Factor VII Deficient Patients Research Articles

Genetics analysis of Belarusian pediatric patients with factor VII deficiency

IntroductionCoagulation factor VII (FVII) deficiency (OMIM 227500) is the most common of the rare hereditary coagulation disorders characterized by autosomal recessive inheritance with variable penetrance. The estimated incidence of coagulation factor VII deficiency is 1:500,000. Clinical heterogeneity is a special feature of this coagulation disorder, the severity of which ranges from severe to mild or even asymptomatic forms. Materials and methodsIn the study were included three unrelated pediatric patients (3 female) with confirmed factor VII deficiency and members of their families (2 male and 2 female) Genetic analysis was carried out by next generation sequencing using Nextera XT, examining all exon and the exon/intron boundaries of F7 gene using a genetic analyzer MiSeq (Illumina, USA). All clinically significant observations were confirmed by Sanger sequencing. ResultsWe identified the pathogenic variant in all pediatric patients with factor VII deficiency in F7 gene. Four unique variants were identified: two missense mutation (c.1061C>T, p.Ala354Val; c.283G>A, p.Glu95Lys), one frameshift variant (c.1391delC, p.Pro464His fsTer32), one point mutation of proximal promoter region (c.1–32A>C). Genetic analysis indicated that patient 1 had heterozygous compound of maternal missense mutation c.1061 C > T and frameshift variant c.1391delC and paternal point mutation of proximal promoter region c.1–32A>C. Patient 2 was identified homozygous of two mutation c.1061C > T and c.1391delC, while her both parents were heterozygous of this mutations. In patient 3 was detected heterozygous compound of missense mutation c.1061C>Tand missense mutation c.283G > A. DNA samples of parents of patient 3 was unavailable for genetic analysis. All these variants have been previously reported in the EAHAD F7 databases, except for the missense variant c.283G > A, p. Glu95Lys, which is classified as variant of uncertain significance. ConclusionWe have performed genetic analysis for the identification of pathogenic variants in coagulation factor VII deficiency patients for the first time in Belarus. Genetic analysis of coagulation factor VII deficiency patients is useful to confirm diagnosis, to determine the carrier status and genetic counseling.

Factor VII deficiency: A cause of (or risk factor for) bleeding?

Among the rare bleeding disorders factor VII deficiency is the most common, but correlating deficiency with bleeding phenotype is challenging. In their study Lou and colleagues investigate a large cohort of unrelated factor VII deficient patients providing a further perspective on the link between genotype and phenotype in this disorder. Commentary on: Lou et al. Structural and functional characterization of novel F7 mutations identified in Chinese factor VII deficient patients. Br J Haematol. 2023;202:623-635.

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.

Phenotypic and genotypic characterization of two factor VII deficiency patients from southeastern China.

The congenital factor VII deficiency (FVIID) is a rare autosomal recessive haemorrhagic disease caused by mutations in the F7 gene. The aim of this study was to identify the mutations causing FVII deficiency and explain the genotype-phenotype association in two unrelated Chinese patients. Mutation detection was conducted by sequencing the whole F7 gene coding exons, exon-intron boundaries and the untranslated regions of 3' and 5'. Then, the genetic information was analyzed to predict the structures of the mutated proteins. A total of four different mutations were detected, including three missense mutations (c.64G>A, c.286A>G, and c.722C>A, predicting p.Gly22Ser, p.Arg96Gly, p.Thr241Asn, respectively) and one insertion mutation (c.204_205insCGGC, predicting p. Leu68Argfs ∗ 37), among which two were reported for the first time (p.Arg96Gly, p.Leu68Argfs ∗ 37). Multiple sequence alignments of FVII protein revealed that the residues p.Arg96 and p.Thr241 were highly conserved. The novel missense mutation p.Arg96Gly was determined as damaging with online software Polyphen-2 and SIFT. We investigated two asymptomatic patients diagnosed with severe FVII deficiency and identified two novel mutations (the mutation p.Arg96Gly and p.Leu68Argfs ∗ 37). Identification of the F7 mutations was important for genetic counseling and accurate prediction of the inheritance pattern.

AryoSeven RT (Coagulation factor VIIa, recombinant) safety and efficacy study among congenial factor VII deficient patients in Iraq

BACKGROUND: Recombinant activated factor VII (FVII) is a product onetime evolved to stop bleeding occurring in hemophilia A and B patients with inhibitor, congenital FVII deficiency, Glanzmann disease, and in life-threatening bleeding. AIM: The aim was to evaluate the safety and efficacy of the coagulation factor VIIa, recombinant (AryoSeven RT) among congenital FVII deficiency patients at different centers in Iraq. METHODOLOGY: This is a prospective, observational, noninterventional study done at 5 medical centers in Iraq and it included 22 patients with FVII deficiency (congenital form) older than 14 years of age. Patients are recorded and followed for 6 months and they are subjected to AryoSeven RT depending on each patient individually. There were 3 main visits and 3 unscheduled visits for each patient during the study. Effectiveness evaluation was performed 6 h after each intervention. Adverse drug reactions related to the administration of AryoSeven RT were reported for each patient during each visit. RESULTS: A total of 22 participants were enrolled, classified into 18 (82%) were female and 4 (18%) were male. The mean age was 27.5 ± 14.0 years. Among 91 bleeding events, AryoSeven RT efficacy was effective in 89 events, excellent in 1 event, and partially effective in also 1 event. There was a reduction of PT from baseline (57.3 ± 15.2 s) to (13.9 ± 6.2 s) after 1st dose of AryoSeven RT and more reduction after 2nd dose of therapy (13.4 ± 4.4 s) and these were statistically significant (P = 0.001). Regarding FVII activity, there was a significant increase from baseline (8.4% ± 8.0%) to (95.8% ± 46.6%) after 1st dose and (131.8% ± 40.1%) after 2nd dose of AryoSeven RT with P = 0.001 for both. No major adverse events were reported except for headache in one participant (4.5%), and injection site reactions in three participants (13.6%).) CONCLUSION: AryoSeven RT is safe and effective clinically and by laboratory data in stopping bleeding in patients older than 14 years with inherited FVII deficiency.

Factor VII deficiency: a novel missense variant and genotype\u2013phenotype correlation in patients from Southern Italy

This study aimed at attempting to correlate genotype and phenotype in factor VII deficiency. Here, we present molecular and clinical findings of 10 patients with factor VII deficiency. From 2013 to 2016, 10 subjects were referred to our center because of a prolonged prothrombin time identified during routine or presurgery examinations or after a laboratory assessment of a bleeding episode. Mutation characterization was performed using the bioinformatics applications PROMO, SIFT, and Polyphen-2. Structural changes in the factor VII protein were analyzed using the SPDB viewer tool. Of the 10 variants we identified, 1 was responsible for a novel missense change (c.1199G>C, p.Cys400Ser); in 2 cases we identified the c.-54G>A and c.509G>A (p.Arg170His) polymorphic variants in the 5′-upstream region of the factor VII gene and exon 6, respectively. To our knowledge, neither of these polymorphic variants has been described previously in factor VII-deficient patients. In silico predictions showed differences in binding sites for transcription factors caused by the c.-54G>A variant and a probable damaging effect of the p.Cys400Ser missense change on factor VII active conformation, leading to breaking of the Cys400-Cys428 disulfide bridge. Our findings further suggest that, independently of factor VII levels and of variants potentially affecting factor VII levels, environmental factors, e.g., trauma, could heavily influence the clinical phenotype of factor VII-deficient patients.

Management of Arthropathy in Moderately Deficient Factor VII Patients: Results From Hospital Developed Treatment Protocol

Background: Factor VII deficiency (FVIId) is a rare inherited bleeding disorder whose prevalence is estimated to be 1 in 300,000 - 500,000 in general population. In India, the epidemiological data on factor VII (FVII) disorder are scarce. Serious arthropathy is observed in cases which are severely affected with spontaneous bleeding and hemarthrosis. In such cases, orthopedic surgery is required. Fresh frozen plasma, prothrombin complex concentrates, factor VII concentrates - plasma derived and recombinant factor VII (rFVII) are different types of preparations which are available as therapeutic options in treatment for bleeding occurring during or after surgery in FVIId patients. The main objective of our study was to give a result of the treatment protocol for FVIId patients undergoing orthopedic surgery in our hospital and compare its results with other studies conducted around the world. Methods: A retrospective study on patients admitted during 2008 - 2014 was carried out with 10 patients diagnosed with FVIID, of whom six undergone surgery at Kasturba Hospital, Manipal, west coastal region of southern India. Results: FVII baseline plasma levels were less than 10 IU/dL in our patients. Three patients underwent complete hip replacement, while rest of the three patients underwent various other arthroscopic procedures. rFVII was administered every 8 hours on the surgery day, followed by ever 12 - 24 hours for subsequent days in hospital depending on the type of surgery that the patient underwent. FVII levels in plasma were determined once before and once after the surgery, but the dosing of rFVII was not dependent on it. Dosing of rFVII on the day of surgery was 10 - 25 μg/kg and on following days, it was 15 - 30 μg/kg. The number of dosing on patients ranged from 16 to 31. None of our patients developed serious bleeding episode, thus no blood transfusion was required. Conclusion: Our study results show that when rFVII is administered according to our treatment regimen, it is effective for patients with arthropathy. It also proves that rFVII is the best hemostatic agent for FVII patients. J Hematol. 2016;5(3):94-98 doi: http://dx.doi.org/10.14740/jh296e

Phenotypic and genotypic characterization of four factor VII deficiency patients from central China.

Hereditary coagulation factor VII deficiency (FVIID) is a rare autosomal, recessive inherited hemorrhagic disorder related to a variety of mutations or polymorphisms throughout the factor VII (FVII) gene (F7). The aims of this study were to characterize the molecular defect of the F7 gene in four unrelated patients with FVIID and to find the genotype-phenotype correlation. All nine exons, exon-intron boundaries, and 5' and 3'-untranslated regions of the F7 gene were amplified by PCR and the purified PCR products were sequenced directly. Suspected mutations were confirmed by another PCR and sequencing of the opposite strand. Family studies were also performed. A total of five unique lesions were identified, including three missense mutations (c.384A>G, c.839A>C, c.1163T>G, predicting p.Tyr128Cys, p.Glu280Ala and p.Phe388Cys substitution, respectively) and two splice junction mutations (c.572-1G>A, c.681+1G>T), among which two (p.Glu280Ala, p.Phe388Cys) were novel. A previously reported mutation p.Tyr128Cys was seen in the homozygous state in two unrelated patients. The other two cases were both compound heterozygotes of a missense mutation and a splicing site mutation. Multiple sequence alignment using DNAMAN analysis showed that all the missense mutations were found in residues that highly conserved across species and vitamin K-dependent serine proteases. Online software Polyphen and SIFT were used to confirm the pathogenic of the missense mutation. p.Tyr128Cys seems to be a hotspot of the F7 gene in ethnic Han Chinese population.

Increased volume of distribution for recombinant activated factor VII and longer plasma-derived factor VII half-life may explain their long lasting prophylactic effect

Prophylaxis with plasma-derived or recombinant activated factor VII is beneficial in severe factor VII deficiency. To understand why prophylactic treatment with both products is efficacious, we conducted a pharmacokinetic study. Ten factor VII deficient patients were treated with either recombinant activated (20 μg/kg) or plasma-derived (25 IU/kg) factor VII in a cross-over design. Pharmacokinetic parameters were analyzed through activated factor VII activity, factor VII clotting activity, and factor VII antigen levels on depicted time points. Factor VII activity half-lifes, determined by non-compartmental and one-compartmental analysis (results in brackets), were shorter for recombinant activated (1.4h; 0.7h) than for plasma-derived factor VII (6.8h; 3.2h); both recombinant activated (5.1h; 2.1h and plasma-derived factor VII (5.8h; 3.2h) resulted in longer half-lives of factor VII antigen. Activated factor VII half-lives (based on activated factor VII activity levels) were significantly higher compared to factor VII clotting activity (1.6h; 0.9h). Volumes of distribution were significantly higher for activated factor VII (236 ml/kg; 175 ml/kg, measured by activated factor VII) as compared to plasma-derived factor VII (206 ml/kg; 64 ml/kg, measured by factor FVII activity), suggesting a plasma- and extracellular fluid distribution for recombinant activated factor VII. Recombinant activated factor VII showed significantly shorter half-lifes than plasma-derived factor VII. Volumes of distribution were significantly higher for treatment with recombinant activated factor VII. The longer half-life for plasma-derived factor VII, compared to recombinant activated factor VII, and the increased volume of distribution for recombinant activated factor VII, compared to plasma-derived factor VII may further elucidate the beneficial effect of prophylactic treatment of both products.

Genotype and phenotype relationships in 10 Pakistani unrelated patients with inherited factor VII deficiency

Inherited factor VII (FVII) deficiency is one of the commonest rare bleeding disorders. It is characterized by a wide molecular and clinical heterogeneity and an autosomal recessive pattern of inheritance. Factor VII-deficient patients are still scarcely explored in Pakistan although rare bleeding disorders became quite common as a result of traditional consanguineous marriages. The aim of the study was to give a first insight of F7 gene mutations in Pakistani population. Ten unrelated FVII-deficient patients living in Pakistan were investigated (median FVII:C = 2%; range = 2-37%). A clinical questionnaire was filled out for each patient and direct sequencing was performed on the coding regions, intron/exon boundaries and 5' and 3' untranslated regions of the F7 gene. Nine different mutations (eight missense mutations and one located within the F7 promoter) were identified on the F7 gene. Five of them were novel (p.Cys82Tyr, p.Cys322Ser, p.Leu357Phe, p.Thr410Ala, c-57C>T, the last being predicted to alter the binding site of transcription factor HNF-4). Half of the patients had single mutations in Cys residues involved in disulfide bridges. The p.Cys82Arg mutation was the most frequent in our series. Six of seven patients with FVII:C levels below 10% were homozygous in connection with the high percentage of consanguinity in our series. In addition, we graded the 10 patients according to three previously published classifications for rare bleeding disorders. The use of the bleeding score proposed by Tosetto and co-workers in 2006 appears to well qualify the bleeding tendency in our series.

Prophylaxis in congenital factor VII deficiency: indications, efficacy and safety. Results from the Seven Treatment Evaluation Registry (STER)

Because of the very short half-life of factor VII, prophylaxis in factor VII deficiency is considered a difficult endeavor. The clinical efficacy and safety of prophylactic regimens, and indications for their use, were evaluated in factor VII-deficient patients in the Seven Treatment Evaluation Registry. Prophylaxis data (38 courses) were analyzed from 34 patients with severe factor VII deficiency (<1-45 years of age, 21 female). Severest phenotypes (central nervous system, gastrointestinal, joint bleeding episodes) were highly prevalent. Twenty-one patients received recombinant activated factor VII (24 courses), four received plasma-derived factor VII, and ten received fresh frozen plasma. Prophylactic schedules clustered into "frequent" courses (three times weekly, n=23) and "infrequent" courses (≤ 2 times weekly, n=15). Excluding courses for menorrhagia, "frequent" and "infrequent" courses produced 18/23 (78%) and 5/12 (41%) "excellent" outcomes, respectively; relative risk, 1.88; 95% confidence interval, 0.93-3.79; P=0.079. Long term prophylaxis lasted from 1 to >10 years. No thrombosis or new inhibitors occurred. In conclusion, a subset of patients with factor VII deficiency needed prophylaxis because of severe bleeding. Recombinant activated factor VII schedules based on "frequent" administrations (three times weekly) and a 90 μg/kg total weekly dose were effective. These data provide a rationale for long-term, safe prophylaxis in factor VII deficiency.

Management of factor VII‐deficient patients undergoing joint surgeries – preliminary results of locally developed treatment regimen

Inherited factor VII (FVII) deficiency is a rare coagulation disorder with variable haemorrhagic manifestations. In severely affected cases spontaneous haemarthroses leading to advanced arthropathy have been observed. Such cases may require surgery. Therapeutic options for bleeding prevention in FVII deficient patients undergoing surgery comprise various FVII preparations but the use of recombinant activated factor VII (rFVIIa) seems to be the treatment of choice. To present the outcome of orthopaedic surgery under haemostatic coverage of rFVIIa administered according to the locally established treatment regimen in five adult patients with FVII baseline plasma levels below 10 IU dL(-1). Two patients required total hip replacement (THR); three had various arthroscopic procedures. Recombinant activated factor VII was administered every 8 h on day of surgery (D0) followed by every 12-24 h for the subsequent 9-14 days, depending on the type of surgery. Factor VII plasma coagulation activity (FVII:C) was determined daily with no predefined therapeutic target levels. Doses of rFVIIa on D0 ranged from 18 to 37 μg kg(-1) b.w. and on the subsequent days--from 13 to 30 μg kg(-1) b.w. Total rFVIIa dose per procedure ranged from 16 to 37.5 mg, and the total number of doses per procedure was 16-31. None of our patients developed excessive bleeding including those in whom FVII:C trough levels returned nearly to the baseline level on the first post-op day. Preliminary results demonstrate that rFVIIa administered according to our treatment regimen is an effective and safe haemostatic agent for hypoproconvertinaemia patients undergoing orthopaedic surgery.

Recombinant factor VIIa treatment for asymptomatic factor VII deficient patients going through major surgery

Factor VII deficiency is the most common among the rare autosomal recessive coagulation disorders worldwide. In factor VII deficient patients, the severity and clinical manifestations cannot be reliably determined by factor VII levels. Severe bleeding tends to occur in individuals with factor VII activity levels of 2% or less of normal. Patients with 2-10% factor VII vary between asymptomatic to severe life threatening haemorrhages behaviour. Recombinant factor VIIa (rFVIIa) is the most common replacement therapy for congenital factor VII deficiency. However, unlike haemophilia patients for whom treatment protocols are straight forward, in asymptomatic factor VII deficiency patients it is still debatable. In this study, we demonstrate that a single and very low dose of recombinant factor VIIa enabled asymptomatic patients with factor VII deficiency to go through major surgery safely. This suggestion was also supported by thrombin generation, as well as by thromboelastometry.

Pharmacokinetics of Factor VII

Abstract 2259 Introduction:In Congenital Bleeding Disorders (CBD), efficacy of Replacement Therapy (RT) can be indirectly measured on the basis of pharmacokinetic (PK) methods. Therapeutic concentrations of clotting factors in the blood-stream at a given time depend on the dose and frequency of RT and the fall off patterns specific for each clotting factor (i.e. PK properties). The issue of the frequency of RT administration is particularly relevant in Factor VII (FVII) deficiency, a CBD characterized by the lack of a rare protein with a very short half-life. Recombinant FVIIa (rFVIIa), plasma-derived FVII (pdFVII) concentrates and Fresh Frozen Plasma (FFP) are used for on-demand or prophylaxis replacement despite reported half-lives in the range of 2–5 hours. Very limited information is available with reference to the pharmacokinetic parameters of infused FVII in FVII deficiency. The same holds for the In Vivo Recovery (IVR). In this study, we evaluated the PK of rFVIIa in 11 severe (FVIIc <2%) FVII deficient patients. Further, evaluation of “incremental” IVR was performed in 116 patients with a FVII deficiency (90 for rFVIIa, 19 for pdFVII concentrates and 7 for FFP). Methods & Results:Eleven severe FVII-deficient individuals in the non-bleeding state were given rFVIIa doses ranging from 16 to 24 μg/Kg/bw (mean 19.7, median 20). Pharmacokinetic parameters of rFVIIa were analyzed with reference to FVIIc post-infusion levels. Analyses of the PK parameters are detailed in Tab. 1. In Tab. 2 results regarding the IVR analyses of rFVIIa, pdFVII and FFP are reported, on the basis of FVIIc 15' after replacement. IVR data were also evaluated with reference to the baseline FVIIc, age and FVII mutation zygosity.Tab. 1Pharmacokinetic parameters of rFVIIa in 11 patients with severe FVII deficiencyCorr_XYTerminal HL (h)AUC (U*h/ml)Vz (ml/Kg)CL (ml/h/Kg)MRT (h)T1/2 (h)Vss (ml/Kg)Mean0.994.5190378.8215.623.282.7351.77Median0.993.581,9882.670.512.862.081.56SD0.0262.472,055124.6626.362.041.4283.59Min. value−12.0813.90.410.132.782.010.66Max value0.9011.157,197331679.886.86225Tab. 2In Vivo Recovery of FFP, pdFVII concentrates and rFVIa.ProductIncremental IVR (U/dl/U/Kg)Cases(n)Mean (SD)Median (range)Kruskal-wallis test (ordinal Anova)1. FFP70,62 (0,28)0,58 (0,33–1,13)P<0.0001 POST hoc analysis: (1) FFP differs from pdFVII (2) rFVIIa differs from pdFVII (3) pdFVII differs from FFP and pdFVII2. pdFVII192,5 (1,28)2,27 (0,56–6)3. rFVIIa900,59 (0,54)0,46 (0,02–3,03)All1160,91 (0,99)0,57 (0,02–6) Conclusions:PK data are characterized by an optimal correspondence between FVIIc levels and time; data variability is ample considering that all individuals were adults or teen-agers. Terminal half-life appeared longer than the Mean Residence Time (MRT) or T1/2, a data that can be interpreted as a reduction of the factor flow from the plasma pool to the extravascular space at the end of the fall off curve; this is confirmed by the Apparent volume of distribution based on the terminal phase (Vz) that is higher than the Apparent Volume of distribution at equilibrium (Vss). MRT and T1/2 are in keeping with previous studies and appear lower than those already reported for the pdFVII concentrates. Quite variable is also the Clearance (CL) showing that metabolic degradation and/or FVIIa vascular uptake greatly differ among patients. The latter aspect points towards the need for a CL individualized evaluation for patients who are eligible for continuous infusion protocols. Incremental IVRs of rFVIIa and FFP were lower (p< 0.001) than those calculated for the pdFVII concentrates. The difference between the recoveries of rFVIIa and pdFVII can either be ascribed to the FVIIc assay (only FVIIa assayed in the case of rFVIIa administration, FVII zymogen and FVIIa assayed in the case of pdFVII concentrates), to a more rapid disappearance rate of FVIIa from the vascular compartment or, finally, to a more rapid uptake by the FVIIa receptors (TF on the pericytes and the PC receptor on the endothelial cells). No difference was found between IVRs in children and adults nor between individuals with baseline FVIIc <2% or ≥ 2%. Also, no differences were found between patients homozygous or compound heterozygous for FVII gene lesions. Disclosures:No relevant conflicts of interest to declare.

Variability of clinical manifestation of factor VII-deficiency in homozygous and heterozygous subjects of the European F7 gene mutation A294V

Inherited factor VII deficiency (FVIID) is a rare autosomal bleeding disorder. Subjects with reduced FVII activity and identified F7 gene mutation are registered in the International Greifswald registry of FVIID.[1][1] The mutation A294V is the most frequent among 717 FVIID patients in Central and

Factor VII Deficiency - A Restrospective Case Review.

Factor VII deficiency is a rare autosomal recessive disorder. Its incidence is thought to be 1 in 500,000. Symptoms vary from mild to severe. Factor VII deficient patients usually do not experience bleeding if their level of factor VII is less than 10%. Manifestations are seen with levels less than 5%, and severe bleeding can occur with levels less than 1%. Surgical hemostasis is obtained with levels greater than 25%. Factor VII deficiency is notable for causing a prolonged PT with a normal aPTT, making the diagnosis easy to determine.This is a descriptive study based on a population of patients from our community based teaching hospital with severe Factor VII deficiency. We reviewed lab data and found any patients with less than a 5% factor deficiency from March 2004- June 2006. In our experience we have noted varying manifestations in moderate factor deficiency patients. We describe four patients with varying symptoms, all with factor levels less than 3%. Their charts were reviewed, and three of the patients were available for a telephone interview.Patient A is a 75 yo African American female found to have factor deficiency after an increased Prothrombin time (PT) of 31.2 seconds, INR 5.9, and Partial thromboplastin time (PTT) of 34.9 seconds on routine blood work. This patieny's factor level was found to be 1.86%. Patient A denied any history of bleeding complications, including an uncomplicated tooth extraction. Patient B is a 46 yo African American female with a long history of bleeding complications. Laboratory data revealed a PT of 26 seconds, INR 4.2, PTT 22 seconds and a Factor level of 1%. She experienced years of heavy menstrual periods and nose bleeds. A hysterectomy was performed secondary to bleeding fibroids. She required multiple doses of novoseven as well as FFP. Patient C was diagnosed at the age of 11. Laboratory results revealed a factor level of 1.87 %, and a PT of 25.1 seconds and an INR of 4.1. She has had minor bleeding events, such as gum bleeding. She did receive FFP prior to a foot surgery, and tooth extraction. Patient D is a 46 year old Hispanic man found to have and INR of 4.3 and, factor VII 1.45. Pt had an uncomplicated cholocystectomy.This is a descriptive study of four different patients with factor VII levels of less than 2%. These four cases demonstrate the wide range of clinical manifestations that factor VII patients may experience. One patient did require novoseven prior to a hysterectomy. Though, as our cases illustrate, some patients do not experience any bleeding manifestations, and therefore, prophylactic plasma may not be required. Furthermore, treatment of factor VII deficient patients needs to be individualized, and guided by personal history.Coagulation Studies of our PatientsPatientProthrombin TimeINRFactor VIIA31.25.91.86%B264.21%C25.14.11.87%D464.31.45%

Anti- and Procoagulant Activities in Factor VII-Deficient Subjects

The clinical feature in patients with congenital factor VII deficiency is in part dependent on the underlying genetic defect, but the mechanisms influencing the genotype–phenotype correlation remain to be fully elucidated. In addition, thromboembolic events have been reported. Compensatory mechanisms involving vitamin K-dependent factors have been suggested. We have measured anticoagulant activities in 25 factor VII-deficient subjects (factor VII activity ≤36%) and 23 age-matched controls and correlated these to the vitamin K-dependent procoagulant activities. Two of the patients had a history of thromboembolism. The factor VII-deficient patients were found to have a significantly lower protein C activity than the controls [0.84 U/ml (95% CI 0.78; 0.89) vs. 0.98 U/ml (95% CI 0.91; 1.05), P=.004]. In addition, the protein C activity was correlated to that of factor VII ( r=.36; P=.014), factor IX ( r=.45; P=.002) and factor X ( r=.50; P=.0006), respectively. The level of prothrombin fragment 1+2 was correlated to the protein C ( r=.40; P=.012) and to the factor VII activity ( r=.42; P=.011). No differences between patients and controls were seen regarding total and free protein S, antithrombin, plasminogen activator inhibitor-1 (PAI-1) and tissue factor pathway inhibitor (TFPI). Seven of the patients were found to have the Factor V Leiden mutation, but none of them had experienced any thromboembolic event. The present data support the notion that compensatory hemostatic mechanisms might exist in that the protein C activity was found to be decreased in the factor VII-deficient subjects. Whether this could influence the clinical feature, including the risk of thromboembolic events in association with replacement therapy, remains to be evaluated.

Current therapy for rare factor deficiencies.

Haemophilia A and B and von Willebrand disease account for 80-85% of all inherited bleeding disorders. The other 15% are represented by deficiencies of fibrinogen, prothrombin, or factors V, VII, X, XI, or XIII. In addition, acquired factor deficiencies are seen in a variety of conditions ranging from malignancies to autoimmune disorders. The spectrum of symptoms in these conditions varies from severe and life-threatening haemorrhage to a mild bleeding diathesis. The diagnosis depends on demonstration of decreased activity of one of the clotting factors. Due to the rarity of each of the individual factor deficiencies, purified factor concentrates are not as readily available as they are for haemophilia A and B. Treatment of rare clotting factor deficiencies consists of the most purified blood product available that contains the missing factor. Depending on which factor is deficient, either purified concentrates, prothrombin complex concentrates, cryoprecipitate, or fresh frozen plasma can be used. In addition, recombinant factor VIIa is available for treating factor VII deficient patients.

Current status of hemophilia patients and recombinant coagulation factor concentrates in Japan.

The first recombinant factor VIII concentrate was introduced in 1987 to treat hemophilia A patients, and the product was licensed in the United States in 1992. More than 10 years have passed since the recombinant products have been used for treatment of hemophilia A. The new therapeutic options seem to be safe and effective through the gathered experiences. Recently, recombinant factor VIIa concentrate has become available to treat hemophilia patients with inhibitor and factor VII deficiency patients in Europe and also recombinant factor IX for the treatment of hemophilia B has been licensed in the United States and Europe. The usage of recombinant coagulation factors has expanded the routine therapy for hemophilia in many countries. In Japan, the consumption of recombinant factor VIII is increasing year by year, because many patients have started to think that the recombinant technology seems to be safe. Unfortunately, though, the factor VIIa and factor IX products have not been licensed yet in Japan. This article discusses the current status of patients with hemophilia and recombinant coagulation factor products in Japan.

Use of Recombinant, Activated Factor VII in the Treatment of Congenital Factor VII Deficiencies

Background and Objectives: Factor VII (FVII) deficiency is a rare coagulation disorder, historically treated with prothrombin complex concentrates or plasma–derived FVII concentrates. We treated such patients (n = 17) with a recombinant, activated FVII preparation. Materials and Methods: Twenty–seven spontaneous bleeding episodes were treated and 7 major and 13 minor surgical interventions were carried out. The dosages employed ranged from 8.08 to 70.5 Ìg/kg body weight. Results: A mean dose between 22 and 26 Ìg/kg was sufficient to normalise the prothrombin time. Fifteen haemarthroses were treated with single doses and results were excellent in 13 cases. In 5/6 bleeding episodes of other types, the treatment gave either excellent or at least effective results. Haemostasis was secured in the 7 major and 13 minor surgical interventions. One patient developed antibodies 4–5 weeks after an extremely high dose. Otherwise, there were no side effects and no evidence of a thrombotic tendency. Conclusion: This recombinant concentrate is efficacious in FVII–deficient patients. It is safe since any risk of transmission of blood–borne viruses is eliminated.