Factor V and Combined Factor V and VIII Deficiencies

Abstract

Within the coagulation cascade, factor V (FV) is one essential nonenzymatic cofactor of the prothrombinase complex, which catalyzes the conversion of prothrombin into thrombin [1]. This enzyme complex consists of activated FV (FVa), calcium, phospholipids, and activated factor X (FXa). FVa increases the concentration of FXa at the membrane surface by acting as a receptor for FXa and allosterically alters the active site of FXa to optimize its ability to cleave prothrombin. By stabilizing the complex and increasing the rate at which FXa cleaves prothrombin, FVa enhances prothrombin activation by five orders of magnitude when compared with FXa alone.Human FV deficiency is an autosomal recessive bleeding disorder, characterized by low levels of FV associated with bleeding symptoms ranging from mild to severe [2]. In most of the affected individuals, the phenotype is characterized by the concomitant deficiency of FV activity and antigen (type I deficiency); however, about 25% of the patients have normal antigen levels (type II deficiency), thus indicating the presence of a dysfunctional protein [3]. Prevalence of factor V deficiency has been estimated to be 1/1000 000 in the general population [4]. The worldwide distribution of FV deficiency can be derived from two large data collections: the last World Federation of Hemophilia (WFH) global survey (http://www1.wfh.org) and the EN-RBD project, European Network of Rare Bleeding Disorders: (www.rbdd.eu) reporting that patients affected by FV deficiency represent 8-10% of the total number of patients affected with RBDs.The first case of a congenital FV deficiency (OMIM 227400), transmitted with an autosomal recessive inheritance pattern, was reported in 1954 by Kingsley in two South African families of Dutch ancestry [5]. FV cDNA was cloned only in 1987, and the amino acid sequence of the protein was determined [6]. The entire genomic structure of the F5 gene was characterized in 1992 [7]. A reduction of the circulating FV level can also been observed in combined FV and FVIII deficiency. Deficiency of FV can also arise because of acquired inhibitors to FV and defects that affect the storage and processing of FV [8,9]. Factor V proteinAlthough most of the human FV protein is present in plasma, approximately 20-25% of the circulating FV is found within platelet α-granules. The source of platelet FV seems to be plasmatic [10,11], but a publication by Suehiro et al. reported that human megakaryocytes can endocytose and synthesize FV into proteolyzed forms that can be stored bound to the protein multimerin in α-granules [12].FV shows high functional and structural homology with factor VIII (FVIII) [13]. Both proteins have the same A1-A2-B-A3-C1-C2 structure: the three A domains of FV and FVIII share approximately 30% of amino acid identity and with the triplicated A domain of ceruloplasmin, the major plasma copper-transport protein [14]. The large B domain, having no homology with other proteins, is proteolitically removed during activation of FV and FVIII. Both C domains are...