Factor V Research Articles

Spatial Computational Hepatic Molecular Biomarker Reveals LSEC Role in Midlobular Liver Zonation Fibrosis in DILI and NASH Liver Injury

The liver is structurally organized into zonation, where Liver Sinusoidal Endothelial Cells (LSECs) play a crucial role during chronic liver injury and the early stages of fibrosis. Fibrosis can be reversed if diagnosed early at the molecular level in zonation before progressing to advanced stages like bridging fibrosis. This study identified zonation marker genes using scRNA-seq and spatial transcriptomics molecular profiling technologies in a normal and diseased fibrotic human liver. DGE analysis was performed over LSECs, and we identified the top 20 expressed genes in the periportal, perivenous, and intermediate acinar zones. Multi-omics and scRNA-seq analysis over Visium images and ECs liver cells showed OIT3, DNASE1L3, CLEC4G, LYVE1, FCN2, and CRHBP as commonly expressed mid-lobular zonation-specific genes. Also, this study detected STAB2, F8, AQP1, TEK, TIMP3, TIE1, and CTSL genes as expressed in DILI and NASH EC populations. The connection between LSEC marker genes in zone 2 and liver fibrosis holds significant promise for advancing our understanding in developing new therapeutic strategies for fibrosis reversal and designing computational molecular biomarkers in NASH and DILI fibrotic liver diseases.

Use of crushed tranexamic acid tablets in water for paediatric patients with bleeding disorders.

Ε-Aminocaproic acid oral solution (EACA OS) is the only commercially available antifibrinolytic for patients who cannot swallow tablets. Insurance denials and high costs remain barriers to its use. To determine the safety and efficacy of crushed tranexamic acid tablets in water (cTXAw) for children with bleeding disorders. We retrospectively reviewed records of children (<10 years) with bleeding disorders who received cTXAw or EACA OS from 1 December 2018, through 31 July 2022, at Mayo Clinic (Rochester, Minnesota). Bleeding outcomes were defined according to ISTH criteria. Thirty-two patients were included (median age, 3 years; male, n=23). Diagnoses were VWD (n=17), haemophilia (n=5), FVII deficiency (n=3), inherited platelet disorder (n=4), ITP (n=2), and combined FV and FVII deficiencies (n=1). Thirty-two courses of cTXAw (monotherapy 24/32; mean duration 6 days) and fifteen courses of EACA (monotherapy 12/15; mean duration 5 days) were administered. No surgical procedures (n=28) were complicated by bleeding. Of the 19 bleeding events, 16 had effective haemostasis, two had no reported outcome, and one had no response. cTXAw and EACA were equally effective in preventing and treating bleeding (p value>.1). No patients had adverse effects. Eight of 19 patients (42%) who were initially prescribed EACA OS did not receive it because of cost or insurance denial. The estimated average wholesale price of one treatment was $94 for cTXAw and $905 for EACA OS. CTXAw appears to be an effective, safe, and low-cost alternative option to EACA OS for young children with bleeding disorders.

Diagnosis and treatment of venous thromboembolism during pregnancy relate to genetic polymorphism.

Previous research had shown that age, a positive family history, comorbidities, major surgical operations, gestation, and use of several medications could increase the incidence of venous thromboembolism (VTE). With the development of medical and clinical individualized treatment, many people exposed to above risk factors did not develop VTE, suggested that genetic factors are also involved in the development of VTE. In this review, we aim to summarize VTE diagnosis and treatment in pregnancy women related to gene polymorphism. A comprehensive electronic search using PubMed, MEDLINE, EMBASE and Web of Science was conducted to find relevant journal articles with key search terms including: "pregnancy OR pregnant," "venous thromboembolism OR VTE," "deep vein thrombosis OR DVT," "pulmonary embolism OR PE," and "genetic OR gene." Prominent publications from establishment of database till present were analysed to achieve a deeper understanding of VTE during pregnancy relate to genetic polymorphism, and the information was then collated to form this review. The literature review revealed that inherited thrombophilia significantly associated with the development of VTE, especially the factor V Leiden (FVL) and prothrombin gene mutation (PGM). Furthermore, the role of methylenetetrahydrofolate reductase (MTHFR) gene mutation in the development of pregnancy-related VTE remains controversial, further study is required. In the present study, Marburg I polymorphism (G511E), c.1538G>A and c.1601G>A in Factor V (FV), JAK2V617F mutation were reported as an independent risk factor for VTE, there is no sufficient evidence to confirm the gene mutation is related to VTE during pregnancy, these factors appearing as another promising potential diagnostic marker of VTE during pregnancy. Besides, the dosages of heparin in the treatment of VTE during pregnancy need be adjusted according to gene polymorphism of these population, particularly FVL or PGM carriers, and this area is not studied deeply, it is worth further study. Inherited thrombophilia significantly associated with the development of VTE, especially the FVL and PGM, however the relation between MTHFR gene mutation and pregnancy-related VTE remains controversial, further study is needed. In addition, the dosages of heparin in the treatment of VTE during pregnancy suggested to adjusted based on gene polymorphism in FVL and PGM, and establish better prediction models is a direction of future research.

Molecular mechanism analysis of a family with hereditary coagulation F Ⅺ deficiency caused by compound heterozygous mutations

A 34 year old female patient was scheduled to undergo surgical resection due to a "breast nodule". Preoperative examination revealed an activated partial thromboplastin time (APTT) of 66.2 seconds, coagulation factor Ⅺ activity (FⅪ: C) of 2%, and FⅪ antigen (FⅪ: Ag) of 40.3%. The patient and family members showed no abnormal bleeding symptoms. Diagnosed as hereditary coagulation factor Ⅺ deficiency. Genetic testing revealed that the F11 gene had a heterozygous nonsense mutation in exon 10, c.1107C>A (p.Tyr351stop), and a heterozygous missense mutation in exon 13, c.1562A>G (p.Tyr503Cys). The father and son were p Heterozygous carriers of Tyr351stop mutation, while the mother and daughter are p Heterozygous carriers of Tyr503Cys mutations. The in vitro expression results showed that p The Tyr351stop mutation resulted in a significant decrease in the transcription level of F11 gene, while p The Tyr503Cys mutation has no effect on the transcription level and protein expression level of F11 gene, but it leads to a significant decrease in the level of FⅪ:C in the cell culture supernatant.

Whole F8 gene sequencing identified pathogenic structural variants in the remaining unsolved patients with severe hemophilia A

BackgroundNo F8 genetic abnormality is detected in approximately 1% to 2% of patients with severe hemophilia A (HA) using conventional genetic approaches. In these patients, deep intronic variation or F8 disrupting genomic rearrangement could be causal. ObjectivesThe study aimed to identify the causal variation in families with a history of severe HA for whom genetic investigations failed. MethodsWe performed whole F8 gene sequencing in 8 propositi. Genomic rearrangements were confirmed by Sanger sequencing of breakpoint junctions and/or quantitative polymerase chain reaction. ResultsA structural variant disrupting F8 was found in each propositus, so that all the 815 families with a history of severe HA registered in our laboratory received a conclusive genetic diagnosis. These structural variants consisted of 3 balanced inversions, 3 large insertions of gained regions, and 1 retrotransposition of a mobile element. The 3 inversions were 105 Mb, 1.97 Mb, and 0.362 Mb in size. Among the insertions of gained regions, one corresponded to the insertion of a 34 kb gained region from chromosome 6q27 in F8 intron 6, another was the insertion of a 447 kb duplicated region from chromosome 9p22.1 in F8 intron 14, and the last one was the insertion of an Xq28 349 kb gained in F8 intron 5. ConclusionAll the genetically unsolved cases of severe HA in this cohort were due to structural variants disrupting F8. This study highlights the effectiveness of whole F8 sequencing to improve the molecular diagnosis of HA when the conventional approach fails.

Genetic variant detection in a South African haemophilia B population.

Haemophilia B is characterised by a deficiency of factor IX (FIX) protein due to genetic variants in the FIX gene (F9). Genetic testing may have a vital role in effectively managing haemophilia B. However, in many developing countries, comprehensive genetic variant detection is unavailable. This study aimed to address the lack of genetic data in our country by conducting genetic variant detection on people affected by haemophilia B in our region. Twenty-one participants were screened with a direct Sanger sequencing method to identify variants in the F9 gene. The identified variants were then compared to previously published variants and/or to a reference database. A total of ten F9 genetic changes were detected, with five of them being novel. These identified variants were distributed across different domains of the FIX protein. Only one participant had a history of inhibitor formation against FIX replacement therapy. Notably, this participant had two distinct genetic changes present adjacent to each other. Thus, we hypothesise that the presence of multiple variants within the same functional region of the gene may increase the risk for inhibitor development. The discovery of novel pathogenic variations in the F9 gene highlights the importance of genetic analysis in specific geographical regions. The possible link between a complex variant and inhibitor formation illustrates the potential role that genetic screening has as a pre-treatment tool in predicting treatment reactions and outcomes.

The identification of a novel compound heterozygous mutation in hereditary human coagulation factor VII deficiency following a bamboo leaf green snake bite.

Hereditary factor VII (FVII) deficiency is an uncommon autosomal recessive disorder associated with mutations in the F7 gene, and laboratory investigations usually reveal isolated prolongation in prothrombin time (PT)/international normalized ratio (INR). Venom-induced consumptive coagulopathy (VICC) is distinguished by the activation of the coagulation pathway, which is triggered by procoagulant toxins in snake venom. Diagnosing snakebites in patients with hereditary FVII deficiency presents a challenge because prolonged time PT/INR is considered the most valuable diagnostic method for VICC. Therefore, it is possible that certain patients may not promptly receive an accurate diagnosis of hereditary FVII deficiency. We present a pedigree featuring hereditary FVII deficiency, which was diagnosed through Sanger sequencing, following a bamboo leaf green snake bite.

Study of Factor VIII Inhibitor and F8 Gene Mutations in Persons with Hemophilia A from Benin

Aim: determine the prevalence of a FVIII inhibitors and identify the genetic mutations associated with their development in beninese personne with hemophilia (PwH) A. Study Design: this is cross-sectional descrptive study conducted from June 2022 to May 2023 in hemophilia treatment centers in Benin. Methodology: Inhibitor screening was carried out systematically in all PwHs A receiving FVIII infusion through determination of the circulating anticoagulant index and the Nijmegen-Bethesda assay. The molecular study strategy used for the F8 gene associated with hemophilia A is dependent on the severity of the hemophilia. Other data were collected either from patients' responses to the questionnaire or by studying their medical records and the center's hemophilia registry. Results: Of the 97 PwHs A followed up, 57 had been treated with FVIII infusion. Of these, 21 had developed inhibitors, representing a frequency of 36.8% of treated PwHs A and 43.75% of severe PwHs. None of the moderate or mild PwHs A had developed anti-FVIII antibodies. PwHs A with inhibitors had a median age of 11 years, ranging from 1 to 66 years. The Nijmegen-Bethesda test revealed 11 high responders and 10 low responders. Mutation analysis of the F8 gene revealed seven cases of intron 22 inversion, seven cases of nonsense mutations, three cases of deletion and one case of missense mutation. Mutations weren’t identified in three patients because their DNA did not amplify on long-distance PCR. In terms of therapy, immune tolerance induction wasn’t achieved in any of the 21 patients, but they are treated with emicizumab and bypass depending on the context. Conclusion: Although a cross-sectional study with a limited sample size, this study provides valuable information on beninese PwHs A with inhibitors. The frequency of inhibitors is high in treated PwHs A, and almost all patients who have developed inhibitors have high-risk genetic mutations.

The Identification of a Novel Compound Heterozygous Mutation in Hereditary Human Coagulation Factor VII (FVII) Deficiency Following a Bamboo Leaf Green Snake Bite

Hereditary factor VII (FVII) deficiency is an uncommon autosomal recessive disorder associated with mutations in the F7 gene and laboratory investigations usually reveal isolated prolongation in prothrombin time (PT)/International normalized ratio (INR). Venom-induced consumptive coagulopathy (VICC) is distinguished by the activation of the coagulation pathway, which is triggered by procoagulant toxins in snake venom. Diagnosing snakebites in patients with hereditary FVII deficiency presents a challenge due to the fact that prolonged time PT/ INR is considered the most valuable diagnostic method for VICC. Therefore, it is possible that certain patients may not promptly receive an accurate diagnosis of hereditary FVII deficiency. We present a pedigree featuring hereditary FVII deficiency, which was diagnosed through Sanger sequencing, following a bamboo leaf green snake bite.

Coagulation factor V in breast cancer: a p53-regulated tumor suppressor and predictive marker for treatment response to chemotherapy

BackgroundPatients with cancer are at an increased risk of developing coagulation complications, and chemotherapy treatment increases the risk. Tumor progression is closely linked to the hemostatic system. Breast cancer tumors express coagulation factor V (FV), an essential factor in blood coagulation. The functional role of FV during treatment with chemotherapy is poorly understood and was explored in this study. ObjectivesWe aimed to investigate the role of FV in breast cancer progression by exploring associations with treatment response, gene regulation, and the functional effects of FV. MethodsThe receiver operating characteristic plotter was used to explore the predictive value of FV mRNA (F5) expression for treatment with FEC (5-fluorouracil, anthracycline, and cyclophosphamide). Breast cancer cohorts were analyzed to study treatment response to FEC. The effect of chemotherapy on F5 expression, the regulation of F5, and the functional effects of FV dependent and independent of chemotherapy were studied in breast cancer cell lines. ResultsF5 tumor expression was significantly higher in responders to FEC than in nonresponders. In vitro experiments revealed that anthracycline treatment increased the expression of F5. Inhibition and knockdown of p53 reduced the anthracycline-induced F5 expression. Mutation of a p53 half-site (c.158+1541/158+1564) in a luciferase plasmid reduced luciferase activity, suggesting that p53 plays a role in regulating F5. FV overexpression increased apoptosis and reduced proliferation slightly during anthracycline treatment. ConclusionOur study identified F5 as a p53-regulated tumor suppressor candidate and a promising marker for response to chemotherapy. FV may have functional effects that are therapeutically relevant in breast cancer.

The role of microRNAs in defining LSECs cellular identity and in regulating F8 gene expression.

Introduction: Coagulation Factor VIII (FVIII) plays a pivotal role in the coagulation cascade, and deficiencies in its levels, as seen in Hemophilia A, can lead to significant health implications. Liver sinusoidal endothelial cells (LSECs) are the main producers and contributors of FVIII in blood, a fact we have previously elucidated through mRNA expression profiling when comparing these cells to other endothelial cell types. Methods: Our current investigation focuses on small microRNAs, analyzing their distinct expression patterns across various endothelial cells and hepatocytes. Results: The outcome of this exploration underscores the discernible microRNAs expression differences that set LSECs apart from both hepatocytes (193 microRNAs at p < 0.05) and other endothelial cells (72 microRNAs at p < 0.05). Notably, the 134 and 35 overexpressed microRNAs in LSECs compared to hepatocytes and other endothelial cells, respectively, shed light on the unique functions of LSECs in the liver. Discussion: Our investigation identified a panel of 10 microRNAs (miR-429, miR-200b-3p, miR-200a-3p, miR-216b-5p, miR-1185-5p, miR-19b-3p, miR-192-5p, miR-122-5p, miR-30c-2-3p, and miR-30a-5p) that distinctly define LSEC identity. Furthermore, our scrutiny extended to microRNAs implicated in F8 regulation, revealing a subset (miR-122-5p, miR-214-3p, miR-204-3p, and miR-2682-5p) whose expression intricately correlates with F8 expression within LSECs. This microRNA cohort emerges as a crucial modulator of F8, both directly through suppression and indirect effects on established F8-related transcription factors. The above microRNAs emerged as potential targets for innovative therapies in Hemophilia A patients.

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.

Decoding the complexity of on-target integration: characterizing DNA insertions at the CRISPR-Cas9 targeted locus using nanopore sequencing

BackgroundCRISPR-Cas9 technology has advanced in vivo gene therapy for disorders like hemophilia A, notably through the successful targeted incorporation of the F8 gene into the Alb locus in hepatocytes, effectively curing this disorder in mice. However, thoroughly evaluating the safety and specificity of this therapy is essential. Our study introduces a novel methodology to analyze complex insertion sequences at the on-target edited locus, utilizing barcoded long-range PCR, CRISPR RNP-mediated deletion of unedited alleles, magnetic bead-based long amplicon enrichment, and nanopore sequencing.ResultsWe identified the expected F8 insertions and various fragment combinations resulting from the in vivo linearization of the double-cut plasmid donor. Notably, our research is the first to document insertions exceeding ten kbp. We also found that a small proportion of these insertions were derived from sources other than donor plasmids, including Cas9-sgRNA plasmids, genomic DNA fragments, and LINE-1 elements.ConclusionsOur study presents a robust method for analyzing the complexity of on-target editing, particularly for in vivo long insertions, where donor template integration can be challenging. This work offers a new tool for quality control in gene editing outcomes and underscores the importance of detailed characterization of edited genomic sequences. Our findings have significant implications for enhancing the safety and effectiveness of CRISPR-Cas9 gene therapy in treating various disorders, including hemophilia A.

Factor VIII as a Novel Biomarker for Diagnosis, Prognosis, and Therapy Prediction in Human Cancer and Other Disorders.

Coagulation factor VIII (FVIII) is an essential cofactor in the coagulation cascade, encoded by the F8 gene on the long arm of chromosome X (Xq28). FVIII is normally circulated in complex with Von Willebrand factor (VWF) and has relevant emerging extracoagulative functions. Dysregulation of FVIII is associated with tumor progression, and could be used as a novel biomarker for tumor screening and monitoring. In breast cancer, bladder cancer, colorectal carcinoma, esophageal carcinoma, hepatocellular carcinoma and lung cancer, F8 is regarded as an oncogene. In coronary heart disease, hemophilia A and liver disease, F8 dysregulation has been recognized as a potential biomarker for disease diagnosis and prognosis. However, the basis of these differential expression levels remains to be understood. In this review, which is a mixture of literature review and bioinformatics analysis we described the biological functions and characteristics of FVIII, and also its expression level in non-malignant disorders and various cancers.

De Novo Noninversion Variants Implicated in Sporadic Hemophilia A: A Variant Origin and Timing Study.

Sporadic hemophilia A (HA) enables the persistence of HA in the population. F8 gene inversion originates mainly in male germ cells during meiosis. To date, no studies have shown the origin and timing of HA sporadic noninversion variants (NIVs); herein, we assume that HA-sporadic NIVs are generated as a de novo variant. Of the 125 registered families with HA, 22 were eligible for inclusion. We conducted a linkage analysis using F8 gene markers and amplification refractory mutation system-quantitative polymerase chain reaction to confirm the origin of the sporadic NIVs (~0% mutant cells) or the presence of a mosaic variant, which requires further confirmation of the origin in the parent. Nine mothers, four maternal grandmothers, and six maternal grandfathers were confirmed to be the origin of sporadic NIVs, which most likely occurred in the zygote within the first few cell divisions and in single sperm cells, respectively. Three mothers had mosaic variants, which most likely occurred early in postzygotic embryogenesis. All maternal grandparents were free from sporadic NIV. In conclusion, F8 NIVs in sporadic HA were found to be caused primarily by de novo variants. Our studies are essential for understanding the genetic pathogenesis of HA and improving current genetic counseling.

Pleiotropic effects of different exonic nucleotide changes at the same position contribute to hemophilia B phenotypic variation

BackgroundThe disease-causing effects of genetic variations often depend on their location within a gene. Exonic changes generally lead to alterations in protein production, secretion, activity, or clearance. However, owing to the overlap between proteins and splicing codes, missense variants can also affect messenger RNA splicing, thus adding a layer of complexity and influencing disease phenotypes. ObjectivesTo extensively characterize a panel of 13 exonic variants in the F9 gene occurring at 6 different factor IX positions and associated with varying severities of hemophilia B (HB). MethodsComputational predictions, splicing analysis, and recombinant factor IX assays were exploited to characterize F9 variants. ResultsWe demonstrated that 5 (38%) of 13 selected F9 exonic variants have pleiotropic effects. Although bioinformatic approaches accurately classified effects, extensive experimental assays were required to elucidate and deepen the molecular mechanisms underlying the pleiotropic effects. Importantly, their characterization was instrumental in developing tailored RNA therapeutics based on engineered U7 small nuclear RNA to mask cryptic splice sites and compensatory U1 small nuclear RNA to enhance exon definition. ConclusionOverall, albeit a multitool bioinformatic approach suggested the molecular effects of multiple HB variants, the deep investigation of molecular mechanisms revealed insights into the HB phenotype–genotype relationship, enabling accurate classification of HB variants. Importantly, knowledge of molecular mechanisms allowed the development of tailored RNA therapeutics, which can also be translated to other genetic diseases.

АССОЦИАЦИЯ ПОЛИМОРФИЗМА ГЕНОВ СИСТЕМЫ ГЕМОСТАЗА С КЛИНИКО-ЛАБОРАТОРНЫМИ ПОКАЗАТЕЛЯМИ У ПАЦИЕНТОВ С ИНФАРКТОМ МИОКАРДА

The article presents the analysis of the association between polymorphic variants of the FGA, FGG, F2, F5, F11, F13, PAI-1, and GP6 genes and clinical, instrumental, and laboratory data in patients with myocardial infarction from the Republic of Belarus. It has been demonstrated that in patients with myocardial infarction, there exist statistically significant correlations between polymorphic variants of the genes F11 (rs2289252 and rs2036914), F13 (rs5985), F5 (rs6025), PAI-1 (rs1799889), FGG (rs2066865), and a variety of laboratory values and functional indicators of the myocardium. A comprehensive analysis of the genetic component (DNA polymorphism) and the outcomes of dynamic follow-up of the patient in hospital enable clinicians to accurately assess potential hazards of the occurrence and unfavorable progression of a number of diseases including myocardial infarction.

Molecular identification of the most frequent pathotypes of Escherichia coli in calves with diarrhoea in the Cajamarca region of Peru

Background: Colibacillosis caused by Escherichia coli causes significant economic losses in the livestock sector worldwide and is one of the calves' leading causes of diarrhoea. Aim: This study aimed to identify the most frequent E. coli molecularly pathotypes in calves with diarrhoea in six provinces of the Cajamarca region in the northern highlands of Peru. Methods: Twenty-eight herds of dairy cattle under a semi-intensive rearing system were evaluated; 95 samples were isolated from calves with diarrhoea up to the first month of life, 62 males and 33 females, during the rainy season. Results: The presence of virulence genes of E. coli strains was more prevalent in males; the astA (89.47%), st (83.15%) and f5 (57.89%) genes were more expressed, and the lt (17.89%) and stx2 (1.05%) genes were less expressed. The eae gene (21.05%) was more present in females. Conclusion: When E. coli strains express virulence genes astA, st and f5 and their atypical double, triple and quadruple combination between different observed pathotypes, they give rise to the formation of several pathotypes by the horizontal transfer of virulence genes, which can cause colibacillosis processes in more virulent calves, which is one of the most important causes of diarrhoea in calves in the region of Cajamarca, compromising the sanitary viability in the herds.

Patient with congenital factor VII deficiency undergoing brain tumor neurosurgery successfully treated with recombinant factor VIIa and fresh frozen plasma: A case report and literature review

Rationale: Congenital factor VII deficiency is the most common among rare bleeding disorders, characterized by spontaneous or traumatic bleeding. The clinical manifestation is heterogeneous, ranging from asymptomatic phenotype to life-threatening hemorrhages. Intracranial hemorrhage is a common complication of brain tumor neurosurgery, which significantly challenges the perioperative management of patients with hemostatic defects. Patient concerns: This report presented a 55-year-old man with congenital factor VII deficiency, who had no history of hemorrhage or family history. He underwent a craniotomy for the treatment of papillary craniopharyngioma. Diagnoses: The patient was diagnosed as papillary craniopharyngioma, factor VII deficiency, and atrial fibrillation. Interventions: To prevent bleeding, a total of 8 doses of recombinant activated factor VII and 1 dose of fresh frozen plasma were administered as the perioperative replacement therapy. This scheme was guided by a pharmacodynamic evaluation, laboratory tests, and imaging examinations. Outcomes: No excessive surgical bleeding was observed during the 22-day treatment. The patient was found to have compound heterozygous mutations, Ala304Thr (c.910G &gt; A) and IVS5-2A &gt; G (c.572-2A &gt; G), in the F7 gene. Lessons: This is the first reported case in which surgical hemorrhage secondary to brain tumor resection was successfully controlled in the presence of congenital factor VII deficiency. Perioperative coagulation state, hemostasis, and thrombosis events should be closely observed, and the interval and dosage of recombinant factor VIIa should be adjusted accordingly.

Complete F9 Gene Deletion, Duplication, and Triplication Rearrangements: Implications for Factor IX Expression and Clinical Phenotypes.

Factor IX (FIX) plays a critical role in blood coagulation. Complete deletion of F9 results in severe hemophilia B, whereas the clinical implications of complete F9 duplication and triplication remain understudied. To investigate the rearrangement mechanisms underlying complete F9 deletion (cases 1 and 2), duplication (cases 3 and 4), and triplication (case 5), and to explore their association with FIX expression levels and clinical impacts. Plasma FIX levels were detected using antigen and activity assays. CNVplex technology, optical genome mapping, and long-distance polymerase chain reaction were employed to characterize the breakpoints of the chromosomal rearrangements. Cases 1 and 2 exhibited FIX activities below 1%. Case 3 displayed FIX activities within the reference range. However, cases 4 and 5 showed a significant increase in FIX activities. Alu-mediated nonallelic homologous recombination was identified as the cause of F9 deletion in case 1; FoSTeS/MMBIR (Fork Stalling and Template Switching/microhomology-mediated break-induced replication) contributed to both F9 deletion and tandem duplication observed in cases 2 and 3; BIR/MMBIR (break-induced replication/microhomology-mediated break-induced replication) mediated by the same pair of low-copy repeats results in similar duplication-triplication/inversion-duplication (DUP-TRP/INV-DUP) rearrangements in cases 4 and 5, leading to complete F9 duplication and triplication, respectively. Large deletions involving the F9 gene exhibit no apparent pattern, and the extra-hematologic clinical phenotypes require careful analysis of other genes within the deletion. The impact of complete F9 duplication and triplication on FIX expression might depend on the integrity of the F9 upstream sequence and the specific rearrangement mechanisms. Notably, DUP-TRP/INV-DUP rearrangements significantly elevate FIX activity and are closely associated with thrombotic phenotypes.