Coinheritance of Factor V (FV) Leiden enhances thrombin formation and is associated with a mild bleeding phenotype in patients homozygous for the FVII 9726+5G>A (FVII Lazio) mutation

Abstract

We investigated the role of thrombophilic mutations as possible modifiers of the clinical phenotype in severe factor VII (FVII) deficiency. Among 7 patients homozygous for a cross-reacting materialnegative (CRM ؊ ) FVII defect (9726؉5G>A, FVII Lazio), the only asymptomatic individual carried FV Leiden. Differential modulation of FVII levels by intragenic polymorphisms was excluded by a FVII to factor X (FX) gene haplotype analysis. The coagulation efficiency in the FV Leiden carrier and a noncarrier was evaluated by measuring FXa, FVa, and thrombin generation after extrinsic activation of plasma in the absence and presence of activated protein C (APC). In both patients coagulation factor activation was much slower and resulted in significantly lower amounts of FXa and thrombin than in a normal control. However, more FXa and thrombin were formed in the plasma of the patient carrying FV Leiden than in the noncarrier, especially in the presence of APC. These results were confirmed in FV-FVII doubly deficient plasma reconsti- IntroductionCoagulation factor VII (FVII) is a vitamin K-dependent glycoprotein that plays a key role in the initiation of coagulation. 1 Following vascular damage, membrane-bound tissue factor (TF) forms a Ca 2ϩ -dependent complex either with FVII (which is then converted to FVIIa by a single proteolytic cleavage) or directly with circulating FVIIa, present in blood at a very low concentration. TF-bound FVIIa activates factor X (FX) to FXa, which, together with its cofactor factor Va (FVa), converts prothrombin to thrombin. In addition, the TF/FVIIa complex can also activate factor IX to FIXa, which, after forming a complex with factor VIIIa (FVIIIa), contributes to FXa generation and thereby to thrombin formation via the intrinsic pathway. In plasma, the activity of the TF/FVIIa complex is down-regulated by the tissue factor pathway inhibitor (TFPI), which acts via the formation of a quaternary complex with FXa, FVIIa, and TF. 2 Thrombin generation is ultimately shut down by activated protein C (APC), which proteolytically inactivates FVa and FVIIIa, the essential cofactors of the prothrombin-and intrinsic FX-activating complexes. 3 Severe FVII deficiency 4,5 affects about 1 in 500 000 individuals in the general population and is inherited as an autosomal recessive trait with variable penetrance. Severely affected patients may develop life-threatening hemorrhages and require substitutive treatment with plasma concentrates or recombinant FVIIa. 6 Several intragenic mutations that impair gene expression or protein secretion (CRM Ϫ deficiency) or alter protein function (CRM ϩ deficiency) have been described (FVII Mutation Database, http://europium.csc.mrc.ac.uk). Moreover, a few intragenic polymorphisms 7-10 that modulate plasma levels of FVII 8,[10][11][12] are known.The FVII gene is located on chromosome 13 (13q34-qter), next to the FX gene, 13,14 and comprises 9 exons and 8 introns. 15 A polymorphic minisatellite, consisting of a variable number of 37-nucleotide tandem repeats, spans the 3Ј ...

Inheritance of Factor VII and Protein S Deficiency Together with Factor V Leiden Mutation

“…It is well documented that FV Leiden or other thrombophilic factors like PT20210 G>A mutation or protein C deficiency coexisting with factor deficiencies like FVIII, FIX, or FVII may delay the onset of hemorrhagic symptoms and decrease the severity of clinical findings [2,3,4,5,6]. In vitro production of thrombin has been demonstrated to increase in these patients [2][3][4][5][6][7] .…”

“…In vitro production of thrombin has been demonstrated to increase in these patients [2][3][4][5][6][7] .…”

“…Coexistent FV Leiden mutation was found at frequencies ranging from normal (8.8%) 19,20 to elevated (14.2%) in patients with FVII deficiency (normal carriage incidence: 1%-8.5%; in Turkey: 7.9%) 2,22,23 . The frequency of the FV HR2 allele was very high in asymptomatic patients with FVII A294V mutation, unlike in the symptomatic ones (30% vs. 5.5%; normal population: 7.4%) 7 .…”

“…The frequency of the FV HR2 allele was very high in asymptomatic patients with FVII A294V mutation, unlike in the symptomatic ones (30% vs. 5.5%; normal population: 7.4%) 7 . PT G20210A mutation was reported at 4.4%, 0%, and 0% in FVII-deficient patients 19 , in a subgroup of FVII-deficient patients with FVII Lazio mutation 2 , and in a subgroup of FVII-deficient patients with FVII A294V mutation 7 , respectively. Depending on the literature, we can state that the characteristic genotype/ phenotype discrepancy in FVII deficiency may be due to compensatory hemostatic regulatory mechanisms such as increased frequency in FV Leiden mutation, although there are exceptions 20 , FV HR2 allele 7 , or…”

“…The factor V Leiden (FV Leiden) mutation delays the inactivation of activated FV and thus leads to hypercoagulation 2 . Both heterozygous and homozygous forms of this disease are known to be associated with a high risk of recurrent thrombosis.…”