Diagnostic biomarker for ACTN1 macrothrombocytopenia

Kunishima, Shinji; Kitamura, Katsumasa; Yasutomi, Motoko; Kobayashi, Ryōji

doi:10.1182/blood-2015-08-666180

Cited by 6 publications

(3 citation statements)

References 9 publications

(12 reference statements)

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“…The field is rapidly evolving and new diagnostic parameters are being identified, such as non‐muscle myosin heavy chain IIB expression in platelets, indicating platelet disorders related to RUNX 1 or FLI1 mutations, or detection of non‐muscle myosin heavy chain IIA in the granulomere zone of surface‐activated spreading platelets, indicating ACTN1 macrothrombocytopenia . It might become possible to assess these features also on a simple blood smear in the future.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…New substantial diagnostic perspectives rely on the identification of specific changes in platelet proteins being recognizable by diagnostic antibodies. A possible diagnostic pattern for ACTN1-related thrombocytopenia has been proposed upon observing the peculiar distribution of MYH9 protein in the granulomere area of surface-activated platelets [103]. Besides, alteration in MYH10 distribution has been reported as a sign of thrombocytopenia due to FLI1 or RUNX1 mutations [104].…”

Section: Limitations Related To This Methods and New Perspectivesmentioning

confidence: 99%

Diagnosis of Inherited Platelet Disorders on a Blood Smear

Zaninetti

Greinacher

2020

JCM

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Inherited platelet disorders (IPDs) are rare diseases featured by low platelet count and defective platelet function. Patients have variable bleeding diathesis and sometimes additional features that can be congenital or acquired. Identification of an IPD is desirable to avoid misdiagnosis of immune thrombocytopenia and the use of improper treatments. Diagnostic tools include platelet function studies and genetic testing. The latter can be challenging as the correlation of its outcomes with phenotype is not easy. The immune-morphological evaluation of blood smears (by light- and immunofluorescence microscopy) represents a reliable method to phenotype subjects with suspected IPD. It is relatively cheap, not excessively time-consuming and applicable to shipped samples. In some forms, it can provide a diagnosis by itself, as for MYH9-RD, or in addition to other first-line tests as aggregometry or flow cytometry. In regard to genetic testing, it can guide specific sequencing. Since only minimal amounts of blood are needed for the preparation of blood smears, it can be used to characterize thrombocytopenia in pediatric patients and even newborns further. In principle, it is based on visualizing alterations in the distribution of proteins, which result from specific genetic mutations by using monoclonal antibodies. It can be applied to identify deficiencies in membrane proteins, disturbed distribution of cytoskeletal proteins, and alpha as well as delta granules. On the other hand, mutations associated with impaired signal transduction are difficult to identify by immunofluorescence of blood smears. This review summarizes technical aspects and the main diagnostic patterns achievable by this method.

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“…It may be possible to distinguish some of these alternate diagnoses using phenotype tests such as flow cytometry or platelet ultrastructural analysis. 4,22,23 However, these tests are not widely available in clinical laboratories, are expensive, and are poorly standardized at present. In contrast, sequence analysis of a panel of multiple genes associated with macrothrombocytopenia is faster and more cost-effective than Sanger sequencing of each individual gene.…”

Section: Gene Panelsmentioning

confidence: 99%

Genetic Techniques Used in the Diagnosis of Inherited Platelet Disorders

Mumford

Westbury

2019

Semin Thromb Hemost

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Recent advances in genetic analysis are bringing huge benefits to patients with rare genetic disorders, including those with inherited disorders of platelet number and function. Modern clinical hematological practice now has a range of genetic techniques available to enable the precision diagnosis of inherited platelet disorders (IPDs). There are some features of this disparate group of inherited disorders that present specific challenges to establishing an accurate genetic diagnosis. This review aims to introduce the techniques that are relevant for the genetic diagnosis of IPDs and will discuss the key considerations necessary for their application to the clinic.

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Diagnostic biomarker for ACTN1 macrothrombocytopenia

Cited by 6 publications

References 9 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

Diagnosis of Inherited Platelet Disorders on a Blood Smear

Genetic Techniques Used in the Diagnosis of Inherited Platelet Disorders

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