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Transfusion Medicine Reviews Oct 2020Inherited platelet disorders are rare but they can have considerable clinical impacts, and studies of their causes have advanced understanding of platelet formation and... (Review)
Review
Inherited platelet disorders are rare but they can have considerable clinical impacts, and studies of their causes have advanced understanding of platelet formation and function. Effective hemostasis requires adequate circulating numbers of functional platelets. Quantitative, qualitative and combined platelet disorders with a bleeding phenotype have been linked to defects in platelet cytoskeletal elements, cell surface receptors, signal transduction pathways, secretory granules and other aspects. Inherited platelet disorders have variable clinical presentations, and diagnosis and management is often challenging. Evaluation begins with detailed patient and family histories, including a bleeding score. The physical exam identifies potential syndromic features of inherited platelet disorders and rules out other causes. Laboratory investigations include a complete blood count, blood film, coagulation testing and Von Willebrand factor assessment. A suspected platelet function disorder is further assessed by platelet aggregation, flow cytometry, platelet dense granule release and/or content, and genetic testing. The management of platelet function disorders aims to minimize the risk of bleeding and achieve adequate hemostasis when needed. Although not universal, platelet transfusion remains a crucial component in the management of many inherited platelet disorders.
Topics: Antifibrinolytic Agents; Blood Platelet Disorders; Blood Platelets; Combined Modality Therapy; Genetic Markers; Genetic Testing; Humans; Phenotype; Platelet Transfusion
PubMed: 33082057
DOI: 10.1016/j.tmrv.2020.09.006 -
Haemophilia : the Official Journal of... Jul 2016Genetic diagnosis in families with inherited platelet disorders (IPD) is not performed widely because of the genetic heterogeneity of this group of disorders and because... (Review)
Review
Genetic diagnosis in families with inherited platelet disorders (IPD) is not performed widely because of the genetic heterogeneity of this group of disorders and because in most cases, it is not possible to select single candidate genes for analysis using clinical and laboratory phenotypes. Next-generation sequencing (NGS) technology has revolutionized the scale and cost-effectiveness of genetic testing, and has emerged as a valuable tool for IPD. This review examines the potential utility of NGS as a diagnostic tool to streamline detection of causal variants in known IPD genes and as a vehicle for new gene discovery.
Topics: Blood Platelet Disorders; Genetic Testing; Genomics; High-Throughput Nucleotide Sequencing; Humans; Phenotype; Platelet Glycoprotein GPIb-IX Complex; Sequence Analysis, DNA; Thrombocytopenia
PubMed: 27405671
DOI: 10.1111/hae.12964 -
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 -
Israel Journal of Medical Sciences Jul 1965
Topics: Blood Coagulation Factors; Blood Platelet Disorders; Blood Platelets; Microscopy, Electron
PubMed: 5856133
DOI: No ID Found -
Clinical Laboratory Jan 2017Inherited platelet function disorders (IPFDs) are a wide spectrum of qualitative platelet disorders with variable bleeding tendency, ranging from mild bleeding to severe... (Review)
Review
BACKGROUND
Inherited platelet function disorders (IPFDs) are a wide spectrum of qualitative platelet disorders with variable bleeding tendency, ranging from mild bleeding to severe life-threatening episodes. Diagnosis and classification of IPFDs is a challenge worldwide. The present study aims to present a proper classification, describe the molecular basis and clinical presentations as well as some diagnostic clues for these disorders.
METHODS
All relevant publications were searched using appropriate keywords.
RESULTS
IPFDs can be divided into four major groups including defects of platelet surface glycoproteins, platelet granules and secretion disorders, platelet signaling defects, and transcription-related platelet disorders. Some of these disorders, such as Glanzman thrombasthenia, are more common, with severe bleeding, while most of these disorders are extremely rare with mild bleeding.
CONCLUSIONS
A proper classification, accompanied by familiarity with diagnostic clinical and laboratory features of IPFDs, can be helpful in in-time and exact diagnosis of these complicated bleeding disorders.
Topics: Blood Platelet Disorders; Blood Platelets; Genetic Markers; Genetic Predisposition to Disease; Hemostasis; Heredity; Humans; Molecular Diagnostic Techniques; Pedigree; Phenotype; Platelet Function Tests; Prognosis; Severity of Illness Index
PubMed: 28164499
DOI: 10.7754/Clin.Lab.2016.160607 -
Blood May 2017
Topics: Animals; Blood Platelet Disorders; Humans
PubMed: 28416504
DOI: 10.1182/blood-2017-04-773507 -
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 -
Current Opinion in Hematology Sep 2019The increasing use of high throughput sequencing and genomic analysis has facilitated the discovery of new causes of inherited platelet disorders. Studies of these... (Review)
Review
PURPOSE OF REVIEW
The increasing use of high throughput sequencing and genomic analysis has facilitated the discovery of new causes of inherited platelet disorders. Studies of these disorders and their respective mouse models have been central to understanding their biology, and also in revealing new aspects of platelet function and production. This review covers recent contributions to the identification of genes, proteins and variants associated with inherited platelet defects, and highlights how these studies have provided insights into platelet development and function.
RECENT FINDINGS
Novel genes recently implicated in human platelet dysfunction include the galactose metabolism enzyme UDP-galactose-4-epimerase in macrothrombocytopenia, and erythropoietin-producing hepatoma-amplified sequence receptor transmembrane tyrosine kinase EPHB2 in a severe bleeding disorder with deficiencies in platelet agonist response and granule secretion. Recent studies of disease-associated variants established or clarified roles in platelet function and/or production for the membrane receptor G6b-B, the FYN-binding protein FYB1/ADAP, the RAS guanyl-releasing protein RASGRP2/CalDAG-GEFI and the receptor-like protein tyrosine phosphatase PTPRJ/CD148. Studies of genes associated with platelet disorders advanced understanding of the cellular roles of neurobeachin-like 2, as well as several genes influenced by the transcription regulator RUNT-related transcription factor 1 (RUNX1), including NOTCH4.
SUMMARY
The molecular bases of many hereditary platelet disorders have been elucidated by the application of recent advances in cell imaging and manipulation, genomics and protein function analysis. These techniques have also aided the detection of new disorders, and enabled studies of disease-associated genes and variants to enhance understanding of platelet development and function.
Topics: Animals; Blood Platelet Disorders; Blood Platelets; Humans
PubMed: 31348050
DOI: 10.1097/MOH.0000000000000525 -
Seminars in Thrombosis and Hemostasis Sep 2013Sticky platelet syndrome (SPS) is a thrombophilic thrombocytopathy with familial occurrence and autosomal dominant trait, characterized by an increased in vitro platelet... (Review)
Review
Sticky platelet syndrome (SPS) is a thrombophilic thrombocytopathy with familial occurrence and autosomal dominant trait, characterized by an increased in vitro platelet aggregation in response to low concentrations of adenosine diphosphate (ADP) and/or epinephrine (EPI). According to aggregation pattern, three types of the syndrome can be identified (hyperresponse after both reagents, Type I; EPI alone, Type II; ADP alone, Type III). Clinically, the syndrome is associated with both venous and arterial thrombosis. In pregnant women, complications such as fetal growth retardation and fetal loss have been reported. The first thrombotic event usually occurs before 40 years of age and without prominent acquired risk factors. Antiplatelet drugs generally represent adequate treatment. The use of other antithrombotics is usually ineffective and may result in the recurrence of thrombosis. In most patients, low doses of antiplatelet drugs (acetylsalicylic acid, 80-100 mg/d) lead to normalization of hyperaggregability. Combination of SPS with other thrombophilic disorders has been described. Despite several studies investigating platelet glycoproteins' role in platelets' activation and aggregation, the precise defect responsible for the syndrome remains unknown. The aim of this review is to summarize authors' own experience about SPS and the clinical data indexed in selected databases of medical literature (PubMed and Scopus).
Topics: Blood Platelet Disorders; Female; Fetal Growth Retardation; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Pregnancy; Pregnancy Complications, Hematologic; Syndrome; Thrombophilia
PubMed: 23934738
DOI: 10.1055/s-0033-1353394 -
Seminars in Thrombosis and Hemostasis Apr 2023This review summarizes the time that has passed from the initial registration of the cells that turned out to be platelets up to today's advanced methodologies in... (Review)
Review
This review summarizes the time that has passed from the initial registration of the cells that turned out to be platelets up to today's advanced methodologies in platelet investigation. The first reports of "granular masses" appeared in the 1840s, but these "granular masses" remained an unsolved mystery until the 1870s. The breakthrough came in the 1873-1882 period. The cells that later turned out to be platelets were further identified by the German Professor Max Schultze, and later by Osler, who described their disk-like structure. These initial descriptions of platelets were expanded by impressive studies performed by the Italian Pathologist Bizzozero who uncovered the anatomy of platelets and described their role, first in experimental thrombosis and later in the clotting process. Nearly 20 years later, in 1906, Wright published the discovery of megakaryocytes as platelet precursors. Shortly thereafter, the clinical proof of concept illustrating the pivotal role of platelets in arresting bleeding was revealed by Duke who introduced the bleeding time test, also in this period. To investigate platelet function more specifically, light transmission aggregometry was introduced in 1962 and remains the gold standard today. This method inspired the development of several devices employing whole blood using different principles for evaluating platelet function. As of today, flow cytometry is the most advanced method and holds promise to provide new insights into platelet activation. Additionally, advances in genetic testing by the use of next-generation sequencing will allow further improvement of our ability to diagnose inherited platelet disorders.
Topics: Humans; Blood Platelets; Blood Platelet Disorders; Platelet Activation; Blood Coagulation; Hemostasis
PubMed: 36368689
DOI: 10.1055/s-0042-1758119