Fifth Åland Island conference on von Willebrand disease

Berntorp, Erik; Ågren, Anna; Aledort, Louis M.; Blombäck, Margareta; Cnossen, Marjon H.; Croteau, Stacy E.; Depka, Mario von; Federici, Augusto B.; Goodeve, Anne; Goudemand, Jenny; Mannucci, Pier Mannuccio; Mourik, Marjon J; Önundarson, Páll T.; Rodeghiero, Francesco; Szántó, Tímea; Windyga, Jerzy

doi:10.1111/hae.13475

Cited by 9 publications

(14 citation statements)

References 111 publications

(311 reference statements)

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“…Of note, data from a large French study of VWD 68,69 were generally consistent with those from the multicenter Spanish PCM-EVW-ES study. The percentage of patients with type 1 and type 3 VWD was similar in the French and Spanish studies, although there was some variation in the distribution of type 2 subtypes.…”

Section: Functional Studies Employing Cell Linessupporting

confidence: 70%

Update on Molecular Testing in von Willebrand Disease

Batlle

Pérez‐Rodríguez

Corrales

et al. 2019

Semin Thromb Hemost

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Diagnosis of von Willebrand disease (VWD) depends on personal and family history of bleeding and confirmatory laboratory testing. Currently available phenotypic tests for VWD contain potential sources for error that may distort results. Despite an exponential growth of information about the von Willebrand factor gene (VWF), the role of molecular diagnosis in VWD is still controversial. Due to the complexity and high cost of conventional molecular analyses, some investigators have recommended limiting this approach to distinguish suspected type 2N VWD from hemophilia A, type 2B from platelet-type VWD, and the exploration of type 3 VWD. New genetic methodologies and approaches are becoming available, but there is still some reluctance for their implementation in VWD diagnosis. This article discusses the pros and cons of molecular testing in VWD considering the experience obtained through the multicenter project “Molecular and Clinical Profile of VWD in Spain (PCM-EVW-ES).”

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Section: Functional Studies Employing Cell Linessupporting

confidence: 70%

Update on Molecular Testing in von Willebrand Disease

Batlle

Pérez‐Rodríguez

Corrales

et al. 2019

Semin Thromb Hemost

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“…For example, low VWF collagen binding (VWF:CB) compared with Ag is generally evident in type 2A VWD, but only in some cases of type 2M. A generally accepted consensus is to define type 2A and type 2M using a cut-off value below 0.6 for VWF activity/protein ratio [4][5][6][7][8] ; that is VWF:RCo/VWF:Ag (-RCo/Ag), 7 VWF:GPIbM/Ag, VWF:GPIbR/Ag, and/or low VWF:-CB/Ag (CB/Ag). 8 Differential phenotypic diagnosis can be assisted by performing multimeric analysis.…”

mentioning

confidence: 99%

Type 2A and 2M von Willebrand Disease: Differences in Phenotypic Parameters According to the Affected Domain by Disease-Causing Variants and Assessment of Pathophysiological Mechanisms

Woods

Paiva

Primrose

et al. 2021

Semin Thromb Hemost

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Type 2A and 2M von Willebrand disease (VWD) broadly show similar phenotypic parameters, but involve different pathophysiological mechanisms. This report presents the clinical and laboratory profiles of type 2A and type 2M patients genotypically diagnosed at one large center. Higher bleeding score values and a higher incidence of major bleeding episodes were observed in type 2A compared with type 2M, potentially reflective of the absence of large and intermediate von Willebrand factor (VWF) multimers in 2A. In type 2A, most of disease-causing variants (DCVs) appeared to be responsible for increased VWF clearance and DCV clustered in the VWF-A1 domain resulted in more severe clinical profiles. In type 2M, DCV in the VWF-A1 domain showed different laboratory patterns, related to either reduced synthesis or shortened VWF survival, and DCV in the VWF-A2 domain showed patterns related mainly to shortened survival. VWF-type 1 collagen binding/Ag (C1B/Ag) showed different patterns according to DCV location: in type 2A VWD, C1B/Ag was much lower when DCVs were located in the VWF-A2 domain. In type 2M with DCV in the VWF-A1domain, C1B/Ag was normal, but with DCV in the VWF-A2 domain, C1B/Ag was low. The higher frequency of major bleeding in VWD 2M patients with DCV in the VWF-A2 domain than that with DCV in the VWF-A1 domain could be a summative effect of abnormal C1B/Ag, on top of the reduced VWF-GPIb binding. In silico modeling suggests that DCV impairing the VWF-A2 domain somehow modulates collagen binding to the VWF-A3 domain. Concomitant normal FVIII:C/Ag and VWFpp/Ag, mainly in type 2M VWD, suggest that other nonidentified pathophysiological mechanisms, neither related to synthesis/retention nor survival of VWF, would be responsible for the presenting phenotype.

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“…Consistent with the lack of selection for VWF fragments spanning the platelet-binding A1 domain, patient I-1’s alloantibodies did not inhibit the ristocetin cofactor activity of infused VWF[24]. Patients II-1 and II-2, brothers both homozygous for a large deletion in VWF (c.658_7887del)[23], developed inhibitors with highly similar profiles in the selection of phage-displayed VWF fragments. Similar immunoreactivity to the D3, A1, A3, and D4 domains of mature VWF were found in both patients (Figure 2).…”

Section: Resultsmentioning

confidence: 94%

“…Magnetic protein G beads (New England Biolabs) were blocked in antibody selection buffer and used to immobilize 10-15μg polyclonal rabbit anti-VWF (Dako A0082, lots 00045319 and 00051141) or immunoglobulin G (IgG) in platelet poor plasma (PPP) from patients diagnosed with an inhibitor against VWF. Following informed consent with protocols approved by Institutional Review Boards of the University of Michigan and of Boston Children’s Hospital, PPP containing anti-VWF alloantibodies were collected from previously described pediatric patients diagnosed with type 3 VWD and inhibitors to plasma-derived VWF concentrate[23, 24]. PPP was prepared by centrifugation as previously described[1].…”

Section: Methodsmentioning

confidence: 99%

Phage Display Broadly Identifies Inhibitor-reactive Regions in von Willebrand Factor

Yee

Dai

Croteau

et al. 2021

Preprint

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Background: Correction of von Willebrand factor (VWF) deficiency with replacement products containing VWF can lead to the development of anti-VWF alloantibodies (i.e., VWF inhibitors) in patients with severe von Willebrand disease (VWD). Objective: Locate inhibitor-reactive regions within VWF using phage display. Methods: We screened a phage library displaying random, overlapping fragments covering the full length VWF protein sequence for binding to a commercial anti-VWF antibody or to immunoglobulins from three type 3 VWD patients who developed VWF inhibitors in response to treatment with plasma-derived VWF. Immunoreactive phage clones were identified and quantified by next generation DNA sequencing (NGS). Results: NGS markedly increased the number of phage analyzed for locating immunoreactive regions within VWF following a single round of selection and identified regions not recognized in previous reports using standard phage display methods. Extending this approach to characterize VWF inhibitors from three type 3 VWD patients (including two siblings homozygous for the same VWF gene deletion) revealed patterns of immunoreactivity distinct from the commercial antibody and between unrelated patients, though with notable areas of overlap. Alloantibody reactivity against the VWF propeptide is consistent with incomplete removal of the propeptide from plasma-derived VWF replacement products. Conclusion: These results demonstrate the utility of phage display and NGS to characterize diverse anti-VWF antibody reactivities.

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Fifth Åland Island conference on von Willebrand disease

Cited by 9 publications

References 111 publications

Update on Molecular Testing in von Willebrand Disease

Update on Molecular Testing in von Willebrand Disease

Type 2A and 2M von Willebrand Disease: Differences in Phenotypic Parameters According to the Affected Domain by Disease-Causing Variants and Assessment of Pathophysiological Mechanisms

Phage Display Broadly Identifies Inhibitor-reactive Regions in von Willebrand Factor

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