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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10990/790

Autori: Cifu', Adriana
Supervisore afferente all'Università: CURCIO, FRANCESCO
Titolo: To investigate in vitro the pathogenic mechanism of anti-PS/PT antibodies to better define their role in the diagnosis of APS syndrome
Abstract (in inglese): 1. ABSTRACT Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by vascular thrombosis (venous or arterial) and/or adverse obstetric outcomes accompanied by persistent and elevated levels of antiphospholipid (aPL) antibodies. According to the 2006 revised international classification criteria, the presence of one among anti-beta2 glycoprotein I (aβ2GPI) IgG or IgM, anti-cardiolipin (aCL) IgG or IgM and the lupus anticoagulant (LA) is indicated for a definite diagnosis of APS. However, not infrequently, none of the “criteria” antibodies can be demonstrated. Only recently the so-called “seronegative APS” was definitely recognized as a distinctive setting, or better re-defined by the demonstration of new classes of aPL antibodies, such as the autoantibodies directed against prothrombin (aPT and aPS/PT). In the next future, these autoantibodies, particularly aPS/PT, could become additional serological classification criteria for APS especially to recognized patients negative for classical aPL. The combination of aβ2GPI, aPS/PT and LA demonstrates the best diagnostic accuracy for APS and aPS/PT were recently recommended as a surrogate of LA when specific inhibitors and/or analytical variables may affect its interpretation. Despite these recommendations, very few clinical laboratories include aPS/PT in routine analyzes so far. Moreover, no definite recommendations are available to guide the therapeutic approach in patients positive only for aPS/PT antibodies. To clarify their role in APS diagnosis and treatment, a better comprehension of its pathogenic mechanisms is needed. Thus, the principal aim of this thesis is to investigate the pathogenic mechanism underlying the thrombotic manifestations associated to the presence of aPS/PT. To address this issue, the biological effects sustained in vitro by aPS/PT were compared to those sustained by aβ2GpI, the most studied and recognized player in APS, by developing an experimental model able to investigate the thrombotic effect of these autoantibodies on monocytes and endothelial cells. Beside this principal study, to improve the risk management of APS patients, the plasmatic activity of the PAF-AH (Platelet Activating Factor Acetylhydrolase) was investigated as a new potential prognostic biomarker. PAF-AH is a specific marker of vascular inflammation dependent to common lipid metabolism markers (i.e. LDL) which is involved in the atherosclerotic plaque instability. Obtained data on the TF mRNA expression and Nitric Oxide production (colorimetric assay), confirmed that aPS/PT and aβ2GpI exert similar pro-thrombotic effects on monocytes and endothelial cells. On the contrary, the different effect of aβ2GpI and aPS/PT on mRNA expression of IL1β and NLRP3, and the different impact on PAF-AH activity (colorimetric assay), may suggest that these classes of antibodies probably activate different metabolic pathways. Moreover, plasmatic PAF-AH activity in patients with positive aPL antibodies appeared to be independent to common lipid metabolism markers (i.e. LDL). Based on these results, PAF-AH plasmatic activity may represent a new prognostic biomarker also in the context of aPL antibodies, to identify patients at major risk and favouring more tailored therapeutic interventions. Further prospective studies on selected patients are ongoing
Parole chiave: Antiphospholipid Syndrome
MIUR : Settore MED/05 - Patologia Clinica
Lingua: eng
Data: 29-mar-2017
Corso di dottorato: Dottorato di ricerca in Scienze e tecnologie cliniche
Ciclo di dottorato: 28
Università di conseguimento titolo: Università degli Studi di Udine
Luogo di discussione: Udine
Altre informazioni: Co-supervisore: Martina Fabris
Citazione: Cifu', A. To investigate in vitro the pathogenic mechanism of anti-PS/PT antibodies to better define their role in the diagnosis of APS syndrome. (Doctoral Thesis, Università degli Studi di Udine, 2017).
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