinal cysteine loss (p.C524Y) disclosed after a thrombotic episode
No full textType 2B von Willebrand disease with or without large multimers: A distinction of the two sides of the disorder is long overdue
No full textMost, but not all patients with type 2B von Willebrand disease (VWD)-which features gain-of-function mutations in the A1 domain of von Willebrand factor (VWF)-have no circulating large VWF multimers. Similarities and differences were analysed in 33 type 2B patients, 12 with a normal and 21 with an abnormal multimer pattern, to see whether they should be considered separately. The minimum aggregating dose of ristocetin was similarly reduced in both patient groups, and modulated by their underlying VWF mutations. Platelet VWF content was normal in all patients lacking in large multimers, but sometimes reduced in those with a normal multimer pattern. All the former patients and none of the latter had persistent or transient thrombocytopenia. A short VWF half-life (affecting plasma VWF levels) was seen in both groups, but more pronounced in patients without large multimers. Bleeding scores were also high in all patients, but more so in those without large multimers, apparently regardless of their platelet count. The marked phenotypic heterogeneity of type 2B VWD concerns not only patients' VWF multimer pattern, but also their bleeding risk, and consequently their appropriate treatment too. Hence the need to clearly distinguish between type 2B VWD with normal or abnormal VWF multimers
The labyrinths of Peter Sís. Picture books to travel through space and time
No full textThis essay assumes the concept of the labyrinth in a broad sense, as a picture, as a symbol and as a geometric structure, but also as a narrative structure and as a metaphor: the labyrinth of History, the labyrinths of the mind, the labyrinths of life. The study takes into consideration the special relationship that links spatiality and identity in the Czech-born American artist Peter Sís’s work and examines a selection of the many ‘labyrinths’ present in the author’s biographical and autobiographical picture books, which seem designed to make the reader travel in space and time and to take him off the usual routes. Sís’s illustrations actually seem to be imbued with the mentality of the time the story is set in, furthermore telling biographies far away in time or stories that take place in distant lands, the author invites his young readers into the meanders of personal and collective memory. Moreover, Sís’s books can be considered a means to introduce young readers to topological structures, projective forms and the codes of cartographic language, a means to develop their spatial and reading and prefiguration skills
Cryptic noncanonical splice site activation is part of the mechanism that abolishes multimer organization in the c.2269_2270del von Willebrand factor
No full textWe report a new pathogenic mechanism in von Willebrand disease involving the use of a noncanonical splicing site. The proband, carrying the homozygous c.2269_2270del mutation previously classified as a type 3 mutation, showed severely reduced plasma and platelet von Willebrand factor antigen levels and functions, and no factor VIII binding capacity. A particular von Willebrand factor multimer pattern emerged in plasma, characterized by the presence of only two oligomers: the dimer and an unusually large band, with no intermediate components. There were von Willebrand factor multimers in platelets, but each band ran more slowly than the normal counterpart. No anti- von Willebrand factor antibodies were detectable. The proband was classified as having severe type 1 von Willebrand disease. Seeking the relationship between phenotype and genotype, we found the c.2269_2270del mutation associated with three different RNAs: r.2269_2270del (RNAI), giving a truncated von Willebrand factor protein; r.[2269_2270del;2282_2288del] (RNAII), resulting from activation of a cryptic "AG" splicing site; and r.[2269_2270del;2281_2282insAG] (RNAIII), where the wild-type "AG"acceptor of exon 18 was retained due to the noncanonical 2279-2280 "CG" acceptor splicing site being used. The aberrant RNAII and RNAIII caused the alteration of the furin cleavage and binding sites, respectively, both resulting in a von Willebrand factor protein characterized by the persistence of von Willebrand factor propeptide, as confirmed by Western blot analysis of the recombinant mutated von Willebrand factor molecules produced in vitro. Taken together, these findings explain the residual von Willebrand factor synthesis, slower-running multimers, and absent factor VIII binding capacity. The apparently pure gene null mutation c.2269_2270del profoundly alters von Willebrand factor gene splicing, inducing a complex RNA expression pattern
A model‐based protocol for the diagnosis of von Willebrand disease
No full textVon Willebrand disease (VWD) is one of the main inherited coagulation disorders. It is caused by a deficiency and/or a dysfunction of the von Willebrand factor (VWF), a fundamental multimeric glycoprotein involved in the hemostasis process. Correct detection of the disease is not an easy task because the disease manifests itself in many variants and a high intra-subject variability is observed. For these reasons, the diagnostic clinical trials typically rely on a 24-h sampling protocol, which makes the overall test long, stressful, and costly. Using a new pharmacokinetic model derived from Galvanin et al.'s 2014 study, this study aims at i) assessing the theoretical possibility to perform a shorter clinical test and ii) proposing a set of model-based diagnostic methods as a support for the clinical team. A preliminary information analysis is performed in order to understand which sampling instants are more informative for model identification. This allowed us to propose a novel, 8-h diagnostic protocol, which is still able to ensure model identifiability. Three alternative diagnostic methods are then proposed based on this short-length clinical protocol. One of them directly uses the pharmacokinetic model, whereas the other two are based on the use of three indices (two pharmacokinetic indices, namely clearance, total VWF released, and as third index the basal multimer ratio) to formulate the diagnosis problem as a classification one. The classification problem is then solved using K-nearest neighbours and linear discriminant analysis. Results show the theoretical feasibility of a VWD diagnosis based on a shorter protocol
laboratorio di rappresentazione
No full textargomenti ed esiti del corso: laboratorio di Rappresentazion
Towards the optimal design of a minimum set of clinical trials for the identification and characterization of VWD
No full textVon Willebrand disease is one of the most severe inherited bleeding disorders in humans, characterized by qualitative and/or quantitative defects of the von Willebrand factor protein. Diagnosis is difficult due to the high heterogeneity of the disease. Pharmacokinetic models have been recently proposed and applied to help in the disease characterization and diagnosis. However, the complexity of the models requires long and invasive dynamic non-routine tests to be carried out on the subjects to achieve a statistically satisfactory estimate of the individual metabolic parameters. In this work, it is demonstrated how the use of basal clinical tests and a shorter dynamic clinical test may allow for the identification of a mechanistic model of the disease. An existing mechanistic model of von Willebrand disease has been modified to account for the basal tests, where new model equations are derived using response surface methodology. Results show a good agreement between the model response and the clinical data
No von Willebrand factor domains other than A1 are involved in type 2B von Willebrand disease: what the p.R924Q and p.A2178S variants teach us
No full textThe Lesson Learned from the New c.2547-1G>T Mutation Combined with p.R854Q: When a Type 2N Mutation Reveals a Quantitative von Willebrand Factor Defect
No full textType 2N is a rare von Willebrand disease (VWD) variant involving an impairment in the factor VIII (FVIII) carrier function of von Willebrand factor (VWF). It has a phenotype that mimics hemophilia A, and FVIII binding to VWF (VWF:FVIIIB) is tested to differentiate between the two disorders. Type 2N VWF defects may also be associated with quantitative VWF mutations (type 2N/type 1), further complicating the identification of cases. We report on a new quantitative VWF mutation (c.2547-1G > T) revealed by a p.R854Q type 2N mutation acting as homozygous despite being carried as a heterozygous defect. The proband had near-normal VWF levels (initially ruling out a defective VWF synthesis) and slightly reduced FVIII levels, while a VWF:FVIIIB test showed significantly reduced binding. Routine tests on type 2N homozygotes or heterozygotes combined with quantitative VWF defects in our cohort showed reduced FVIII levels in both groups, but it was only in the former that the FVIII/VWF antigen (VWF:Ag) ratio was always significantly reduced. The two tests are therefore not enough to identify all forms of type 2N VWD. While relatives of type 2N homozygotes usually have normal FVIII levels and FVIII/VWF:Ag ratios, relatives of type 2N/type 1 may have high FVIII/VWF:Ag ratios, but their VWF:FVIIIB and/or VWF:FVIIIB/VWF:Ag ratios are always low. Measuring FVIII and VWF levels may therefore suggest type 2N VWD in patients carrying type 2N mutations alone, but not in type 2N combined with quantitative VWF defects. The VWF:FVIIIB test should consequently be included when exploring VWF function, whatever VWD patient's phenotype
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