Several hundreds of studies recently investigated mean platelet volume (MPV) as measured by electronic cell counters in a wide variety of acquired diseases, and most of them found that platelet size ...was significantly increased with respect to healthy subjects. On this basis, it has been suggested that MPV can be used for diagnostic purposes. Moreover, investigation of subjects with arterial thrombosis not only revealed that their platelets were larger than those of controls, but also found that a high MPV predicted poor prognosis. Despite the large amount of available data, the pathogenesis of increased platelet size in these conditions is unclear. In particular, we do not know whether the increased platelet size is the cause or the consequence of thrombosis. Differences in MPV between patients and controls are usually very small and they reach the statistical significance because of the large number of investigated patients and the standardized methodology for MPV measurement. In real life, the wide variability of MPV possibly due to platelet count, sex, age, and ethnicity, as well as the very poor standardization of the methodologies used for MPV measurement, makes it impossible to decide whether an individual patient has normal or instead slightly increased MPV. So, MPV has presently no role in making diagnosis and defining prognosis in any acquired illness.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
From Medical Genetics, Department of Reproductive and Developmental Science, IRCCS Burlo Garofolo Childrens Hospital, University of Trieste, Italy (AS,MDS); IRCCS G.Gaslini Childen's Hospital, ...Genova, Italy (CD, AC); IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy (FL, PN, CA, VR, MZ, CLB); 4 Laboratory of Medical Genetics, Department of Internal Medicine, Cardioangiology and Hepatology, University of Bologna, Italy (SF, MS); Telethon Institute of Genetics and Medicine, Naples, Italy (FDB)
Corresponding author: Carlo L. Balduini, Clinica Medica III, Fondazione IRCCS Policlinico San Matteo. Università di Pavia, piazzale Golgi, 27100 Pavia, Italy. E-mail: c.balduini{at}smatteo.pv.it
Background and Objectives: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients.
Design and Methods: We diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences.
Results: In all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor- and interferon- was increased during pancytopenia as compared to controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course.
Interpretation and Conclusions: These results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor.
Key words: congenital amegakaryocytic thrombocytopenia, CAMT, c-MPL , thrombopoietin receptor, mutations.
Related Article
Inherited thrombocytopenias
Alan T. Nurden, Paquita Nurden
Haematologica 2007 92: 1158-1164.
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A form of autosomal dominant macrothrombocytopenia is characterized by mild or no clinical symptoms, normal platelet function, and normal megakaryocyte count. Because this condition has so far ...received little attention, patients are subject to misdiagnosis and inappropriate therapy. To identify the molecular basis of this disease, 12 Italian families were studied by linkage analysis and mutation screening. Flow cytometry evaluations of platelet membrane glycoproteins (GPs) were also performed. Linkage analysis in 2 large families localized the gene to chromosome 17p, in an interval containing an excellent candidate, the GPIbα gene. GPIbα, together with other proteins, constitutes the plasma von Willebrand factor (vWF) receptor, which is altered in Bernard-Soulier syndrome (BSS). In 6 of 12 families, a heterozygous Ala156Val missense substitution was identified. Platelet membrane GP studies were performed in 10 patients. Eight were distinguished by a reduction of GPs comparable to that found in a BSS heterozygous condition, whereas the other 2, without the Ala156Val mutation, had a normal content of platelet GPs. In conclusion, the current study provides evidence that most (10 of 12) patients with an original diagnosis of autosomal dominant macrothrombocytopenia shared clinical and molecular features with the heterozygous BSS phenotype. The remaining 2 affected subjects represented patients with “true” autosomal dominant macrothrombocytopenia; the GPIb/IX/V complex was normally distributed on the surface of their platelets. Thus, the diagnosis of heterozygous BSS must always be suspected in patients with inherited thrombocytopenia and platelet macrocytosis.
Abstract MYH9 -related disease ( MYH9- RD) is a rare autosomal dominant syndromic disorder caused by mutations in MYH9 , the gene encoding for the heavy chain of non-muscle myosin IIA (myosin-9). ...MYH9 -RD is characterized by congenital macrothrombocytopenia and typical inclusion bodies in neutrophils associated with a variable risk of developing sensorineural deafness, presenile cataract, and/or progressive nephropathy. The spectrum of mutations responsible for MYH9 -RD is limited. We report five families, each with a novel MYH9 mutation. Two mutations, p.Val34Gly and p.Arg702Ser, affect the motor domain of myosin-9, whereas the other three, p.Met847_Glu853dup, p.Lys1048_Glu1054del, and p.Asp1447Tyr, hit the coiled-coil tail domain of the protein. The motor domain mutations were associated with more severe clinical phenotypes than those in the tail domain.
Summary
The transcription factor GATA-1, together with its cofactor FOG-1, regulates erythropoiesis and megakaryocytopoiesis. Mutations in the DNA or FOG-1 binding sites of its N-terminal zinc finger ...result in different illnesses. Alterations of the FOG-1 face are responsible for dyserythropoietic anemia with thrombocytopenia while R216Q, the only mutation identified in the DNA face, induces X-linked thrombocytopenia with thalassemia (XLTT). The former disorder has been studied in detail whereas little is known about the latter since only one family has been investigated. We studied a second family with an R216Q, showing that XLTT and dyserythropoietic anemia with thrombocytopenia, even if different clinical entities, are closely related disorders. In both cases, patients present mild dyserythropoiesis, red cell hemolysis, severely defective maturation of megakaryocytes, macrothrombocytopenia with α-granule deficiency, and abnormalities of the cytoplasmic membrane system. However, a thalassemia minor phenotype has only been described in patients with XLTT whereas severe anemia and thrombocytopenia with evident defects of platelet composition and function may be observed only in dyserythropoietic anemia with thrombocytopenia.
Molecular diagnostics of inherited platelet disorders (IPD) has been revolutionized by the implementation of high‐throughput sequencing (HTS) approaches. A conclusive diagnosis using HTS tests can be ...obtained quickly and cost‐effectively in many, but not all patients. The expanding use of HTS tests has raised concerns regarding complex variant interpretation and the ethical implications of detecting unsolicited findings such as variants in IPD genes RUNX1, ETV6, and ANKRD26, which are associated with increased leukemic risk. This guidance document has been developed and written by a multidisciplinary team of researchers and clinicians, with expertise in hematology, clinical and molecular genetics, and bioethics, alongside a RUNX1 patient advocacy representative. We recommend that for clinical diagnostics, HTS for IPD should use a multigene panel of curated diagnostic‐grade genes. Critically, we advise that an HTS test for clinical diagnostics should only be ordered by a clinical expert that is: (a) fully aware of the complexity of genotype‐phenotype correlations for IPD; (b) able to discuss these complexities with a patient and family members before the test is initiated; and (c) able to interpret and appropriately communicate the results of a HTS diagnostic report, including the implication of variants of uncertain clinical significance. Each patient should know what an HTS test could mean for his or her clinical management before initiating a test. We hereby propose an exemplified informed consent document that includes information on these ethical concerns and can be used by the community for implementation of HTS of IPD in a clinical diagnostic setting. This paper does not include recommendations for HTS of IPD in a research setting.
Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia. We identified a family with autosomal dominant ...thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell-precursor acute lymphoblastic leukemia (ALL). Whole-exome sequencing identified a heterozygous single-nucleotide change in ETV6 (ets variant 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain, segregating with thrombocytopenia and elevated MCV. A screen of 23 families with similar phenotypes identified 2 with ETV6 mutations. One family also had a mutation encoding p.Pro214Leu and one individual with ALL. The other family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping. Functional characterization of these mutations showed aberrant cellular localization of mutant and endogenous ETV6, decreased transcriptional repression and altered megakaryocyte maturation. Our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Assessment of platelet secretion is crucial for diagnosing suspected inherited platelet function disorders (IPFD). A previous survey of the SSC on Platelet Physiology of the ISTH and a comprehensive ...review highlighted that most of the platelet secretion assays (PSAs) lack standardization and validation. The aim of this study was to provide expert consensus guidance on the use of PSAs for IPFD diagnosis. We surveyed 26 experts from 10 different countries using the RAND/UCLA methodology, to attain a consensus on sensitivity, specificity, feasibility, time to readout, and cost of most PSAs. Answers were then graded in three categories: appropriate, uncertain, and inappropriate. Equivocal or misinterpretable statements required a second and third round survey involving 14 of the original 26 experts. We report here the consolidated results of the entire procedure. There was uniform agreement on several general statements, including that PSAs should be performed in hemostasis laboratories as first line diagnostic tests even in patients with normal platelet aggregation, and should include a δ‐granule secretion marker. Among the specific assays examined, lumiaggregometry, other luciferin/luciferase‐based assays, high‐performance liquid chromatography methods, radiolabeled‐serotonin based assays, and whole‐mount transmission electron microscopy were rated as appropriate for the measurement of δ‐granule release, and platelet P‐selectin expression by flow cytometry and released proteins by ELISA for α‐granule release. For most of the other PSAs, the expert opinions were widely dispersed. Lack of expert consensus on many PSAs clearly indicates an unmet need for rigorous standardization, multicenter comparison of results, and validation of PSAs for clinical laboratory practice.
The improvement of molecular biology technologies and the increasing number of researchers interested in inherited thrombocytopaenias (ITs) has led to a significant expansion in knowledge of the ...genetic basis and clinical features of the different types of IT. In particular, it is now well known that an inherited ‘low platelet count’ can be the unique abnormal laboratory finding of the disease, combined with a bleeding tendency usually proportionate to the extent of the thrombocytopaenia, or can associate with different congenital and/or acquired signs and symptoms, or with predisposition to other diseases. Therefore, recognising syndromic forms and their main features is crucial for the proper management of patients, who rely on appropriate follow-up and treatments beyond those for simply preventing and/or treating bleeding. Among all syndromic ITs, this review aims to describe those predisposing to hematological malignancies (such as the familial platelet disorder with predisposition to acute myelogenous leukaemia and the ANKRD26-related thrombocytopaenia), and to bone marrow aplasia (with particular regard to congenital amegakaryocytic thrombocytopaenia), as well as to summarise the main characteristics of MYH9-related diseases, one of the most frequent forms of IT, which expose patients to the risk of developing additional features such as cataract, sensorineural deafness, alteration of liver enzymes, and/or a glomerulonephritis that usually evolves into end-stage renal failure.
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