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Introduction: Inherited factor VII deficiency is the most common autosomal recessive inherited bleeding disorder, with an estimated incidence of one per 500 000 cases in the general population. Bleeding manifestations correlate poorly with circulating FVII levels. During pregnancy, increases in FVII levels can occur in women with mild-moderate FVII deficiencies but not in those with severe deficiency., Aim: We present five pregnant patients with FVII deficiency and describe the management during their pregnancies and peripartum periods., Methods: Retrospective analysis of six pregnancies in five women with FVII deficiency followed during pregnancy and delivery at an academic medical centre between January 2013 and December 2019., Results: Of the five patients, two had severe, one with moderate and two with mild FVII deficiency. Early postpartum haemorrhage (PPH) occurred in two patients. One of the two severe FVII-deficient patients had PPH with a laceration at delivery despite replacement therapy with recombinant factor VII. The other PPH occurred in a patient with mild FVII deficiency who delivered twins by caesarean section under general anaesthesia. Neuraxial anaesthesia was utilized in only one woman with mild deficiency whose FVII level normalized at the end of the pregnancy., Conclusions: Management of delivery for women with FVII deficiency should be addressed on a case-by-case basis at centres with expertise in rare bleeding disorders, maternal foetal medicine and obstetric anaesthesiology. These management discussions should factor the patient's bleeding history, third trimester PT, FVII level, multiple gestation and mode of delivery., (© 2020 John Wiley & Sons Ltd.)

Introduction: A paucity of data exists on the incidence, diagnosis and treatment of bleeding in women with inherited factor VII (FVII) deficiency., Aim: Here we report results of a comprehensive analysis from two international registries of patients with inherited FVII deficiency, depicting the clinical picture of this disorder in women and describing any gender-related differences., Methods: A comprehensive analysis of two fully compatible, international registries of patients with inherited FVII deficiency (International Registry of Factor VII deficiency, IRF7; Seven Treatment Evaluation Registry, STER) was performed., Results: In our cohort (N = 449; 215 male, 234 female), the higher prevalence of mucocutaneous bleeds in females strongly predicted ensuing gynaecological bleeding (hazard ratio = 12.8, 95% CI 1.68-97.6, P = 0.014). Menorrhagia was the most prevalent type of bleeding (46.4% of patients), and was the presentation symptom in 12% of cases. Replacement therapies administered were also analysed. For surgical procedures (n = 50), a receiver operator characteristic analysis showed that the minimal first dose of rFVIIa to avoid postsurgical bleeding during the first 24 hours was 22 μg kg(-1) , and no less than two administrations. Prophylaxis was reported in 25 women with excellent or effective outcomes when performed with a total weekly rFVIIa dose of 90 μg kg(-1) (divided as three doses)., Conclusion: Women with FVII deficiency have a bleeding disorder mainly characterized by mucocutaneous bleeds, which predicts an increased risk of ensuing gynaecological bleeding. Systematic replacement therapy or long-term prophylaxis with rFVIIa may reduce the impact of menorrhagia on the reproductive system, iron loss and may avoid unnecessary hysterectomies., (© 2016 John Wiley & Sons Ltd.)

Rare coagulation disorders (RCDs) include the inherited deficiencies of fibrinogen, factor (F) II, FV, combined FV and VIII, FVII, FX, combined FVII and X, FXI, FXIII and combined congenital deficiency of vitamin K-dependent factors (VKCFDs). Despite their rarity, a deep comprehension of all these disorders is essential to really understand haemostasis. Indeed, even if they share some common features each RCD has some particularity which makes it unique. In this review, we focus on three disorders: fibrinogen, FVII and FXIII., (© 2016 John Wiley & Sons Ltd.)

Factor VII (fVII) deficiency is a rare congenital bleeding disorder in which fVII activity level and bleeding tendency do not completely correlate. Pregnancy and delivery present a significant haemostatic challenge to women with fVII deficiency. Treatment with recombinant factor VIIa (rfVIIa) carries a thrombotic risk and the literature is not clear whether prophylaxis is necessary prior to delivery. The aim of this study was to define management, haemorrhagic and thrombotic complications of pregnant women with fVII deficiency through a systematic review. Medical databases (PubMed, MEDLINE, CINAHL, Academic Search Premier, Cochrane Library, Web of Science and Scopus) were searched using "factor VII deficiency" and "pregnancy" or "surgery." Overall 34 articles, four abstracts, and three institutional cases were reviewed. Literature from 1953 to 2011 reported 94 live births from 62 women with fVII deficiency. The median fVII activity was 5.5%. Haemostatic prophylaxis was used in 32% of deliveries. Without prophylaxis, 40 vaginal deliveries and 16 caesarean sections were completed. The odds of receiving prophylaxis were 2.9 times higher in women undergoing caesarean section compared to vaginal delivery. Post-partum haemorrhage occurred in 10% of deliveries with prophylaxis and 13% of deliveries without prophylaxis. The fVII level did not significantly differ between women who did and did not receive prophylaxis. We present the only systematic review of the management of pregnancy in fVII deficient women. No difference in post-partum haemorrhage was seen in deliveries with and without prophylaxis. Therefore, we recommend that rfVIIa be available in the case of haemorrhage or surgical intervention, but not as mandatory prophylaxis., (© 2013 John Wiley & Sons Ltd.)

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., (© 2012 Blackwell Publishing Ltd.)

Rare bleeding disorders (RBDs) include the inherited deficiencies of fibrinogen, factor (F)II, FV, FV+FVIII, FVII, FX, FXI and FXIII. There have been remarkable advances in understanding the molecular profiles that lead to each type of coagulation factor deficiency. However, as a consequence of their rarity, clinical data regarding the characteristics of bleeding symptoms and their management remain limited. The clinical manifestations in different RBDs are heterogeneous, and the residual plasma coagulant factor level does not always predict bleeding tendency. In this review, we describe the general features and recent advances in understanding three such deficiencies: FXI, FVII and fibrinogen deficiencies., (© 2012 Blackwell Publishing Ltd.)

The use of recombinant FVIIa (rFVIIa) to control bleed in individuals with FVII deficiency has been proven to be effective. The main problems associated with its use are that it requires frequent bolus injections to counteract its short half-life and high cost. Our study aimed to evaluate whether any advantage could be gained by providing rFVIIa by continuous infusion during surgery with regard to haemostatic efficacy, safety and cost. The prospective study included 10 patients with severe FVII deficiency, who underwent 25 surgical procedures (13 major and 12 minor procedures) and were treated with rFVIIa administered by continuous infusion. Tranexamic acid was given concomitantly every 8 h. Prothrombin time, FVII:C assay and thrombin generation assay were used to monitor the treatment. The mean total dose given was 10 mg during a major surgery and 4.4 mg during a minor surgery for a mean treatment duration of 7.5 and 4.0 days respectively. This corresponds to a reduction of 70-90% in drug usage and medication cost compared with bolus injections. Except for one major perioperative bleeding, excellent haemostasis was achieved in all procedures. One patient developed a transient inhibitory activity. None of these events affected the postoperative course or prolonged the hospital stay. Our study demonstrated that continuous infusion of rFVIIa during surgery is safe, effective and highly cost effective., (© 2011 Blackwell Publishing Ltd.)

Factor VII (FVII) deficiency is the most frequent among rare congenital bleeding disorders, accounting for one symptomatic individual per 500,000 population, apparently without any racial/ethnic predilection. FVII deficiency prevalence in the general population is probably higher because of the presence of asymptomatic and poorly symptomatic individuals. In accordance with the role of FVII as part of the initiating complex of the extrinsic coagulation pathway, laboratory diagnosis is easy, because FVII deficiency is the only congenital bleeding disorder characterized by isolated prolonged prothrombin time. Molecular diagnosis is available, and a broad spectrum of mutations has been characterized in the FVII gene, which is located in chromosome 13. Clinical manifestations are heterogeneous, ranging from severe life-threatening haemorrhages, such as cerebral, gastrointestinal, and joint haemorrhages, to miscellaneous minor bleeding. The main clinical features in our database (International Registry on Congenital FVII Deficiency database, n = 515) are as follows: (i) the absence of a clear-cut and consistent correlation between bleeding symptoms and FVII clotting levels; (ii) an excess of symptomatic women compared with men; (iii) frequent surgery-related bleeding, which is often a diagnostic tool in previously asymptomatic individuals. Several therapeutic options are possible, including plasma-derived and recombinant products, but therapeutic schedules, optimal dosages, and administration times still have to be precisely defined, and clinical studies, including online registries such as the Seven Treatment Evaluation Registry, are actually ongoing to achieve in a better manner a safe, rational and standardized substitution treatment for this congenital disorder.

Recombinant activated coagulation factor VII (rFVIIa) was developed initially for treatment of patients with hemophilia and neutralizing antibodies ("inhibitors") to coagulation factors VIII or IX. Owing to the unique and selective mechanism of action of rFVIIa and encouraged by clinical experience with other circumstances of inadequate hemostasis, a broad development program has been pursued to test potential efficacy and evaluate safety of this biologic for indications other than hemophilia. This review summarizes the current development of rFVIIa, focusing on results of prospective, randomized clinical trials.

Recombinant factor VIIa (rFVIIa) has been used in haemophilia bleeding since its introduction in 1996. It has been found to be safe and effective in the majority of patients with haemophilia who have developed inhibitors. There is increasing use of rFVIIa in many off-label bleeding conditions, but there is a paucity of randomized studies regarding the use of rFVIIa in children. This review will attempt to address and summarize the studies focusing on the role of rFVIIa in both haemophilia and non-haemophilia bleeding conditions in children. rFVIIa has been administered as both bolus and continuous infusions, and at varying doses. Furthermore, adverse events have not reportedly increased in children despite growing experience with its use in the paediatric population.

We report the case of an 8-year-old boy with no prior abnormal bleeding history who presented with severe central abdominal pain following a freak accident at a local ice rink. Clinical examination confirmed a tender periumbilical mass. An ultrasound scan confirmed a large haemorrhagic fluid collection adjacent to the second part of his duodenum that was causing a subacute small-bowel obstruction. He was found to have a persistently prolonged prothrombin time between 17.3 and 18.1 s but normal liver function tests. There was no suggestion of dietary vitamin K deficiency. Further investigations confirmed factor VII deficiency with levels between 30.4 and 33.6 IU dL-1. His prothrombin time did not normalize with intravenous vitamin K. He was subsequently treated with three 30 microg kg-1 body weight doses of novoseven at 4-h interval and made an excellent recovery. The haematoma virtually resolved completely confirmed by a follow-up ultrasound scan 3 months after the initial event.

The aim was to review the pregnancy and obstetric outcome in women with factor VII (FVII) deficiency. The study group contained women with FVII deficiency, registered with Haemophilia centre and Haemostasis Unit at the Royal Free Hospital, London. The women were interviewed and case notes were reviewed. The main outcome measures were changes in FVII levels in pregnancy, maternal and perinatal outcome. The FVII levels ranged from 7-36 IU dL(-1) in the 13 women included in the study. There were a total of 14 pregnancies in seven women. Ten pregnancies in four women were prior to the diagnosis of FVII deficiency. Following the diagnosis of FVII deficiency, there were four pregnancies in three women. There was an increase in the FVII level during pregnancy in these women from a mean baseline level of 33 IU dL(-1) to a mean of 73 IU dL(-1). These women received recombinant FVIIa replacement during labour and delivery. There were two early pregnancy losses, both associated with excessive haemorrhage. There was only one postpartum haemorrhage in the study. There is a significant increase in FVII levels in pregnancy in women with heterozygous FVII deficiency. The risk of bleeding in early pregnancy might be higher than that at term, due to inadequate rise in the FVII level in early pregnancy.

Recombinant activated factor VII (rFVIIa) can be used as an alternative therapy in patients with FVII deficiency. However, as the drug has a very short half-life, continuous infusion could be a meaningful administration modality. We report the case of a 30-year-old woman with moderate FVII deficiency and human immunodeficiency virus infection who underwent a caesarean section delivery. She was treated with a continuous infusion of rFVIIa and did not suffer any bleeding complication. The continuous infusion of rFVIIa was a safe and effective therapeutic approach for our patient, maintaining her levels of FVII:C and avoiding bleeding during caesarean section and afterwards.

The use of replacement FVII is critical to the successful treatment of life-threatening bleeds in newborns and infants with severe FVII deficiency (<1%). However, the clinical efficacy, optimum dosage and pharmacologic recovery of rFVIIa in such children has not been studied systematically. This report is a case of an infant with severe FVII deficiency (FVII:C at 0%) and massive intracranial haemorrhage in which successful use of rFVIIa (NovoSeven) was carefully monitored. The drug was administered by intravenous bolus through a central line every 4 h at each of three dose levels: 15 microg kg-1, 22 microg kg-1 and 30 microg kg-1. FVII:C was >100% between 30 and 180 min after each infusion with mean trough levels above 25% for all three dose levels. There was no evidence of hyper-coagulation as indicated by measurements of the platelet count, D-dimer, plasma protamine paracoagulant and fibrinogen levels in spite of high FVII:C concentration. In this infant, rFVIIa was well-tolerated, maintained effective haemostasis with good clinical outcome, and produced consistent therapeutic mean trough levels above 25% FVII:C even at 15 microg kg-1 every 4 h.

Inhibitors to factor VIII (FVIII) or IX (FIX) in patients with haemophilia A or B create a challenging problem for the treatment of these patients. Recombinant FVIIa (rFVIIa; NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark) is a realistic treatment option, owing to its specific mode of action and lack of immunogenicity. This was a multicentre, open-label, compassionate-use trial in patients with severe haemophilia A (FVIII:C < 1%) or B (FIX:C < 1%) with inhibitors, acquired antibodies to FVIII or FIX, or FVII deficiency (FVII:C < 5%), for whom alternative therapies had failed or were contraindicated. Patients received rFVIIa treatment for life- or limb-threatening bleeding episodes or for coverage during essential surgery. The mean rFVIIa dose was approximately 90 microg kg-1 for haemophilia A/B and acquired inhibitor patients, and 25 microg kg-1 for FVII-deficient patients. Efficacy data for 67 treatment episodes (45 bleeding episodes, 22 surgical procedures) are presented; seven patients were treated for a concurrent serious bleeding episode and surgical procedure. At the end of treatment, rFVIIa was effective or partially effective in 85% of serious bleeding episodes. During surgery, bleeding was assessed as none or less than or equivalent to normal in 91% of surgical procedures; postoperatively, 91% of procedures were associated with no or minimal oozing. During 60 separate treatment episodes, 26 adverse events (22 nonserious, four serious) were reported in 15 patients, during 17 bleeding episodes or surgical procedures. Only 10 were considered as having a possible, probable, or unknown relationship with rFVIIa; of these, fever (n=2) and thrombophlebitis (n=3) were the most common. There was no evidence of disseminated intravascular coagulation. In conclusion, rFVIIa is an effective, well-tolerated treatment for serious bleeding episodes and bleeding associated with surgical procedures in patients with severe haemophilia A/B with inhibitors, acquired inhibitors, or FVII deficiency.

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 Ig/kg body weight., Results: A mean dose between 22 and 26 Ig/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.

Congenital factor VII deficiency is a rare (1:500,000) autosomally recessive coagulopathy with variable expression and high penetration. In infants the most devastating presentation is that of intracranial haemorrhage. An infant is described with severe factor VII deficiency who developed postnatal intracranial haemorrhage. The baby was treated with factor VII concentrate (ImmunoA.G., Vienna, Austria). Three weeks after the haemorrhage he developed a dural venous sinus thrombosis. Although factor VII-deficient patients may need treatment with factor VII concentrate, this needs to be carefully monitored because of the thrombotic risk.