Papers by Teresa Seara Sevivas
Molecular therapy. Nucleic acids, Jun 1, 2023
Blood Advances, Sep 19, 2018
• Eltrombopag increased proplatelet formation from cultured DIAPH1related disorder megakaryocytes... more • Eltrombopag increased proplatelet formation from cultured DIAPH1related disorder megakaryocytes and improved platelet counts in vivo.
Orphanet Journal of Rare Diseases, Dec 1, 2014
Background: The diagnostic evaluation of inherited platelet disorders (IPDs) is complicated and t... more Background: The diagnostic evaluation of inherited platelet disorders (IPDs) is complicated and time-consuming, resulting in a relevant number of undiagnosed and incorrectly classified patients. In order to evaluate the spectrum of IPDs in individuals with clinical suspicion of these disorders, and to provide a diagnostic tool to centers not having access to specific platelets studies, we established the project "Functional and Molecular Characterization of Patients with Inherited Platelet Disorders" under the scientific sponsorship of the Spanish Society of Thrombosis and Haemostasis. Patients/methods: Subjects were patients from a prospective cohort of individuals referred for clinical suspicion of IPDs as well as healthy controls. Functional studies included light transmission aggregation, flow cytometry, and when indicated, Western-blot analysis of platelet glycoproteins, and clot retraction analysis. Genetic analysis was mainly performed by sequencing of coding regions and proximal regulatory regions of the genes of interest. Results: Of the 70 cases referred for study, we functionally and molecularly characterized 12 patients with Glanzmann Thrombasthenia, 8 patients with Bernard Soulier syndrome, and 8 with other forms of IPDs. Twelve novel mutations were identified among these patients. The systematic study of patients revealed that almost one-third of patients had been previously misdiagnosed. Conclusions: Our study provides a global picture of the current limitations and access to the diagnosis of IPDs, identifies and confirms new genetic variants that cause these disorders, and emphasizes the need of creating reference centers that can help health care providers in the recognition of these defects.
Transfusion, 1996
Background: Treatment of hemophilia patients with recombinant factor VIII concentrates has not pr... more Background: Treatment of hemophilia patients with recombinant factor VIII concentrates has not previously been associated with anaphylaxis.Study Design and Methods: A 5‐week‐old boy with severe hemophilia A developed dyspnea, cyanosis, hypotension, and a diffuse urticarial rash following treatment with a recombinant factor VIII (Recombinate). To identify the cause of anaphylaxis in this patient, the vial lot was examined for the presence of endotoxin, and a checkerboard immunoblotting technique was used to test serum and/or plasma samples from the patient and mother for the presence of antibodies (IgA, IgG, IgE, and IgM) to Recombinate‐related antigens (recombinant factor VIII, von Willebrand factor, human serum albumin, Chinese hamster ovary proteins, bovine serum albumin, mouse monoclonal anti‐human factor VIII, polyethylene glycol 3350), and to ethylene oxide, the agent used to sterilize the infusion equipment.Results: No immune response directed against the Recombinate‐related a...
Jornal Brasileiro De Nefrologia, Aug 2, 2018
Journal of Thrombosis and Haemostasis, 2019
Scientific Reports, 2018
Usher syndrome is a rare disorder causing retinitis pigmentosa, together with sensorineural heari... more Usher syndrome is a rare disorder causing retinitis pigmentosa, together with sensorineural hearing loss. Due to the phenotypic and genetic heterogeneity of this disease, the best method to screen the causative mutations is by high-throughput sequencing. In this study, we tested a semiconductor chip based sequencing approach with 77 unrelated patients, as a molecular diagnosis routine. In addition, Multiplex Ligation-dependent Probe Amplification and microarray-based Comparative Genomic Hybridization techniques were applied to detect large rearrangements, and minigene assays were performed to confirm the mRNA processing aberrations caused by splice-site mutations. The designed panel included all the USH causative genes (MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2, USH2A, ADGRV1, WHRN and CLRN1) as well as four uncertainly associated genes (HARS, PDZD7, CEP250 and C2orf71). The outcome showed an overall mutation detection ratio of 82.8% and allowed the identification of 42 novel putativ...
Research and Practice in Thrombosis and Haemostasis, 2017
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Haemophilia : the official journal of the World Federation of Hemophilia, 2017
Journal of thrombosis and haemostasis : JTH, Aug 23, 2016
Since the discovery of antithrombin deficiency, 50 years ago, few new thrombophilic defects have ... more Since the discovery of antithrombin deficiency, 50 years ago, few new thrombophilic defects have been identified, all with weaker risk of thrombosis than antithrombin deficiency. To identify new thrombophilic mechanisms. We studied 30 patients with antithrombin deficiency but no defects in the gene encoding this key anticoagulant (SERPINC1). A high proportion of these patients (8/30: 27%) had increased hypoglycosylated forms of antithrombin. All N-glycoproteins tested in these patients (α1-antitrypsin, FXI, transferrin) had electrophoretic, HPLC and Q-TOF patterns indistinguishable from those of the congenital disorders of glycosylation (rare recessive multisystem disorders). However, all except one had no mental disability. Moreover, intermittent antithrombin deficiency and hypoglycosylation was recorded in 5 out of these 8 patients, all associated with moderate alcohol intake. Genetic analysis, including whole exome sequencing, revealed mutations in different genes involved in the...
Thrombosis and haemostasis, Jul 21, 2016
The key haemostatic role of antithrombin and the risk of thrombosis associated with its deficienc... more The key haemostatic role of antithrombin and the risk of thrombosis associated with its deficiency support that the low incidence of antithrombin deficiency among patients with thrombosis might be explained by underestimation of this disorder. It was our aim to identify mutations in SERPINC1 causing transient antithrombin deficiency. SERPINC1 was sequenced in 214 cases with a positive test for antithrombin deficiency, including 67 with no deficiency in the sample delivered to our laboratory. The p.Val30Glu mutation (Antithrombin Dublin) was identified in five out of these 67 cases, as well as in three out of 127 cases with other SERPINC1 mutations. Genotyping in 1593 patients with venous thrombosis and 2592 controls from two populations, revealed a low prevalent polymorphism (0.3 %) that moderately increased the risk of venous thrombosis (OR: 2.9; 95 % CI: 1.07-8.09; p= 0.03) and identified one homozygous patient with an early thrombotic event. Carriers had normal anti-FXa activity,...
Thrombosis and haemostasis, Jul 17, 2016
The diagnosis of von Willebrand disease (VWD), the most common inherited bleeding disorder, is ch... more The diagnosis of von Willebrand disease (VWD), the most common inherited bleeding disorder, is characterised by a variable bleeding tendency and heterogeneous laboratory phenotype. The sequencing of the entire VWF coding region has not yet become a routine practice in diagnostic laboratories owing to its high costs. Nevertheless, next-generation sequencing (NGS) has emerged as an alternative to overcome this limitation. We aimed to determine the correlation of genotype and phenotype in 92 Portuguese individuals from 60 unrelated families with VWD; therefore, we directly sequenced VWF. We compared the classical Sanger sequencing approach and NGS to assess the value-added effect on the analysis of the mutation distribution in different types of VWD. Sixty-two different VWF mutations were identified, 27 of which had not been previously described. NGS detected 26 additional mutations, contributing to a broad overview of the mutant alleles present in each VWD type. Twenty-nine probands (...
TTP is a rare severe thrombotic microangiopathy due to the presence of ultra large von Willebrand... more TTP is a rare severe thrombotic microangiopathy due to the presence of ultra large von Willebrand factor multimers (ULVWFM) in circulation. The aetiology has been linked to a congenital deficiency or inhibition of ADAMTS13 (AD13) activity by autoantibodies. The presence of autoantibodies can be related to mutations and polymorphisms (SNPs) in the AD13 gene. We present the data on 11 patients (3M, 8F, mean age 25) with microangiopathic haemolytic anaemia (Hb 5–9 g/dL), thrombocytopenia (Plt 4–58 · 109/L), high LDH (549–11430 IU/mL); 5 of them had neurological symptoms. In 9 patients no acute episode precipitating factor was identified; in 1 case TTP episodes occurred during 4 pregnancies resulting in fetal deaths; 2 patients had autoimmune disease. The follow-up was 1 to 13 years. Study: At diagnosis and in remission: AD13 Ag, activity and IgG anti-AD13 (Technozym ELISA), vWFM (SDS electrof./W.Blot). AD13 gene mutations screening (PCR/sequencing). According to AD13 studies (acute epi...
Thrombosis Research, 2014
PMM2-CDG, the most frequent congenital disorder of N-glycosylation, is an autosomal recessive dis... more PMM2-CDG, the most frequent congenital disorder of N-glycosylation, is an autosomal recessive disease with a multisystem presentation. PMM2-CDG patients show an increased risk for thrombosis, which might be in part due to spontaneous platelet aggregations as previously described. A potential hypoglycosylation of platelet proteins in these patients might explain this increased reactivity, as removal of sialic acid from platelets, particularly of GPIbα, leads to enhance platelet aggregation and clearance from the circulation. This study is the first one that has evaluated the glycosylation status of platelet proteins in 6 PMM2-CDG patients using different approaches including immunoblot, RCA 120 lectin binding to platelets and expression of different membrane platelet N-glycoproteins by flow cytometry, as well as by platelet N-glycoproteome analysis. RCA 120 lectin binding to the platelet membrane of PMM2-CDG patients showed evidence for decreased sialic acid content. However, immunoblot and flow cytometric analysis of different platelet N-glycoproteins, together with the more sensitive 2D-DIGE analysis, suggest that platelet N-glycoproteins, including GPIbα, seem to be neither quantitatively nor qualitatively significantly affected. The increased binding of RCA 120 lectin could be explained by the abnormal glycosylation of hepatic proteins being attached to the platelets. Conclusions: This is the first study that has evaluated the platelet N-glycoproteome. Our findings suggest that platelet proteins are not significantly affected in PMM2-CDG patients. Further studies are still warranted to unravel the mechanism(s) that increase(s) the risk of thrombosis in these patients.
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Papers by Teresa Seara Sevivas