title: Transient desialylation in combination with a novel antithrombin deficiency causing a severe and recurrent thrombosis despite anticoagulation therapy.
abstract: An in-depth focused study of specific cases of patients with recurrent thrombosis may help to identify novel circumstances, genetic and acquired factors contributing to the development of this disorder. The aim of this study was to carry out a detailed and sequential analysis of samples from a patient suffering from early and recurrent venous and arterial thrombosis. We performed thrombophilic tests, biochemical, functional, genetic and glycomic analysis of antithrombin and other plasma proteins. The patient carried a new type I antithrombin mutation (p.Ile218del), whose structural relevance was verified in a recombinant model. Experiments with N-glycosidase F and neuraminidase suggested a nearly full desialylation of plasma proteins, which was confirmed by mass spectrometry analysis of transferrin glycoforms. However, partial desialylation and normal patterns were detected in samples collected at other time-points. Desialylation was noticeable after arterial events and was associated with low antithrombin activity, reduced platelet count and glomerular filtration rate. This is the first description of a global and transient desialylation of plasma proteins associated with thrombosis. The decrease in the strong electronegative charge of terminal glycans may modulate hemostatic protein-protein interactions, which in combination with a strong prothrombotic situation, such as antithrombin deficiency, could increase the risk of thrombosis.
authors.affiliation: Centro Regional de Hemodonación. Servicio de Hematología y Oncología Médica. Hospital Universitario Morales Meseguer. IMIB-Arrixaca. Universidad de Murcia, Murcia, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Revilla
authors.affiliation: Centro Regional de Hemodonación. Servicio de Hematología y Oncología Médica. Hospital Universitario Morales Meseguer. IMIB-Arrixaca. Universidad de Murcia, Murcia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII) Madrid, Spain.
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: de la Morena-Barrio
authors.affiliation: Centro Regional de Hemodonación. Servicio de Hematología y Oncología Médica. Hospital Universitario Morales Meseguer. IMIB-Arrixaca. Universidad de Murcia, Murcia, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Miñano
authors.affiliation: Centro Regional de Hemodonación. Servicio de Hematología y Oncología Médica. Hospital Universitario Morales Meseguer. IMIB-Arrixaca. Universidad de Murcia, Murcia, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: López-Gálvez
authors.affiliation: Centro Regional de Hemodonación. Servicio de Hematología y Oncología Médica. Hospital Universitario Morales Meseguer. IMIB-Arrixaca. Universidad de Murcia, Murcia, Spain.
authors.forename: Mara
authors.initials: M
authors.lastname: Toderici
authors.affiliation: Centro Regional de Hemodonación. Servicio de Hematología y Oncología Médica. Hospital Universitario Morales Meseguer. IMIB-Arrixaca. Universidad de Murcia, Murcia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Padilla
authors.affiliation: Servicio de Hematología. Hospital Universitario Ramón y Cajal. Madrid, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: García-Avello
authors.affiliation: Centro Regional de Hemodonación. Servicio de Hematología y Oncología Médica. Hospital Universitario Morales Meseguer. IMIB-Arrixaca. Universidad de Murcia, Murcia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII) Madrid, Spain.
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Lozano
authors.affiliation: Department of Neurology, Laboratory for Genetic, Endocrine and Metabolic Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
authors.affiliation: Centro Regional de Hemodonación. Servicio de Hematología y Oncología Médica. Hospital Universitario Morales Meseguer. IMIB-Arrixaca. Universidad de Murcia, Murcia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII) Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Corral
authors.affiliation: Centro Regional de Hemodonación. Servicio de Hematología y Oncología Médica. Hospital Universitario Morales Meseguer. IMIB-Arrixaca. Universidad de Murcia, Murcia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII) Madrid, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects / Q000627:therapeutic use; D001780:Blood Coagulation Tests; D005260:Female; D005337:Fibrin / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010375:Pedigree; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000378:metabolism; D015912:Thrombolytic Therapy / Q000009:adverse effects; D019851:Thrombophilia / Q000097:blood / Q000235:genetics* / Q000473:pathology; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000925:Anticoagulants; D005337:Fibrin; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase