Congenital Factor V Deficiency Research Articles

Clinical, Laboratory, and Molecular Aspects of Factor V Deficiency.

Factor V (FV) is a glycoprotein that plays a pivotal role in hemostasis, being involved in coagulant and anticoagulant pathways. Congenital FV deficiency is a rare bleeding disorder with an incidence of 1 per million live births, considering the most severe homozygous form. FV deficiency is diagnosed using routine coagulation tests and FV activity assays. Several mutations, including missense, nonsense, and frameshift, have been detected in the F5 gene. Clinical symptoms are variable, ranging from mild ecchymoses and mucosal bleeding to life-threatening intracranial hemorrhage. The mainstay of treatment includes fresh-frozen plasma, preferentially virus-inactivated. In this narrative review, we provide an update of the main laboratory, molecular, clinical, and therapeutic features of inherited FV deficiency.

Acquired Factor V Deficiency After Carbapenem Administration: A Case Report

Factor V (FV) deficiency is a coagulation disorder (congenital or acquired). Unlike congenital FV deficiency, mixing tests for prothrombin time and activated partial thromboplastin time are not corrected in acquired FV cases. A 79-year-old male was admitted to the intensive care unit after an emergency operation due to gastric ulcer perforation. While receiving antibiotic treatment for septic shock, the coagulation profile began to show prolongation of prothrombin time and activated partial thromboplastin time. FV deficiency (< 1%) following meropenem administration was diagnosed . The patient did not show spontaneous bleeding or bleeding tendency. With fresh frozen plasma transfusion, steroid administration, and discontinuation of meropenem, the blood coagulation profile test result was normalized 20 days after diagnosis. His follow-up FV level increased to 78.7%. Although abnormalities in coagulation profiles are common in sepsis patients, in our patient, timely recognition and hematological consultation allowed early diagnosis and proper management of FV deficiency.

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.

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.

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

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

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

AbstractCoagulation factor V (FV), present in plasma and platelets, is indispensable to thrombin formation, yet patients with undetectable plasma FV seldom experience major bleeding. We used thrombin generation assays to explore the role of platelet FV in 4 patients with severe congenital FV deficiency (3 with plasma FV clotting activity [FV:C] < 1%). When triggered with tissue factor (TF) concentrations up to 50pM, platelet-poor plasma (PPP) from the patients with undetectable plasma FV showed no thrombin generation, whereas platelet-rich plasma (PRP) formed thrombin already at 1 to 5pM of TF. Thrombin generation in PRP from the FV-deficient patients was enhanced to near-normal levels by platelet activators (collagen or Ca2+-ionophore) and could be completely suppressed by specific FV inhibitors, suggesting FV dependence. Accordingly, platelet FV antigen and activity were measurable in all FV-deficient patients and platelet FVa could be visualized by Western blotting. Normalization of the tissue factor pathway inhibitor (TFPI) level, which is physiologically low in FV-deficient plasma, almost completely abolished thrombin generation in PRP from the FV-deficient patients. In conclusion, patients with undetectable plasma FV may contain functional FV in their platelets. In combination with low TFPI level, residual platelet FV allows sufficient thrombin generation to rescue these patients from fatal bleeding.

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.

Identification of three F5 gene mutations associated with inherited coagulation factor V deficiency in two Chinese pedigrees.

To investigate the molecular defects in two Chinese pedigrees with inherited factor V (FV) deficiency. A 37-year-old male (proband 1) and an 18-month-old boy (proband 2) were diagnosed as inherited coagulation FV deficiency by severely reduced plasma levels of FV activity and antigen. All 25 exons and their flanking sequence of F5 gene were amplified by polymerase chain reaction (PCR) for both probands and the PCR products were directly sequenced. Total RNA was extracted from the peripheral lymphocytes of proband 1 for detecting the changes at mRNA level. The homozygous deletion IVS8 -2A>G was identified in the F5 gene of proband 1 and complementary DNA (cDNA) analysis revealed the abolishment of the canonical splicing site by the mutation and the activation of the cryptic acceptor site 24 bp upstream instead. The insertion introduced eight additional amino acids (AA) into the FV protein. Two heterozygous mutations of F5 gene were discovered in proband 2. The 2238-9del AG in exon 13 introduced a premature termination code at 689 AA and the substitution of G6410 by T in exon 23 lead to the missense mutation Gly2079Val. Three F5 gene mutations, IVS8 -2A>G, 2238-9del AG and G6410T, have been identified in two Chinese pedigree with congenital FV deficiency, respectively.

Homozygous factor V-deficient patients show resistance to activated protein C whereas heterozygotes do not

Resistance to activated protein C (APC resistance) was assessed in plasma from patients with heterozygous and homozygous factor V (FV) deficiency. Because of the identity of the new APC cofactor with non-activated FV, it was expected that the lower the FV level the higher the APC resistance in plasma. Heterozygotes for the FV defect (both antigen and activity levels around 40%) did not show APC resistance in plasma. In contrast, homozygous patients for the same defect (less than 1% antigen and activity levels), had obvious APC resistance. Whether this finding was consistent with a spurious APC resistance or whether it truly reflected the lack of the APC cofactor activity in congenital FV deficiency remains to be clarified. Mixing (1:1) plasma from patients with a homozygous FV defect with pooled normal plasma (PNP) corrected both procoagulant and anticoagulant FV activities. Whenever severely APC-resistant plasma was used in place of PNP, only procoagulant activity was corrected and APC resistance was not affected. This suggests that homozygous FV-deficient plasma completely lacks the cofactor, i.e. the second APC cofactor, which can correct APC resistance in plasma. This indirectly confirms that the second APC cofactor is related to FV.

The Treatment of Patients with Factor-V Deficiency

Two patients with congenital factor-V deficiency and a third with a combined deficiency of factor V and factor VIII are described. Under cover of fresh frozen plasma, tooth extractions were performed on two of these patients and spontaneous bleeding arrested. It is concluded that the achievement of a blood level of factor V of 20 per cent once daily is sufficient to assure adequate haemostasis. A low recovery of factor V activity in the plasma following infusion was found. However, in spite of this, adequate blood levels were easily attained due to the excellent preservation of factor V activity in the stored fresh frozen plasma.