<i>TBXA2R</i> gene variants associated with bleeding

Mundell, Stuart J; Mumford, Andrew D

doi:10.1080/09537104.2018.1499888

Cited by 16 publications

(12 citation statements)

References 21 publications

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“…This process may be induced by various physiological agonists such as adenosine diphosphate (ADP), the platelet activating factor (4FAP) and thromboxane A2 (TXA2) [1]. TXA2 is an eicosanoid derived from arachidonic acid produced in the platelet through the action of cyclooxygenase enzyme 1 (COX1), it has a short half-life, with an autocrine effect over platelets achieving platelet aggregation, granule liberation and vasoconstriction [1][2][3].…”

Section: Discussionmentioning

confidence: 99%

Thromboxane A2 Deficit Diagnosis in a Patient with Suspicion of Von Willebrand Disease

Echeverri-Fernandez¹,

Varela²,

Jaramillo³

2021

TCR

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Thromboxane A2 receptor deficiency is a qualitative platelet disorder that partially impedes adequate platelet signaling and aggregation. Generally, these patients have mild hemorrhagic manifestations in basal conditions, but may show severe bleeding when faced with a hemostatic challenge. We present the case of a 30-year-old female patient that arrives at the Hematology service with an undiagnosed bleeding disorder. She presented hemorrhagic complications during an augmentation mammoplasty and during an exodontia procedure, yet, during a C-section she presented none. At the first consultation she had normal coagulation factor levels by coagulometry, and normal platelet aggregation test for ADP, ristocetin, collagen and epinephrine. A platelet aggregation test for arachidonic acid confirmed thromboxane A2 deficit disorder. Thromboxane A2 deficit disorder is a rare qualitative platelet disorder that requires an extensive knowledge of coagulation and platelet function and tests, and a high level of clinical suspicion. These tests are especially difficult to interpret during pregnancy due to normal modifications to bodily function during this process.

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Section: Discussionmentioning

confidence: 99%

Thromboxane A2 Deficit Diagnosis in a Patient with Suspicion of Von Willebrand Disease

Echeverri-Fernandez¹,

Varela²,

Jaramillo³

2021

TCR

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“…Both patients presented with thrombocytopenia and a secretion defect which suggest the platelet phenotype and the CNVs in FLI1 to be associated with their disorders. Thromboxane receptor deficiency is an autosomal recessive or dominant disorder characterized by bleeding symptoms associated with quantitative or qualitative defects within the thromboxane receptor (Mundell & Mumford, 2018). Although we did not find any plausible candidate SNVs in the 119 candidate genes or the thromboxane receptor in patient 45, we did note a rare CNV duplication in the TBXA2R gene and deduce that either alone or in combination with variants in GP6 and SLFN14 which were also detected, could be causative of the patient's thrombocytopenia and bleeding.…”

Section: Discussionmentioning

confidence: 99%

Section: Oligogenic Findings In Patient Cohortmentioning

confidence: 99%

A comprehensive bioinformatic analysis of 126 patients with an inherited platelet disorder to identify both sequence and copy number genetic variants

et al. 2020

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Inherited bleeding disorders (IBDs) comprise an extremely heterogeneous group of diseases that reflect abnormalities of blood vessels, coagulation proteins, and platelets. Previously the UK-GAPP study has used whole-exome sequencing in combination with deep platelet phenotyping to identify pathogenic genetic variants in both known and novel genes in approximately 40% of the patients. To interrogate the remaining "unknown" cohort and improve this detection rate, we employed an IBD-specific gene panel of 119 genes using the Congenica Clinical Interpretation Platform to detect both single-nucleotide variants and copy number variants in 126 patients. In total, 135 different heterozygous variants in genes implicated in bleeding disorders were identified. Of which, 22 were classified pathogenic, 26 likely pathogenic, and the remaining were of uncertain significance. There were marked differences in the number of reported variants in individuals between the four patient groups: platelet count (35), platelet function (43), combined platelet count and function (59), and normal count (17). Additionally, we report three novel copy number variations (CNVs) not previously detected. We show that a combined single-nucleotide variation (SNV)/CNV analysis using the Congenica platform not only improves detection rates for IBDs, suggesting that such an approach can be applied to other genetic disorders where there is a high degree of heterogeneity.

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“…Globally, three more families were later reported with autosomal dominant transmission; two had missense mutations with a dominant-negative effect linked to impaired receptor dimerization while a third had a frameshift variant, a stop codon and reduced TPexpression. 60 , 64 …”

Section: Other Platelet Primary Receptor Defectsmentioning

confidence: 99%

Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy

et al. 2020

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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.

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TBXA2R gene variants associated with bleeding

Cited by 16 publications

References 21 publications

Thromboxane A2 Deficit Diagnosis in a Patient with Suspicion of Von Willebrand Disease

Thromboxane A2 Deficit Diagnosis in a Patient with Suspicion of Von Willebrand Disease

A comprehensive bioinformatic analysis of 126 patients with an inherited platelet disorder to identify both sequence and copy number genetic variants

Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy

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