Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders

Noris, Patrizia; Biino, Ginevra; Pecci, Alessandro; Civaschi, Elisa; Savoia, Anna; Seri, Marco; Melazzini, Federica; Loffredo, Giuseppe; Russo, Giovanna; Bozzi, Valeria; Notarangelo, Lucia Dora; Gresele, Paolo; Heller, Paula G.; Pujol-Moix, Núria; Kunishima, Shinji; Cattaneo, Marco; Bussel, James B.; Candia, Erica De; Cagioni, Claudia; Ramenghi, Ugo; Barozzi, Serena; Fabris, Fabrizio; Balduini, Carlo L.

doi:10.1182/blood-2014-03-564328

Cited by 122 publications

(131 citation statements)

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“…We found very mild but significant increases in platelet diameter distribution width and platelet diameter large cell ratio, which indicate that a mild platelet anisocytosis and a slightly increased proportion of large platelets were frequent features of the investigated patients. In agreement with previous findings, 8 empirical measurement of the percentage of platelets larger than half an erythrocyte gave similar results to the assessment of platelet diameter large cell ratio by image analysis (data not shown). Conversely, the increased mean platelet diameter distribution width detected by image analysis did not correspond to increased mean platelet distribution width values ETV6-related thrombocytopenia haematologica | 2016; 101 (11) 1337 …”

Section: Clinical Picturesupporting

confidence: 80%

“…Parameters relative to platelet diameter were measured by software-assisted image analysis on blood smears, as reported elsewhere. 8 The following previously defined parameters were computed: mean platelet diameter, platelet diameter distribution width, platelet diameter large cell ratio, and platelet diameter small cell ratio. 8 The percentage of large platelets was also estimated empirically, as previously reported 8 and detailed in the Online Supplementary Information.…”

Section: Basic Blood Cell Studiesmentioning

confidence: 99%

“…8 The following previously defined parameters were computed: mean platelet diameter, platelet diameter distribution width, platelet diameter large cell ratio, and platelet diameter small cell ratio. 8 The percentage of large platelets was also estimated empirically, as previously reported 8 and detailed in the Online Supplementary Information. Surface expression of platelet glycoproteins (GP) was investigated by flow cytometry as reported, whereas platelet aggregation was evaluated using the densitometric method described by Born.…”

Section: Basic Blood Cell Studiesmentioning

confidence: 99%

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Clinical and pathogenic features of ETV6 -related thrombocytopenia with predisposition to acute lymphoblastic leukemia

et al. 2016

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Section: Clinical Picturesupporting

confidence: 80%

Section: Basic Blood Cell Studiesmentioning

confidence: 99%

Section: Basic Blood Cell Studiesmentioning

confidence: 99%

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Clinical and pathogenic features of ETV6 -related thrombocytopenia with predisposition to acute lymphoblastic leukemia

et al. 2016

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Section:  Platelet Featuresmentioning

confidence: 66%

“…Thrombocytopenia is usually mild to moderate and, in some cases, platelet counts may be low-normal or even normal. Platelet size is not affected, similar to other inherited myeloid malignancy syndromes associated with thrombocytopenia, such as ETV6-and ANKRD26-related thrombocytopenias , which are also characterized by normal-sized platelets [21].Thrombocytopenia is due to abnormal megakaryocyte maturation and polyploidization and impaired proplatelet formation [22]. Dysmegakaryopoiesis is the most prominent abnormality in bone marrow smears, and is evident even before leukemic transformation [8,22].…”

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confidence: 81%

RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)

Schlegelberger

Heller

2017

Seminars in Hematology

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In this review, we discuss disease-causing alterations of RUNT-related transcription factor 1 (RUNX1), a master regulator of hematopoietic differentiation. Familial platelet disorder with predisposition to myeloid leukemia (FPDMM) typically present with 1) mild to moderate thrombocytopenia with normal-sized platelets; 2) functional platelets defects leading to prolonged bleeding; and 3) an increased risk to develop MDS, AML or T-ALL.Hematological neoplasms in carriers of a germline RUNX1 mutation need additional secondary mutations or chromosome aberrations to develop. If a disease-causing mutation is known in the family, it is important to prevent hematopoietic stem cell transplantation from a sibling or other relative carrying the familial mutation. First experiments introducing a wild-type copy of RUNX1 into iPSC lines from patients with FPDMM appear to demonstrate that by gene correction reversal of the phenotype may be possible.  Definition of RUNX1 deficiency/ FPDMMRUNT-related transcription factor 1 (RUNX1), previously named core binding factor A2 (CBFA2) and acute myeloid leukemia 1 (AML1), is a master regulator of hematopoiesis [1]. It is involved in the most frequent chromosome translocations in leukemia (i.e. t(12;21)/RUNX1/ETV6 in pediatric acute lymphoblastic leukemia, t(8;21)/RUNX1/RUNX1T1 in acute myeloid leukemia (AML), and t(3;21)/RUNX1/EVI1 in therapy-related AML or chronic myeloid leukemia in blast phase [2,3]. Moreover, somatic RUNX1 mutations have recently been identified as recurrent abnormalities in myelodysplastic syndromes (MDS) and AML [4]. These somatic changes are associated with poor prognosis in AML and MDS indicating an increased resistance against exposure to genotoxic agents. RUNX1 mutations seem to trigger progression into MDS and AML in Fanconi anemia and severe congenital neutropenia [5,6]. Song et al. (1999) were the first to describe heterozygous germline RUNX1 mutations in six families, each carrying a different mutation. Individuals carrying germline RUNX1 may be asymptomatic throughout lifetime or develop familial platelet disorder with myeloid malignancies (i.e. FPDMM, OMIM 601399). Characteristic features are 1) mild to moderate thrombocytopenia; 2) functional platelets defects leading to prolonged bleeding; and 3) an increased risk to develop MDS, AML or T-ALL. There is a great phenotypic heterogeneity. FPDMM is inherited in an autosomal dominant fashion with incomplete penetrance and variable expressivity.  Diagnostic criteria to identify persons at riskSince the diagnosis of FPDMM in a patient with leukemia carries important critical implications for the patient and also for her/his family, it is important to recognize clinical features pointing to this genetic predisposition [7]. An important clinical feature is persisting thrombocytopenia or aspirin-like platelet disorder, which are not explained by other reasons.Thorough pedigree analysis may identify first or second degree relatives with bleeding tendency or hematological neoplasms. It has to be kept i...

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Bioprinting Soft 3D Models of Hematopoiesis using Natural Silk Fibroin‐Based Bioink Efficiently Supports Platelet Differentiation

Di Buduo,

Lunghi,

Kuzmenko

et al. 2024

Advanced Science

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Hematopoietic stem and progenitor cells (HSPCs) continuously generate platelets throughout one's life. Inherited Platelet Disorders affect ≈ 3 million individuals worldwide and are characterized by defects in platelet formation or function. A critical challenge in the identification of these diseases lies in the absence of models that facilitate the study of hematopoiesis ex vivo. Here, a silk fibroin‐based bioink is developed and designed for 3D bioprinting. This bioink replicates a soft and biomimetic environment, enabling the controlled differentiation of HSPCs into platelets. The formulation consisting of silk fibroin, gelatin, and alginate is fine‐tuned to obtain a viscoelastic, shear‐thinning, thixotropic bioink with the remarkable ability to rapidly recover after bioprinting and provide structural integrity and mechanical stability over long‐term culture. Optical transparency allowed for high‐resolution imaging of platelet generation, while the incorporation of enzymatic sensors allowed quantitative analysis of glycolytic metabolism during differentiation that is represented through measurable color changes. Bioprinting patient samples revealed a decrease in metabolic activity and platelet production in Inherited Platelet Disorders. These discoveries are instrumental in establishing reference ranges for classification and automating the assessment of treatment responses. This model has far‐reaching implications for application in the research of blood‐related diseases, prioritizing drug development strategies, and tailoring personalized therapies.

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Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders

Abstract: Key Points Measurement of platelet diameters in 376 patients resulted in a new classification of inherited thrombocytopenias based on platelet size. Measurement of platelet diameters is a useful tool for differential diagnosis of inherited thrombocytopenias.

Cited by 122 publications

References 14 publications

Clinical and pathogenic features of ETV6 -related thrombocytopenia with predisposition to acute lymphoblastic leukemia

Clinical and pathogenic features of ETV6 -related thrombocytopenia with predisposition to acute lymphoblastic leukemia

RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)

Bioprinting Soft 3D Models of Hematopoiesis using Natural Silk Fibroin‐Based Bioink Efficiently Supports Platelet Differentiation

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