Congenital coagulation factor V deficiency with intracranial hemorrhage.

BACKGROUND: 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. METHODS: 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. RESULTS: The coagulation tests revealed a significantly prolonged prothrombin time (PT) of 51 s and an activated partial thromboplastin time (APTT) of 73.7 s. 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. CONCLUSION: 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.

Clinical Phenotype and Genetic Analysis of Twins With Congenital Coagulation Factor V Deficiency.

OBJECTIVE: The aim was to investigate the clinical characteristics and molecular pathogenic mechanism of twins with congenital factor V (FV) deficiency. METHODS: We comprehensively analyzed the clinical manifestations and laboratory test results of a set of twins and their parents and performed point mutation analysis with direct high-throughput exon sequencing. RESULTS: The prothrombin time and activated partial thromboplastin time were prolonged for both probands, and the FV activity levels were 13.0% and 9.8%. Next-generation sequencing showed that the affected individuals harbored a paternal c.5113A>C (p.S1705R) and a maternal c.4949C>T (p.A1650V) heterozygous variants in the FV gene, which conformed to an autosomal recessive inheritance pattern. This is the first report of these point mutations. The older boy also had a congenital patent foramen ovale. CONCLUSION: In this set of twins, missense mutations of the FV gene were related to congenital FV deficiency but unrelated to the patent foramen ovale observed in the older boy.

Hereditary factor V deficiency from heterozygous mutations with a novel variant p.Pro798Leufs∗13 in the F5 gene.

To explore the causative mutation for autosomal recessive inheritance factor V (FV) deficiency in a Chinese family. Relative coagulation indexes and the FV antigen were tested by the one-stage clotting method and ELISA, respectively. At the same time, the calibrated automated thrombogram (CAT) was used to analyze the mutant protein function. All 25 exons, flanking sequences, 5' and 3' untranslated regions of the F5 were amplified by PCR and sequenced directly, while each suspected variant was verified by reverse sequencing. The possible impact of the mutant was analyzed by the corresponding bioinformatics software. The phenotypic tests showed that the proband's FV activity has decreased to 24%, whereas the FV antigen has also reduced to 28%. The genetic analysis revealed that she was a compound heterozygote for a frameshift variant from small deletion in the exon 13 (c.2390_2390delC, p.Pro798Leufs∗13) and a missense mutation in the exon 25 (c.6665A>G, p.Asp2222Gly). Meanwhile, the online bioinformatics software indicated that the frameshift variant was disease-causing. The pathogenic variant p.Pro798Leufs∗13 and the benign variant p.Asp2222Gly largely account for the decrease of the FV deficiency in this Chinese family, of which the pathogenic variant is firstly reported in the world.

A novel mutation (Ser951LeufsTer8) in F5 gene leads to hereditary coagulation factor V deficiency.

The current study aims to explore the phenotype and genotype of a novel mutation (Ser951LeufsTer8) of F5 gene combined with polymorphism (R485K) in a family of hereditary coagulation factor V deficiency. The factor V activity and antigen were tested with clotting assay and ELISA. The F5 gene was amplified by PCR with direct sequencing and TA-clone-sequenced. The protein structure and harmfulness of the mutation were studied by Swiss-PdbViewer and bioinformatics software. The prothrombin time and activated partial thromboplastin time of proband were significantly prolonged, factor V activity and factor V antigen both were reduced to less than 20%. Sequencing analysis detected proband with Ser951LeufsTer8 and R485K (Arg513Lys), four family members with novel mutation and their factor V activity and factor V antigen were all decreased about 50%. The Ser951LeufsTer8 is associated with decrease in the factor V level of the family, and it is the first mutation report in the position (Ser951LeufsTer8) with factor V deficiency.

Congenital Factor V deficiency: perioperative management (case report).

Factor V congenital deficiency is a rare hereditary disease, it exposes patients to hemorrhagic risk, with high morbi-mortality. Its management is a real challenge for practitioners. Perioperative management of patients with Factor V congenital deficiency needs anesthetists, hematologists and surgeons to work in close collaboration.

Clinical and laboratory diagnosis of autoimmune factor V inhibitors: A single institutional experience.

BACKGROUND: Coagulation factor V inhibitors (FV-i) may occur in patients with congenital FV deficiency or previously hemostatically normal patients (autoimmune (AI)-FV-i). Most of the published literature is confined to case reports. OBJECTIVE: Describe clinical and laboratory features of AI-FV-i identified through the Special Coagulation Laboratory at Mayo Clinic, Rochester, Minnesota. METHODS: In this retrospective study individuals with FV-i screens performed from January 1999 to February 2017 were identified through the special coagulation laboratory database. Clinical presentation, management, and outcomes were collected for our institutional patients while detailed laboratory data was collected for all tested patients. RESULTS: Of patients with FV-i managed at our institution, 2/8 (25%) patients experienced no bleeding. There was no correlation between inhibitor titers and/or FV activity (FV:C) levels and clinical bleeding. Hemostatic management included fresh frozen plasma, platelet transfusion, activated prothrombin complex concentrates, and recombinant factor VIIa. Only 2 patients received immunomodulatory treatment. FV-i mixing studies with normal pooled plasma (n = 26) demonstrated inhibition on immediate mix but progressive inhibition after 1 h of incubation could not be demonstrated. 71% of platelet neutralization procedures were falsely positive while 59% of DRVVT assays were indeterminate. CONCLUSION: FV-i demonstrates immediate inhibition on mixing studies; however our limited data does not support a time dependent inhibition. Our clinical cohort confirms the variable clinical phenotype for individuals with FV-i and supports the notion that management of FV-i should be guided by clinical symptoms and not FV:C or FV-i titer.

[Factor V congenital deficiency: about a case]. / Déficit congénital en facteur V: à propos d'un cas.

Factor V congenital deficiency is a rare coagulation disorder initially described by Owren in 1947 and known as para hemophilia. It is transmitted through autosomal-recessive inheritance and homozygous cases are usually symptomatic. Factor V is an essential cofactor in the conversion of prothrombin to thrombin by activated factor X. In the absence of factor V, thrombin generation is slowed down and fibrin formation is delayed. This results in a bleeding tendency. We report a case of factor V congenital deficiency in an infant with recurrent epistaxis.

[CONGENITAL DEFICIENCY OF COAGULATION FACTOR V].

The study was designed to investigate the 5 year old girl with rare bleeding disorder -deficiency of coagulation factor V. The diagnosis was based on detail family history, physical examination and para-clinical data analyses. The age of patient, purpura, this has been detected from early age, positive family history, non-controlled, longtime bleeding, inadequate trauma of the tongue, which did not resolve after surgery, strong hypocoagulation, which was slightly improved, after several plasma transfusions. This allowed us to suggest the existence of the congenital coagulopathy, which was confirmed by the investigation of coagulation factors - particularly the deficiency of factor V was detected.

Miscarriage and recurrent miscarriage in patients with congenital factor V deficiency: a report of six cases in Iran.

Miscarriage and recurrent miscarriage have not been reported in women with congenital factor V (FV) deficiency. Here we describe cases of both miscarriage and recurrent miscarriage in women with congenital FV deficiency (FVD). We investigated six women with FVD from the southeast of Iran who had experienced miscarriage and recurrent miscarriage. Consequent diagnosis was made by routine coagulation tests as well as FV activity and antigen assays. To evaluate the presence of an inhibitor, a mixing study via prothrombin time (PT) assay was performed. All patients were investigated, and found to be negative for antiphospholipid syndrome. Demographic data and clinical presentations were obtained by standard questionnaire. The factor assays determined that all six women were suffering from moderate FVD. One had experienced eight miscarriages, while the others experienced two (two patients), three, and four episodes. Only one patient had a single miscarriage. Three of the women experienced successful delivery without medical intervention. Miscarriage and recurrent miscarriage should be considered as possible presentations of FVD to prevent its life-threatening consequences.

Congenital combined deficiency of coagulation factors: a study of seven patients.

Combined deficiency of coagulation factors is considered as an extremely rare bleeding disorder (RBD) inherited in an autosomal recessive pattern. This disorder is more likely to occur in regions with a high rate of consanguineous marriages or in restricted communities. Sistan and Baluchistan, a province in southeast of Iran with a high rate of consanguinity, is a clear model of such regions with a very high prevalence of recessively inherited disorders. The aim of this study was to report the frequency of combined factor deficiency in this province. This descriptive study was conducted on 358 patients with RBD. Demographic information and medical history of each patient were recorded, and the patients were examined by a physician. Routine screening tests were carried out for all patients, and further coagulation tests including coagulation factor activity and antigen assays were subsequently performed for all suspected patients. Among 358 patients, four were found to be affected with combined factor (F)V and FVIII deficiency (F5F8D). In addition, one patient with combined deficiency of FVII-FXIII, one with combined FVII-FX and one with combined FVIII-FIX deficiency were identified. In Sistan and Baluchistan Province, coinheritance of recessively inherited disorders like combined coagulation factor deficiencies was surprisingly higher than expected.

Inherited factor V deficient neonate with galactosaemia.

OBJECTIVES: Reporting a case of inherited factor V deficiency and galactosemia. METHODS: A neonate was admitted with hematoma, jaundice, splenomegaly, diarrhea, anemia, abdominal ascites and bilateral cataracts that diagnosis of galactosaemia and factor V deficiency was established. RESULTS: Coinheritance of both coagulation disorder and metabolic disorder is very rare episode that was identified in a neonate. CONCLUSION: Our case indicates that in mild bleeding episodes of neonates that imitate of coagulation disorders should be considered promptly by pediatricians.

Extraction of four wisdom teeth in a patient with congenital factor V deficiency hemophilia.

Congenital factor V deficiency was first described by Owren in 1947.(1) It is thought to be transmitted by an autosomal recessive gene (q23-24)(2) found in 1 out of every 1 million population and usually with no gender or race correlation.(3) To date, ~150 cases have been reported in the world literature.(3) The description of rare case of this disease is justified, because they may add further information about the condition of the hemorrhagic tendency. The object of the present paper was to report the bleeding control for extraction of 4 wisdom teeth with congenital factor V deficiency hemophilia and review the literature.

[Goldman Antopol syndrome associated with bilateral congenital severe factor V deficiency]. / Syndrome d'Antopol Goldman bilatéral associé à un déficit congénital sévère en facteur V.

Antopol-Goldman lesions are extremely rare. This kind of lesion is a subepithelial pelvic hematoma. This syndrome is certainly of rare occurrence and that is why a differential diagnosis of urothelial cancer in young patients who had problems with clotting must be raised. We reported a case of a 43-year-old haemophiliac with a severe congenital factor V deficit and presenting a bilateral and asynchronous Antopol Goldman syndrome. The diagnosis has been based on CT scans. The subepithelial aetiology bleeding has been shown on selective renal arteriography that allowed to cover a micro-aneurysm through the setting up of a vascular stent and a selective embolization.

Factor 5 mutation profile in German patients with homozygous and heterozygous factor V deficiency.

Coagulation factor V (FV) plays an important role in the blood coagulation cascade as part of the prothrombinase complex. FV deficiency is a rare autosomal recessive bleeding disorder with variable phenotypic expression. Thus, our study reports 39 patients with FV deficiency. In 36 cases, we were able to identify a causative mutation. Of these, 20 patients were heterozygous for the identified mutation, nine were homozygous, six were compound heterozygous and one proband was pseudohomozygous. In the remaining patients, no mutation was found. A total of 42 genetic alterations (of which 33 were uniquely different mutations), comprising 19 missense mutations, eight nonsense mutations, four small deletions and two splice site mutations, were identified by this study. Twenty-three of these were novel sequence variations not previously described in the literature. Interestingly, all changes found in exon 13 resulted in null alleles as either nonsense mutations or small deletions. The overall profile of these new mutations corresponds well with the data published in the F5 database. In those cases, where data were available, information on FV activity levels and/or bleeding history is given. Interestingly, some patients with mild FV deficiency (FV:C about 50% of normal) also exhibited bleeding episodes. Our data substantially contribute to the broadening and better understanding of the FV deficiency mutational spectrum. Identifying the molecular basis of mutations underlying this rare coagulation disorder will allow more insight into the mechanisms involved in the variable clinical phenotypes of patients with FV deficiency.

Advances in understanding the bleeding diathesis in factor V deficiency.

Coagulation factor V (FV), present in plasma and platelets, is an indispensable clotting factor, as demonstrated by the uniform lethality of FV knock-out mice. Surprisingly, however, severe FV deficiency is rarely fatal in humans. In fact, although several cases of life-threatening intracranial haemorrhage have been reported in FV-deficient newborns, many patients with undetectable FV levels experience only mild to moderate bleeding and do not require routine prophylaxis. While the reasons for this variable phenotypic expression are largely unknown, several observations from different laboratories indicate platelets as crucial players in FV deficiency. Moreover, we have recently shown that plasma levels of tissue factor pathway inhibitor are considerably reduced in FV-deficient plasma, which results in enhanced thrombin generation especially at very low FV levels (<2%). The present review discusses and integrates these findings in the context of the biology of FV and the clinical features of FV deficiency.

Identification of four novel mutations in F5 associated with congenital factor V deficiency.

Coagulation factor V (FV) deficiency is a rare bleeding disorder characterized by low coagulant and antigen levels of FV with bleeding symptoms ranging from mild to severe. Only a limited number of mutations have been reported because of the large size of the factor V gene (F5) as well as the low prevalence. In this study, we have identified four novel mutations in F5 in five unrelated patients with congenital FV deficiency. All the patients, including two with undetectable FV activity, were asymptomatic and were found to have prolonged prothrombin time and activated partial thromboplastin time during preoperative screening or routine examinations. All four mutations found in this study are either missense or in-frame deletion. This is in contrast with previous reports of a high frequency of mutations introducing premature termination codons in inherited FV deficiency. Missense mutations of F5 might produce a mild phenotype and are not frequently diagnosed. Although FV deficiency is a very rare disorder with a predicted incidence of one in 1 million, this study suggests that the numbers of F5 mutations, especially missense mutations, are higher than estimated.

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

Severe factor V (FV) deficiency is associated with mild to severe bleeding diathesis, but many patients with FV levels lower than 1% bleed less than anticipated. We used calibrated automated thrombography to screen patients with severe FV deficiency for protective procoagulant defects. Thrombin generation in FV-deficient plasma was only measurable at high tissue factor concentrations. Upon reconstitution of FV-deficient plasma with purified FV, thrombin generation increased steeply with FV concentration, reaching a plateau at approximately 10% FV. FV-deficient plasma reconstituted with 100% FV generated severalfold more thrombin than normal plasma, especially at low tissue factor concentrations (1.36 pM) or in the presence of activated protein C, suggesting reduced tissue factor pathway inhibitor (TFPI) levels in FV-deficient plasma. Plasma TFPI antigen and activity levels were indeed lower (P < .001) in FV-deficient patients (n = 11; 4.0 +/- 1.0 ng/mL free TFPI) than in controls (n = 20; 11.5 +/- 4.8 ng/mL), while persons with partial FV deficiency had inter-mediate levels (n = 16; 7.9 +/- 2.5 ng/mL). FV immunodepletion experiments in normal plasma and surface plasmon resonance analysis provided evidence for the existence of a FV/TFPI complex, possibly affecting TFPI stability/clearance in vivo. Low TFPI levels decreased the FV requirement for minimal thrombin generation in FV-deficient plasma to less than 1% and might therefore protect FV-deficient patients from severe bleeding.