GENETIC AND BIOCHEMICAL COMPONENTS WHICH MODULATE THE INDIVIDUAL RISK OF BLEEDING IN COAGULATION FACTOR VII DEFICIENCY

While hemophilia A and B, which are X linked coagulation deficiencies, have been extensively investigated, the rare autosomal coagulation disorders, such as factor VII (FVII) deficiency, are only partially known. We propose to define the molecular bases of FVII deficiency and the additional components influencing the hemorrhagic phenotype in a large number of patients (>100). This remarkable number of patients, higher than expected for a rare disorder, has been collected in the frame of the International Registry for FVII deficiency, a clinical and epidemiological "initiative". As indicated by findings in human and in a mouse model, the complete deficiency of FVII is not compatible with life. A major goal is thus a very detailed definition of the residual FVII levels and of their relationships with hemorrhagic symptoms. We plan to detect the causative mutations as well as the genetic and biochemical factors able to increase or decrease the limiting amounts of the residual FVII function, thus preventing or favouring the onset of hemorrhagic symptoms. The presence of modifiers will be investigated in the coagulation cascade, in genes and factors interacting with FVII, such as specific inhibitors, protein and lipid cofactors which are essential to the FVII catalytic function. The presence among patients of several identical mutations will favour the analysis of modifiers. The proposed research would provide the molecular bases for an improved and individually oriented therapeutic approach.