High incidence of intracranial bleeding in factor V-deficient patients with homozygous F5 splicing mutations.

Perioperative Management of Hereditary Factor V Deficiency: Timing of Plasma Administration is Critical in Maximizing Hemostatic Potency of Transfused Factor V

Acquired factor V deficiency in a patient without evidence of a classical inhibitor

Response to TFPI-inhibition in severe factor v deficiency with a novel compound heterozygous mutation

Congenital factor V deficiency (FVD) is a rare bleeding disorder. In this study, we investigated the genetic basis in an African American patient with factor V activity 3%. Custom sequence capture and targeted next-generation (NGS) sequencing of the F5 gene were undertaken followed by PCR and Sanger sequencing. Two novel variants were identified. In silico analyses correlated clinically with the patient's factor V activity and hemorrhagic tendency. A review of the literature regarding these genomic alterations is presented. We described two novel mutations causing moderate FVD. The first, Chr1:g.169483698C>A with cDNA change (F5):c.6529-1G>T, occurred in a conserved nucleotide at the canonical acceptor splice site of intron 24. The second, Chr1:g.169515775C>T with cDNA change (F5):c.1667G>A, was a missense variant of exon 11, affecting a highly conserved amino acid in the A2 domain. Further research into the mechanisms of F5 mutations leading to FVD and residual factor V expression are needed.

Congenital coagulation factor V (FV) deficiency is a very rare hemorrhagic disease with an incidence of approximately one in a million. The common clinical manifestations of FV deficiency include ecchymosis and mucosal bleeding. Life-threatening intracranial bleeding is rare. It has been reported in several cases. However, the molecular basis has been established in only a few cases. We reported a 2-month-old girl with congenital FV deficiency and intracranial hemorrhage. Coagulation screening combined with clinical manifestations was performed to diagnose congenital FV deficiency. Genetic testing was performed to identify the pathogenic genes. A literature review was included to emphasize the clinical manifestation, diagnosis, and treatment for congenital FV deficiency with intracranial bleeding. The coagulation tests revealed a significantly prolonged prothrombin time (PT) of 51 s and an activated partial thromboplastin time (APTT) of 73.7s. The patient had a plasma FV activity of 0.9%. Genetic testing showed compound heterozygous mutations of the patient's FV gene. A literature review showed that patients with homozygous or compound heterozygous variants of the FV gene were often associated with a severe bleeding phenotype. Our study provides a direction for the rapid and accurate diagnosis and treatment for FV deficiency to avoid life-threatening bleeding. Infants with spontaneous cranial hematoma and intracranial hemorrhage should be investigated for underlying hemostatic defects. Congenital coagulation factor deficiency should be considered. Once congenital FV deficiency is diagnosed, fresh frozen plasma (FFP) should be given on a regular basis. Liver transplantation may be performed in severe cases.

Severe Factor V Deficiency Caused by a Novel Compound Heterozygous Mutation: Factor V G1617V and 1-Bp Insertion

Residual platelet factor V ensures thrombin generation in patients with severe congenital factor V deficiency and mild bleeding symptoms

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Activated protein C (APC) resistance (Dahlback et al, 1993) is a common risk factor for venous thromboembolism (Bucciarelli et al, 1999). This phenotype is highly associated with the F5 R506Q (F5 rs6025; factor V Leiden, FVL) mutation (Bertina et al, 1994). Heterozygous and homozygous discrepancies between F5 R506Q genotype and phenotype (APC resistance), known as pseudo-homozygosity, have been described (Castaman et al, 1997; Brugge et al, 2005). This incidental phenomenon suggests that, based on APC-resistance testing, there is a homozygous F5 R506Q mutation, yet, genetic testing only shows a heterozygous F5 R506Q mutation (Simioni et al, 1996). In such cases, polymorphisms located on the second factor V (FV) protein coding allele (i.e. wild-type for F5 R506Q) cause intracellular decreased FV protein production, leading to reduced FV activity (Castoldi et al, 1998). In contrast, the phenomenon “pseudo-wild-type” FVL, suggesting a wild-type F5 R506Q according to APC resistance testing but heterozygous F5 R506Q mutation by genetic testing, is infrequently described (Dargaud et al, 2003; Asselta et al, 2004). In these two studies, the polymorphisms responsible for the reduced FV protein levels were found to be located on the same FV protein coding allele, together with the F5 R506Q mutation.

To screen potential mutation and explore the underlying mechanism for a consanguineous pedigree featuring hereditary coagulation factor Ⅴ (FⅤ) deficiency. Clinical diagnosis was validated by coagulant parameter assays of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), FⅤ procoagulant activity (FⅤ:C) and FⅤ antigen (FⅤ:Ag). Potential mutations of the F5 gene in the proband and his family members were analyzed by direct DNA sequencing of PCR products of all exons, exon-intron boundaries and 3', 5' untranslated regions. Suspected mutation was confirmed by reverse sequencing. The PT and APTT in the proband were significantly prolonged, which measured 23.5 s (reference range 11.8-14.8 s) and 50.5 s (reference range 27.0-41.0 s), respectively. FⅤ activity and FⅤ antigen of the proband were significantly reduced to 8% and <1%, respectively. PT and APTT in the younger sister of the proband were also significantly prolonged (24.1 s and 62.4 s, respectively). Her FⅤ activity and FⅤ antigen were also significantly decreased (7% and <1%, respectively). PT and APTT of other family members were within the normal range. The homozygous missence mutation causing T→C transition at position 29170 in exon 5 of F5 gene has resulted in a Phe190Ser substitution in the proband. His younger sister was also homozygous for Phe190Ser. Heterozygosity for Phe190Ser was confirmed in his elder brother, elder sister, two daughters and niece, and their FⅤ activity were slightly decreased (57%, 73%, 72%, 66% and 75%, respectively). A normal wild type was observed in two younger brothers of the proband, and their FⅤ activity and FⅤ antigen were in the normal range. Homozygous missence mutation of Phe190Ser has been found in above family featuring hereditary FⅤ deficiency. The homozygous missence mutation was inherited from the parents by consanguineous marriage. Phe190Ser probably underlies may underlie the pathogenesis of hereditary FⅤ deficiency in this pedigree.

Severe factor V deficiency: exon skipping in the factor V gene causing a partial deletion of the C1 domain

Congenital coagulation factor VII (FVII) deficiency is a rare disorder caused by mutation in F7 gene. Herein, we reported a patient who had unexplained hematuria and vertigo with consanguineous parents. He has been diagnosed as having FVII deficiency based on the results of reduced FVII activity (2.0%) and antigen (12.8%). The thrombin generation tests verified that the proband has obstacles in producing thrombin. Direct sequencing analysis revealed a novel homozygous missense mutation p.Trp284Gly. Also noteworthy is the fact that the mutational residue belongs to structurally conserved loop 140s, which majorly undergo rearrangement after FVII activation. Model analysis indicated that the substitution disrupts these native hydrophobic interactions, which are of great importance to the conformation in the activation domain of FVIIa.

Identification and Characterization of Primary Factor VII Gene Mutations and Incidentally Detected Secondary MTHFR and ITGA2 Genetic Variants in a Factor VII Deficiency Cohort: A Single-Hemophilia Center Study

Homozygous F5 deep‐intronic splicing mutation resulting in severe factor V deficiency and undetectable thrombin generation in platelet‐rich plasma

Low plasma levels of tissue factor pathway inhibitor in patients with congenital factor V deficiency