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Deficiencies in coagulation factors I (FI), FII, FV, combined FV and FVIII (CF5F8) and vitamin K-dependent coagulation factors FVII, FX, FXI, and FXIII have been referred to as rare bleeding disorders (RBDs), rare coagulation factor deficiencies (RCFDs), or recessively inherited coagulation disorders. Fibrinogen was most likely the first member of this group to be identified, with reports of its discovery spanning from 1859 to 1966. If not, then the first coagulation factor to be identified was prothrombin in 1894, and the last coagulation factor to be found was FX in 1956, about 60 years later. The first patient to be diagnosed with an RBD was a 9-year-old boy with afibrinogenemia in 1920 and the vitamin K-dependent coagulation factors deficiency was the most recent RBD in this group to be identified in a 3-month-old child in 1966. The initial therapeutic option for nearly all patients with RBDs was whole blood transfusion; this was replaced in 1941 by fresh frozen plasma (FFP), and then in later years by cryoprecipitate and coagulation factor concentrates. Fibrinogen concentrate was the first coagulation factor concentrate produced in 1956. Coagulation factor concentrate is now available for FI, FVII, FX, FXI, and FXIII; however, FFP and/or platelet transfusion are the only treatments available for FV deficiency. The only recombinant concentrates available for RBDs are for FVII and FXIII, which date from 1988 and the 2000s, respectively. Even though the clinical presentations, diagnosis, and management of lesser-known bleeding disorders have improved significantly in recent decades, more studies are needed to reveal the hidden aspects of these disorders in order to overcome diagnostic and therapeutic challenges and ultimately improve the quality of life for those who are affected. [ABSTRACT FROM AUTHOR]

Congenital factor VII (FVII) deficiency, the most frequent among the recessively inherited disorders of blood coagulation, is characterized by a wide range of symptoms, from mild mucosal bleeds to life-threatening intracranial hemorrhage. Complete FVII deficiency may cause perinatal lethality. Clinically relevant thresholds of plasma levels are still uncertain, and modest differences in low FVII levels are associated with large differences in clinical phenotypes. Activated FVII (FVIIa) expresses its physiological protease activity only in a complex with tissue factor (TF), which triggers clotting at a very low concentration. Knowledge of the FVIIa–TF complex helps to interpret the clinical findings associated with low FVII activity as compared with other rare bleeding disorders and permits effective management, including prophylaxis, with recombinant FVIIa, which, however, displays a short half-life. Newly devised substitutive and nonsubstitutive treatments, characterized by extended half-life properties, may further improve the quality of life of patients. Genetic diagnosis has been performed in thousands of patients with FVII deficiency, and among the heterogeneous F7 mutations, mostly missense changes, several recurrent variants show geographical distribution and identity by descent. In the general population, common F7 polymorphisms explain a large proportion of FVII level variance in plasma through FVII-lowering effects. Their combination with pathogenic variants may impact on the frequent detection of FVII coagulant levels lower than normal, as well as on mild bleeding conditions. In the twenties of this century, 70 years after the first report of FVII deficiency, more than 200 studies/reports about FVII/FVII deficiency have been published, with thousands of FVII-deficient patients characterized all over the world. [ABSTRACT FROM AUTHOR]

Factor VII (FVII) deficiency is a rare but significant inherited autosomal recessive coagulation disorder, occurring with a frequency of 1 in 300,000-500,000 people. The disorder is characterised by a wide range of bleeding symptoms that do not always correlate with plasma FVII levels, from asymptomatic conditions to severe haemorrhages. We present the case of a 2-year-old boy who was admitted to hospital for prolonged nosebleeds. Laboratory tests showed significant coagulation abnormalities: prolonged prothrombin time and international normalised ratio, directing suspicion to a rare coagulation disorder. Further diagnostics at a specialised centre confirmed congenital factor VII deficiency. The boy was observed to have repeated episodes of nosebleeds, and haematoma formation in the area of the knees, elbows, and fingers, even with minor trauma. Factor VII deficiency is a rare coagulation disorder, so each described case is important to better understand the clinical spectrum and therapeutic options.

The potential use of TEG/ROTEM® in evaluating the bleeding risk for rare coagulation disorders needs to be assessed, considering the common mismatch among laboratory tests and the clinical manifestations. As a result, there is currently no published data on the use of viscoelastic tests to assess coagulation in FVII deficient patients undergoing elective neurosurgery. We describe the case of a patient affected by severe FVII deficiency who underwent microvascular decompression (MVD) craniotomy for hemifacial spasm (HFS). The ROTEM® did not show a significant coagulopathy according to the normal ranges, before and after the preoperative administration of the recombinant activated FVII, but a substantial reduction in EXTEM and FIBTEM Clotting Times was noted. The values of coagulation in standard tests, on the contrary, were indicative of a coagulopathy, which was corrected by the administration of replacement therapy. Whether this difference between ROTEM® and standard tests is due to the inadequacy of thromboelastographic normal ranges in this setting, or to the absence of clinically significant coagulopathy, has yet to be clarified. Neurosurgery is a typical high bleeding risk surgery; additional data is required to clarify the potential role for thromboelastographic tests in the perioperative evaluation of the FVII deficient neurosurgical patients. [ABSTRACT FROM AUTHOR]

Performing cardiac surgery on patients with bleeding diatheses poses significant challenges since these patients are at an increased risk for complications secondary to excessive bleeding. Despite its rarity, patients with factor VII (FVII) deficiency may require invasive procedures such as cardiac surgery. However, we lack guidelines on their pre-, peri-, and post-operative management. As FVII deficiency is rare, it seems unlikely to design and learn from large clinical studies. Instead, we need to base our clinical decision-making on single reported cases and registry data. Herein, we present the rare case of a patient with FVII deficiency who underwent double valve surgery. Pre-operatively, activated recombinant FVII (rFVIIa) was administered to reduce the risk of bleeding. Nevertheless, the patient experienced major bleeding. This case highlights the significance of FVII deficiency in patients undergoing cardiac surgery and emphasizes the importance of adequate and appropriate transfusion of blood products for these patients. [ABSTRACT FROM AUTHOR]

rFVIIa, a human recombinant activated coagulation factor VII, has been used worldwide for more than two decades for the treatment of bleeding episodes and prevention of bleeding in patients undergoing surgery/invasive procedures with congenital haemophilia A or B with inhibitors (CHwI A or B), acquired haemophilia (AH), congenital factor VII deficiency and Glanzmann thrombasthenia (GT), refractory to platelet transfusion. The approved dosage, administration and indication of rFVIIa in the US, Europe and Japan differ, depending on the needs of the patient population and regulatory practices. This review presents an overview of the current status and future prospects, including that from a Japanese perspective, of using rFVIIa in the treatment of approved indications. The efficacy and safety of rFVIIa in the approved indications has been demonstrated in several randomised and observational studies and data from registries. The overall incidence of thrombosis across all approved indications in a retrospective safety assessment of clinical trials and registries, prelicensure studies and postmarketing surveillance studies of rFVIIa use was 0.17%. Specifically, the risk of thrombotic events was 0.11% for CHwI, 1.77% for AH, 0.82% for congenital factor VII deficiency and 0.19% for GT. Emerging non-factor therapies such as emicizumab have changed the treatment landscape of haemophilia A, including preventing bleeding in patients with CHwI. However, rFVIIa will continue to play a significant role in the treatment of such patients, particularly during breakthrough bleeding or surgical procedures. [ABSTRACT FROM AUTHOR]

Background: Synonymous variants are non‐pathogenic due to non‐substitution of amino acids. However, synonymous exonic terminal nucleotide substitutions may affect splicing. Splicing variants are easily analyzed at RNA level for genes expressed in blood cells. Minigene analysis provides another method for splicing variant analysis of genes that are poorly or not expressed in peripheral blood. Methods: Whole exome sequencing was performed to screen for potential pathogenic mutations in the proband, which were validated within the family by Sanger sequencing. The pathogenicity of the synonymous mutation was analyzed using the minigene technology. Results: The proband harbored the compound heterogeneous variants c. [291G >A; 572‐50C >T] and c.681 + 1G >T in F7, of which the synonymous variant c.291G >A was located at the terminal position of exon 3. Minigene analysis revealed exon3 skipping due to this mutation, which may have subsequently affected protein sequence, structure, and function. Conclusion: Our finding confirmed the pathogenicity of c.291G >A, thus extending the pathogenic mutation spectrum of F7, and providing insights for effective reproductive counseling. [ABSTRACT FROM AUTHOR]

Factor VII (FVII) deficiency is a rare bleeding disorder that can be classified as congenital or acquired, and the majority of acquired cases are due to vitamin K deficiency or liver disease. Isolated acquired FVII deficiency is a rare occurrence and has been associated with inhibitors or auto-antibodies. Here, we describe a patient with polycythemia vera who developed systemic mastocytosis and FVII deficiency simultaneously. FVII deficiency was not caused by inhibitors and improved with antineoplastic treatment. Acquired FVII deficiency has been reported in cases of sepsis, possibly due to proteolytic degradation induced by the activation of monocytes or endothelial cells. Malignancies have been shown to cause a depletion in circulating FVII through the direct binding of cancer cells. This case report suggests a potential association between SM associated with a hematological neoplasm (SM-AHN) and acquired FVII deficiency. Further evaluations are recommended in patients with systemic mastocytosis to gain a better understanding of the relationship between pathological mast cells and clotting factor concentrations.

Factor VII (FVII) deficiency is a rare bleeding disorder that can be classified as congenital or acquired, and the majority of acquired cases are due to vitamin K deficiency or liver disease. Isolated acquired FVII deficiency is a rare occurrence and has been associated with inhibitors or auto-antibodies. Here, we describe a patient with polycythemia vera who developed systemic mastocytosis and FVII deficiency simultaneously. FVII deficiency was not caused by inhibitors and improved with antineoplastic treatment. Acquired FVII deficiency has been reported in cases of sepsis, possibly due to proteolytic degradation induced by the activation of monocytes or endothelial cells. Malignancies have been shown to cause a depletion in circulating FVII through the direct binding of cancer cells. This case report suggests a potential association between SM associated with a hematological neoplasm (SM-AHN) and acquired FVII deficiency. Further evaluations are recommended in patients with systemic mastocytosis to gain a better understanding of the relationship between pathological mast cells and clotting factor concentrations. [ABSTRACT FROM AUTHOR]

Congenital factor VII (FVII) deficiency is a rare genetic bleeding disorder characterized by deficient or reduced activity of coagulation FVII. It is caused by genetic variants in the F7 gene. We aimed to evaluate the rate of detection of pathogenic variants in the F7 gene in a large group of patients with FVII deficiency and investigate the correlations between the F7 genotype and FVII activity (FVII:C). Moreover, the influence of the common genetic variant rs6046: c.1238G>A; p.(Arg413Gln), designated as the M2 allele, on FVII:C was investigated. Genetic analysis of the F7 gene was performed on 704 index patients (IPs) using either direct Sanger- or next-generation sequencing. Genetic variants were detected in 390 IPs, yielding a variant detection rate (VDR) of 55%. Notably, the VDR exhibited a linear decline with increasing FVII:C levels. We identified 124 genetic variants, of which 48 were not previously reported. Overall, the frequency of the M2 allele was considerably higher in patients with mild deficiency (FVII:C > 20 IU/dl). Furthermore, IPs lacking an identified pathogenic variant exhibited a significantly higher prevalence of the M2 allele (69%) compared to IPs with a disease-causing variant (47%). These results strongly support the association of the M2 allele with decreased FVII:C levels. This study shows the utility of FVII:C as a predictive marker for identifying pathogenic variants in patients with FVII deficiency. The M2 allele contributes to the reduction of FVII:C levels, particularly in cases of mild deficiency. [ABSTRACT FROM AUTHOR]

Growing evidence supports the importance of factor (F) XI activation for thrombosis and hemostasis as well as inflammation and complement systems. In this study, we evaluated the effect of activated FXI (FXIa) on the detection of factor deficiencies by global hemostasis assays of thrombin generation (TG), plasmin generation (PG), and clot formation and lysis (CFL). An absorbance and fluorescence microplate assay was used to simultaneously observe TG, PG, and CFL in FV-, FVII-, FVIII-, and FIX-deficient plasmas supplemented with purified factors. Coagulation was initiated with tissue factor with or without FXIa in the presence of tissue plasminogen activator. Thrombin and plasmin peak heights (TPH and PPH), maximal clot density (MCD), times to clotting (CT), thrombin and plasmin peaks (TPT and PPT) and clot lysis (LyT) and a new parameter, clot lifetime (LiT), were evaluated. TG/CFL were elevated by the FXIa at low FV (below 0.1 IU/mL), and at FVIII and FIX above 0.01 IU/mL. FXIa affected PG only at low FV and FVII. At high factor concentrations, FXIa reduced MCD. Thrombin and plasmin substrates had effect on CT, LyT, LiT and MCD parameters. FXIa reveals new relationships between TG, PG and CFL parameters in factor deficiencies suggesting potential benefits for discrimination of bleeding phenotypes. • Similar to Tissue factor (TF), factor XIa (FXIa) can mediate thrombosis and hemostasis • Thrombin and plasmin generation (TG and PG), Clot Formation and Lysis (CFL) were studied after activation with TF and FXIa • Addition of FXIa to TF reveals new relationships between TG/PG and CFL parameters in coagulation factors deficient plasmas • CFL parameters differ between TG and PG assays [ABSTRACT FROM AUTHOR]

Objective Development of alloantibodies against coagulation factor VII (FVII) is the main therapeutic challenge in severe congenital FVII deficiency. About 7% of patients with severe congenital FVII deficiency develop an inhibitor against FVII. In this research, the relationship between interleukin (IL)-10 and tumor necrosis factor-alpha (TNF)-α gene variants and inhibitor development was evaluated for a group of Iranian patients with severe congenital factor VII deficiency. Methods Patients with FVII deficiency were divided into 2 groups: 6 cases and 15 controls. Genotyping was performed using the amplification-refractory mutation system polymerase chain reaction. Results We found that IL-10 rs1800896 A>G gene variant is associated with the risk of FVII inhibitor development (OR = 0.077, 95% CI = 0.016–0.380, P =.001), whereas the TNFα-rs1800629G>A variant has no relation with inhibitor development in severe FVII deficiency. Conclusion The results show that the IL-10 rs1800896 A>G variant increases the risk of developing an inhibitor in patients with severe congenital FVII deficiency. [ABSTRACT FROM AUTHOR]

Background: Congenital factor VII (FVII) deficiency, a rare bleeding disorder resulting from mutations in the F7 gene with autosomal recessive inheritance, exhibits clinical heterogeneity that lacks a strong correlation with FVII:C levels. The objective of this study was to discern genetic defects and assess their associations with the clinical phenotype in a substantial cohort comprising 785 white women exhibiting FVII:C levels below the age-dependent cut-off percentage. Patients and Methods: Individuals with verified inherited factor VII deficiency underwent i) genotyping using the Sanger method and multiplex ligation-dependent probe amplification (MLPA) to identify F7 mutations, including common polymorphic variants. Additionally, they were ii) categorized based on clinical bleeding scores (BS). Thrombophilic variants and blood groups were also determined in the study participants. Results: The probands in this study encompassed both asymptomatic individuals (referred for a laboratory investigation due to recurrent prolonged prothrombin time; n = 221) and patients who manifested mild, moderate, or severe bleeding episodes (n = 564). The spectrum of bleeding symptoms included epistaxis, gum bleeding, gastrointestinal bleeding, hematuria, postoperative bleeding, and gynecologic hemorrhage. The median ISTH bleeding score (BS) recorded within a two-year period prior to the work-up was 2 (0–17). Notably, this score was significantly higher in symptomatic women compared to their asymptomatic counterparts (3 versus 0; p < 0.001). The corresponding PBAC score before hormonal treatment stood at 225 (5–1200), exhibiting a positive correlation with the ISTH BS (rho = 0.38; p = 0.001). Blood group O was more prevalent in symptomatic women compared to asymptomatic individuals (58 versus 42%; p = 0.01). Among the 329 women (42%), known and novel mutations in the F7 gene, encompassing coding regions, exon/intron boundaries, and the promoter region, were identified, while common polymorphisms were detected in 647 subjects (95%). Logistic regression analysis, adjusted for clinical and laboratory data (including blood group, FVII activity, the presence of F7 gene mutations and/or polymorphisms, thrombophilia status, and additional factor deficiencies) revealed that older age at referral (increase per year) (odds/95% CI: 1.02/1.007–1.03), the presence of blood group O (odds/95% CI: 1.9/1.2–3.3), and the coexistence of further bleeding defects (odds/95% CI: 1.8/1.03–3.1) partially account for the differences in the clinical bleeding phenotype associated with FVII deficiency. Conclusion: The clinical phenotype in individuals with FVII deficiency is impacted by factors such as age, blood group, and the concurrent presence of other bleeding defects. [ABSTRACT FROM AUTHOR]

Factor VII (FVII) is an important, vitamin K-dependent clotting factor. Acquired FVII deficiency is a rare entity that is associated with serious bleeding complications. We report a case of acquired FVII deficiency in a patient with recurrent chronic myeloid leukemia in blast crisis who developed bilateral retinal hemorrhages. The coagulopathy was corrected with the initiation of chemotherapy and subsequent reduction in peripheral blast count. [ABSTRACT FROM AUTHOR]

Abstract Background Factor VII deficiency is a rare bleeding disorder caused by a deficiency of clotting factor VII. However, there have been some case reports of venous thrombosis in patients with factor VII deficiency, especially underlying the prothrombotic risk factors exposure. Patients with factor VII deficiency require special considerations before undergoing surgery to minimize the risk of bleeding or thrombogenesis. Case presentation Here, we described a patient with early-stage thymoma and severe factor VII deficiency who experienced an unprovoked thrombotic episode before thymectomy and a fatal thrombotic event after surgery. By adopting gene screening, a reported homozygous F7 mutation (p.His408Gln) and a novel heterozygous PROS1 mutation (p.Pro147Ala) were identified. The former resulted in severe factor VII deficiency but did not protect against thrombosis, and the latter was correlated with normal expression and cofactor activities of protein S through the thrombin generation test. The perioperative infusion of recombinant factor VII concentrate and the absence of antithrombotic prophylaxis may collectively contribute to her fatal thrombotic event after surgery. Conclusions For the patients with severe factor VII deficiency undergoing surgery, uniform replacement therapy may not be recommended, and antithrombotic prophylaxis should be used in the case with thrombotic history to minimize the risk of bleeding and thrombogenesis.

Acquired isolated factor VII (FVII) deficiency is a rare but important discovery in patients with plasma cell disorders with significant therapeutic and prognostic implications. The present analysis and review of cases reported in the literature is intended to highlight disease-related characteristics associated with this rare clotting defect, clinical manifestations and outcome, and potential underlying mechanisms, and to provide guidance on how to manage these patients in terms of prophylactic and therapeutic measures. The discovery of acquired FVII deficiency in a patient with multiple myeloma (MM) or monoclonal gammopathy of uncertain significance (MGUS) should prompt an evaluation for AL amyloidosis, particularly for amyloid hepatosplenic involvement, whenever not previously documented. Acquired FVII deficiency in patients with MM and AL amyloidosis is frequently associated with severe bleeding diathesis, also related to a number of concomitant predisposing factors, adversely affecting the outcome. The prompt institution of a rapidly acting therapy is crucial to prevent severe bleeding complications and positively impact outcome. Recombinant activated factor VII (rVIIa) may represent a useful supportive care measure, both in treating active bleeding and in the peri-procedural setting. However, further clinical experience is needed to optimize the therapeutic management of this rare disorder. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

• The p.Thr241Asn missense mutation in congenital Factor VII deficiency was frequent. • This mutation may be candidate as a good tool for mutational screening in this area. • Two novel mutations and seven missense mutations were identified on the F7 gene. [ABSTRACT FROM AUTHOR]

Background: Factor VII deficiency is a rare bleeding disorder caused by a deficiency of clotting factor VII. However, there have been some case reports of venous thrombosis in patients with factor VII deficiency, especially underlying the prothrombotic risk factors exposure. Patients with factor VII deficiency require special considerations before undergoing surgery to minimize the risk of bleeding or thrombogenesis. Case presentation: Here, we described a patient with early-stage thymoma and severe factor VII deficiency who experienced an unprovoked thrombotic episode before thymectomy and a fatal thrombotic event after surgery. By adopting gene screening, a reported homozygous F7 mutation (p.His408Gln) and a novel heterozygous PROS1 mutation (p.Pro147Ala) were identified. The former resulted in severe factor VII deficiency but did not protect against thrombosis, and the latter was correlated with normal expression and cofactor activities of protein S through the thrombin generation test. The perioperative infusion of recombinant factor VII concentrate and the absence of antithrombotic prophylaxis may collectively contribute to her fatal thrombotic event after surgery. Conclusions: For the patients with severe factor VII deficiency undergoing surgery, uniform replacement therapy may not be recommended, and antithrombotic prophylaxis should be used in the case with thrombotic history to minimize the risk of bleeding and thrombogenesis. [ABSTRACT FROM AUTHOR]

Acquired isolated factor VII deficiency is a rare bleeding disorder and has been reported in 31 cases. This is in contrast to congenital factor VII deficiency, which while also infrequent is the most common rare congenital bleeding disorder. Acquired isolated factor VII deficiency has been described primarily in patients with solid malignancies, sepsis, and in the presence of anti-factor VII autoantibodies. We report a case of acute myelogenous leukemia with an associated trisomy 8 cytogenetic abnormality presenting with factor VII deficiency. The factor VII deficiency cleared after induction chemotherapy and with the disappearance of the cytogenetic and molecular abnormalities. We discuss a possible link between trisomy 8 and vitamin K metabolism, which might result in acquired factor VII deficiency in acute myelogenous leukemia.

Bleeding disorders can exacerbate gastrointestinal bleeding in inflammatory bowel disease (IBD) at the time of diagnosis or flares. Factor VII (FVII) deficiency is a life-threatening rare congenital bleeding disorder in childhood. This study describes three adolescent patients with IBD accompanied by acquired FVII deficiency. This is the first case series of patients with IBD accompanied by FVII deficiency. We hypothesized that inflammation, accelerated consumption, disease severity, and weight loss can cause decreased FVII activity in patients diagnosed with IBD. To control intestinal bleeding, we must keep in mind factor deficiencies in IBD. [ABSTRACT FROM AUTHOR]

Summary: Congenital factor VII (FVII) deficiency is a rare bleeding disorder characterised by a wide molecular and clinical heterogeneity. We investigated the clinical phenotype of 193 patients and F7 genotype of 55/193 patients with FVII deficiency throughout China and showed their current status of management. The most frequent bleeding symptoms were epistaxis (44.6%), cutaneous (38.9%), oral cavity (40.4%) bleeding and menorrhagia (44.3% of females of reproductive age). Fatal central nervous system bleeding and disabling joint bleeding occurred in three patients each. The majority of patients (89.6%) had FVII activity (FVII:C) ≤10% and the proportion of symptomatic patients in this group (79.8%) was significantly higher than that in the groups with FVII:C >10%–25% (41.7%) and >25%–50% (37.5%) (χ2 = 13.641, p = 0.001). Major bleeds occurred only in patients with FVII:C ≤10%. In total 55 patients underwent genotype analysis: most variants were missense (62.5%) and most patients had homozygous/compound heterozygous (85.4%) variants. Prothrombin complex concentrates (72.4%) were the most frequently used on‐demand replacement therapy. Prophylaxis before delivery decreased the risk of postpartum bleeding in women (χ2 = 69.243, p = 0.000). Our study provides useful information on the phenotype, genotype and current status of FVII‐deficiency patients management and may promote further exploration and care of this population in the future. [ABSTRACT FROM AUTHOR]

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.

To examine the clinical characteristics and prevalence of congenital bleeding disorders (CBDs), with emphasis on congenital factor VII (FVII) deficiency and other rare bleeding disorders, in adolescent and young adult females referred to a hemophilia treatment center (HTC) for evaluation and management of heavy menstrual bleeding (HMB) and iron deficiency anemia (IDA) In this single-center retrospective study, we reviewed the clinical characteristics and prevalence of CBDs in postmenarchal females, younger than 22 years of age, referred to an HTC from 2015 to 2021 for evaluation of HMB with or without IDA. One hundred females, with a mean age of 15 years (range 9-20 years), met initial study criteria, and 95 were included in the final analysis. Forty-five (47%) females were ultimately diagnosed with a CBD. The most prevalent diagnoses were FVII deficiency and type 1 von Willebrand disease (VWD) (42.3%, n = 19 each). Forty-two percent of patients with FVII deficiency had a low-for-age FVII activity level, 21.1% were only positive for the FVII R353Q variant associated with borderline FVII levels, whereas 36.8% had both a low-for-age FVII activity level and a positive R353Q variant. Eighty percent of patients with a CBD were found to have relatives with abnormal bleeding symptoms. Congenital FVII deficiency is prevalent among female adolescents experiencing HMB with or without IDA. In addition to VWD, evaluation for this specific factor deficiency should be considered as part of the initial CBD workup. Presence of abnormal bleeding history in the family could also help to predict presence of a CBD. [ABSTRACT FROM AUTHOR]

Factor VII deficiency is a rare bleeding disorder showing an autosomal recessive pattern of inheritance. Data from our country on this particular entity is lacking. Especially the specific mutations associated with this disease are not well documented. The disease can have a wide spectrum of presentation from asymptomatic to catastrophic central nervous system or gastrointestinal system bleed. It can often present early in the neonatal period or be detected quite later in life. The genotype and phenotype correlation is also not well understood. Here, we report a case of recurrent bleeding in an infant boy who was otherwise absolutely well. His investigations had revealed isolated prolonged prothrombin time which remained uncorrected despite administration of injection vit K. Specific assay for factor VII level revealed that its value less than 1%. Sequencing of the F7 gene revealed our patient to be homozygous for mutation of promoter consensus sequence of F7 gene (-94C > T).

Factor VII and XI deficiencies are rare bleeding disorders typically associated with mild or provoked bleeding. This case report describes a patient with factor VII and XI deficiencies with an unprovoked episode of lower extremity hematoma causing compartment syndrome requiring multiple surgeries, extensive transfusion of blood products, and ultimately amputation. [ABSTRACT FROM AUTHOR]

Abstract It is important to obtain coagulation tests to assess bleeding risk in trauma patients undergoing emergency surgery when a bleeding disorder may be obscured. Identifying specific clotting factor defects is critical in successful patient management.

Factor VII deficiency is a rare inheritable bleeding disorder that can be challenging to manage. Blood activity levels do not correlate with bleeding risk, and prophylaxis is a more difficult treatment option than for people with haemophilia due to the short half-life of factor VII. Acute bleeding manifestations and long-term complications are similar to those associated with haemophilia. This case study illustrates the psychological and physical impact of severe factor VII deficiency on a woman with impaired mobility due to haemarthropathy who must retain her independence to provide care for her elderly parents. She self-manages her joint pain and bleeding risk, but her life is limited by the need to avoid injury and her reluctance to engage fully with health services.

Congenital factor VII (FVII) deficiency is a rare genetic disorder with autosomal recessive inheritance, characterized by molecular and clinical heterogeneity. This article reports four Moroccan cases of FVII deficiency within the same family, two of which were associated with Gilbert's syndrome. The index case was a 15-year-old girl with a history of menorrhagia and jaundice. Upon examination, she presented with indirect hyperbilirubinemia, iron deficiency anemia, and a prolonged prothrombin time (PT). FVII deficiency was confirmed with a factor VII level of 45%. Her mother, a 30-year-old woman with sarcoidosis and a history of postpartum hemorrhage, was found to have jaundice and an FVII deficiency at 42%. The brother of the index case, an eight-year-old boy who was asymptomatic, was discovered to have FVII deficiency during family screening, with a level of 41%. Similarly, the six-year-old sister, also asymptomatic, had an FVII level of 33%. The prevalence of homozygous FVII deficiency is rare, and the risk is increased in consanguineous marriages. Clinical presentations vary widely, ranging from asymptomatic cases to severe bleeding episodes. Diagnosis is based on a prolonged PT with a normal activated partial thromboplastin time (aPTT) and is confirmed through FVII assays. Severe cases may require prophylactic treatment, and recombinant activated FVII (rFVIIa) is the recommended therapy for bleeding episodes. In conclusion, FVII deficiency is the most common of the rare coagulation factor deficiencies. This study explores familial congenital factor VII deficiency, characterized by varied presentations from asymptomatic to mild hemorrhagic symptoms. Early diagnosis and family screening are essential. Management includes symptomatic treatment, tranexamic acid for menorrhagia, and fresh frozen plasma or recombinant factor VIIa for bleeding episodes., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Ghouzraf et al.)

BackgroundIn congenital Factor (F) VII deficiency bleeding phenotype and intrinsic FVII activity levels don't always correlate. Patients with FVII activity levels

Introduction: Factor VII deficiency is a rare inherited autosomal recessive bleeding disorder with a global prevalence of 1/500,000. Most cases remain asymptomatic, and cases with severe clinical presentation are rarely reported.Case Presentation: A newborn male with no relevant maternal antenatal history, delivered via vacuum-assisted cesarean section, presented with a large cephalohematoma after delivery. Poor appetite, pale appearance, and bulging fontanelles were observed 2 days later, progressing to hypovolemic shock. Further imaging examination revealed a large intracranial hemorrhage. Serial laboratory examination revealed remarkable coagulopathy with prolonged prothrombin time and factor VII deficiency (T homozygous mutation. Brain hemorrhage was resolved with high-dose factor VII replacement therapy with recombinant activated factor VII. However, repeated hemothorax and intracranial hemorrhage were detected. Therefore, the patient was under regular factor VII supplementation with a rehabilitation program for cerebral palsy.Conclusions: A case of factor VII deficiency with large cephalohematoma and intracranial hemorrhage after birth is described herein, which was treated with high-dose replacement therapy. Variants of the FVII:c 681+1 G>T (IVS6+1G>T) homozygous genotype may present with a severe phenotype at the neonatal stage. We aim to share a unique neonatal presentation with a certain genotype and treatment experience with initial replacement therapy, followed by regular prophylactic dosage.

Abstract Background Congenital coagulation factor (F) VII deficiency is a rare bleeding disorder caused by mutations in the F7 gene. The missense factor FVII variant p.Q160R is the disease-causing mutation in all Norwegian FVII deficient patients and results in reduced biological activity and antigen levels of FVII in patient plasma. Previous in vitro studies on this variant demonstrated impaired intracellular trafficking and reduced secretion, possibly due to protein misfolding. The aim of the study was therefore to assess the impact of chemical chaperones on cellular processing and secretion of this variant using a cell model based on overexpression of the recombinant protein. Results Through screening of compounds, we identified 4-phenylbutyrate (4-PBA) to increase the secretion of recombinant (r) FVII-160R by ~ 2.5-fold. Additionally, treatment with 4-PBA resulted in a modest increase in specific biological activity. Intracellular localization studies revealed that upon treatment with 4-PBA, rFVII-160R was secreted through Golgi and Golgi reassembly-stacking protein (GRASP)-structures. Conclusions The present study demonstrates that the chemical chaperone 4-PBA, restores intracellular trafficking and increases the secretion of a missense FVII variant with functional properties in the extrinsic coagulation pathway.

Objective: Rare disease. Background: Factor VII (FVII) deficiency is the most common autosomal-recessive bleeding disorder. FVII activity level (FVII: C) of 10-20% is often used as the threshold for administering activated recombinant FVII (rFVIIa) for patients undergoing major surgery. However, rFVIIa is expensive and carries the risk of a thromboembolic event, and thus should only be administered when truly indicated. Case Report: A 22-year-old woman with 8% FVII: C underwent a hepatectomy. Although there were no clinical signs of bleeding, peri-operative administration of rFVIIa was recommended by the hematologist (first dose at surgical incision, then 4 h later, then every 12 h until 48 h postoperatively). Intraoperatively, serials of ROTEM analysis were performed to evaluate the effect of rFVIIa administration. No significant effect of rFVIIa was seen on NATEM. Surgery was unremarkable, without any significant blood loss. The patient developed radial artery thrombosis 24 h postoperatively, the arterial line was removed, and rFVIIa was discontinued (PT: 14.6, FVII: C 36%). On POD 3, INR was elevated (3.15, FVII: C 3%). To correct INR, the patient was transfused 8 units of FFP, despite any signs of clinical bleeding. However, INR and FVII: C did not correct and the patient was discharged on POD 7 in a stable condition. Conclusions: Even with FVII: C of 8%, the ROTEM analysis revealed a normal coagulation status. The administration of rFVIIa did not improve the already normal baseline coagulation profile, but rather potentially led to an accelerated coagulation or hypercoagulable state and may have led to the radial artery thrombosis. We endorse the use of viscoelastic testing for hemostasis assessment and factor replacement in congenital FVII deficiency. [ABSTRACT FROM AUTHOR]

A few case reports suggest that 10 to 30 IU/kg of pdFVII or 20-30 mcg/kg of rFVIIa twice or three times a week is sufficient to prevent major bleeds,9 despite the plasma half-life of rFVIIa being only 2-8 hour.10 It has been suggested that the biological effect of rFVIIa may be longer because of its extravascular redistribution.11 Starting treatment early in life raises the question on how to manage regular administrations of low doses of rFVIIa. Keywords: eptacog alfa; factor VII deficiency; prophylaxis; rFVIIa; sub-dural haematoma EN eptacog alfa factor VII deficiency prophylaxis rFVIIa sub-dural haematoma e487 e490 4 07/21/21 20210701 NES 210701 Inherited factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder. They were then aliquoted in individual 1 mL syringes, under sterile condition using a laminar flow hood as previously reported.2 Each syringe contained 0.3 mL of rFVIIa, meaning that 6 syringes could be made from only one 2.2 mL vial of rFVIIa (1.2 mg/2.2 mL). However, preparation of rFVIIa syringe aliquots was done in every clinical situation requiring several infusions of rFVIIa (Table 1). [Extracted from the article]

(1) Background: Congenital factor (F) VII deficiency is caused by mutations in the F7 gene. Patients with modest differences in FVII levels may display large differences in clinical severity. The variant p.A354V-p.P464Hfs is associated with reduced FVII antigen and activity. The aim of the study was to investigate the clinical manifestation of this variant and the underlying molecular mechanisms. (2) Methods: Analyses were conducted in 37 homozygous patients. The recombinant variant was produced in mammalian cells. (3) Results: We report a large variation in clinical phenotypes, which points out genetic and acquired components beyond F7 mutations as a source of variability. In contrast, patients displayed similarly reduced FVII plasma levels with antigen higher than its activity. Comparative analysis of the recombinant variant and of plasma samples from a subset of patients indicated the presence of an elongated variant with indistinguishable migration. Treatment of cells with the chemical chaperone 4-phenylbutyrate (4-PBA) improved the intracellular trafficking of the variant and increased its secretion to the conditioned medium up to 2-fold. However, the effect of 4-PBA on biological activity was marginal. (4) Conclusions: Chemical chaperones can be used as biochemical tools to study the intracellular fate of a trafficking-defective FVII variant. [ABSTRACT FROM AUTHOR]