13 research outputs found
Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States
Von Willebrand disease (VWD) is the most common inherited bleeding disorder, and type 1
VWD is the most common VWD variant. Despite its frequency, diagnosis of type 1 VWD
remains the subject of much debate. In order to study the spectrum of type 1 VWD in the United
States, the Zimmerman Program enrolled 482 subjects with a previous diagnosis of type 1 VWD
without stringent laboratory diagnostic criteria. VWF laboratory testing and full length VWF
gene sequencing were performed for all index cases and healthy control subjects in a central
laboratory. Bleeding phenotype was characterized using the ISTH Bleeding Assessment Tool.
At study entry, 64% of subjects had VWF:Ag or VWF:RCo below the lower limit of normal,
while 36% had normal VWF levels. VWF sequence variations were most frequent in subjects
with VWF:Ag < 30 IU/dL (82%) while subjects with type 1 VWD and VWF:Ag ≥ 30 IU/dL had
an intermediate frequency of variants (44%). Subjects whose VWF testing was normal at study
entry had a similar rate of sequence variations as the healthy controls at 14% of subjects. All
subjects with severe type 1 VWD and VWF:Ag ≤ 5 IU/dL had an abnormal bleeding score, but
otherwise bleeding score did not correlate with VWF:Ag level. Subjects with a historical
diagnosis of type 1 VWD had similar rates of abnormal bleeding scores compared to subjects
with low VWF levels at study entry. Type 1 VWD in the United States is highly variable, and
bleeding symptoms are frequent in this population
The common VWF single nucleotide variants c.2365A>G and c.2385T>C modify VWF biosynthesis and clearance
Thrombosis and Hemostasi
Haemophilia A and von Willebrand's disease.
Contains fulltext :
88434.pdf (publisher's version ) (Closed access)SUMMARY: Deficient or defective coagulation factor VIII (FVIII) and von Willebrand factor (VWF) can cause bleeding through congenital deficiency or acquired inhibitory antibodies. Recent studies on type 1 von Willebrand's disease (VWD), the most common form of the disease, have begun to explain its pathogenesis. Missense mutations of varying penetrance throughout VWF are the predominant mutation type. Other mutation types also contribute while about one-third of patients have no mutation identified. Enhanced clearance and intracellular retention contribute to pathogenic mechanisms. Chromogenic substrate (CS) methods to determine FVIII coagulant activity have several advantages over one-stage methods, which include minimal influence by variable levels of plasma components, notably lupus anticoagulant. Direct proportionality between FVIII activity and FXa generation results in high resolution at all FVIII levels, rendering the CS method suitable for measuring both high and low levels of FVIII activity. FVIII inhibitors in patients with inherited or acquired haemophilia A present several challenges in their detection and accurate quantification. The Nijmegen method, a modification of the Bethesda assay is recommended for inhibitor analysis by the International Society on Thrombosis and Haemostasis. Understanding potential confounding factors including heparin and residual FVIII in test plasma, plus optimal standardization can reduce assay coefficient of variation to 10-20%.These areas are all explored within this article.1 juli 201
HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. UKHCDO Inhibitor Working Party
Polymorphic variation within the VWF gene contributes to the failure to detect mutations in patients historically diagnosed with type 1 von Willebrand disease from the MCMDM-1VWD cohort
Thrombosis and Hemostasi
Investigation of the Role of Copy Number Variation In the Pathogenesis of Type 1 Von Willebrand Disease
Investigation of the Role of Copy Number Variation In the Pathogenesis of Type 1 Von Willebrand Disease
Thrombosis and Hemostasi
Curated disease-causing genes for bleeding, thrombotic, and platelet disorders: Communication from the SSC of the ISTH
Thrombosis and Hemostasi