Progetto Ministero della Salute- Bando Malattie Rare: "DETERMINANTS OF RESPONSE TO SUBSTITUTIVE/ANTICOAGULANT TREATMENTS IN RARE COAGULATION DISORDERS: FROM MOLECULAR MECHANISMS TO IMPROVED THERAPEUTIC/DIAGNOSTIC" PROTOCOLS

The inherited alterations of the coagulation pathway are associated to rare bleeding deficiencies and complications of anticoagulant treatment. Adverse events following treatment/prophylaxis are still major clinical issues, which require an in depth analysis of both genetic and acquired components modulating the treatment response. INHERITED DEFICIENCY OF COAGULATION FACTOR VII (F7 OMIM 227500)- The deficiency of the plasma serine protease triggering blood coagulation, factor VII (FVII) is inherited as an autosomal recessive trait (1/250,000-500,000) and is associated to bleeding tendency. A large proportion of homozygotes and compound heterozygotes for FVII deficiency, in particular those with levels <1% (Bernardi et al, J Thromb Haemost. 2009;7:774-9), experience severe hemorrhagic symptoms, not rarely life-threatening (central nervous system and gastrointestinal bleeds), or causing substantial handicap (hemarthrosis, muscle hematoma). Findings in patients and animal models indicate that the complete absence of FVII is lethal. Most FVII deficient patients are treated by infusion of fresh frozen plasma, prothrombin complex concentrates or plasma-derived FVII. Due to the very low FVII concentration in plasma (10 nM), the "contamination" with other vitamin K-dependent proteins is very high. In the last decade recombinant activated proteins (FVIIa, NovoSeven) opened new perspectives in the treatment of this disease. However, the short half-life of FVII/a in plasma (1-2 hours) requires very frequent administrations. Other drawbacks include the occurrence of thrombotic events, a concern that is related to the use of supra-physiological levels of FVII/a, and the development of inhibitory antibodies, an issue extensively investigated for hemophilia but poorly defined for FVII deficiency. Treatment demands vary considerably amongst FVII deficient patients and their correlation with the molecular defects is still to be defined. INHERITED ALTERATIONS OF THE VITAMIN K CYCLE- Full activity of several coagulation factors requires proper carboxylation of glutamate residues into Y-carboxyglutamate, which depends on vitamin K in the reduced form as essential cofactor of Y-glutamyl carboxylase (GGCX) and on continuous regeneration of the reduced cofactor by vitamin K epoxide reductase (VKORC1). Rare and specific mutations in genes encoding these enzymes are responsible for the vitamin Kdependent clotting factor deficiency type 1 (VKCFD1, OMIM 277450) and type 2 (VKCFD2, OMIM 607473) respectively. Both autosomal recessive bleeding disorders (Zhang & Ginsburg J Thromb Haemost 2004; 1564-72) are characterized by clinical phenotypes ranging from mild to severe, part of which corrected by vitamin K supplementation. Vitamin K antagonists (VKAs) (i.e. Coumarins), which block the recycling of vitamin K cofactor, are widely used as orally administered anticoagulants for therapy and prophylaxis of thromboembolic conditions. An altered VKA response (COUMARIN RESISTANCE/SENSITIVITY, OMIM #122700) is one of the most important causes of bleeding or thrombotic complications in anticoagulation therapy. Rare cases present with a quite dramatic clinical phenotype, ranging from elevated sensitivity to complete resistance. Variants of VKORC1 and of Cytochrome P450 (CYP) 2C9, which is the main enzyme for rate-limiting metabolism of oral anticoagulants, are the main determinants of variance in VKA dosage (Oldenburg et al, Thromb Haemost 2007; 98:570-8). Better knowledge of these issues is mandatory to define appropriate prophylaxis and therapeutic protocols.