The heterogeneous clinical manifestations and the unpredictable nature of C1-INH-HAE require the identification of biomarkers and the development of accompanying bioassays. To contribute to this purpose this thesis focused on four topics:I. The expression of bradykinin receptors. B1R and B2R are potential therapeutic targets. Molecular imaging agents enable the visualization and quantification of the receptors at a cellular level. Specific fluorescent ligands were prepared and used as imaging agents in order to examine the expression of the receptors on EA.hy926 and THP1 cell lines and subsequently, on the surface of patients’ endothelial cells in resting conditions or during an attack. The detection of naturally expressed receptors was not successful due to low expression or due to low affinity of the ligands. Further investigation is required to develop a diagnostic tool and proceed in human blood samples.II. Activation of PLG with p.Lys330Glu variant. The alteration of PLG glycosylation patterns was examined in heterozygous and homozygous carriers of PLG p.Lys330Glu variant, previously described as pathogenic for HAE-PLG. In the homozygous patient, a reversal of the glycosylation pattern was observed, while the heterozygous subjects presented the two glycoforms at the same level. A plasmin-specific chromogenic assay was developed in order to measure the PLG susceptibility to activation. Both homozygous and heterozygous carriers displayed a significantly high susceptibility to activation by streptokinase and urokinase. The qualitative in vivo impact of p.Lys330Glu on the protein may result in increased plasmin formation and excessive bradykinin production through kallikrein-kinin system activation.III. Association of genetic variants with the severity of C1-INH-HAE. The concomitant carriage of variants on genes encoding for proteins involved in bradykinin metabolism and function may modify the clinical expression of C1-INH-HAE. Using NGS technology the study aimed to detect and classify rare variants (MAF≤1%) in 54 genes other than SERPING1 and to associate the carriage of 18 selected functional SNPs (MAF≥1%) with C1-INH-HAE patients’ age at disease onset, disease severity based on CALS score and need for LTP, regardless the SERPING1 mutational status and separately in patients carrying a missense SERPING1 variant. In the first group of patients, the presence of the C allele of F12-rs1801020 was significantly associated with an increase at disease severity; the presence of SERPING1-rs28362944 increased 2.5-fold the probability of LTP need; SERPING1-rs4926 was associated with later disease onset; F13B-rs6003, SERPINA1-rs28929474 and PLAU-rs2227564 were significantly associated with the severity of the disease. In carriers of a missense SERPING1 mutation, the presence of the C allele of F12-rs1801020 was significantly associated with an increase at disease severity; the presence of SERPING1-rs28362944 increased 4.2-fold the probability of LTP need; SERPINA1-rs17580 and SERPINE1-rs6092 were significantly associated with earlier and later age at disease onset, respectively; CPN1-rs61751507 and F2-rs1799963 were significantly associated with decrease of need for LTP and disease severity, respectively; KLKB1-rs3733402 and KLK1-rs5515 were associated with both the age at disease onset and the disease severity. Further analyses should be done in order to conclude on the contribution of the detected rare variants to the disease, their functional effects and their clinical validity.IV. Global data sharing. In order for both researchers and physicians to assess the available genetic data, they need to be classified and shared in public, user-friendly, easily accessible databases. To this aim, we classified and submitted in ClinVar database 45 SERPING1 variants previously detected in C1-INH-HAE patients of the Laboratory of Immunology and Histocompatibility of the UTH, accompanied by the supporting clinical evidence.