Genetic Architecture of the 3D-Fibrin Meshwork in Pregnancy Maintenance

Background. Unexplained miscarriage is a frequent pregnancy complication. Aetiology includes genetic abnormalities, infections, implantation dysfunctions and immunological disorders, uterine/endocrine abnormalities, lifestyle risk factors and maternal age. Given that complexity, the pathophysiological mechanisms and the dynamic changes at maternal-foetal interface have to be clearly stated. Embryo implantation process and wound-healing phases share common paths as tissue remodeling, controlled inflammation and angiogenesis to preserve and modify uterine walls, tuned by controlled immune milieu. In this line, maternal fibrin 3D-organization and fibrinogen levels play key role in embryo implantation and pregnancy maintenance. Study design. To explore the genetic architecture of the 3D-fibrin meshwork at the maternal/foetus interface, we investigated coagulation Factor XIII (F13A1 and F13B) and fibrinogen cluster (FGA and FGB) gene variants in a group of women who experienced spontaneous early pregnancy loss (EPL, n=123) and women who undergone voluntary pregnancy interruption (VPI, n=107). Principal Component Analysis (PCA) accounting for genetic and biochemical variables and logistic regression have been performed to disclose positive/negative associations. Finally, 3D-architecture of fibrin scaffolds obtained from selected “extreme genotypes” were analysed by SEM analysis. Results. Single gene analyses found statistical significance in F13A1 V34L (P=0.04), F13B H95R (P=0.03) and FGB -455GA (P=0.04) gene variants by comparing EPL versus VPI ascribing different risk scores. PCA analyses confirmed significant interactions among FXIII and Fibrinogen (gene variants and levels) ascribing significant risk scores: ORF13B,FGB,PLT,PT=0.6; 0.46-0.84;P=0.002, and ORF13A,FGB,age,Fib=0.5; 0.40-0.73;P<0.0001. Finally, we reported significant differences in the nanofibers organization (i.e. SEM analysis of pore size, fibres length and diameter, number of branch-points) according to different gene variants and case subgroup. Conclusions. Genetically driven 3D-fibrin architecture, by influencing secretome niche, angiogenesis and inflammation may in turn predispose to pregnancy maintenance and outcome.