Outcomes of global coagulation assays in patients with Philadelphia-negative myeloproliferative neoplasms with respect to genetic determinants of clonal progression

Lucchesi, Alessandro (2022) Outcomes of global coagulation assays in patients with Philadelphia-negative myeloproliferative neoplasms with respect to genetic determinants of clonal progression, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze biomediche e neuromotorie, 34 Ciclo. DOI 10.48676/unibo/amsdottorato/10318.
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Classical myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders that manifest with inflammation, promotion of atherosclerosis, hypercoagulability, fibrosis, and clonal evolution. The complex biological background lends itself to multi-omics studies. We have previously shown that reduced platelet fibrinogen receptor (PFR) expression may follow hyperactivation of plasma-dependent mechanisms, such as tissue factor (TF) release, unbalanced thrombin generation, involvement of protease-activated receptors (PARs). Acetylsalicylic acid (ASA) helped to restore the expression of PFRs. In this study, we enrolled 53 MPN patients, subjecting them to advanced genetic testing (panel of 30 genes in NGS), global coagulation testing (Rotational Thromboelastometry - ROTEM) and cytofluorometric determination of PFRs. ROTEM parameters appear to differ considerably depending on the type of pathology under investigation, cell count, and selected mutations. Essential thrombocythemia (ET) and CALR mutation appear to correlate with increased efficiency of both classical coagulation pathways, with significantly more contracted clot formation times (CFTs). In contrast, primary myelofibrosis (PMF) and polycythemia vera (PV) show greater imbalances in the hemostatic system. PV, probably due to its peculiar hematological features, shows a lengthening of the CFT and, at the same time, a selective contraction of parameters in INTEM with the increase of platelets and white blood cells. PMF - in contrast - seems to exploit the extrinsic pathway more to increase cell numbers. The presence of DNMT3A mutations is associated with reduced clotting time (CT) in EXTEM, while ASXL1 causes reduced maximal lysis (ML). EZH2 could be responsible for the elongation of CFT in INTEM assay. In addition, increased PFR expression is associated with history of hemorrhage and sustained CT time in FIBTEM under ASA prophylaxis. Our findings corroborate the existing models on the connection between fibrosis, genetic complexity, clonal progression, and hypercoagulability. Global coagulation assays and PFR expression are potentially useful tools for dynamic evaluation of treatments’ outcomes.

Tipologia del documento
Tesi di dottorato
Lucchesi, Alessandro
Dottorato di ricerca
Settore disciplinare
Settore concorsuale
Parole chiave
MPN, coagulation, thromboelastometry, ROTEM, platelet, myelofibrosis, polycythemia, thrombosis, haemorrhage, thrombin
Data di discussione
20 Giugno 2022

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