Glanzmann thrombasthenia

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 αIIbβ3 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 αIIbβ3 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

Inherited thrombocytopenias: history, advances and perspectives

Over the last 100 years the role of platelets in hemostatic events and their production by megakaryocytes have gradually been defined. Progressively, thrombocytopenia was recognized as a cause of bleeding, first through an acquired immune disorder; then, since 1948, when Bernard-Soulier syndrome was first described, inherited thrombocytopenia became a fascinating example of Mendelian disease. The platelet count is often severely decreased and platelet size variable; associated platelet function defects frequently aggravate bleeding. Macrothrombocytopenia with variable proportions of enlarged platelets is common. The number of circulating platelets will depend on platelet production, consumption and lifespan. The bulk of macrothrombocytopenias arise from defects in megakaryopoiesis with causal variants in transcription factor genes giving rise to altered stem cell differentiation and changes in early megakaryocyte development and maturation. Genes encoding surface receptors, cytoskeletal and signaling proteins also feature prominently and Sanger sequencing associated with careful phenotyping has allowed their early classification. It quickly became apparent that many inherited thrombocytopenias are syndromic while others are linked to an increased risk of hematologic malignancies. In the last decade, the application of next-generation sequencing, including whole exome sequencing, and the use of gene platforms for rapid testing have greatly accelerated the discovery of causal genes and extended the list of variants in more common disorders. Genes linked to an increased platelet turnover and apoptosis have also been identified. The current challenges are now to use next-generation sequencing in first-step screening and to define bleeding risk and treatment better

Independent adjudicator assessments of platelet refractoriness and rFVIIa efficacy in bleeding episodes and surgeries from the multinational Glanzmann’s thrombasthenia registry

Glanzmann’s thrombasthenia (GT) is a rare congenital bleeding disorder associated with decreased platelet aggregation due to qualitative/quantitative deficiencies of the fibrinogen receptor. Severe bleeding episodes and perioperative bleeding are typically managed with platelet transfusions, although patients can develop antiâ platelet antibodies or experience clinical refractoriness. The GT Registry (GTR) was established to collect efficacy/safety data on hemostatic treatments for GT, including recombinant factor VIIa (rFVIIa). At the request of the United States Food and Drug Administration, three hematology experts evaluated platelet refractoriness, antibody status, and rFVIIa efficacy data on a caseâ byâ case basis to support a potential indication for rFVIIa in GT. Adjudication included 195 patients with 810 events (619 severe bleeding episodes, 192 surgeries), and a consensus algorithm was developed to describe adjudicators’ coding of refractoriness and antibody status based on treatment patterns over time. Most rFVIIaâ treated events were in patients without refractoriness or antibodies. Adjudicators rated most rFVIIaâ treated bleeding episodes as successful (251/266, 94.4%; rFVIIa only, 101/109, 92.7%; rFVIIaâ ±â plateletsâ ±â other agents, 150/157, 95.5%); efficacy was consistent in patients with platelet refractorinessâ ±â antibodies (75/79, 94.9%), antibodies only (10/10, 100.0%), and neither/unknown (166/177, 93.8%). Adjudicators also rated most rFVIIaâ treated surgeries as successful (159/160, 99.4%; rFVIIa only, 65/66, 98.5%; rFVIIaâ ±â plateletsâ ±â other agents, 94/94, 100.0%); efficacy was consistent in patients with platelet refractorinessâ ±â antibodies (69/70, 98.6%), antibodies only (24/24, 100.0%), and neither/unknown (66/66, 100.0%). Unblinding the adjudicators to investigator efficacy ratings changed few assessments. Doses of rFVIIa were narrowly distributed, regardless of other hemostatic agents used.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137322/1/ajh24741.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137322/2/ajh24741_am.pd

Enfermedad de Glanzmann: elementos clínicos y conducta terapéutica

Introduction: Glanzmann's disease is a rare disorder, with a worldwide distribution that predominates in the Asian region; it has specific symptoms and emergent treatment. Objective: to describe the clinical elements and the therapeutic behavior of Glanzmann's disease. Method: a bibliographic review was carried out in the databases SciELO, Scopus, ClinicalKey and PubMed. The combination of terms was used as a search strategy, using the name of the disease, clinic and treatment. 21 references were selected. Development: there are three subtypes of Glanzmann's thrombasthenia. The clinical manifestations are variable and include mucocutaneous and gastrointestinal hemorrhages, presence of hemarthrosis, intracranial hemorrhage, and visceral hematoma. Prophylaxis is recommended before major surgeries and avoiding the use of drugs that affect platelet function such as non-steroidal anti-inflammatory drugs and aspirin. The only curative measure for patients with recurrent bleeding episodes or who are refractory to platelet transfusions is allogeneic hematopoietic cell transplantation. Conclusions: the clinical method that includes the search for history and a rigorous physical examination, accompanied by complementary tests, plays an important role in the diagnosis of rhombobastenia. In this way, therapeutics focuses on controlling acute symptoms and platelet transfusions, with several options such as gene therapy still under study; all in order to improve the quality of life and extend it.Introducción: la enfermedad de Glanzmann es un trastorno poco común, con una distribución a nivel mundial que predomina en la región asiática; posee sintomatología específica y tratamiento emergente.Objetivo: describir los elementos clínicos y la conducta terapéutica de la enfermedad de Glanzmann.Método: se realizó una revisión bibliográfica en las bases de dato SciELO, Scopus, ClinicalKey y PubMed. Se empleó como estrategia de búsqueda la combinación de términos, al emplear el nombre de la enfermedad, clínica y tratamiento. Se seleccionaron 21 referencias.Desarrollo: existen tres subtipos de la trombastenia de Glanzmann. Las manifestaciones clínicas son variables e incluyen hemorragias mucocutáneas y gastrointestinales, presencia de hemartrosis, hemorragia intracraneal y hematoma visceral. Se recomienda profilaxis antes de cirugías mayores y evitar el uso de medicamentos que afecten la función plaquetaria como los antinflamatorios no esteroideos y la aspirina. La única medida curativa para pacientes con episodios recurrentes de sangrado o que son refractarios a trasfusiones plaquetarias es el trasplante de células hematopoyéticas alogénicas.Conclusiones: el método clínico que incluye la búsqueda de antecedentes y un examen físico riguroso, acompañado de exámenes complementarios, juega un importante papel en el diagnóstico de la rombobastenia. De esta forma la terapéutica se enfoca en controlar los síntomas agudos y transfusiones plaquetarias, con varias opciones como la terapia génica aún en estudio; todo con el fin de mejorar la calidad de vida y extenderla

Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg2+ homeostasis and cytoskeletal architecture

Mg2+ plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg2+](i) in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic alpha-kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7(fl/fl-Pf4Cre)) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7(fl/fl-Pf4Cre) MKs, which is rescued by Mg2+ supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice

A mutation of the human EPHB2 gene leads to a major platelet functional defect.

The ephrin transmembrane receptor family of tyrosine kinases is involved in platelet function. We report the first EPHB2 variant affecting platelets in 2 siblings (P1 and P2) from a consanguineous family with recurrent bleeding and normal platelet counts. Whole-exome sequencing identified a c.2233C>T variant (missense p.R745C) of the EPHB2 gene. P1 and P2 were homozygous for this variant, while their asymptomatic parents were heterozygous. The p.R745C variant within the tyrosine kinase domain was associated with defects in platelet aggregation, αIIbβ3 activation, and granule secretion induced by G-protein-coupled receptor (GPCR) agonists and convulxin, as well as in thrombus formation on collagen under flow. In contrast, clot retraction, flow-dependent platelet adhesion, and spreading on fibrinogen were only mildly affected, indicating limited effects on αIIbβ3 outside-in signaling. Most importantly, Lyn, Syk, and FcRγ phosphorylation, the initial steps in glycoprotein VI (GPVI) platelet signaling were drastically impaired in the absence of platelet-platelet contact, indicating a positive role for EPHB2 in GPVI activation. Likewise platelet activation by PAR4-AP showed defective Src activation, as opposed to normal protein kinase C activity and Ca2+ mobilization. Overexpression of wild-type and R745C EPHB2 variant in RBL-2H3 (rat basophilic leukemia) cells stably expressing human GPVI confirmed that EPHB2 R745C mutation impaired EPHB2 autophosphorylation but had no effect on ephrin ligand-induced EPHB2 clustering, suggesting it did not interfere with EPHB2-ephrin-mediated cell-to-cell contact. In conclusion, this novel inherited platelet disorder affecting EPHB2 demonstrates this tyrosine kinase receptor plays an important role in platelet function through crosstalk with GPVI and GPCR signaling

The Decommissioning of the Trino Nuclear Power Plant

Following a referendum in Italy in 1987, the four Nuclear Power Plants (NPPs) owned and operated by the state utility ENEL were closed. After closing the NPPs, ENEL selected a ''safestore'' decommissioning strategy; anticipating a safestore period of some 40-50 years. This approach was consistent with the funds collected during plant operation, and was reinforced by the lack of both a waste repository and a set of national free release limits for contaminated materials in Italy. During 1999, twin decisions were made to privatize ENEL and to transform the nuclear division into a separate subsidiary of the ENEL group. This group was renamed Sogin and during the following year, ownership of the company was transferred to the Italian Treasury. On formation, Sogin was asked by the Italian government to review the national decommissioning strategy. The objective of the review was to move from a safestore strategy to a prompt decommissioning strategy, with the target of releasing all of the nuclear sites by 2020. It was recognized that this target was conditional upon the availability of a national LLW repository together with interim stores for both spent fuel and HLW by 2009. The government also agreed that additional costs caused by the acceleration of the decommissioning program would be considered as stranded costs. These costs will be recovered by a levy on the kWh price of electricity, a process established and controlled by the Regulator of the Italian energy sector. Building on the successful collaboration to develop a prompt decommissioning strategy for the Latina Magnox reactor (1), BNFL and Sogin agreed to collaborate on an in depth study for the prompt decommissioning of the Sogin PWR at Trino. BNFL is currently decommissioning six NPPs and is at an advanced stage of planning for two further units, having completed a full and rigorous exercise to develop Baseline Decommissioning Plans (BDP's) for these stations. The BDP exercise utilizes the full range of BNFL decommissioning experience and knowledge to develop a strategy, methodology and cost for the decommissioning of NPPs. Over the past year, a prompt decommissioning strategy for Trino has been developed. The strategy has been based on the principles of minimizing waste products that require long term storage, maximizing 'free release' materials and utilizing existing and regulatory approved technologies

Gain-of-Function Mutation in Filamin A Potentiates Platelet Integrin αβ Activation

OBJECTIVE: Dominant mutations of the X-linked filamin A () gene are responsible for filaminopathies A, which are rare disorders including brain periventricular nodular heterotopia, congenital intestinal pseudo-obstruction, cardiac valves or skeleton malformations, and often macrothrombocytopenia. APPROACH AND RESULTS: We studied a male patient with periventricular nodular heterotopia and congenital intestinal pseudo-obstruction, his unique X-linked allele carrying a stop codon mutation resulting in a 100-amino acid-long FLNa C-terminal extension (NP_001447.2: ). Platelet counts were normal, with few enlarged platelets. FLNa was detectable in all platelets but at 30% of control levels. Surprisingly, all platelet functions were significantly upregulated, including platelet aggregation and secretion, as induced by ADP, collagen, or von Willebrand factor in the presence of ristocetin, as well as thrombus formation in blood flow on a collagen or on a von Willebrand factor matrix. Most importantly, patient platelets stimulated with ADP exhibited a marked increase in αβ integrin activation and a parallel increase in talin recruitment to β, contrasting with normal Rap1 activation. These results are consistent with the mutant FLNa affecting the last step of αβ activation. Overexpression of mutant FLNa in the HEL megakaryocytic cell line correlated with an increase (compared with wild-type FLNa) in PMA-induced fibrinogen binding to and in talin and kindlin-3 recruitment by αβ. CONCLUSIONS: Altogether, our results are consistent with a less binding of mutant FLNa to β and the facilitated recruitment of talin by β on platelet stimulation, explaining the increased αβ activation and the ensuing gain-of-platelet functions