Hereditary Factor VII Deficiency Research Articles

Analysis of three Chinese pedigrees affected with Hereditary factor Ⅶ deficiency due to compound heterozygous variants of F7 gene

To analyze the types of genetic variants and clinical characteristics of three Chinese pedigrees affected with Hereditary coagulation factor Ⅶ (FⅦ) deficiency. Three pedigrees who had visited the First Affiliated Hospital of Wenzhou Medical University between December 2021 and October 2022 were selected as the study subjects. Prothrombin time (PT), activated partial thromboplastin time (APTT) and FⅦ activity (FⅦ:C) were measured in the three probands and their pedigree members. All exons and their flanking sequences were analyzed by direct sequencing, and candidate variants were verified by reverse sequencing. The corresponding variant loci in the family members were also analyzed. ClustalX-2.1-win was used to analyze the conservation of the variant loci. Varcards and Spcards online software was used to predict the pathogenicity of the variants. Pymol software was used to analyze the changes in protein structure and molecular forces. Three cases of hereditary FⅦ deficiency were found to have decreased FⅦ:C, prolonged PT and normal APTT. Genetic analysis identified a total of four genetic variants, and all three probands had harbored compound heterozygous variants of the F7 gene, including p.Cys389Gly and p.His408Gln in proband 1, p.Cys389Gly and IVS6+1G>T in proband 2, and IVS6+1G>T and IVS1a+5G>A in proband 3. Conservation analysis showed that both the p.Cys389 and p.His408 loci are highly conserved among orthologous species. Analysis with Varcards and Spcards software showed that these variants were pathogenic. Protein modeling analysis showed that the p.Cys389Gly and p.His408Gln variants may result in altered protein structures and changes in hydrogen bonds. The clinical manifestations of the three FⅦ-deficient probands may be attributed to the compound heterozygous variants of p.Cys389Gly/p.His408Gln, p.Cys389Gly/IVS6+1G>T and IVS6+1G>T/IVS1a+5G>A of the F7 gene. The combination of the three compound heterozygous variants was unreported previously.

The identification of a novel compound heterozygous mutation in hereditary human coagulation factor VII deficiency following a bamboo leaf green snake bite.

Hereditary factor VII (FVII) deficiency is an uncommon autosomal recessive disorder associated with mutations in the F7 gene, and laboratory investigations usually reveal isolated prolongation in prothrombin time (PT)/international normalized ratio (INR). Venom-induced consumptive coagulopathy (VICC) is distinguished by the activation of the coagulation pathway, which is triggered by procoagulant toxins in snake venom. Diagnosing snakebites in patients with hereditary FVII deficiency presents a challenge because prolonged time PT/INR is considered the most valuable diagnostic method for VICC. Therefore, it is possible that certain patients may not promptly receive an accurate diagnosis of hereditary FVII deficiency. We present a pedigree featuring hereditary FVII deficiency, which was diagnosed through Sanger sequencing, following a bamboo leaf green snake bite.

The Identification of a Novel Compound Heterozygous Mutation in Hereditary Human Coagulation Factor VII (FVII) Deficiency Following a Bamboo Leaf Green Snake Bite

Hereditary factor VII (FVII) deficiency is an uncommon autosomal recessive disorder associated with mutations in the F7 gene and laboratory investigations usually reveal isolated prolongation in prothrombin time (PT)/International normalized ratio (INR). Venom-induced consumptive coagulopathy (VICC) is distinguished by the activation of the coagulation pathway, which is triggered by procoagulant toxins in snake venom. Diagnosing snakebites in patients with hereditary FVII deficiency presents a challenge due to the fact that prolonged time PT/ INR is considered the most valuable diagnostic method for VICC. Therefore, it is possible that certain patients may not promptly receive an accurate diagnosis of hereditary FVII deficiency. We present a pedigree featuring hereditary FVII deficiency, which was diagnosed through Sanger sequencing, following a bamboo leaf green snake bite.

Structural and functional characterization of novel F7 mutations identified in Chinese factor VII-deficient patients.

Hereditary factor VII (FVII) deficiency is a rare recessive bleeding disorder with an estimated prevalence of 1/500 000. We had investigated 50 unrelated Chinese patients with FVII deficiency and identified, in total, 25 mutations, including 18 missense mutations and 5 splicing mutations, on the F7 gene. The nucleotide transition c.1224T>G (p.His408Gln) in exon 9 constitutes a hotspot of mutation, with 19 patients harbouring this genetic variance. Few patients were homozygous or compound heterozygous for deleterious mutations, such as non-sense mutations, large insertion or deletions, indicating that complete deficiency of FVII may not be compatible with life. The eight novel mutations identified in the study, including one small deletion (p.Glu49GlyfsTer101), three type I missense mutations, p.Cys238Phe, p.Gly420Asp, p.Ala252Val and four type II missense mutations, p.Val336Met, p.Ser342Gly, p.Gly432Ser and p.Ile213Asn, were further analysed by in vitro expression and functional studies. The laboratory phenotype and structural analysis confirmed the functional consequence of p.Ile213Asn mutation involving cleavage and activation site. The molecular dynamic simulations and binding energy calculations along with functional probing of p.Gly432Ser mutation revealed the critical role of residue Gly432 in the binding between activated factor VII (factor VIIa) and tissue factor.

A novel compound heterozygous variant linked to hematuria in a family with hereditary factor VII deficiency.

Hereditary factor VII deficiency (FVIID) is a rare congenital autosomal recessive bleeding disorder. In clinical manifestations, its onset is caused by variant of the F7 gene (NM_019616) with strong heterogeneity. We identified a family with hematuria caused by a novel F7 compound heterozygous variant and investigated the FVIID-dependent mechanism impacted by these variants. Coagulation factors in the proband were functionally verified. We located pathogenic variants in relevant genes using next-generation sequencing after target enrichment and verified them by Sanger sequencing. We examined the coagulation activity and secretion pattern of recombinant FVII variants expressed in cells and observed their location and stability by immunofluorescence. We found a missense variant c.1207G>A (p.Gly403Ser) and a frameshift variant c.154_155del (p.Arg53fs) in the F7 gene of the proband. FVII activity tests showed that the variants significantly decreased its presence in the cell culture supernatant. Moreover, the R53fs mutant lacked the FVII functional domain and had no detectable activity. Immunofluorescence indicated that the p.Gly403Ser variant was distributed to the cell membrane and cytoplasm, whereas the FVII R53fs variant was not detected. Deficient FVII protein function and severe coagulation disorder are the likely causes of hematuria and other bleeding symptoms in the proband. The newly discovered F7 gene variants enrich the spectrum of hereditary FVII deficiency and provide a new foundation for the diagnosis and treatment of this type of coagulation disorder.

Analysis of a Chinese pedigree affected with hereditary factor VII deficiency caused by compound heterozygous variants of F7 gene

To explore the molecular basis for a Chinese pedigree affected with hereditary coagulation factor VII (FVII) deficiency. The coding regions of F7 gene were amplified by PCR and sequenced. Suspected variants were confirmed by reverse sequencing and validated in other members from the pedigree. Pathogenicity of the variants was analyzed with multiple bioinformatic tools. Genetic analysis revealed that the proband has carried compound heterozygous c.985T>C (p.Ser329Pro) and c.1091G>A (p.Arg364Gln) variants in exon 8 of the F7 gene. Her mother, brother and son were heterozygous for c.985T>C (p.Ser329Pro), while her father was heterozygous for c.1091G>A (p.Arg364Gln). Phylogenetic analysis suggested that both p.Ser329 and p.Arg364 are highly conserved among homologous species. Online bioinformatic software predicted both variants to be deleterious. Protein model analysis suggested that the Pro329 side chain may form a new hydrogen bond with Leu333. The Pro benzene ring may clash with Glu325 in the p.Ser329Pro variant model. The p.Arg364Gln variant have two additional hydrogen bonds compared with wild type Arg364. Both variants may lead to alteration of the protein structure. The p.Ser329Pro and p.Arg364Gln variants in exon 8 of the F7 gene probably account for the reduced FVII in this pedigree.

Genetic analysis and clinical features of a pedigree affected with hereditary coagulation factor Ⅶ deficiency caused by compound heterozygotic mutations

To detect potential mutations of the coagulation factor Ⅶ (F7) gene in a pedigree affected with hereditary FⅦ deficiency and explore its molecular pathogenesis. The FⅦ antigen (FⅦ:Ag) was analyzed by an enzyme-linked immunosorbent assay (ELISA) method. Prothrombin time (PT), FⅦ activity (FⅦ:C) and other coagulant parameters were quantified with an one-stage clotting assay. The F7 gene was amplified by PCR and sequenced. Mutational sites were confirmed by reverse sequencing. Impact of amino acid substitution was assessed using SIFT and PolyPhen-2 software. Structure of the mutant protein was analyzed using Swiss-pdb Viewer software based on the three-dimensional structure in the Protein Data Bank. The propositus had prolonged PT (36.3 s), with FⅦ:C and FⅦ:Ag significantly reduced to 2% and 44%, respectively. Her father, mother, younger sister and daughter had slightly prolonged PT and reduced FⅦ:C (86%-120%). The FⅦ:Ag of her father and younger sister were also reduced. DNA sequencing revealed that the propositus has carried compound heterozygous mutations (Lys341Glu and IVS6-1G>A) of the F7 gene. Her father and younger sister were heterozygous for the IVS6-1G>A mutation, while her mother and daughter were heterozygous for the Lys341Glu mutation. Bioinformatics analysis indicated that Lys341Glu mutation may affect the stability and function of the FⅦ protein. The Lys341Glu and IVS6-1G>A mutations probably underlie the reduced activity of FⅦ in this pedigree.

Genetic Diagnosis and Phenotype Analysis for 3 Patients with Hereditary Coagulation Factor Ⅶ Deficiency

To investigate the gene mutations types and the clinical characteristics in 3 patients with hereditary coagulation factor Ⅶ deficiency. The phenotype diagnosis was validated by detecting the coagulation parameters including prothrombin time (PT)，activated partial thromboplastin time (APTT), fibrinogen (FIB), FⅦ activity (FⅦ: C) and specific antigens (FⅦ: Ag) of proband and its family members. All exons, exon-intron boundaries, 5＇ untranslated regions and 3＇ untranslated regions of F7 gene were amplified with PCR. Potential mutations were detected by direct sequencing of purified PCR products. Suspected mutations were confirmed by sequencing of the opposite strand. A total of 5 different mutations were identified in 3 patients with hereditary coagulation factor Ⅶ deficiency and family members, including 4 misssense mutations and 1 splice site mutation. Out of 3 cases of hereditary coagulation factor Ⅶ deficiency 2 had double heterozygous mutation, I had homozygous mutations. Patient 1 had p.His408Gln with p.Arg413Gln double heterozygous mutations, her sister had p.His408Gln with p.Arg413Gln double heterozygous mutations, another one had p.His408Gln mono-heterozygous mutation, their correspo FⅦ: C were 5%, 3%, 75%. Patient 2 had p.Arg364Gln with p.His408Gln double heterozygous mutations, her brother had p.Arg364Gln with IVS6-1G＞A double heterozygous mutations, their corresponding FⅦ: C were 2.0%, 2.0%. Patient 3 had p.Arg337Cys homozygous mutation, FⅦ: C was 3.0%. A total of 5 different mutations were identified in 3 patients with hereditary coagulation factor Ⅶ deficiency, the p.His408Gln is a common mutation, the FⅦ: C and FⅦ: Ag have no correlation with clinical phenotypes.

Clinical and genotypic analysis of two Chinese pedigrees affected with hereditary coagulable factor VII deficiency

To explore molecular etiology and clinical characteristics of two pedigrees affected with hereditary factor VII(FVII) deficiency. The nine exons and flanking sequences of the F7 gene of the probands were amplified by PCR. The amplicons were analyzed by direct sequencing. Suspected mutations were subjected to SWISS-MODEL modeling and analysis of protein structure change by Pymol software and conservation of amino acids across various species. For proband of pedigree 1, the prothrombin time (PT), FVII activity (FVII:C) and FVII antigen (FVII:Ag) were 36.3 s, 3%, 53.56%, respectively. Sequencing revealed a compound heterozygous variants of c.80_81delCT and c.1371G>T(p.Arg439Ser). His son carried a heterozygous c.1371G>T (p.Arg439Ser) variant. For proband of pedigree 2, the PT, FVII:C and FVII:Ag were 22.3 s, 4%, 1.58%, respectively. Sequencing has revealed a compound heterozygous c.278G>T(p.Arg75Met) missense variant in exon 3 and c.1278T>G (p.His408Gln) in exon 9 of the F7 gene. His mother and son both carried a heterozygous c.278G>T(p.Arg75Met) variant. Three-dimensional simulation and homology analysis revealed that the p.Arg439Ser and p.Arg75Met can respectively alter part of hydrogen bonds and two highly conserved amino acids. Two novel heterozygous missense variants of the F7 gene [c.1371G>T(p.Arg439Ser) and c.278G>T(p.Arg75Met)] probably account for the decrease of factor VII in the two pedigrees.

Analysis of the gene in a hereditary coagulation factor Ⅶ deficiency pedigree

Analysis of the gene in a hereditary coagulation factor Ⅶ deficiency pedigree

Genetic analysis of a pedigree with hereditary coagulation factor Ⅶ deficiency

To identify potential mutations in a family affected with inherited factor Ⅶ (FⅦ) deficiency. Prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, FⅦ activity (FⅦ:C) and other coagulant parameters of the proband and 15 family members were measured. Potential mutations were screened in the pedigree by polymerase chain reaction and direct DNA sequencing. The PT of the proband and his younger brother was significantly prolonged to 39.0 s and 30.1 s, respectively. FⅦ:C of the proband and his younger brother was obviously reduced to 2% and 3%, respectively. FⅦ:C of his grandmother, maternal grandmother, aunt, father, mother, maternal uncle and maternal aunt was all below the normal range (80%-108%), which measured 68%, 54%, 71%, 73%, 62%, 72% and 59%, respectively. The other coagulant parameters were in the normal range. Two heterozygous mutations, g.11349G>A and g.11482T>G, both reside in exon 8 of the F7 gene, have resulted in p.Arg304Gln and p.His348Gln substitutions, were identified in the proband. The same mutations were also found in the proband's younger brother. Four maternal members in this family (grandmother, mother, maternal uncle and maternal aunt of the proband) were heterozygous for the p.Arg304Gln mutation, while three paternal members (grandmother, aunt and father of the proband) were heterozygous for the p.His348Gln mutation. The proband had inherited two independent mutations of the F7 gene including g.11349G>A and g.11482T>G from his mother and father, respectively. The compound heterozygous mutation probably explains the low FⅦ concentrations in this pedigree.

Factor VII Deficiency In African American Individuals. Presentation, Diagnosis and Management.A Single Medical Center Experience

Background Factor VII (FVII), a vitamin K-dependent glycoprotein serine protease, is produced by the liver and plays a fundamental role in the activation of the extrinsic coagulation pathway. Hereditary factor VII deficiency is a rare coagulation disorder with autosomal recessive inheritance and an approximate prevalence of 1:500,000. Clinical manifestations vary from no symptoms to severe bleeding events and often correlate poorly with plasma levels of factor VII. Therapy for factor VII deficiency depends on the severity and the type of bleeding and includes fresh frozen plasma (FFP), antifibrinolytics and recombinant factor VIIa (rFVIIa). Recent data from the STER registry suggests that bleeding symptoms on presentation and factor VII activity level can be used to identify clinical variants and guide replacement therapy. The majority of patients enrolled in this registry were from European countries. Patients of African American origin remain poorly characterized. Aims We present our experience with diagnosis and management of patients, predominantly African American, in a large academic institution. We retrospectively reviewed the data on seven patients diagnosed with isolated factor VII deficiency and their management. Results Six of the seven patients followed in our institution were African American. Of them, three were female and three were male. A six month old girl was diagnosed during treatment for sepsis. She had no bleeding symptoms (FVII activity 27% on presentation, 32% one month later). The other two female patients presented with obstetrical bleeding (FVII <3% and 11% respectively). Of the male patients, two six year old twins had epistaxis (FVII activity 12%). Another six year old boy presented with trauma-associated hemorrhage, but had no prior history of bleeding (FVII 4%). Follow up data were available on five of the patients. Duration of follow up ranged from 6 months to more than 10 years. None of the patients had spontaneous bleeding, regardless of their presentation or level of FVII activity. The patients with bleeding and those who needed surgery received FFP (two patients prior to making the diagnosis) and rFVIIa (four patients). The doses used were 10-25mcg/kg in one or two applications. No bleeding and no thrombotic complications were observed with this therapy. None of the patients received antifibrinolytics. The one White Caucasian patient was a 25 year old male who presented with bleeding after trauma (FVII activity was 10%) and was managed with rFVIIa (25mcg/kg). Conclusion Our data demonstrates that, in African American patients, factor VII deficiency presents with variable clinical findings. There was poor correlation between the FVII levels and the clinical phenotype. Management with rFVIIa, used at the time of surgery or trauma at low to intermediate doses, was sufficient to prevent bleeding and was not associated with any significant complications. Disclosures: No relevant conflicts of interest to declare.

A Spectrum of Clinical and Laboratory Findings and Treatment Modalities in Patients with Factor VII Deficiency- A Single Medical Center Experience,

Abstract 3306▪▪This icon denotes a clinically relevant abstract Introduction:Factor VII, a vitamin K dependent glycoprotein serine protease secreted by the liver, has a fundamental role in the activation of the extrinsic coagulation pathway. It is found in the plasma as a zymogen, and is activated by tissue factor and calcium. Hereditary factor VII deficiency is a rare coagulation disorder with autosomal recessive inheritance found approximately at a prevalence of 1:500,000. In Israel, factor VII deficiency is found mostly in Sephardic Jews of Iranian, Moroccan and Tunisian origin as well as in the Druze population. Bleeding symptoms usually occur in homozygotes or compound heterozygotes. In symptomatic patients, the clinical severity of bleeding ranges from mild to severe (such as intracranial bleeding) and does not always correlate with plasma levels of factor VII activity. However, patients with factor VII activity of less than 1% may present with symptoms similar to severe hemophilia. Patients with factor VII activity of 5% or more usually present with milder bleeding such as epistaxis, gingival bleeding, menorrhagia or bruising. Therapy for factor VII deficiency depends on severity and type of the bleeding. Treatment includes fresh frozen plasma (FFP), tranexamic acid and recombinant factor VIIa (Novoseven). Aims:The study goal was to find correlation between level of factor VII activity, bleeding complications and treatment modalities that were used in symptomatic patients or in those undergoing surgical procedures. Patients and methods:We performed a retrospective study of 125 patients with decreased levels of factor VII, referred to our department between 1990–2010. 56 patients with isolated deficiency of factor VII were included in the study. Patients with combined deficiencies or liver disease were excluded. Demographics, clinical symptoms and their correlation to levels of factor VII, as well as treatment modalities were investigated. A factor VII activity level below 50 % was considered as decreased. The data collection was performed after approval of hospital Helsinki committee. Results:Of 56 patients with isolated factor VII deficiency there were 29 males and 27 females. 31/56 (55.4%) of the patients were Jews of Sephardic origin. 18/56 (32%) of the patients had relatives with known factor VII deficiency. The activity of factor VII ranged from <1%-49%. There was no significant difference in factor VII activity levels between the symptomatic (mean = 20.87, SD = 17.9) and the asymptomatic patients (mean = 23.13, SD = 17.4). 11/56 (19.6%) of the patients had clinical symptoms of bleeding, 6 of them had factor VII level<10 %. No life threatening bleeding was reported. Most episodes of bleeding related to factor VII deficiency were epistaxis and menorrhagia. Less common bleeding included hematoma and gingival bleeding. Only 9% of the symptomatic patients required treatment with FFP or tranexamic acid. Recommendation for prophylactic treatment such as FFP and/or tranexamic acid prior to surgical procedure was given in 19 patients. The post operative period was uneventful in all the patients. 5 patients did not receive any prophylactic treatment for different surgical procedures and no significant post operative bleeding was observed. Conclusions:Though factor VII deficiency had been described in the literature as a rare disease, we collected and analyzed a large cohort of 56 patients with this disorder in a single medical center. Most of our patients were Sephardic Jews. There had been several reports of excessive bleeding which complicated surgery, especially of the oropharynx and urogenital tract in patients with factor VII deficiency. Levels of 15–25% are recommended for surgery, but the plasma factor VII level required for surgery has been not formally established. We did not find statistically significant differences in factor VII activity levels between the symptomatic patients and the asymptomatic ones (P value<0.36). No life threatening bleeding occurred; only one patient required acute treatment to stop the bleeding. There was no uniform protocol used for prophylactic treatment, which was usually based on “old” drugs such as FFP and tranexamic acid. There was no need for Novoseven. We conclude that treatment guidelines based on the family, personal, surgical history and laboratory results are required for optimal treatment of patients with inherited factor VII deficiency. Disclosures:No relevant conflicts of interest to declare.

Recurrent mutations and genotype–phenotype correlations in hereditary factor VII deficiency in Korea

Coagulation factor VII (FVII) deficiency is a rare hereditary coagulopathy caused by mutations in the F7 gene. The aims of this study were to characterize the molecular defect of F7 in Korean patients with FVII deficiency and to find genotype-phenotype correlations. Study individuals consisted of 14 unrelated Korean patients with FVII deficiency with residual FVII activities ranging from 1 to 34%. To identify causative mutations, we performed PCR amplification and direct sequencing of all exons and flanking sequences of F7 gene. In all 14 patients, one (N = 4) or two (N = 10) mutant alleles were identified. A total of 11 unique mutations were detected, of which four were novel (c.-1C>T, p.V54RfsX53, p.R59_R60dupRR, and p.L314 V). Four recurrent mutations were observed in 86% of patients (12 of 14) (C389G, C115X, G343S, and c.572-1G>A) and accounted for 71% of all mutant alleles (17 of 24). The residual FVII activity was more than 5% in all six asymptomatic patients (21%, range 6-34%), whereas it was 5% or less in all eight symptomatic patients (2%, range 1-5%). In addition, the mean residual FVII activity in four patients with a single mutant allele was 23.6% (range 3-34%), which was significantly higher than that in 10 patients with two mutant alleles that was 4.6% (range 1-19%) (P = 0.023). In summary, the data from this study on the largest number of FVII deficiency in Korea showed recurrent mutations in this population and suggested genotype-phenotype correlations.

An inherited coagulation factor VII deficiency pedigree caused by homozygous mutation of His348Gln

To investigate the gene mutation and the molecular pathogenesis of an inherited coagulation factor VII (F VII) deficiency pedigree with consanguineous marriage. The diagnosis was validated by coagulant parameter assay on the prothrombin time (PT), activated partial thromboplastin time, fibrinogen and coagulation factor activity. F VII gene mutations were analyzed in the proband and other family members by direct DNA sequencing of the PCR products of all exons, exon-intron boundaries and 5'and 3' untranslated sequences. The mutations were confirmed by reverse sequencing. The values of PT and F VII activity in the proband were significantly abnormal, they were 30.9 s and 3% respectively. The PT of her daughter, father and mother was slightly extended to 21.2 s, 16.3 s and 16.1 s respectively, and the F VII activity was reduced to 22%, 25% and 35% respectively. The coagulant parameters of her younger brother were within normal range. Homozygous T-->G transition at position 11482 in exon 8 was identified in the proband resulting in His348Gln, and heterozygosity for His348Gln was confirmed in her daughter and her parents, and the normal wild-type was observed in her younger brother. Homozygous missense mutation of His348Gln was found in a pedigree of hereditary F VII deficiency. The mutation was inherited from her heterozygote parents.

Canine specific ELISA for coagulation factor VII

Canine coagulation factor VII (FVII) deficiency can be hereditary or acquired and may cause life threatening bleeding episodes if untreated. FVII procoagulant activity can be measured by FVII activity (FVII:C), but assays for measurement of canine specific FVII antigen (FVII:Ag) have not been available to date. In this study, a canine specific ELISA for measurement of FVII:Ag in plasma was developed and validated. The FVII:Ag ELISA correctly diagnosed homozygous and heterozygous hereditary FVII deficiency. Together with activity based assays, such as FVII:C, the FVII:Ag ELISA should be valuable in the diagnosis of hereditary canine FVII deficiency.

Bilateral Subdural Hematomas in an Adult With Hereditary Factor VII Deficiency: A Complication of Sit-ups and Inversion?

A 57-year-old man of northern Italian and Polish descent with a late-onset, mild form of hereditary factor VII deficiency developed bilateral intracranial subdural hematomas after performing sit-ups while he was in a head-down position on an inversion table. The pertinence of the Valsalva maneuver and increased intracranial venous and intraocular pressure associated with sit-ups and other exercises in the causation of subdural hematomas and other types of intracranial and ocular hemorrhage are discussed in this study.

Hereditary Factor VII Deficiency in the Alaskan Klee Kai Dog

Background: Hereditary factor VII (FVII) deficiency is characterized as a mild bleeding disorder in Beagles, caused by a missense mutation in exon 5 of the FVII gene. An Alaskan Klee Kai dog with severe bleeding after trauma was diagnosed with FVII deficiency based on coagulation testing. Molecular analyses were undertaken to identify the genetic basis of the defect in this breed. Hypothesis: FVII deficiency in Alaskan Klee Kai dogs is caused by a mutation in the FVII gene. Animals: Eighteen client‐owned Alaskan Klee Kai. Methods: Coagulation screening tests and factor assays were performed to characterize the coagulopathy. All coding regions of the propositus' FVII gene were sequenced. Amplification of exon 5, sequencing, and Mnl I restriction digest experiments were performed to screen for a point mutation in the remaining 17 dogs. Results: FVII deficiency was diagnosed in 6 dogs with a median FVII activity (FVII:C) of 5% (reference range, 50–150%). All FVII‐deficient Alaskan Klee Kai were homozygous for the same mutation as FVII‐deficient Beagles (ie, a G to A transition), resulting in substitution of glycine 96 by glutamic acid. An overlap in the FVII: C values obtained from heterozygote and wild‐type dogs precluded accurate detection of carriers without genetic screening. Conclusions and Clinical Importance: FVII deficiency may be associated with a bleeding tendency and should be considered in Alaskan Klee Kai dogs with prolonged prothrombin times. Plasma FVII:C accurately identifies affected dogs, but deoxyribonucleic acid testing is required for identification of carriers.

Molecular basis of hereditary factor VII deficiency in India: five novel mutations including a double missense mutation (Ala191Glu; Trp364Cys) in 11 unrelated patients

We have studied the molecular basis of factor (F) VII deficiency in 11 unrelated Indian patients. Mutations were identified in all 11 and included 5 missense, 2 nonsense and a frame shift mutation. Five of these were novel. These mutations were considered to be causative of disease because of their nature, evolutionary conservation and molecular modeling. This is the first report of mutations in patients with FVII deficiency from southern India.

A rodenticide exposed and bleeding Beagle dog with hereditary factor VII deficiency

AbstractObjective: To report a complex presentation of an acquired and hereditary coagulopathy in a dog.Case summary: A 5‐year‐old spayed female Beagle presented for lethargy, anorexia, cough, and stiff gait, and was diagnosed with a spontaneous hemothorax. The patient recovered from this bleeding episode suspected to be secondary to anticoagulant rodenticide intoxication, but was subsequently diagnosed with factor VII (FVII) deficiency, a hereditary coagulopathy. Diagnostic approach and management of FVII deficiency is described.New or unique information provided: This paper describes an unusual presentation of an inherited hemostatic disorder. Utilization of available screening and diagnostic tools, and appropriate interpretation of test results facilitate identification and management of this inherited coagulopathy.