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International Journal of Molecular... Apr 2021Platelets play a major role in hemostasis as ppwell as in many other physiological and pathological processes. Accordingly, production of about 10 platelet per day as... (Review)
Review
Platelets play a major role in hemostasis as ppwell as in many other physiological and pathological processes. Accordingly, production of about 10 platelet per day as well as appropriate survival and functions are life essential events. Inherited platelet disorders (IPDs), affecting either platelet count or platelet functions, comprise a heterogenous group of about sixty rare diseases caused by molecular anomalies in many culprit genes. Their clinical relevance is highly variable according to the specific disease and even within the same type, ranging from almost negligible to life-threatening. Mucocutaneous bleeding diathesis (epistaxis, gum bleeding, purpura, menorrhagia), but also multisystemic disorders and/or malignancy comprise the clinical spectrum of IPDs. The early and accurate diagnosis of IPDs and a close patient medical follow-up is of great importance. A genotype-phenotype relationship in many IPDs makes a molecular diagnosis especially relevant to proper clinical management. Genetic diagnosis of IPDs has been greatly facilitated by the introduction of high throughput sequencing (HTS) techniques into mainstream investigation practice in these diseases. However, there are still unsolved ethical concerns on general genetic investigations. Patients should be informed and comprehend the potential implications of their genetic analysis. Unlike the progress in diagnosis, there have been no major advances in the clinical management of IPDs. Educational and preventive measures, few hemostatic drugs, platelet transfusions, thrombopoietin receptor agonists, and in life-threatening IPDs, allogeneic hematopoietic stem cell transplantation are therapeutic possibilities. Gene therapy may be a future option. Regular follow-up by a specialized hematology service with multidisciplinary support especially for syndromic IPDs is mandatory.
Topics: Blood Platelet Disorders; Blood Platelets; Genetic Testing; Hemostasis; High-Throughput Nucleotide Sequencing; Humans; Platelet Function Tests; Platelet Transfusion; Rare Diseases
PubMed: 33926054
DOI: 10.3390/ijms22094521 -
Journal of Thrombosis and Haemostasis :... Aug 2016Mild inherited bleeding disorders are relatively common in the general population. Despite recent advances in diagnostic approaches, mild inherited bleeding disorders... (Review)
Review
Mild inherited bleeding disorders are relatively common in the general population. Despite recent advances in diagnostic approaches, mild inherited bleeding disorders still pose a significant diagnostic challenge. Hemorrhagic diathesis can be caused by disorders in primary hemostasis (von Willebrand disease, inherited platelet function disorders), secondary hemostasis (hemophilia A and B, other (rare) coagulant factor deficiencies) and fibrinolysis, and in connective tissue or vascular formation. This review summarizes the currently available diagnostic methods for mild bleeding disorders and their pitfalls, from structured patient history to highly specialized laboratory diagnosis. A comprehensive framework for a diagnostic approach to mild inherited bleeding disorders is proposed.
Topics: Blood Coagulation; Blood Platelet Disorders; Blood Platelets; Coagulants; Fibrinolysis; Genetic Testing; Hematology; Hemophilia A; Hemophilia B; Hemorrhage; Hemorrhagic Disorders; Hemostasis; Humans; Mutation; von Willebrand Diseases
PubMed: 27208505
DOI: 10.1111/jth.13368 -
Blood Dec 2019A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes,...
A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multidisciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbor variants associated with rare bleeding, thrombotic, or platelet disorders (BTPDs). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count, and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 745 unique variants, including copy number variants (CNVs) and intronic variants, as pathogenic, likely pathogenic, or variants of uncertain significance. Half of these variants (50.9%) are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BTPDs. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 894 index patients providing evidence that introducing an HTS genetic test is a valuable addition to laboratory diagnostics in patients with a high likelihood of having an inherited BTPD.
Topics: Blood Platelet Disorders; Female; Gene Dosage; Hemorrhage; Hemostasis; High-Throughput Nucleotide Sequencing; Humans; Male; Thrombosis
PubMed: 31064749
DOI: 10.1182/blood.2018891192 -
Nature Reviews. Cardiology Mar 2021The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in... (Review)
Review
The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.
Topics: Administration, Inhalation; Anticoagulants; Blood Coagulation Disorders; Blood Platelet Disorders; COVID-19; Endothelium, Vascular; Endothelium-Dependent Relaxing Factors; Epoprostenol; Heart Disease Risk Factors; Humans; Iloprost; Inflammation; Nitric Oxide; Platelet Aggregation Inhibitors; SARS-CoV-2; Systemic Inflammatory Response Syndrome; Thrombosis; Thrombotic Microangiopathies; Vascular Diseases; Vasodilator Agents; Venous Thromboembolism; COVID-19 Drug Treatment
PubMed: 33214651
DOI: 10.1038/s41569-020-00469-1 -
Hamostaseologie Oct 2023
Topics: Humans; COVID-19; Thrombin; Platelet Glycoprotein GPIb-IX Complex; Blood Platelet Disorders
PubMed: 37857294
DOI: 10.1055/s-0043-1776437 -
Journal of Thrombosis and Haemostasis :... Jun 2015We have proposed that modified platelets could potentially be used to correct intrinsic platelet defects as well as for targeted delivery of therapeutic molecules to... (Review)
Review
We have proposed that modified platelets could potentially be used to correct intrinsic platelet defects as well as for targeted delivery of therapeutic molecules to sights of vascular injury. Ectopic expression of proteins within α-granules prior to platelet activation has been achieved for several proteins, including urokinase, factor (F) VIII, and partially for FIX. Potential uses of platelet-directed therapeutics will be discussed, focusing on targeted delivery of urokinase as a thromboprophylactic agent and FVIII for the treatment of hemophilia A patients with intractable inhibitors. This presentation will discuss new strategies that may be useful in the care of patients with vascular injury as well as remaining challenges and limitations of these approaches.
Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelet Disorders; Blood Platelets; Factor V Deficiency; Gene Transfer Techniques; Genetic Predisposition to Disease; Genetic Therapy; Hemophilia A; Humans; Platelet Transfusion; Treatment Outcome; Urokinase-Type Plasminogen Activator
PubMed: 26149015
DOI: 10.1111/jth.12938 -
Ugeskrift For Laeger Oct 2021Inherited platelet disorders (IPD) cover a heterogenous group of disorders with large differences in severity, disease mechanisms and prevalence. Pathogenic variants in... (Review)
Review
Inherited platelet disorders (IPD) cover a heterogenous group of disorders with large differences in severity, disease mechanisms and prevalence. Pathogenic variants in more than 60 different genes, associated with megakaryocyte or platelet number and/or function, are causal of IPD. Due to disease heterogeneity IPDs are often difficult to diagnose, problematic to manage and underestimated. In the past decade, genetic diagnostics using whole-genome sequencing has revolutionised the field by identifying numerous novel genes involved in IPD aetiology as described in this review.
Topics: Blood Platelet Disorders; Blood Platelets; Humans; Whole Genome Sequencing
PubMed: 34709163
DOI: No ID Found -
Blood Reviews Jan 2017Recent years have seen increasing recognition of a subgroup of inherited platelet function disorders which are due to defects in transcription factors that are required... (Review)
Review
Recent years have seen increasing recognition of a subgroup of inherited platelet function disorders which are due to defects in transcription factors that are required to regulate megakaryopoiesis and platelet production. Thus, germline mutations in the genes encoding the haematopoietic transcription factors RUNX1, GATA-1, FLI1, GFI1b and ETV6 have been associated with both quantitative and qualitative platelet abnormalities, and variable bleeding symptoms in the affected patients. Some of the transcription factor defects are also associated with an increased predisposition to haematologic malignancies (RUNX1, ETV6), abnormal erythropoiesis (GATA-1, GFI1b, ETV6) and immune dysfunction (FLI1). The persistence of MYH10 expression in platelets is a surrogate marker for FLI1 and RUNX1 defects. Characterisation of the transcription factor defects that give rise to platelet function disorders, and of the genes that are differentially regulated as a result, are yielding insights into the roles of these genes in platelet formation and function.
Topics: Blood Platelet Disorders; Blood Platelets; Disease Susceptibility; Gene Expression Regulation; Germ-Line Mutation; Hemostasis; Humans; Structure-Activity Relationship; Thrombopoiesis; Transcription Factors
PubMed: 27450272
DOI: 10.1016/j.blre.2016.07.002 -
Journal of Thrombosis and Haemostasis :... Sep 2019The past decade has brought unprecedented advances in our understanding of megakaryocyte (MK) biology and platelet production, processes that are strongly dependent on... (Review)
Review
The past decade has brought unprecedented advances in our understanding of megakaryocyte (MK) biology and platelet production, processes that are strongly dependent on the cytoskeleton. Facilitated by technological innovations, such as new high-resolution imaging techniques (in vitro and in vivo) and lineage-specific gene knockout and reporter mouse strains, we are now able to visualize and characterize the molecular machinery required for MK development and proplatelet formation in live mice. Whole genome and RNA sequencing analysis of patients with rare platelet disorders, combined with targeted genetic interventions in mice, has led to the identification and characterization of numerous new genes important for MK development. Many of the genes important for proplatelet formation code for proteins that control cytoskeletal dynamics in cells, such as Rho GTPases and their downstream targets. In this review, we discuss how the final stages of MK development are controlled by the cellular cytoskeletons, and we compare changes in MK biology observed in patients and mice with mutations in cytoskeleton regulatory genes.
Topics: Actins; Animals; Blood Platelet Disorders; Blood Platelets; Blood Proteins; Cytoplasmic Granules; Cytoskeleton; Formins; Genes, Reporter; Humans; Mice; Mice, Knockout; Nonmuscle Myosin Type IIA; Organelle Biogenesis; Thrombopoiesis; Tubulin
PubMed: 31220402
DOI: 10.1111/jth.14544 -
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