Browsing by Subject "Platelet function"

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    Dawning of the age of genomics for platelet granule disorders: improving insight, diagnosis and management
    (Wiley, 2016-12-16) Bariana, Tadbir K.; Ouwehand, Willem H.; Guerrero López, José Antonio; Gomez, Keith; Medicina Interna
    Inherited disorders of platelet granules are clinically heterogeneous and their prevalence is underestimated because most patients do not undergo a complete diagnostic work-up. The lack of a genetic diagnosis limits the ability to tailor management, screen family members, aid with family planning, predict clinical progression and detect serious consequences, such as myelofibrosis, lung fibrosis and malignancy, in a timely manner. This is set to change with the introduction of high throughput sequencing (HTS) as a routine clinical diagnostic test. HTS diagnostic tests are now available, affordable and allow parallel screening of DNA samples for variants in all of the 80 known bleeding, thrombotic and platelet genes. Increased genetic diagnosis and curation of variants is, in turn, improving our understanding of the pathobiology and clinical course of inherited platelet disorders. Our understanding of the genetic causes of platelet granule disorders and the regulation of granule biogenesis is a work in progress and has been significantly enhanced by recent genomic discoveries from high-powered genome-wide association studies and genome sequencing projects. In the era of whole genome and epigenome sequencing, new strategies are required to integrate multiple sources of big data in the search for elusive, novel genes underlying granule disorders.
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    Genetic variants of the extra-large stimulatory Gs protein alpha-subunit and risk of thrombotic and haemorrhagic disorders
    (Wiley, 2004-04-27) González-Conejero Hilla, Rocío; Corral de la Calle, Javier; Guerrero López, José Antonio; Iniesta Valera, Juan Antonio; Rivera Pozo, José; Arriba de la Fuente, Felipe de; Vicente García, Vicente; Medicina Interna
    A polymorphism of the gene encoding the extra-large stimulatory G-protein a-subunit (XLas), originally identified in three patients with a bleeding tendency, involved a 36-bp insertion and two missense changes. A paternallyinherited insertion displayed a moderate platelet Gsa over-expression, which lead to platelet hypo-reactivity. These data prompted us to investigate the genetic, functional and clinical relevance of this polymorphism in the Mediterranean population. We included 414 healthy subjects and three case/ control studies: 263 consecutive patients with a first episode of primary intracerebral haemorrhage, 195 patients with deep venous thrombosis, and 104 patients with cerebrovascular disease. Controls were selected by approximating criteria to match selected risk factors to patients. Moreover, we performed studies of platelet function. We developed a simple method to determine the methylated allele, by digestion of genomic DNA with Sma I before polymerase chain reaction amplification. We identified two new rare variants, resulting from the loss of repeat units 7 and 5. The AB genotype was present in 3Æ6% of healthy population and the prevalence of the B allele was similar among cases and controls. Accordingly, the non-methylated B allele did not modify either the expression of platelet Gsa or the platelet response to Gs-agonists. Thus, our study suggests a minor functional role of XLas polymorphism in thrombotic or in haemorrhagic disorders.
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    TRAP-induced platelet reactivity is inhibited by omega-3 fatty acid-derived prostaglandin E3 (PGE3)
    (MDPI, 2024-12-16) Osete Albaladejo, José Miguel; García Candel, Faustino; Fernández Gómez, Francisco José; Blanquer Blanquer, Miguel; Marín Atucha, Noemí; García-Estañ López, Joaquín; Iyú Espinosa, David; Fisiología; Facultades de la UMU::Facultad de Medicina
    Background: Prostaglandins are naturally occurring local mediators that can participate in the modulation of the cardiovascular system through their interaction with Gs/Gi-coupled receptors in different tissues and cells, including platelets. Thrombin is one of the most important factors that regulates platelet reactivity and coagulation. Clinical trials have consistently shown that omega-3 fatty acid supplementation lowers the risk for cardiovascular mortality and morbidity. Since omega-3 fatty acids are the main precursors of PGE3 in vivo, it would be relevant to investigate the effects of PGE3 on Thrombin Receptor Activating Peptide (TRAP-6)-induced platelet reactivity to determine the receptors and possible mechanisms of action of these compounds. Methods: We have measured platelet aggregation, P-selectin expression, and vasodilator-stimulated phosphoprotein (VASP) phosphorylation to evaluate platelet reactivity induced by TRAP-6 to determine the effects of PGE3 on platelet function. Results: We assessed the ability of DG-041, a selective prostanoid EP3 receptor antagonist, and of ONO-AE3-208, a selective prostanoid EP4 receptor antagonist, to modify the effects of PGE3. PGE3 inhibited TRAP-6-induced platelet aggregation and activation. This inhibition was enhanced in the presence of a Gi-coupled EP3 receptor antagonist and abolished in the presence of a Gs-coupled EP4 receptor antagonist. The effects of PGE3 were directly related to changes in cAMP, assessed by VASP phosphorylation. Conclusions: The general effects of PGE3 on human platelet reactivity are the consequence of a balance between activatory and inhibitory effects at receptors that have contrary effects on adenylate cyclase. These results indicate a potential mechanism by which omega-3 fatty acids underlie cardioprotective effects.