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Blood May 2017
Topics: Animals; Blood Platelet Disorders; Humans
PubMed: 28416504
DOI: 10.1182/blood-2017-04-773507 -
Journal of Thrombosis and Haemostasis :... Sep 2022Assessment of platelet secretion is crucial for diagnosing suspected inherited platelet function disorders (IPFD). A previous survey of the SSC on Platelet Physiology of... (Review)
Review
Expert opinion on the use of platelet secretion assay for the diagnosis of inherited platelet function disorders: Communication from the ISTH SSC Subcommittee on Platelet Physiology.
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.
Topics: Blood Platelet Disorders; Blood Platelets; Communication; Expert Testimony; Hemostasis; Humans; Multicenter Studies as Topic; Platelet Function Tests; Thrombasthenia
PubMed: 35770723
DOI: 10.1111/jth.15781 -
Platelets Jan 2021We and others recently described families with germline heterozygote mutations in ETV6 leading to autosomal dominant highly penetrant thrombocytopenia, red cell...
We and others recently described families with germline heterozygote mutations in ETV6 leading to autosomal dominant highly penetrant thrombocytopenia, red cell macrocytosis and predisposition to leukemia.The bone marrow of affected individuals shows erythroid dysplasia and hyperplasia of small, hypolobulated immature megakaryocytes suggesting a differentiation arrest. This discovery led to subsequent studies that confirmed our findings and to additional larger studies that demonstrated a 1% frequency of germline ETV6 mutations among 4405 individuals with acute lymphoblastic leukemia. Additionally, a 4.5% prevalence of ETV6 germline mutations was reported in families with inherited thrombocytopenia. Preliminary data suggest that decreased ETV6 function leads to MK maturation arrest, impaired platelet production and differentially expressed platelet transcripts among individuals affected with ETV6 mutations when compared to control relatives. Additionally, individuals with some ETV6 mutation exhibit bleeding that appears disproportionate to the mildly reduced platelet count, suggesting a platelet function deficit. Furthermore, recent studies describe decreased ability of platelets from individuals with ETV6 mutations to spread on fibrinogen covered surfaces. Overall, ETV6 germline mutations represent a new cancer predisposition thrombocytopenia with platelet dysfunction.
Topics: Blood Platelet Disorders; Humans; Thrombocytopenia
PubMed: 32406789
DOI: 10.1080/09537104.2020.1760229 -
Blood Mar 2016Megakaryopoiesis is a complex, stepwise process that takes place largely in the bone marrow. At the apex of the hierarchy, hematopoietic stem cells undergo a number of... (Review)
Review
Megakaryopoiesis is a complex, stepwise process that takes place largely in the bone marrow. At the apex of the hierarchy, hematopoietic stem cells undergo a number of lineage commitment decisions that ultimately lead to the production of polyploid megakaryocytes. On average, megakaryocytes release 10(11) platelets per day into the blood that repair vascular injuries and prevent excessive bleeding. This differentiation process is tightly controlled by exogenous and endogenous factors, which have been the topics of intense research in the hematopoietic field. Indeed, a skewing of megakaryocyte commitment and differentiation may entail the onset of myeloproliferative neoplasms and other preleukemic disorders together with acute megakaryoblastic leukemia, whereas quantitative or qualitative defects in platelet production can lead to inherited platelet disorders. The recent advent of next-generation sequencing has prompted mapping of the genomic landscape of these conditions to provide an accurate view of the underlying lesions. The aims of this review are to introduce the physiological pathways of megakaryopoiesis and to present landmark studies on acquired and inherited disorders that target them. These studies have not only introduced a new era in the fields of molecular medicine and targeted therapies but may also provide us with a better understanding of the mechanisms underlying normal megakaryopoiesis and thrombopoiesis that can inform efforts to create alternative sources of megakaryocytes and platelets.
Topics: Animals; Blood Platelet Disorders; Blood Platelets; Genetic Diseases, Inborn; Genome, Human; High-Throughput Nucleotide Sequencing; Humans; Megakaryocytes; Thrombopoiesis
PubMed: 26787733
DOI: 10.1182/blood-2015-07-607952 -
Journal of Thrombosis and Haemostasis :... Jul 2003Inherited platelet-based bleeding disorders include abnormalities of platelet number and function, and are generally classified based on the abnormal functions or... (Review)
Review
Inherited platelet-based bleeding disorders include abnormalities of platelet number and function, and are generally classified based on the abnormal functions or responses. However, a clear distinction is problematic, and in this review, the classification has been based on abnormalities of platelet components that share common characteristics. Inherited thrombocytopenias are rare, but probably underdiagnosed. They are usually classified according to both platelet size and the presence or absence of clinical features other than those deriving from the platelet defect. Hereditary disorders of platelet function can be classified as resulting from: (i) abnormalities of the platelet receptors for adhesive proteins; (ii) abnormalities of the platelet receptors for soluble agonists; (iii) abnormalities of the platelet granules; (iv) abnormalities of the signal-transduction pathways; (v) abnormalities of the membrane phospholipids; and (vi) miscellaneous abnormalities of platelet function. The literature on these disorders is reviewed, and the underlying defects discussed.
Topics: Blood Platelet Disorders; Hemorrhage; Humans; Thrombocytopenia
PubMed: 12871299
DOI: 10.1046/j.1538-7836.2003.00266.x -
Journal of Thrombosis and Haemostasis :... Aug 2020Inherited bleeding and platelet disorders (BPD) are highly heterogeneous and their diagnosis involves a combination of clinical investigations, laboratory tests, and... (Review)
Review
Inherited bleeding and platelet disorders (BPD) are highly heterogeneous and their diagnosis involves a combination of clinical investigations, laboratory tests, and genetic screening. This review will outline some of the challenges that geneticists and experts in clinical hemostasis face when implementing high-throughput sequencing (HTS) for patient care. We will provide an overview of the strengths and limitations of the different HTS techniques that can be used to diagnose BPD. An HTS test is cost-efficient and expected to increase the diagnostic rate with a possibility to detect unexpected diagnoses and decrease the turnaround time to diagnose patients. On the other hand, technical shortcomings, variant interpretation difficulties, and ethical issues related to HTS for BPD will also be documented. Delivering a genetic diagnosis to patients is highly desirable to improve clinical management and allow family counseling, but making incorrect assumptions about variants and providing insufficient information to patients before initiating the test could be harmful. Data-sharing and improved HTS guidelines are essential to limit these major drawbacks of HTS.
Topics: Blood Coagulation Disorders, Inherited; Blood Platelet Disorders; Blood Platelets; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans
PubMed: 32521110
DOI: 10.1111/jth.14945 -
Blood May 2017Transcription factors (TFs) are proteins that bind to specific DNA sequences and regulate expression of genes. The molecular and genetic mechanisms in most patients with... (Review)
Review
Transcription factors (TFs) are proteins that bind to specific DNA sequences and regulate expression of genes. The molecular and genetic mechanisms in most patients with inherited platelet defects are unknown. There is now increasing evidence that mutations in hematopoietic TFs are an important underlying cause for defects in platelet production, morphology, and function. The hematopoietic TFs implicated in patients with impaired platelet function and number include runt-related transcription factor 1, Fli-1 proto-oncogene, E-twenty-six (ETS) transcription factor (friend leukemia integration 1), GATA-binding protein 1, growth factor independent 1B transcriptional repressor, ETS variant 6, ecotropic viral integration site 1, and homeobox A11. These TFs act in a combinatorial manner to bind sequence-specific DNA within promoter regions to regulate lineage-specific gene expression, either as activators or repressors. TF mutations induce rippling downstream effects by simultaneously altering the expression of multiple genes. Mutations involving these TFs affect diverse aspects of megakaryocyte biology, and platelet production and function, culminating in thrombocytopenia and platelet dysfunction. Some are associated with predisposition to hematologic malignancies. These TF variants may occur more frequently in patients with inherited platelet defects than generally appreciated. This review focuses on alterations in hematopoietic TFs in the pathobiology of inherited platelet defects.
Topics: Blood Platelet Disorders; Genetic Diseases, Inborn; Hematopoiesis; Humans; Mutation; Proto-Oncogene Mas; Transcription Factors
PubMed: 28416505
DOI: 10.1182/blood-2016-11-709881 -
Journal of the Royal College of... 1998The statement printed below was agreed at a consensus conference on platelet transfusion organised by the Royal College of Physicians of Edinburgh and held in Edinburgh...
The statement printed below was agreed at a consensus conference on platelet transfusion organised by the Royal College of Physicians of Edinburgh and held in Edinburgh in November 1997. We publish this statement at the request of the organising committee to bring it to the attention of physicians who do not read the haematological literature. The statement will also appear in the British Journal of Haematology in 1998 with the scientific evidence upon which it is based.
Topics: Blood Platelet Disorders; Contraindications; Humans; Platelet Transfusion; Practice Guidelines as Topic; Quality Control; United Kingdom
PubMed: 9597636
DOI: No ID Found -
Platelets Sep 2016Platelet numbers are intricately regulated to avoid spontaneous bleeding or arterial occlusion and organ damage. The growth factor thrombopoietin (TPO) drives platelet... (Review)
Review
Platelet numbers are intricately regulated to avoid spontaneous bleeding or arterial occlusion and organ damage. The growth factor thrombopoietin (TPO) drives platelet biogenesis by inducing megakaryocyte production. A recent study in mice identified a feedback mechanism by which clearance of aged, desialylated platelets stimulates TPO synthesis by hepatocytes. This new finding generated renewed interest in platelet clearance mechanisms. Here, different established and emerging mechanisms of platelet senescence and clearance will be reviewed with specific emphasis on the role of posttranslational modifications.
Topics: Animals; Apoptosis; Blood Platelet Disorders; Blood Platelets; Carrier Proteins; Cellular Senescence; Glycoside Hydrolases; Humans; Lectins; Liver; Lysosomes; Platelet Glycoprotein GPIb-IX Complex; Platelet Membrane Glycoproteins; Polysaccharides; Protein Binding
PubMed: 27135356
DOI: 10.3109/09537104.2016.1171304 -
Blood Jun 1974
Topics: Alcoholism; Blood Cell Count; Blood Platelet Disorders; Duodenum; Edetic Acid; Female; Fractures, Bone; Humans; Leg Injuries; Leukocytes; Liver Cirrhosis; Male; Microscopy, Electron; Middle Aged; Peptic Ulcer; Phagocytosis; Platelet Adhesiveness; Thrombocytopenia
PubMed: 4208779
DOI: No ID Found