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Dalla Valle, Fabio (2013) Studio dell'aggregazione piastrinica con aggregometro ad elettrodi multipli (multiplate) e della disfunzione endoteliale con tecnica ecocolorDoppler in soggetti trombofilici. [Tesi di dottorato]

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Abstract (inglese)

Background: the link between venous thromboembolism (VTE) and arterial thromboembolic events (ATE) is still uncertain. In 2003 Prandoni et al published the first study that reported a connection, in term of etiopathogenesis between VTE and atherosclerosis. During the last few years several other study confirm this association, that could be attributed to common risk factors for the two conditions. The contribution of thrombophilic defects to the link between VTE and ATE has yet to be defined. Thrombophilic conditions (hereditary deficiencies of protein S, protein C and antithrombin) have been recognized as most potent thrombophilic conditions for VTE. Whether hereditary protein S, Protein C or antithrombin deficiency also are involved in the development of ATE need to be confirmed and the evidence of a possible association has been showed mainly from case reports. Blood haemostasis is a complex mechanism influenced from coagulation factors, aggregation proteins, blood cells (platelets, leucocytes) and vascular endothelium. Most of biochemical tests focused on coagulation system asses only a part of this complex mechanism and, in particular, the laboratory tests analyze only the coagulations cascade. But the role of platelets and vascular endothelium is not clear. The contribution of thrombophilic defects as common risk factor between VTE and ATE has yet to be defined compared with nondeficient family members. Moreover in this study the endothelial dysfunction could be the real cause for both conditions VTE and ATE. There are no data concerning the role of platelets function or vascular endothelium function in this thrombophilic patients population.
The aim of the study is to define, in thrombophilic patients (Prot C, Prot S and antithrombin defects) compared with non-deficient family members. the role of platelets function using a new analyzer named Multiplate® whole blood aggregometry that evaluated platelets aggregations in whole blood and to define also the possible implication of endothelial function, by the non-invasive assessment of flow mediated dilatation (FMD) of the brachial artery, by B-mode ultrasonography, using a standardized procedure
Material and Methods: after signing an informed consent, we enrolled patients with thrombophilic defects (cases) and create three subgroups (cases with deficit of protein C, protein S and antithrombin) with and without a history of thromboembolic disease, and subjects without thrombophilic defects (controls). We collected baseline data of all (cases and controls) on previous episodes of VTE and ATE, risk factors for atherosclerosis (i.e. hypertension, diabetes mellitus, cigarette smoking; hyperlipidemia) All patients were tested for thrombophilic defects in addition to their index deficiencies (FV Leiden, G20210 A prothrombin, lupus anticoagulant; PC and PS, AT). Moreover, we study platelets aggregations with a new analyzer named Multiplate® whole blood aggregometry that evaluated platelets aggregations in whole blood with thrombin inibitor (irudin); this instrument identify the electrical impedance (as area under curve, AUC) caused from platelets aggregation. The platelets aggregation was triggered by different activators: adenosine-5 diphosphate (ADP test), arachidonic acid (ASPI test) and thrombin receptor activatin peptide (TRAP -6)
All cases and controls underwent evaluation of endothelial function by the non-invasive assessment of flow mediated dilatation (FMD) of the brachial artery, by B-mode ultrasonography, using a standardized procedure.
Results: patients with thromphilic defects versus controls have similar demographical charatistics. The valutation of the platelets aggregation by Multiplate® with different tests (ASPI, ADP and TRAP) show a different in the two groups but it is no statistically significant; we observed the same results if analyze the three subgroups (Protein C defects, Protein S and antithrombin deficiency) protein separately. The ultrasonography evaluation of endothelial function show that there is a reduction of the flow mediated dilatation (FMD) in patients with thrombophilic defects versus controls. The FMD calculated in thrombophilic patients is statistically significant (3.7±0.5% vs 5.2±0.6% ,p value = 0.015) compared the controls.
Discussion: Our preliminary data show that in patients with thrombophilic deficiency there is increased of platelets aggregation but it’s no statically significant. This results is confirm also in all different subgroups of thromphilic deficiency (Prot C, S, and AT deficiency ). However an endothelial dysfunction is showed in thrombophilic patients compared the controls. Although we speculated with this data, as other study have reported, that endothelial dysfunction rather than coagulation disorders is the main actor in the link between VTE and ATE in thrombophilic subjects. It is yet unclear the role of the different actors (endothelium dysfunction, platelet aggregation and coagulation factors) in the development on VTE and ATE, but this study can show that endothelium dysfunction can be one of the most important trigger factor in the thrombophilic patients

Abstract (italiano)

Introduzione: La correlazione tra malattia trombo embolica venosa e patologia arteriosa è un dato che ormai affascina e riscuote l’interesse di molti studiosi. Già nel 2003 Prandoni et al misero in evidenza tale possibile correlazione; molti altri studi hanno successivamente consolidato tale dato dimostrando anche la condivisione di numerosi fattori di rischio (diabete, ipertensione arteriosa, dislipidemia, fumo di sigaretta). Il complesso meccanismo coagulativo è influenzato da molteplici attori: fattori della coagulazione, cellule ematiche (leucociti, piastrine) e dall’endotelio vascolare. Molte delle indagini tuttora utilizzate per la coagulazione valutano solo una parte di questa complessa cascata coagulativa, ma il ruolo svolto dalle piastrine e dall’endotelio non è ancora chiarito. In particolare, in uno specifico sottogruppo della popolazione, i soggetti trombofilici, i quali presentano un deficit degli inibitori naturali della coagulazione (proteina C, proteina S e antitrombina) e che manifestano una maggiore incidenza della malattia tromboembolica venosa e, anche se in misura differente, dell’aterotrombosi. Lo scopo del nostro studio è stato quello di valutare la funzione endoteliale, attraverso l’utilizzo di tecnica ecografica dell’arteria brachiale della dilatazione flusso mediata (FMD) e l’aggregazione piastrinica, attraverso l’uso di aggregometro basato sull’impedenziometria con elettrodi multipli (Multiplate®), in un gruppo di soggetti con difetto degli inibitori naturali della coagulazione rispetto ad un gruppo di volontari sani.
Materiali e metodi: nel gruppo dei casi sono stati arruolati, dopo consenso informato, 68 soggetti con difetto noto degli inibitori della coagulazione (deficit di Prot C, Prot S o antitrombina) e nel gruppo dei controlli 59 soggetti volontari sani confrontabili per sesso ed età ( 3 anni). Sono stati esclusi dallo studio soggetti con età inferiore ai 18 aa, che si sono rifiutati di firmare il consenso informato, che assumevano terapia anticoagulante o antiaggregante piastrinica o con piastrinopenia (conta piastrinica <150 x109/L) o piastrinosi (conta piastrinica >450 x109/L).
Tutti i soggetti arruolati allo studio sono stati sottoposti a raccolta anamnestica dettagliata relativa a fattori di rischio e precedenti cardiovascolari o tromboembolici venosi; ciascuno di essi inoltre è stato sottoposto a prelievo di 18 ml di sangue venoso per esecuzione di test della coagulazione classica e studio ipercoagulabile (proteina C, proteina S, antitrombina, variante protrombinica, fattore V Leiden anticorpi antifosfolipidi). Su ogni campione di sangue veniva effettuato studio dell’ aggregazione piastrinica con aggregometro ad impedenza ad elettrodi multipli (Multiplate®), che eseguiva contemporaneamente più test (ASPItest, ADPtest e TRAPtest). Infine su ogni soggetto è stato eseguita valutazione ecografica della disfunzione endoteliale mediante valutazione della dilatazione flusso mediata (FMD) con misurazione dell’arteria brachiale prima e dopo iperemia.
Risultati: i soggetti con difetto trombofilico presentavano caratteristiche demografiche sovrapponibili a quelle dei controlli sani. L’incidenza di eventi trombo embolici venosi e risultata ovviamente più elevata nel gruppo dei casi; mentre i soggetti trombofilici hanno mostrato di aver sviluppato in età più giovane eventi cardiovascolari. Nella valutazione dell’aggregazione piastrinica studiata con il Multiplate® , con differenti test di stimolazione (ASPI, ADP e TRAP) sono emerse differenze della AUC (area sotto la curva) che esprime in modo quantitativo l’aggregazione piastrinica che tuttavia non sono risultate statisticamente significative; il dato si è confermato anche nella valutazione dei casi, prendendo in considerazione singolarmente ogni difetto trombofilico. In relazione alla valutazione della disfunzione endoteliale mediante ecografia dell’arteria brachiale si è evidenziato un decremento statisticamente significativo della dilatazione flusso mediata (FMD) nei casi rispetto ai controlli (3.7±0.5% vs 5.2±0.6% , p value = 0.015), mentre sono risultati di dimensioni sovrapponibili il diametro e il flusso basale del vaso.
Discussione: Per quanto riguarda la valutazione aggregometrica su sangue intero, i dati raccolti, non hanno evidenziato una differenza significativa dell’aggregazione piastrinica valutata con i test di induzione (TRAP, ADP, ASPI) nei soggetti trombofilici rispetto ai controlli. Tale dato potrebbe quindi essere interpretato come l’assenza di una “intrinseca” iperaggregabilità delle piastrine di questi soggetti che possa essere l’innesco della cascata trombotica a cui essi vanno più spesso incontro.
In relazione allo studio della funzione endoteliale i dati hanno mostrato che esiste una riduzione della dilatazione dell’arteria brachiale post fase iperemica che in valore percentuale è significativamente piu bassa nei soggetti trombofilici rispetto ai controlli. Il dato quindi sembra confermare che nei soggetti con deficit degli inibitori della coagulazione, con noto incremento dell’incidenza di eventi tromboembolici, sia la disfunzione endoteliale a rappresentare il determinante capace di innescare tale processo

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Tipo di EPrint:Tesi di dottorato
Relatore:Pagnan, Antonio
Dottorato (corsi e scuole):Ciclo 23 > Scuole per il 23simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE CARDIOVASCOLARI
Data di deposito della tesi:29 Gennaio 2013
Anno di Pubblicazione:29 Gennaio 2013
Parole chiave (italiano / inglese):disfunzione endoteliale, aggregometro
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/11 Malattie dell'apparato cardiovascolare
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Codice ID:5679
Depositato il:08 Ott 2013 16:38
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