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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.)

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., Competing Interests: Declarations. Ethical approval: Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. This case report is compliant with the CARE guidelines. Competing interests: MI is Associate Editor at the Journal of Clinical Monitoring and Computing. MB, PF, DM, CP, MC, MG have no conflict of interests to declare. Submission statement: The manuscript has not been previously published or under consideration elsewhere. We confirm that all co-authors have contributed to the clinical management of the case, reviewed the paper and consent to its submission to JCMC., (© 2024. The Author(s).)

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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., (© 2023. The Author(s).)

Prothrombin time (PT) is a key parameter for assessing the severity of liver disease. We present the case of a 37-year-old woman with severe acute liver injury due to autoimmune hepatitis. Although prednisolone drastically improved her hepatocyte function, her PT did not recover to the reference range. A review of her medical records revealed that the patient had normal transaminase levels and prolonged PT 2 years previously. Further examinations of her coagulopathy revealed that she had low factor VII activity, suggesting a diagnosis of factor VII deficiency. Our experience suggests that altered coagulopathy should be considered in cases of liver injury with an extraordinary PT.

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., (© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

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.

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.

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., (Published by Oxford University Press on behalf of American Society for Clinical Pathology 2023.)

Introduction: 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)., Materials and Methods: 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., Results: 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., Conclusions: FXIa reveals new relationships between TG, PG and CFL parameters in factor deficiencies suggesting potential benefits for discrimination of bleeding phenotypes., Competing Interests: Declaration of competing interest The authors declared no conflicts of interest. This paper is an informal communication and represents the authors' best judgment. These comments do not bind or obligate FDA., (Copyright © 2023. Published by Elsevier Ltd.)

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.

Congenital factor VII deficiency is a rare bleeding disorder with variable presentations. Thromboembolism is a well-established complication of this heterogeneous disease. As it is a rare disease, there is no information regarding its treatment when it is present with other comorbidities such as end-stage renal disease. This study describes a 47-year-old male with multiple comorbidities who was recently diagnosed with end-stage renal disease. He had recurrent admissions to the hospital due to thrombotic arteriovenous access failure as well as acute coronary syndrome, despite a high international normalized ratio that was resistant to replacement therapy. Eventually, apixaban became his main treatment regimen. This case needs to be reported because it is rare in terms of including a factor VII deficiency patient with end-stage renal disease, as well as to emphasize the unclear recommendations available for patients with factor VII deficiency and end-stage renal disease. International collaboration may be the best course of action to study enough patients and come up with effective recommendations., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Shakhshir et al.)

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., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

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.

Krüppel-like Factor 7 (KLF7) is a zinc finger transcription factor that has a critical role in cellular differentiation, tumorigenesis, and regeneration. Mutations in Klf7 are associated with autism spectrum disorder, which is characterized by neurodevelopmental delay and intellectual disability. Here we show that KLF7 regulates neurogenesis and neuronal migration during mouse cortical development. Conditional depletion of KLF7 in neural progenitor cells resulted in agenesis of the corpus callosum, defects in neurogenesis, and impaired neuronal migration in the neocortex. Transcriptomic profiling analysis indicated that KLF7 regulates a cohort of genes involved in neuronal differentiation and migration, including p21 and Rac3. These findings provide insights into our understanding of the potential mechanisms underlying neurological defects associated with Klf7 mutations., (© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

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., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

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., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

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., (© 2023. The Author(s).)

Factor X (FX) deficiency is an extremely rare autosomal recessive inherited coagulation defect. We report a case of congenital Factor X-Riyadh deficiency discovered during a routine workup before a dental procedure. During routine work-up for dental surgery, prothrombin time (PT) and the international normalized ratio (INR) were prolonged. The prothrombin time (PT) was found to be 78.4 (normal 11-14 seconds) with an international normalized ratio (INR) of 7.83; the activated partial thromboplastin time (APTT) was 30.7 (normal 25-42 seconds). Specific coagulation factor assays confirmed an FX deficiency (<10 % of normal activity) and a mild factor VII deficiency 37% (normal 48%-124%). Molecular genetic analysis of the whole exome sequence (WES) confirmed the diagnosis of FX deficiency (homozygous pathogenic variant c. 271G>A p {Glu91Lys} chr13:113793685). The patient is currently on regular follow-up and is advised to take oral antifibrinolytic medications for any superficial or mucosal bleeding., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Alasmari et al.)

The prevalence of factor VII deficiency (F7D) is 1 in 500,000. Due to its rarity, the management of bleeding disorders in pregnancy is not well established. We examine a case of an 18-year-old (gravida 1, para 0) woman at approximately 19 weeks gestation with a known history of F7D who presents after a motor vehicle accident. Fetal demise was confirmed necessitating a medical induction. She also had multiple fractures requiring surgical intervention. A multidisciplinary team consisting of orthopedic surgery, obstetrics and gynecology, and hematology/oncology was consulted for optimal timing of factor VII replacement prior to procedures. The patient underwent successful left tibial intramedullary nailing with minimal bleeding. She received factor VII and tolerated an uncomplicated vaginal delivery. Her postpartum and postoperative courses were uncomplicated, requiring one unit of packed red blood cells. The patient was discharged on postpartum day three. Management of this second-trimester abortion with a history of F7D was possible with effective communication and the organization of a multidisciplinary team to account for the risk of thrombosis versus hemorrhage and the availability of factor VII replacement therapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Nguyen et al.)

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%) (χ 2 = 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 (χ 2 = 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., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Congenital coagulation factor VII (FVII) deficiency is a rare, autosomal-recessive haemorrhagic disorder with an estimated incidence of 1:500,000. This disorder is caused by mutations in the F7 gene., Case Description: Here, we report a pedigree of congenital FVII deficiency. The proband was a 30-year-old female with severely low FVII activity and a history of menorrhagia and epistaxis since her childhood who was subsequently diagnosed with congenital compound heterozygous FVII deficiency. A genetic study revealed a novel combination of compound heterozygous mutations (c.64G 〉 A, p.Gly22Ser and c.1027G 〉 A, p.Gly343Ser). Her father and older son had the c.64G 〉 A, p.Gly22Ser (heterozygous) mutation. Her mother and younger son had the c.1027G 〉 A, p.Gly343Ser (heterozygous) mutation. The predicted results of PolyPhen-2 and MutationTaster indicated that these mutations were probably damaging and disease-causing, respectively., Conclusion: In this study, we identified a novel combination of genetic mutations that could expand the mutant library and help in elucidating the pathogenesis of hereditary human coagulation FVII deficiency. A novel combination of compound heterozygous mutations was reported for the first time in Chinese individuals., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Study Objective: 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) DESIGN: 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., Results: 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., Conclusion: 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., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

We investigated the molecular basis of factor VII (FVII) deficiency in a Japanese patient and identified compound heterozygous mutations. Factor VII activity and antigen levels in the patient were less than 5.0% and 6.5% of controls, respectively. All exons, exon-intron boundaries, and the 5' promoter region of F7 from genomic DNA were amplified using polymerase chain reaction (PCR). Sequencing analysis of PCR fragments revealed that the patient was heterozygous for a known T to C substitution at nucleotide position 38, which resulted in the p.Leu13Pro missense mutation (Factor VII Morioka) in the signal peptide region, and a novel mutation in the 5' promoter region (-58G>C). An electrophoretic mobility shift assay showed that the mutation in the promoter region reduced the binding of hepatocyte nuclear factor (HNF). It is presumed that the reduced binding of HNF-4 to the F7 promoter region reduces F7 transcription and thus reduces the synthesis and expression of FVII.

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)., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Family Medicine and Primary Care.)

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., Competing Interests: No conflict of interest are present for the authors of this paper., (© 2022 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Introduction and Importance: In patients with congenital factor VII (FVII) deficiency, perioperative bleeding events are concern, so recombinant activated factor VII (rFVIIa) is favorably used, but the optimal dosage regimen has not clearly established. We report management of a patient with congenital FVII deficiency who underwent laparoscopic cholecystectomy., Case Presentation: A 70-year-male with congenital FVII deficiency was diagnosed as acute cholecystitis, so we planned laparoscopic cholecystectomy. FVII activity and prothrombin time international normalized ratio (PT-INR) were intraoperatively monitored as scheduled. At the start of surgery, FVII activity was 3.1% (75-130%) and PT-INR was 3.37 (0.8-1.2), so 1 mg of rFVIIa was administered. Both of these values then improved to 325.0% and 0.73, respectively. Laparoscopic cholecystectomy was successfully completed without unexpected bleeding or oozing. When FVII activity and PT-INR was re-checked 6 h after the first administration of rFVIIa, these values were 23.9% and 1.53, respectively. Additional 1 mg of rFVIIa was used only once after the operation. The patient was discharged on the sixth day after surgery without postoperative complication., Clinical Discussion: In this case, rFVIIa was used just twice and there were no bleeding events during the perioperative period. Previous reports suggested using 15-30 μg/kg of rFVIIa before surgery and subsequent every 4-6 h in the first 24 h, then increasing the interval to 8-12 h. It is necessary to evaluate optimal dose of rFVIIa based on the risk and surgical invasiveness for each case., Conclusion: Our patient with congenital FVII deficiency uneventfully underwent laparoscopic cholecystectomy., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Factor VII (FVII) deficiency manifests as prolonged prothrombin time (PT) and reduced FVII activity. We report a case of an asymptomatic 60-year-old gentleman with discrepancies in PT and FVII coagulant activity levels (FVII:C) on three different thromboplastin reagents used. Further sequence analysis on genomic DNA showed double heterozygosity for c.1025G>A p.Arg342Gln and c.194C>G p.Ala65Gly in the F7 gene. To date, p.Ala65Gly in exon 2 of the F7 gene represents a novel variant in patients with FVII deficiency and is classified as likely pathogenic. Computational prediction tools support a deleterious effect on the gene. The genotype-phenotype association and the clinical significance of this exon 2 missense variant is proposed in this case report., Competing Interests: The authors report no conflict of interest., (Copyright 2022, Gallardo et al.)

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 (<1%, severe type). The patient was genetically confirmed to have the FVII:c 681+1 G>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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lo, Peng and Chen.)

Factor VII (FVII) deficiency is a hereditary bleeding disorder that significantly increases the risk of hemorrhage during the intrapartum and postpartum periods as well as during surgery. Management often requires careful pre- and post-operative planning, a multi-disciplinary approach, and management at a tertiary center. Most cases in the literature utilized recombinant FVII for treatment. We present a case of a young active duty female who had an undiagnosed FVII deficiency that became apparent during her expedited delivery for fetal distress. Our patient was admitted for delivery while undergoing a work up for an abnormal coagulation panel. Given high suspicion for FVII deficiency, anticipated hemorrhage, and need for cesarean delivery, she was treated with blood products containing FVII. Two days after delivery her diagnosis was confirmed. Available literature discusses the management of known FVII deficiency in pregnancy; however, to the best of our knowledge, there are no cases of an unknown bleeding diathesis incidentally identified just before delivery and later diagnosed as FVII deficiency. This case highlights the appropriate management of an unknown coagulopathy, the significant challenges associated, and the incorporation of a multi-disciplinary team critical to reducing significant maternal morbidity., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Tranexamic acid (TXA) is an antifibrinolytic commonly used to reduce blood loss due to surgical procedures, heavy menstruation, trauma, bleeding disorders, among other uses. Possible adverse reactions associated with TXA include abdominal pain, headache, fatigue, cerebral thrombosis, dizziness, retinal artery occlusion, chromatopsia, and more. We present a case of acute color vision disturbance developed soon after initiation of oral TXA for epistaxis prophylaxis in the setting of factor VII deficiency. To our knowledge we report the only case of color vision disturbance in a pediatric patient and the only case after receiving oral TXA. Soon after discontinuing oral TXA the patient's altered perception of color vision resolved. The patient was subsequently discharged home with a prescription for an alternative antifibrinolytic (aminocaproic acid) and follow-up with neuro-ophthalmology., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Introduction and Importance: Case report of patient with congenital lack of factor VII, suffering from recurrent hematomas and massive menstrual bleedings resulting in severe anemia and multiple hospitalization., Case Presentation: Patient was diagnosed with endometrial hyperplasia and not responding to hormonal treatment and substitution with recombinant factor VII was not effective to reduce the bleedings. This case describes successful laparoscopic technique of using bipolar coagulation and non-absorbable clips., Clinical Discussion: We describe premedication and post-surgical management - which we had to modify from this found in very scarce literature. Despite previous vaginal deliveries without any complications during the puerperium, 20 days after the surgery patient presented with intraperitoneal bleeding after stopping rFVIIa therapy. It was treated medically without the need for re-laparoscopy., Conclusion: Laparoscopic surgery is possible in patients with lack and deficiency of FVIIa, but they need close post-operative surveillance and prolonged supplementation with recombinant FVIIa., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Congenital factor (F) VII deficiency is a rare coagulation factor deficiency with an estimated incidence of 1 per 500,000 individuals. Patients with severe FVII deficiency present a broad range of clinical presentations. Alloimmunization against exogenous FVII, as the main challenge of replacement therapy, is an extremely rare phenomenon that is accompanied by a high rate of life-threatening bleeding, that renders replacement therapy less effective. Due to the importance of the issue, we performed a systematic literature review in order to assess incidence, molecular basis, clinical presentations, and therapeutic challenge and management of inhibitor in congenital FVII deficiency. Strategy of search: This systematic review was performed in accordance with PRISMA guidelines. We performed an English-language literature review in the PubMed, EMBASE, Scopus, and Google Scholar databases, using the following keywords: "factor VII inhibitor", "factor VII inhibitors", "FVII inhibitors", "congenital FVII deficiency", "recombinant factor VII", "anti rFVIIa", "replacement therapy", and "alloantibody"., Results: Out of 380 patients in the 13 studies, 27 had inhibitor against FVII; 18 were male, 7 were female, while the sex of 2 was not stated. The majority (92%) developed a high-titer inhibitor (Bethesda Unit > 5). All patients had severe FVII deficiency (FVII:C < 10%), and the majority received recombinant FVII prior to inhibitor development (N: 24, 89%). Among ten patients with a detected mutation, three subjects had a common non-sense (30%), and two had a deletion (20%)., Conclusions: Inhibitor development is a relatively rare phenomenon seen only in severe FVII deficiency, where it is associated with severe and life-threatening presentations, treatment challenge, and economic burden on the patients and their families.

Objective: To investigate a family with factor VII (FVII) deficiency from Argentina., Patients and Methods: The proposita is a 14-year-old girl who presented with a mild to moderate bleeding tendency. Menorrhagia is controlled with periodical administration of small doses of recombinant FVII concentrate. The mother of the proposita has a similar bleeding tendency., Results: FVII activity in both patients was 20% of normal; FVII antigen was 35% of normal. Molecular biology investigation revealed that the proposita was compound heterozygote between Thr384Met and Arg413Gln. The mother had the same mutations. This was due to the fact that the father of the proposita and her maternal grandfather both carried, in spite of no relation, the same mutation, namely Arg413Gln., Conclusions: The identical defect which presented in the propositaand her mother could be explained by the genetic analysis of the father and maternal grandfather of the proposita who happened to have the same mutation (Arg413Gln)., (© 2020 S. Karger AG, Basel.)

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., Competing Interests: None declared., (© 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Congenital factor VII deficiency is a rare bleeding disorder, with an incidence of 1:500,000. This case report describes an exceptionally unusual combination of congenital factor VII deficiency, multicystic dysplastic kidney disease and bicuspid aortic valve disease, in the same patient., Competing Interests: None to declare., (Copyright 2020, Almadani et al.)

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.)

Hereditary blood coagulation factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder resulting from variants in the gene encoding FVII (F7). Integration of genetic variation with functional consequences on protein function is essential for the interpretation of the pathogenicity of novel variants. Here, we describe the integration of previous locus-specific databases for F7 into a single curated database with enhanced features. The database provides access to in silico analyses that may be useful in the prediction of variant pathogenicity as well as cross-species sequence alignments, structural information, and functional and clinical severity described for each variant, where appropriate. The variant data is shared with the F7 Leiden Open Variation Database. The updated database now includes 221 unique variants, representing gene variants identified in 728 individuals. Single nucleotide variants are the most common type (88%) with missense representing 74% of these variants. A number of variants are found with relatively high minor allele frequencies that are not pathogenic but contribute significantly to the likely pathogenicity of coinherited variants due to their effect on FVII plasma levels. This comprehensive collection of curated information significantly aids the assessment of pathogenicity., (© 2020 The Authors. Human Mutation published by Wiley Periodicals, Inc.)

Objective: To explore the molecular basis for a Chinese pedigree affected with hereditary coagulation factor VII (FVII) deficiency., Methods: The coding regions of F7 gene were amplified by PCR and sequenced. Suspected variants were confirmed by reverse sequencing and validated in other members from the pedigree. Pathogenicity of the variants was analyzed with multiple bioinformatic tools., Results: Genetic analysis revealed that the proband has carried compound heterozygous c.985T>C (p.Ser329Pro) and c.1091G>A (p.Arg364Gln) variants in exon 8 of the F7 gene. Her mother, brother and son were heterozygous for c.985T>C (p.Ser329Pro), while her father was heterozygous for c.1091G>A (p.Arg364Gln). Phylogenetic analysis suggested that both p.Ser329 and p.Arg364 are highly conserved among homologous species. Online bioinformatic software predicted both variants to be deleterious. Protein model analysis suggested that the Pro329 side chain may form a new hydrogen bond with Leu333. The Pro benzene ring may clash with Glu325 in the p.Ser329Pro variant model. The p.Arg364Gln variant have two additional hydrogen bonds compared with wild type Arg364. Both variants may lead to alteration of the protein structure., Conclusion: The p.Ser329Pro and p.Arg364Gln variants in exon 8 of the F7 gene probably account for the reduced FVII in this pedigree.

Objective: To explore the pathogenesis, clinical characteristics, laboratory findings, diagnosis, treatment, and prognosis of congenital factor Ⅶ (FⅦ) deficiency. Methods: Clinical data of 43 patients with congenital FⅦ deficiency diagnosed from April 1999 to September 2019 were retrospectively analyzed. Results: There were 27 females and 16 males. Median age was 16 (1-70) years. Family history was found in 6 cases. There were 29 (67.4%) cases with bleeding symptoms, most common of which were mucocutaneous bleeding (13 cases, 30.2%) , oral bleeding (13 cases, 30.2%) , and epistaxis (9 cases, 20.9%) . Menorrhagia occurred in 11 cases (47.6% of female patients who were in fertile age) . Laboratory findings were characterized by significantly prolonged prothrombin time (PT) , normal partial thromboplastin time (APTT) , and decreased FⅦ activity (FⅦ∶C) . Ten cases received gene mutation analysis and 3 new mutations were found. Fourteen cases (32.6%) were treated with prothrombin complex concentrates (PCC) , 12 (27.9%) with fresh frozen plasma (FFP) , and 3 (7.0%) with human recombinant activated FⅦ (rFⅦa) . Twenty cases (46.5%) with no or mild bleeding symptoms did not receive any replacement therapy. Previous bleeding symptoms recurred in 5 patients (11.6%) , 8 females still had heavy menstrual bleeding, and 9 patients (20.9%) were lost to follow-up. Conclusion: Most patients with congenital FⅦ deficiency have mild or no bleeding symptoms, but have a tendency to excessive bleeding after surgery or trauma. There is no significant correlation between FⅦ∶C and severity of bleeding symptoms. Prophylaxis should be applied in patients with severe bleeding symptoms and rFⅦa is the first choice. Gene mutation test is significant for screening, diagnosis, and prognosis prediction of the disease.

Thrombotic events in bleeding disorders such as hemophilia A or B, Von Willebrand disease, afibrinogenemia, factor VII deficiency, and factor XI deficiency are rare but have been reported. These events usually occur in the presence of prothrombotic risk factors such as recent surgery, trauma, or factor replacement therapy. We present a case of a 68-year-old Hispanic female with a history of factor VII deficiency who presented with shortness of breath, chest pain, and palpitations and was found to have pulmonary embolism. Our patient did not have any of the above-mentioned thrombotic risk factors. Our case and review of the literature show that factor VII deficiency does not provide protection against thrombosis., (© 2019 S. Karger AG, Basel.)

Objective: Factor VII deficiency is the commonest of the rare bleeding disorders with limited knowledge on clinical profile. The objective of this study was to study the prevalence and clinico-hematological profile of factor VII-deficient patients., Methods: It is a retrospective observational study of probable inherited factor VII deficiency covering 18 months. Their clinical profile, family history, investigation and treatment records were studied in detail., Results: The study group comprised of total 12 factor VII deficiency cases with mean age of 17.5 years of onset of symptoms. The commonest symptom was menorrhagia (41.6%) followed by epistaxis (25%) and easy bruisability (16.6%). These 12 patients when categorized according to bleeding severity: severe bleeding - 2, moderate bleeding - 3, mild bleeding - 6 and asymptomatic - 1. All cases had prolonged prothrombin time (PT) with mean PT of 35.4 seconds (range 18-50 seconds) and mean prolongation of PT from upper limit of normal - 19.4 seconds (range 2-34 seconds). Factor VII levels ranged from < 1-40% in these patients. Clinical symptoms were not in concordance with factor levels. Of 12 patients, required treatment other than local measures., Discussion and Conclusion: Inherited factor VII deficiency is the commonest autosomally inherited factor deficiency with marked variation in the age of presentation and clinical symptoms. The laboratory results in form of PT and factor VII levels do not correlate with the severity of clinical presentation. A comprehensive evaluation to exclude acquired causes of factor VII deficiency, e.g. obesity, liver diseases, vitamin K deficiency and acquired inhibitors is required before labeling it as inherited in the absence of family history and molecular studies.

Factor VII (FVII) deficiency is the most common of the Rare Inherited Coagulation Disorders. The inheritance is autosomal recessive but there is variable penetrance. Overall there is poor correlation between the FVII level and the bleeding phenotype. Heterozygotes may have significant bleeding and severe homozygotes, or compound heterozygotes can be asymptomatic. Typically, homozygotes have FVII levels <10% and heterozygotes have levels above that. In most cases bleeding is uncommon with FVII levels>10-20%. A personal and family history is essential to determine the bleeding risk and to plan for surgical and obstetrical prophylaxis. Severe bleeding complications including central nervous system bleeding, gastrointestinal system bleeding and bleeding into the joints occurs in 10-15% of FVII deficient patients. Mucocutaneous bleeding is a common symptom but 30% of patients are asymptomatic. Fifty to 69% of women have heavy menstrual bleeding. Due to the limited number of publications regarding this rare disorder there are no consensus guidelines. There is registry data which has led to the best recommendations for treatment of bleeding episodes, initiation of long-term prophylaxis in addition to surgical plus ante and peripartum prophylaxis. Recombinant FVII concentrate is the best replacement therapy and a review of treatment and prophylaxis dosing is discussed., (Copyright © 2019. Published by Elsevier Ltd.)