Platelet-Type von Willebrand Disease: Toward an Improved Understanding of the “Sticky Situation”

Othman, Maha; Emsley, Jonas

doi:10.1055/s-0033-1364182

Cited by 21 publications

(11 citation statements)

References 31 publications

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“…C), GATA1 or GFI1B macrothrombocytopenia (Fig. D), whereas the observation of platelet agglutinates suggested von Willebrand disease type 2B or platelet‐type von Willebrand disease , two disorders that could not be further characterized by immunofluorescence analysis.…”

Section: Resultsmentioning

confidence: 99%

Diagnosis of inherited platelet disorders on a blood smear: a tool to facilitate worldwide diagnosis of platelet disorders

Greinacher

Pecci

Kunishima

et al. 2017

Journal of Thrombosis and Haemostasis

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Background Many hereditary thrombocytopenias and/or platelet function disorders have been identified, but diagnosis of these conditions remains challenging. Diagnostic laboratory techniques are available only in a few specialized centers and, using fresh blood, often require the patient to travel long distances. For the same reasons, patients living in developing countries usually have limited access to diagnosis. Further, the required amount of blood is often prohibitive for pediatric patients. Objectives By a collaborative international approach of four centers, we aimed to overcome these limitations by developing a method using blood smears prepared from less than 100 μL blood, for a systematic diagnostic approach to characterize the platelet phenotype. Methods We applied immunofluorescence labelling (performed centrally) to standard air-dried peripheral blood smears (prepared locally, shipped by regular mail), using antibodies specific for proteins known to be affected in specific hereditary platelet disorders. Results By immunofluorescence labelling of blood smears we characterized the underlying cause in 877/3217 (27%) patients with suspected hereditary platelet disorders (HPD). Currently about 50 genetic causes for HPD are identified. Among those, the blood smear method was especially helpful to identify MYH9 disorders/MYH9-related disease, biallelic Bernard-Soulier syndrome, Glanzmann thrombasthenia and gray platelet syndrome. Diagnosis could be established for GATA1 macrothrombocytopenia, GFI1B macrothrombocytopenia, ß1-tubulin macrothrombocytopenia, filamin A-related thrombocytopenia and Wiskott-Aldrich syndrome. Conclusion Combining basic and widely available preanalytical methods with the immunomorphological techniques presented here, allows detailed characterization of the platelet phenotype. This supports genetic testing and facilitates diagnosis of hereditary platelet disorders for patients of all ages around the world.

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Section: Resultsmentioning

confidence: 99%

Diagnosis of inherited platelet disorders on a blood smear: a tool to facilitate worldwide diagnosis of platelet disorders

Greinacher

Pecci

Kunishima

et al. 2017

Journal of Thrombosis and Haemostasis

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“…Our observations do not explicitly observe a β‐hairpin conformation, but hydrogen deuterium exchange is significantly less in WT than in the PT‐VWD variants (Figure ), indicating that this sequence is more ordered in WT. Othman and Emsley have suggested that a compact triangular conformation of the β‐switch involving a 3 10 helix stabilized by some hydrogen bonds and salt bridges is disrupted by PT‐VWD mutations. This may explain the apparent asymmetry of the hydrogen exchange observed in the β‐switch for M239V and G233V (Figure B).…”

Section: Discussionmentioning

confidence: 99%

“…Early modeling of the β‐switch sequence suggested two conformers involving either a β‐turn or an amphipathic helix, but the observed crystal structure differences of GPIbα, free and bound to A1, immediately imply that a coil to β‐hairpin transition occurs upon binding, hence the name “β‐switch.” This structural interpretation has led to the hypothesis (Figure ) that PT‐VWD mutations shift this conformational equilibrium in favor of the β‐hairpin structure . Simulations have indicated that even fluid shear flow can induce a β‐hairpin conformation that is accelerated by the mutations …”

Section: Introductionmentioning

confidence: 99%

“…This structural interpretation has led to the hypothesis (Figure 1) that PT-VWD mutations shift this conformational equilibrium in favor of the β-hairpin structure. 40,41 Simulations have indicated that even fluid shear flow can induce a β-hairpin conformation 42 that is accelerated by the mutations. [43][44][45] In this study, hydrogen deuterium exchange mass spectrometry (HXMS) is utilized to test this hypothesis (Figure 1) with the common GPIbα variants G233V, M239V, W230L, D235Y, and a double variant, G233V/M239V, that has found applications in clinical assays of VWF function.…”

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confidence: 99%

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Platelet‐type von Willebrand disease: Local disorder of the platelet GPIbα β‐switch drives high‐affinity binding to von Willebrand factor

Tischer

Machha

Moon‐Tasson

et al. 2019

Journal of Thrombosis and Haemostasis

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Background Mutations in the β‐switch of GPIbα cause gain‐of‐function in the platelet‐type von Willebrand disease. Structures of free and A1‐bound GPIbα suggest that the β‐switch undergoes a conformational change from a coil to a β‐hairpin. Objectives Platelet‐type von Willebrand disease (VWD) mutations have been proposed to stabilize the β‐switch by shifting the equilibrium in favor of the β‐hairpin, a hypothesis predicated on the assumption that the complex crystal structure between A1 and GPIbα is the high‐affinity state. Methods Hydrogen‐deuterium exchange mass spectrometry is employed to test this hypothesis using G233V, M239V, G233V/M239V, W230L, and D235Y disease variants of GPIbα. If true, the expectation is a decrease in hydrogen‐deuterium exchange within the β‐switch as a result of newly formed hydrogen bonds between the β‐strands of the β‐hairpin. Results Hydrogen—exchange is enhanced, indicating that the β‐switch favors the disordered loop conformation. Hydrogen—exchange is corroborated by differential scanning calorimetry, which confirms that these mutations destabilize GPIbα by allowing the β‐switch to dissociate from the leucine‐rich‐repeat (LRR) domain. The stability of GPIbα and its A1 binding affinity, determined by surface plasmon resonance, are correlated to the extent of hydrogen exchange in the β‐switch. Conclusion These studies demonstrate that GPIbα with a disordered loop is binding‐competent and support a mechanism in which local disorder in the β‐switch exposes the LRR—domain of GPIbα enabling high‐affinity interactions with the A1 domain.

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“…In vitro platelet aggregation after stimulation with ristocetin is greatly reduced or absent in patients with biallelic BSS: this diagnosis is confirmed by flow cytometry (see below) . Conversely, an abnormally increased response to ristocetin, sometime associated with spontaneous platelet aggregation upon stirring, suggests platelet‐type or type 2 von Willebrand disease . Some patients with MYH9 ‐RD do not present Döhle‐like bodies at examination of conventionally stained blood films or these inclusions may escape detection because they are faint and/or small .…”

Section: Diagnosis Of Inherited Thrombocytopeniasmentioning

confidence: 93%

Diagnosis and treatment of inherited thrombocytopenias

Pecci

2015

Clinical Genetics

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Knowledge in the field of inherited thrombocytopenias (ITs) has greatly improved over the last 15 years. Several new genes responsible for thrombocytopenia have been identified leading to the definition of novel nosographic entities and to a much better characterization of the phenotypes of these diseases. To date, ITs encompass 22 disorders caused by mutations in 24 genes and characterized by different degrees of complexity and great variability in prognosis. Making a definite diagnosis is important for setting an appropriate follow-up, choosing the best treatments and providing proper counseling. Despite the abovementioned progress, diagnosis of ITs remains difficult and these disorders are still underdiagnosed. The purpose of this review is to provide an updated guide to the diagnosis of ITs based on simple procedures. Moreover, the currently available therapeutic options for these conditions are recapitulated and discussed.

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Platelet-Type von Willebrand Disease: Toward an Improved Understanding of the “Sticky Situation”

Cited by 21 publications

References 31 publications

Diagnosis of inherited platelet disorders on a blood smear: a tool to facilitate worldwide diagnosis of platelet disorders

Diagnosis of inherited platelet disorders on a blood smear: a tool to facilitate worldwide diagnosis of platelet disorders

Platelet‐type von Willebrand disease: Local disorder of the platelet GPIbα β‐switch drives high‐affinity binding to von Willebrand factor

Diagnosis and treatment of inherited thrombocytopenias

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