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California Medicine Jan 1973These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they...
These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs. David W. Martin, Jr., Assistant Professor of Medicine, and Kenneth A. Woeber, Associate Professor of Medicine, under the direction of Dr. Lloyd H. Smith, Jr., Professor of Medicine and Chairman of the Department of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, San Francisco, Ca. 94122.
Topics: Blood Platelet Disorders; Blood Platelets; Cell Survival; Chromium Isotopes; Hypersplenism; Purpura, Thrombocytopenic; Splenomegaly
PubMed: 4734413
DOI: No ID Found -
Haematologica Feb 2021Inherited platelet disorders resulting from platelet function defects and a normal platelet count cause a moderate or severe bleeding diathesis. Since the description of... (Review)
Review
Inherited platelet disorders resulting from platelet function defects and a normal platelet count cause a moderate or severe bleeding diathesis. Since the description of Glanzmann thrombasthenia resulting from defects of ITGA2B and ITGB3, new inherited platelet disorders have been discovered, facilitated by the use of high throughput sequencing and genomic analyses. Defects of RASGRP2 and FERMT3 responsible for severe bleeding syndromes and integrin activation have illustrated the critical role of signaling molecules. Important are mutations of P2RY12 encoding the major ADP receptor causal for an inherited platelet disorder with inheritance characteristics that depend on the variant identified. Interestingly, variants of GP6 encoding the major subunit of the collagen receptor GPVI/FcRγ associate only with mild bleeding. The numbers of genes involved in dense granule defects including Hermansky-Pudlak and Chediak Higashi syndromes continue to progress and are updated. The ANO6 gene encoding a Ca2+-activated ion channel required for phospholipid scrambling is responsible for the rare Scott syndrome and decreased procoagulant activity. A novel EPHB2 defect in a familial bleeding syndrome demonstrates a role for this tyrosine kinase receptor independent of the classical model of its interaction with ephrins. Such advances highlight the large diversity of variants affecting platelet function but not their production, despite the difficulties in establishing a clear phenotype when few families are affected. They have provided insights into essential pathways of platelet function and have been at the origin of new and improved therapies for ischemic disease. Nevertheless, many patients remain without a diagnosis and requiring new strategies that are now discussed.
Topics: Blood Platelet Disorders; Blood Platelets; Genotype; Guanine Nucleotide Exchange Factors; Humans; Phenotype; Thrombasthenia
PubMed: 33147934
DOI: 10.3324/haematol.2020.248153 -
Transfusion Medicine Reviews Oct 2015MicroRNAs (miRNAs) are short ~22-nucleotide noncoding RNA that have been found to influence the expression of many genes and cellular processes by either repressing... (Review)
Review
MicroRNAs (miRNAs) are short ~22-nucleotide noncoding RNA that have been found to influence the expression of many genes and cellular processes by either repressing translation or degrading messenger RNA transcripts. Platelet miRNA expression has been shown to be perturbed during ex vivo storage of platelets and in platelet-associated disorders. Although bioinformatics-based miRNA target predictions have been established, direct experimental validation of the role of miRNAs in platelet biology has been rather slow. Target prediction studies are, nonetheless, valuable in directing the design of appropriate experiments to test specific miRNA:messenger RNA interactions relevant to the underlying mechanisms of platelet function in general and in disease as well as in ex vivo storage-associated "storage lesions," a collective term used to include physiologic, biochemical, and morphologic changes that occur in stored platelets. This brief review will focus on emerging human platelet miRNA studies to emphasize their potential role relevant to transfusion medicine field in terms of regulating platelet signaling pathways, markers of platelet associated disorders, and remote impactors of gene expression (intercellular biomodulators) as well as potential platelet quality markers of storage and pathogen reduction treatments.
Topics: Animals; Blood Platelet Disorders; Blood Platelets; Blood Preservation; Gene Expression Regulation; Genetic Markers; Humans; MicroRNAs; Signal Transduction
PubMed: 26341586
DOI: 10.1016/j.tmrv.2015.08.002 -
Journal of Thrombosis and Haemostasis :... Jun 2015Our understanding of platelets, anucleate cells with a traditional role in hemostasis and inflammation, has developed greatly over the last decade. Platelets' role in... (Review)
Review
Our understanding of platelets, anucleate cells with a traditional role in hemostasis and inflammation, has developed greatly over the last decade. Platelets' role in the systemic response of the body to vascular injury, inflammation, and infection has expanded as has our understanding of their importance to the body's regulation of these processes. One recently explored mechanism by which platelets regulate the body's inflammatory and immune response is through its endogenous RNA. Platelets' messenger RNA (mRNAs) and microRNA (miRNAs) profiles have been shown to reflect disease and disease risk factors and have been correlated with select human clinical phenotypes. Developing an understanding of platelet transcripts in the circulation elucidates how platelets function in both their traditional thrombotic role and non-traditional functions and may have widespread implications in several fields including thrombosis, infection, cancer, and systemic inflammation.
Topics: Animals; Blood Platelet Disorders; Blood Platelets; Gene Expression Regulation; Genetic Predisposition to Disease; Hemostasis; Humans; MicroRNAs; Phenotype; RNA, Messenger; Thrombosis; Transcription, Genetic; Transcriptome
PubMed: 26149043
DOI: 10.1111/jth.12922 -
Platelets Jan 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 dysfunction are unknown. There is now increasing evidence that mutations in hematopoietic TFs are an important underlying cause for the defects in platelet production, morphology, and function. The hematopoietic TFs implicated in the patients with impaired platelet function include Runt related TF 1 (RUNX1), Fli-1 proto-oncogene, ETS TF (FLI1), GATA-binding protein 1 (GATA1), and growth factor independent 1B transcriptional repressor (GFI1B). These TFs act in a combinatorial manner to bind sequence-specific DNA within a promoter region to regulate lineage-specific gene expression, either as activators or as 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, platelet dysfunction, and associated clinical features. Mutations in TFs may occur more frequently in the patients with inherited platelet dysfunction than generally appreciated. This review focuses on the alterations in hematopoietic TFs in the pathobiology of inherited platelet dysfunction.
Topics: Blood Platelet Disorders; Blood Platelets; Cell Differentiation; Gene Expression Regulation; Genetic Association Studies; Genotype; Humans; Megakaryocytes; Mutation; Phenotype; Protein Binding; Proto-Oncogene Mas; Thrombopoiesis; Transcription Factors
PubMed: 27463948
DOI: 10.1080/09537104.2016.1203400 -
Platelets 2020
Review
Topics: Alleles; Animals; Blood Platelet Disorders; Blood Platelets; Endoribonucleases; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Hemorrhage; Humans; Mutation
PubMed: 31378119
DOI: 10.1080/09537104.2019.1648781 -
Hamostaseologie Feb 2023Platelets play an important role regarding coagulation by contributing to thrombus formation by platelet adhesion, aggregation, and α-/δ-granule secretion. Inherited...
Platelets play an important role regarding coagulation by contributing to thrombus formation by platelet adhesion, aggregation, and α-/δ-granule secretion. Inherited platelet disorders (IPDs) are a very heterogeneous group of disorders that are phenotypically and biochemically diverse. Platelet dysfunction (thrombocytopathy) can be accompanied by a reduction in the number of thrombocytes (thrombocytopenia). The extent of the bleeding tendency can vary greatly. Symptoms comprise mucocutaneous bleeding (petechiae, gastrointestinal bleeding and/or menorrhagia, epistaxis) and increased hematoma tendency. Life-threatening bleeding can occur after trauma or surgery. In the last years, next-generation sequencing had a great impact on unrevealing the underlying genetic cause of individual IPDs. Because IPDs are so diverse, a comprehensive analysis of platelet function and genetic testing is indispensable.
Topics: Female; Humans; Blood Platelet Disorders; Blood Coagulation Disorders; Blood Platelets; Hemorrhagic Disorders; Thrombocytopenia
PubMed: 36807820
DOI: 10.1055/a-1987-3310 -
Journal of Thrombosis and Haemostasis :... Feb 2023Inherited platelet disorders (IPDs) are a heterogeneous group of rare diseases that are caused by the defects in early megakaryopoiesis, proplatelet formation, and/or...
BACKGROUND
Inherited platelet disorders (IPDs) are a heterogeneous group of rare diseases that are caused by the defects in early megakaryopoiesis, proplatelet formation, and/or mature platelet function. Although genomic sequencing is increasingly used to identify genetic variants underlying IPD, this technique does not disclose resulting molecular changes that impact platelet function. Proteins are the functional units that shape platelet function; however, insights into how variants that cause IPDs impact platelet proteomes are limited.
OBJECTIVES
The objective of this study was to profile the platelet proteomics signatures of IPDs.
METHODS
We performed unbiased label-free quantitative mass spectrometry (MS)-based proteome profiling on platelets of 34 patients with IPDs with variants in 13 ISTH TIER1 genes that affect different stages of platelet development.
RESULTS
In line with the phenotypical heterogeneity between IPDs, proteomes were diverse between IPDs. We observed extensive proteomic alterations in patients with a GFI1B variant and for genetic variants in genes encoding proteins that impact cytoskeletal processes (MYH9, TUBB1, and WAS). Using the diversity between IPDs, we clustered protein dynamics, revealing disrupted protein-protein complexes. This analysis furthermore grouped proteins with similar cellular function and location, classifying mitochondrial protein constituents and identifying both known and putative novel alpha granule associated proteins.
CONCLUSIONS
With this study, we demonstrate a MS-based proteomics perspective to IPDs. By integrating the effects of IPDs that impact different aspects of platelet function, we dissected the biological contexts of protein alterations to gain further insights into the biology of platelet (dys)function.
Topics: Humans; Proteomics; Proteome; Blood Platelet Disorders; Blood Platelets; Thrombopoiesis
PubMed: 36700500
DOI: 10.1016/j.jtha.2022.11.021 -
Hamostaseologie Feb 2022In patients with normal plasmatic coagulation and bleeding tendency, platelet function defect can be assumed. Congenital platelet function defects are rare. Much more... (Review)
Review
In patients with normal plasmatic coagulation and bleeding tendency, platelet function defect can be assumed. Congenital platelet function defects are rare. Much more commonly they are acquired. The clinical bleeding tendency of platelet function defects is heterogeneous, which makes diagnostic approaches difficult. During the years, a large variety of tests for morphological phenotyping and functional analysis have been developed. The diagnosis of platelet function defects is based on standardized bleeding assessment tools followed by a profound morphological evaluation of the platelets. Platelet function assays like light transmission aggregation, luminoaggregometry, and impedance aggregometry followed by flow cytometry are commonly used to establish the diagnosis in these patients. Nevertheless, despite great efforts, standardization of these tests is poor and in most cases, quality control is lacking. In addition, these tests are still limited to specialized laboratories. This review summarizes the approaches to morphologic phenotyping and platelet testing in patients with suspected platelet dysfunction, beginning with a standardized bleeding score and ending with flow cytometry testing. The diagnosis of a functional defect requires a good collaboration between the laboratory and the clinician.
Topics: Blood Platelet Disorders; Blood Platelets; Humans; Laboratories; Platelet Aggregation; Platelet Function Tests
PubMed: 35196730
DOI: 10.1055/a-1700-7036 -
Hamostaseologie Dec 2021Inherited platelet disorders (IPDs) constitute a large heterogeneous group of rare bleeding disorders. These are classified into: (1) quantitative defects, (2)... (Review)
Review
Inherited platelet disorders (IPDs) constitute a large heterogeneous group of rare bleeding disorders. These are classified into: (1) quantitative defects, (2) qualitative disorders, or (3) altered platelet production rate disorders or increased platelet turnover. Classically, IPD diagnostic is based on clinical phenotype characterization, comprehensive laboratory analyses (platelet function analysis), and, in former times, candidate gene sequencing. Today, molecular genetic analysis is performed using next-generation sequencing, mostly by targeting enrichment of a gene panel or by whole-exome sequencing. Still, the biochemical and molecular genetic characterization of patients with congenital thrombocytopathias/thrombocytopenia is essential, since postoperative or posttraumatic bleeding often occurs due to undiagnosed platelet defects. Depending upon the kind of surgery or trauma, this bleeding may be life-threatening, e.g., after tonsillectomy or in brain surgery. Undiagnosed platelet defects may lead to additional surgery, hysterectomy, pulmonary bleeding, and even resuscitation. In addition, these increased bleeding symptoms can lead to wound healing problems. Only specialized laboratories can perform the special platelet function analyses (aggregometry, flow cytometry, or immunofluorescent microscopy of the platelets); therefore, many IPDs are still undetected.
Topics: Blood Platelet Disorders; Blood Platelets; High-Throughput Nucleotide Sequencing; Humans; Phenotype; Platelet Function Tests
PubMed: 34942659
DOI: 10.1055/a-1665-6249