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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 -
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 -
Journal of Blood Medicine 2015Glanzmann's thrombasthenia (GT) is a genetic platelet surface receptor disorder of GPIIb/IIIa (ITG αIIbβ3), either qualitative or quantitative, which results in faulty... (Review)
Review
Glanzmann's thrombasthenia (GT) is a genetic platelet surface receptor disorder of GPIIb/IIIa (ITG αIIbβ3), either qualitative or quantitative, which results in faulty platelet aggregation and diminished clot retraction. Spontaneous mucocutaneous bleeding is common and can lead to fatal bleeding episodes. Control and prevention of bleeding among patients with GT is imperative, and remains challenging. Local measures, including anti-fibrinolytic therapy, with or without platelet transfusions, used to be the mainstay of therapy. However, in recent years the use of recombinant factor VIIa (rFVIIa) has increased significantly, with excellent response rates in treating and preventing hemorrhage among GT patients. Gene therapy and stem cell transplantation offer a potential cure of this disease, but both are costly and remain experimental at this point. This manuscript offers a comprehensive review of our understanding of GT and the available treatment options.
PubMed: 26185478
DOI: 10.2147/JBM.S71319 -
Orphanet Journal of Rare Diseases Apr 2006Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding syndrome affecting the megakaryocyte lineage and characterized by lack of platelet aggregation. The... (Review)
Review
Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding syndrome affecting the megakaryocyte lineage and characterized by lack of platelet aggregation. The molecular basis is linked to quantitative and/or qualitative abnormalities of alphaIIb beta3 integrin. This receptor mediates the binding of adhesive proteins that attach aggregating platelets and ensure thrombus formation at sites of injury in blood vessels. GT is associated with clinical variability: some patients have only minimal bruising while others have frequent, severe and potentially fatal hemorrhages. The site of bleeding in GT is clearly defined: purpura, epistaxis, gingival hemorrhage, and menorrhagia are nearly constant features; gastrointestinal bleeding and hematuria are less common. In most cases, bleeding symptoms manifest rapidly after birth, even if GT is occasionally only diagnosed in later life. Diagnosis should be suspected in patients with mucocutaneous bleeding with absent platelet aggregation in response to all physiologic stimuli, and a normal platelet count and morphology. Platelet alphaIIb beta3 deficiency or nonfunction should always be confirmed, for example by flow cytometry. In order to avoid platelet alloimmunisation, therapeutic management must include, if possible, local hemostatic procedures and/or desmopressin (DDAVP) administration. Transfusion of HLA-compatible platelet concentrates may be necessary if these measures are ineffective, or to prevent bleeding during surgery. Administration of recombinant factor VIIa is an increasingly used therapeutic alternative. GT can be a severe hemorrhagic disease, however the prognosis is excellent with careful supportive care.
Topics: Blood Platelets; Factor VIIa; Hemorrhage; Humans; Integrin beta3; Platelet Transfusion; Thrombasthenia
PubMed: 16722529
DOI: 10.1186/1750-1172-1-10 -
Clinical and Applied... 2009Glanzmann's thrombasthenia (GT) is an autosomal recessive inherited bleeding disorder due to a defect in platelet function. The hallmark of this disease is severely... (Review)
Review
Glanzmann's thrombasthenia (GT) is an autosomal recessive inherited bleeding disorder due to a defect in platelet function. The hallmark of this disease is severely reduced/absent platelet aggregation in response to multiple physiological agonists. Bleeding signs in GT include epistaxis, bruising, gingival hemorrhage, gastrointestinal hemorrhage, hematuria, menorrhagia, and hemarthrosis. Homozygous or compound heterozygous mutations in the genes of GPIIb and GPIIIa lead to GT. A patient with GT, with no possible causative mutations in GPIIb and GPIIIa genes, may harbor defects in a regulatory element affecting the transcription of these 2 genes. GT occurs in high frequency in certain ethnic populations with an increased incidence of consanguinity such as in Indians, Iranians, Iraqi Jews, Palestinian and Jordanian Arabs, and French Gypsies. Carrier detection in GT is important to control the disorder in family members. Carrier detection can be done both by protein analysis and direct gene analysis.
Topics: Blood Platelets; CD36 Antigens; Humans; Platelet Glycoprotein GPIb-IX Complex; Thrombasthenia
PubMed: 18930954
DOI: 10.1177/1076029608326165 -
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 -
Journal of Blood Medicine 2021Glanzmann thrombasthenia (GT) is the most widely studied inherited disease of platelet function. Platelets fail to aggregate due to a defect in platelet-to-platelet... (Review)
Review
Glanzmann thrombasthenia (GT) is the most widely studied inherited disease of platelet function. Platelets fail to aggregate due to a defect in platelet-to-platelet attachment. The hemostatic plug fails to form and a moderate to severe bleeding diathesis results. Classically of autosomal recessive inheritance, GT is caused by defects within the and genes that encode the αIIbβ3 integrin expressed at high density on the platelet surface and also in intracellular pools. Activated αIIbβ3 acts as a receptor for fibrinogen and other adhesive proteins that hold platelets together in a thrombus. Over 50 years of careful clinical and biological investigation have provided important advances that have improved not only the quality of life of the patients but which have also contributed to an understanding of how αIIbβ3 functions. Despite major improvements in our knowledge of GT and its genetic causes, extensive biological and clinical variability with respect to the severity and intensity of bleeding remains poorly understood. I now scan the repertoire of and gene defects and highlight the wide genetic and biological heterogeneity within the type II and variant subgroups especially with regard to bleeding, clot retraction, the internal platelet Fg storage pool and the nature of the mutations causing the disease. I underline the continued importance of gene profiling and biological studies and emphasize the multifactorial etiology of the clinical expression of the disease. This is done in a manner to provide guidelines for future studies and future treatments of a disease that has not only aided research on rare diseases but also contributed to advances in antithrombotic therapy.
PubMed: 34267570
DOI: 10.2147/JBM.S273053