Perioperative ROTEM® evaluation in a patient affected by severe VII factor deficiency undergoing microvascular decompression craniotomy for hemifacial spasm.

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.

Factor VII Deficiency in Systemic Mastocytosis with an Associated Myeloid Neoplasm.

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.

Genetic Landscape of Factor VII Deficiency: Insights from a Comprehensive Analysis of Pathogenic Variants and Their Impact on Coagulation Activity.

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.

Interleukin 10, but not tumor necrosis factor-alpha, gene variations are associated with factor VII inhibitor development.

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.

The effect of factor XIa on thrombin and plasmin generation, clot formation, lysis and density in coagulation factors deficiencies.

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.

Factor VII Deficiency in an End-Stage Renal Disease Patient With Recurrent Thrombosis: A Case Report.

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.

Acquired factor VII deficiency in pediatric inflammatory bowel disease: Report of three cases.

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.

Acquired Factor VII Deficiency Associated With Chronic Myeloid Leukemia Blast Crisis.

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.

A Case of Autoimmune Hepatitis Complicated by Undiagnosed Factor VII Deficiency: A Pitfall of Coagulopathy.

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.

The rare case of double valve surgery in a patient with factor VII deficiency.

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.

Acquired Isolated Factor VII Deficiency in Plasma Cell Dyscrasias: A Brief Presentation of Two Plasma-Cell-Leukemia-Related Cases and Review of Literature.

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.

Current status and future prospects of activated recombinant coagulation factor VIIa, NovoSeven®, in the treatment of haemophilia and rare bleeding disorders.

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.

Deficiencia congénita de factor VII / Congenital factor VII deficiency

Resumen La deficiencia congénita de factor VII es uno de los desórdenes congénitos de la coagulación más comunes, con una prevalencia a nivel mundial de 1:300,000- 1:500,000. Se presenta el caso de un paciente masculino de 37 semanas y 5 días, nacido por cesárea intraparto y con el antecedente heredofamiliar de muerte de hermano a los 4 días de nacido por hemorragia intracraneal, quien a los 14 días de nacido es llevado a emergencias por sangrado umbilical que persistía después del desprendimiento del cordón. Su abordaje inicial incluyó la toma de tiempos de coagulación, lo que mostró alteración del tiempo de protrombina con tiempo de tromboplastina parcial y fibrinógeno normales. El sangrado, así como el tiempo de protrombina prolongado, persistió a pesar de que se administrara vitamina K en tres ocasiones y de transfundir plasma fresco congelado. Se sospechó defecto congénito de factor VII, que se confirmó con la cuantificación del factor. A los 2 meses y 10 días de edad, se le realizaron estudios moleculares basados en secuenciación masiva de nueva generación (NGS por sus siglas en inglés). El análisis determinó dos variantes heterocigotas: F7, intrón 5, c.430+1G>A y F7, intrón 8, c.805+1G>A. Actualmente, el paciente se maneja con profilaxis 5 días de la semana con factor VII recombinante 200 µg/día intravenoso (280 µg/kg) sin recurrencia de sangrados.

Abstract Factor VII congenital deficiency is one of the most common congenital deficiencies of the blood system, with a worldwide prevalence of 1:300,000- 1:500,000. Here we describe a male patient, born by C section, with the family history of death at 4 days old of a sibling caused by intracranial hemorrhage, who presented bleeding at the umbilical cord site at 14 days old, even after falling of the cord. The initial assessment included laboratory tests with coagulation times revealing prolonged prothrombin time, with normal partial thromboplastin time as well as fibrinogen. The bleeding and the prolonged prothrombin time persisted despite the administration of vitamin K in three doses as well as fresh frozen plasma. Congenital defect of factor VII was suspected and later confirmed by measuring the factor. At the age of 2 months and 10 days, molecular studies based on next-generation massive sequencing (NGS) were performed. The analysis exhibited two heterozygous variants: F7, intron 5, c.430+1G>A y F7, intron 8, c.805+1G>A. Currently the patient is receiving prophylaxis 5 days per week with recombinant factor VII 200 µg/ day intravenous (280 µg/kg) with no recurrent bleeding.

Congenital Factor X-Riyadh (Stuart-Prower) Deficiency With Isolated Prothrombin Time Prolongation: A Case Report.

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.

A case-report of the unprovoked thrombotic event in a patient with thymoma and severe FVII deficiency.

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.

Factor VII Deficiency and Second Trimester Abortion: A Case Report.

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.

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

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

Structural and functional characterization of novel F7 mutations identified in Chinese factor VII-deficient patients.

Hereditary factor VII (FVII) deficiency is a rare recessive bleeding disorder with an estimated prevalence of 1/500 000. We had investigated 50 unrelated Chinese patients with FVII deficiency and identified, in total, 25 mutations, including 18 missense mutations and 5 splicing mutations, on the F7 gene. The nucleotide transition c.1224T>G (p.His408Gln) in exon 9 constitutes a hotspot of mutation, with 19 patients harbouring this genetic variance. Few patients were homozygous or compound heterozygous for deleterious mutations, such as non-sense mutations, large insertion or deletions, indicating that complete deficiency of FVII may not be compatible with life. The eight novel mutations identified in the study, including one small deletion (p.Glu49GlyfsTer101), three type I missense mutations, p.Cys238Phe, p.Gly420Asp, p.Ala252Val and four type II missense mutations, p.Val336Met, p.Ser342Gly, p.Gly432Ser and p.Ile213Asn, were further analysed by in vitro expression and functional studies. The laboratory phenotype and structural analysis confirmed the functional consequence of p.Ile213Asn mutation involving cleavage and activation site. The molecular dynamic simulations and binding energy calculations along with functional probing of p.Gly432Ser mutation revealed the critical role of residue Gly432 in the binding between activated factor VII (factor VIIa) and tissue factor.

Hereditary coagulation factor VII deficiency caused by novel compound heterozygous mutations in a Chinese pedigree: A case report.

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.