von Willebrand’s disease diagnosis and laboratory issues

Castaman, Giancarlo; Montgomery, Robert R.; Meschengieser, Susana S.; Haberichter, Sandra L.; Woods, Adriana Inés; Lazzari, M.A.

doi:10.1111/j.1365-2516.2010.02296.x

Cited by 19 publications

(28 citation statements)

References 40 publications

(44 reference statements)

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“…Challenges in making the available diagnostic tests more uniform and available, as well as introducing newer tests with less potential for error, will be other issues to be addressed in the future. The ristocetin cofactor assay, the gold standard for measurement of VWF function, has significant shortcomings including a wide coefficient of variation and identification of a recent exon 28 single nucleotide polymorphism that is associated falsepositive test results [138,139]. While the collagen-binding assay is not adversely affected by this SNP, this test is not well standardized yet and differences in types of collagen have been demonstrated to significantly influence results.…”

Section: Five-year Viewmentioning

confidence: 97%

“…While the collagen-binding assay is not adversely affected by this SNP, this test is not well standardized yet and differences in types of collagen have been demonstrated to significantly influence results. ELISAbased assays measuring the interaction rGPIba offering a promising alternative to the existing functional assays but further investigation is required [138]. VWF multimers assays which are critical to differentiation of different types of VWD are resource intensive and only available at a limited number of reference labs.…”

Section: Five-year Viewmentioning

confidence: 99%

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An update on type 2B von Willebrand disease

Mikhail

Aldin

Streiff

et al. 2014

Expert Review of Hematology

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Type 2B von Willebrand disease (VWD) accounts for fewer than 5% of all VWD patients. In this disease, mutations in the A1 domain result in increased von Willebrand factor (VWF) binding to platelet GPIbα receptors, causing increased platelet clearance and preferential loss of high molecular weight VWF multimers. Diagnosis is complicated because of significant clinical variations even among patients with identical mutations. Platelet transfusion often provides suboptimal results since transfused platelets may be aggregated by the patients' abnormal VWF. Desmopressin may cause a transient decrease in platelet count that could lead to an increased risk of bleeding. Replacement therapy with factor VIII/VWF concentrates is the most effective approach to prevention and treatment of bleeding in type 2B VWD.

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Section: Five-year Viewmentioning

confidence: 97%

Section: Five-year Viewmentioning

confidence: 99%

An update on type 2B von Willebrand disease

Mikhail

Aldin

Streiff

et al. 2014

Expert Review of Hematology

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“…Such a regulatory role of VWFpp-VWF binding may be more pronounced during diseases in which the mature VWF half-life in circulation is reduced, either due to autoimmune Abs or to mutations such as those identified in type 1C (Vicenza and other mutations), type 2A, type 2B, or platelet-type pseudo-VWD. 43 Under these circumstances, the VWFpp:VWF ratio increases from approximately 1.0 in healthy subjects to 2-11 during disease. 22 Finally, VWF/VWFpp mutations that enhance VWFpp-DЈD3 binding affinity can enhance the role of VWFpp in regulating hemostasis.…”

Section: Vwfpp-vwf-dd3 Interaction Attenuates Vwf-a1 Binding To Platementioning

confidence: 98%

von Willebrand factor (VWF) propeptide binding to VWF D′D3 domain attenuates platelet activation and adhesion

Madabhushi

Shang

Dayananda

et al. 2012

Blood

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Noncovalent association between the von Willebrand factor (VWF) propeptide (VWFpp) and mature VWF aids N-terminal multimerization and protein compartmentalization in storage granules. This association is currently thought to dissipate after secretion into blood. In the present study, we examined this proposition by quantifying the affinity and kinetics of VWFpp binding to mature VWF using surface plasmon resonance and by developing novel anti-VWF D'D3 mAbs. Our results show that the only binding site for VWFpp in mature VWF is in its D'D3 domain. At pH 6.2 and 10mM Ca(2+), conditions mimicking intracellular compartments, VWFpp-VWF binding occurs with high affinity (K(D) = 0.2nM, k(off) = 8 × 10(-5) s(-1)). Significant, albeit weaker, binding (K(D) = 25nM, k(off) = 4 × 10(-3) s(-1)) occurs under physiologic conditions of pH 7.4 and 2.5mM Ca(2+). This interaction was also observed in human plasma (K(D) = 50nM). The addition of recombinant VWFpp in both flow-chamber-based platelet adhesion assays and viscometer-based shear-induced platelet aggregation and activation studies reduced platelet adhesion and activation partially. Anti-D'D3 mAb DD3.1, which blocks VWFpp binding to VWF-D'D3, also abrogated platelet adhesion, as shown by shear-induced platelet aggregation and activation studies. Our data demonstrate that VWFpp binding to mature VWF occurs in the circulation, which can regulate the hemostatic potential of VWF by reducing VWF binding to platelet GpIbα.

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“…von Willebrand's disease (VWD) is characterized by a defect in both primary and secondary haemostasis depending on the platelet–platelet and platelet–endothelium interaction on the one hand and thrombin generation due to reduced FVIII levels on the other hand . Desmopressin (DDAVP) and plasma‐derived VWF/FVIII (von Willebrand factor) concentrates are well‐established therapies in most types of VWD.…”

Section: Introductionmentioning

confidence: 99%

Increased amounts of von Willebrand factor are bound to microparticles after infusion of desmopressin

et al. 2012

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Effects of desmopressin (DDAVP) in platelet disorders and primary haemostasis cannot be attributed solely to the increase in FVIII/VWF (von Willebrand factor), as VWF/FVIII concentrates have no effect in these circumstances. Microparticles (MP) can support haemostasis by expression of phospholipids, tissue factor and VWF on their surface. We hypothesized that significant amounts of VWF are bound to MP after DDAVP administration and that consequently depletion of MP should influence VWF:Ag and VWF:RCo plasma levels. Platelet-poor plasma was either obtained well from healthy controls or before and after DDAVP administration from patients with von Willebrand's disease (type 1 or possible type 1) or patients with other bleeding disorders as controls. Concentrations of MP and VWF parameters were determined before and after MP depletion by different methods (magnetic bead selection, plasma microfiltration, ultracentrifugation). Platelet MP and VWF-bearing MP were significantly increased after DDAVP. MP depletion by magnetic bead selection led to a significant reduction in VWF:Ag (-18.0%) and VWF:RCo (-27.7%) plasma levels without changes in VWF multimer composition. As results were similar for DDAVP control subjects, the amount of VWF bound to circulating microparticles was significantly higher after DDAVP administration compared with healthy controls (reduction -11.7%). DDAVP leads to a release of microparticles and increases the amount of VWF bound to microparticles which might explain the clinical efficacy of DDAVP in platelet disorders.

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von Willebrand’s disease diagnosis and laboratory issues

Cited by 19 publications

References 40 publications

An update on type 2B von Willebrand disease

An update on type 2B von Willebrand disease

von Willebrand factor (VWF) propeptide binding to VWF D′D3 domain attenuates platelet activation and adhesion

Increased amounts of von Willebrand factor are bound to microparticles after infusion of desmopressin

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