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Haematologica Apr 2020Glanzmann thrombasthenia (GT) is an autosomal recessive disorder of platelet aggregation caused by quantitative or qualitative defects in integrins αIIb and β3. These... (Review)
Review
Glanzmann thrombasthenia (GT) is an autosomal recessive disorder of platelet aggregation caused by quantitative or qualitative defects in integrins αIIb and β3. These integrins are encoded by the and genes and form platelet glycoprotein (GP)IIb/IIIa, which acts as the principal platelet receptor for fibrinogen. Although there is variability in the clinical phenotype, most patients present with severe mucocutaneous bleeding at an early age. A classic pattern of abnormal platelet aggregation, platelet glycoprotein expression and molecular studies confirm the diagnosis. Management of bleeding is based on a combination of hemostatic agents including recombinant activated factor VII with or without platelet transfusions and antifibrinolytic agents. Refractory bleeding and platelet alloimmunization are common complications. In addition, pregnant patients pose unique management challenges. This review highlights clinical and molecular aspects in the approach to patients with GT, with particular emphasis on the significance of multidisciplinary care.
Topics: Blood Platelets; Humans; Integrin beta3; Platelet Aggregation; Platelet Function Tests; Platelet Glycoprotein GPIIb-IIIa Complex; Thrombasthenia
PubMed: 32139434
DOI: 10.3324/haematol.2018.214239 -
Equine Veterinary Journal Jan 2021Genetic bleeding disorders can have a profound impact on a horse's health and athletic career. As such, it is important to understand the mechanisms of these diseases... (Review)
Review
Genetic bleeding disorders can have a profound impact on a horse's health and athletic career. As such, it is important to understand the mechanisms of these diseases and how they are diagnosed. These diseases include haemophilia A, von Willebrand disease, prekallikrein deficiency, Glanzmann's Thrombasthenia and Atypical Equine Thrombasthenia. Exercise-induced pulmonary haemorrhage also has a proposed genetic component. Genetic mutations have been identified for haemophilia A and Glanzmann's Thrombasthenia in the horse. Mutations are known for von Willebrand disease and prekallikrein deficiency in other species. In the absence of genetic tests, bleeding disorders are typically diagnosed by measuring platelet function, von Willebrand factor, and other coagulation protein levels and activities. For autosomal recessive diseases, genetic testing can prevent the breeding of two carriers.
Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Factors; Hemorrhage; Hemostasis; Horse Diseases; Horses; Thrombasthenia
PubMed: 32463964
DOI: 10.1111/evj.13290 -
Blood Research Apr 2022Inherited platelet disorders (IPDs) can cause mucocutaneous bleeding due to impaired primary hemostatic function of platelets, thrombocytopenia, or both. Recent advances... (Review)
Review
Inherited platelet disorders (IPDs) can cause mucocutaneous bleeding due to impaired primary hemostatic function of platelets, thrombocytopenia, or both. Recent advances in molecular technology can help identify many genes related to platelet biology, control the overall steps of megakaryopoiesis, and cause IPD. In this article, currently available laboratory tools for diagnosing IPDs with the characteristic laboratory features of each IPD are reviewed, and a general diagnostic approach for the evaluation of IPD patients is presented.
PubMed: 35483920
DOI: 10.5045/br.2022.2021223 -
Seminars in Thrombosis and Hemostasis Mar 2021Decades of preclinical and clinical studies developing gene therapy for hemophilia are poised to bear fruit with current promising pivotal studies likely to lead to... (Review)
Review
Decades of preclinical and clinical studies developing gene therapy for hemophilia are poised to bear fruit with current promising pivotal studies likely to lead to regulatory approval. However, this recent success should not obscure the multiple challenges that were overcome to reach this destination. Gene therapy for hemophilia A and B benefited from advancements in the general gene therapy field, such as the development of adeno-associated viral vectors, as well as disease-specific breakthroughs, like the identification of B-domain deleted factor VIII and hyperactive factor IX Padua. The gene therapy field has also benefited from hemophilia B clinical studies, which revealed for the first time critical safety concerns related to immune responses to the vector capsid not anticipated in preclinical models. Preclinical studies have also investigated gene transfer approaches for other rare inherited bleeding disorders, including factor VII deficiency, von Willebrand disease, and Glanzmann thrombasthenia. Here we review the successful gene therapy journey for hemophilia and pose some unanswered questions. We then discuss the current state of gene therapy for these other rare inherited bleeding disorders and how the lessons of hemophilia gene therapy may guide clinical development.
Topics: Genetic Therapy; Hemorrhagic Disorders; Humans
PubMed: 33636747
DOI: 10.1055/s-0041-1722862 -
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 -
Iranian Journal of Veterinary Research 2020The process of fibrin clot formation is a series of complex and well-regulated reactions involving blood vessels, platelets, procoagulant plasma proteins, natural... (Review)
Review
The process of fibrin clot formation is a series of complex and well-regulated reactions involving blood vessels, platelets, procoagulant plasma proteins, natural inhibitors, and fibrinolytic enzymes. Vasculitis can be caused by a variety of different agents as bacteria, viruses, protozoal, rickettsial organisms, toxic, drugs, medications, and neoplasms. The most common cause of vasculitis is the purpura hemorrhagica, which is associated with exposure to ssp. or less commonly, equine influenza. Deficiencies or defects of the hemostatic components may result in bleeding and/or thrombosis. Inherited alterations of primary hemostasis (von Willebrand disease: vWD and thrombasthenia: GT) and of secondary hemostasis (hemophilia A and prekallikrein: PK deficiency) are scarcely reported in equine clinic. On the contrary, acquired alterations of primary and secondary hemostasis are commonly found. They include thrombocytopenia, platelet dysfunction due to the administration of some drugs and targeted antiplatelet agents, decreased factor synthesis (liver disease or deficiency of vitamin K), release of inactive factors, inhibition of factor activity, or excessive consumption and depletion of factors (platelets, coagulation factors, and anticoagulants factors as antithrombin (AT) and protein C). Disseminated intravascular coagulation (DIC) is the most common and complex hemostatic disorder in horses and appears to be associated with sepsis, inflammatory and ischemic gastrointestinal tract disorders and other systemic severe diseases. These alterations are commonly found in patients in intensive care units.
PubMed: 32368218
DOI: No ID Found -
Cureus Oct 2020Platelets play an important role in hemostasis through platelet plug formation by a phenomenon of adhesion; activation; secretion and aggregation. Defects in platelet... (Review)
Review
Platelets play an important role in hemostasis through platelet plug formation by a phenomenon of adhesion; activation; secretion and aggregation. Defects in platelet hemostatic mechanisms can be congenital or acquired. Congenital platelet disorders are rare and manifestations range from asymptomatic to sometimes severe bleeding. The disorders arise due to diverse mechanisms. Congenital platelet disorders include thrombocytopathies and thrombocytopenia (platelet count <150 x 10/L) or thrombocytosis (platelet count > 450 x 10/L). Congenital thrombocytopathies include disorders of adhesion like von Willebrand's disease or Bernard-Soulier syndrome. The disorders of aggregation include congenital afibrinogenemia and Glanzmann thrombasthenia. Disorders of storage granules are gray platelet syndrome and Quebec platelet disorder. Congenital thrombocythopathy and thrombocytopenia often occur in conjunction. In this article, we have a detailed literature review of these rare thrombocytopathies, their presentation and treatment.
PubMed: 33274150
DOI: 10.7759/cureus.11275 -
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 -
Journal of Blood Medicine 2021Glanzmann thrombasthenia (GT) is a rare autosomal recessive disorder of fibrinogen-mediated platelet aggregation due to a quantitative or qualitative deficit of the αβ... (Review)
Review
Glanzmann thrombasthenia (GT) is a rare autosomal recessive disorder of fibrinogen-mediated platelet aggregation due to a quantitative or qualitative deficit of the αβ integrin at the platelet surface membrane resulting from mutation(s) in and/or . Patients tend to present in early childhood with easy bruising and mucocutaneous bleeding. The diagnostic process requires consideration of more common disorders of haemostasis and coagulation prior to confirming the disorder with platelet light transmission aggregation, flow cytometry of CD41 and CD61 expression, and/or exon sequencing of and . Antifibrinolytic therapy, recombinant activated factor VII, and platelet transfusions are the mainstay of therapy, although the latter may trigger formation of anti-platelet antibodies in GT patients and inadvertent platelet-refractory disease. The management of these patients therefore remains complex, particularly in the context of trauma, labour and delivery, and perioperative care. Bone marrow transplantation remains the sole curative option, although the venue of gene therapy is being increasingly explored as a future alternative for definitive treatment of GT.
PubMed: 34149292
DOI: 10.2147/JBM.S271744