RARE DISEASE
Congenital factor VII deficiency
Congenital factor VII deficiency
Congenital factor VII deficiency
Synonyms: Congenital proconvertin deficiency, Hypoproconvertinemia
Synonyms: Congenital proconvertin deficiency, Hypoproconvertinemia
Synonyms: Congenital proconvertin deficiency, Hypoproconvertinemia
Drug discovery
9
drugs
With orphan designations
Overview
Congenital Factor VII Deficiency is a rare autosomal recessive bleeding disorder caused by mutations in the F7 gene, leading to deficient or dysfunctional coagulation factor VII. Prevalence ranges from 1/300,000 to 1/500,000, with higher rates in consanguineous populations [1][2][16]. Clinical presentation varies widely, from asymptomatic cases to severe bleeding (e.g., intracranial, gastrointestinal, or joint hemorrhages) [1][6][9]. Diagnosis involves isolated prolonged prothrombin time (PT) and confirmation via FVII activity assays [1][2]. Treatment centers on recombinant activated FVII (rFVIIa), plasma-derived products, and fresh frozen plasma (FFP) [3][6][8].
Population
Prevalence: 1/300,000–500,000 globally; higher in regions with consanguinity [1][2][19].
Affects both sexes equally, though women often present earlier due to menorrhagia [6][9][16].
Severe cases typically diagnosed neonatally (e.g., CNS bleeds), while milder forms may remain undetected until adulthood [1][6][11].
Burden
Clinical heterogeneity: No consistent correlation between FVII levels and bleeding severity [1][9][16].
Severe complications: Life-threatening hemorrhage (e.g., intracranial), recurrent hemarthroses, and iron-deficiency anemia [1][4][6].
Psychosocial impact: Reduced quality of life, employment challenges, and activity restrictions (e.g., contact sports) [9][16].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
475 drug discovery papers about Congenital factor VII deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
475 drug discovery papers about Congenital factor VII deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-15 | Perioperative management in a patient with congenital factor VII deficiency following mechanical valve replacement: a case report.
Congenital factor VII deficiency (CFVIID) is a rare hemorrhagic disorder which elevates perioperative bleeding risks. Mechanical prosthesis mandates lifelong anticoagulation, while international normalized ratio (INR) of CFVIID deviates significantly from the normal range which could not accurately reflect the real anticoagulation. Perioperative management for CFVIID patients undergoing mechanical valve replacement are highly challenging, with no clinical guidelines currently available. We reported a 59-year-old CFVIID patient undergoing mechanical valve replacement. Perioperative recombinant activated factor VII (rFVIIa) replacement secured hemostasis. After postoperative cerebral thrombosis, anticoagulation of warfarin was initiated and guided by factor Ⅱ/Ⅹ activity (30-45%) rather than INR. No bleeding or recurrent thrombosis was observed. Perioperative rFVIIa replacement guarantees hemostatic safety for cardiac surgery. Lifelong warfarin anticoagulation is essential for CFVIID patient with mechanical prosthesis. Monitoring factor Ⅱ/Ⅹ activity instead of INR can balance bleeding and thrombosis risks for such cases.
2026-03-22 | Managing heavy menstrual bleeding in adolescents with bleeding disorders: Outcomes from a pragmatic LMIC approach.
Heavy menstrual bleeding (HMB) a common manifestation of bleeding disorders in adolescents contributes to anemia, transfusions, and impaired quality-of-life (QOL). Evidence supporting practical management strategies in resource-limited settings remains limited. This observational study in adolescents with confirmed bleeding disorders with HMB at a tertiary hemophilia treatment centre evaluated menstrual blood loss and QOL after a standard regimen of progesterone, tranexamic acid and iron; blood products or clotting factor concentrates were reserved for refractory bleeding. Twenty adolescents were included (2020-2025); von Willebrand disease (n = 11), chronic immune thrombocytopenia (n = 4), congenital aplastic anemia (n = 3), afibrinogenemia (n = 1), and factor VII deficiency (n = 1). Median PBAC score at presentation was 300 (range 190-500). Eighteen patients (90%) had anemia and prior transfusion exposure. After therapy, median PBAC declined to 100 (range 60-150). Hemoglobin improved steadily and no patient required further red cell transfusion during a median follow-up of four years. Hemostatic products were required only in two patients while on this regimen. Quality-of-life scores improved across physical, emotional, and social domains. A low-cost regimen combining progesterone, antifibrinolytic therapy, and iron effectively controls HMB, corrects anemia, reduces transfusion and factor utilization, and improves QOL in adolescents with bleeding disorders in resource-constrained settings.
2026-02-01 | Vitamin K1 and K2 supplementation in VKCFD1 patients
Introduction Vitamin K dependent clotting factor deficiency type1 (VKCFD1) is a rare congenital disorder caused by mutations in the γ-glutamyl carboxylase ( GGCX ) gene. VKCFD1 patients are homozygous or compound heterozygous. GGCX is essential for the post-translational activation of all vitamin K–dependent proteins (VKDPs), including the coagulation factors II, VII, IX, and X, as well as proteins C, S and Z. In addition, GGCX is required for the activation of VKDPs unrelated to coagulation, such as matrix Gla protein (MGP) and osteocalcin (OC), whose impairment contributes to severe phenotypes, including midfacial hypoplasia and hearing loss. Treatment strategies for VKCFD1 have primarily focused on correcting the coagulation defects through the daily supplementation of phylloquinone (vitamin K₁). Here, we present a therapeutic protocol with supplementation of Vitamin K1 and MK-4, addressing both clotting- and non–clotting-related manifestations in 2 children with VKCFD1. Method Patient 1 is a 3-year-old girl compound heterozygous forc.944G>A (p.Trp315Ter) and c.1A>G, (p.Ala2_Met75del). At 31 weeks of gestation, midface hypoplasia, polyhydramnios and micromelia were noted. Soon after birth, she developed extensive subdural, subarachnoid, and epidural hemorrhages with impending herniation. She has spinal punctiform calcifications. Her atlas arch is hypoplastic without brain stem compression. She shows mild vertebral anomalies. She has hearing loss and relevant pulmonary artery stenosis. Patient 2 is a 4-year-old girl compound heterozygous for c.1616dup (p.His539GlnfsTer8); c.1790C>A (p.Ser597Tyr) and c.1822G>C (p.Glu608Gln). At 32 weeks of gestation, amniocentesis was performed because of facial dysplasia and polyhydramnios. She has a small nasal bridge, hypoplastic alae nasi, protruding forehead, shortned limbs, fingers, atlas arch with narrowing of the craniocervical junction without brainstem compression, mild vertebral anomalies, hearing loss and asymptomatic pulmonary artery stenosis. Plasma uncarboxylated OC (ucOC) was measured using the ELISA kit from Takara (#MK118). Plasma ucMGP levels were determined using the CE-marked chemiluminescent InaKtif MGP assay on the IDS-iSYS system (IDS, Boldon, UK). Results Supplementation with vitamin K₁ (K₁) (10 mg/day) improved activities of vitamin K–dependent (VKD) clotting factors. However, for the non-hematological VKDPs, markedly elevated pathological levels of ucOC and ucMGP were detected in plasma. Therefore, a stepwise increase in the concentration of the vitamin K₂ derivative menaquinone-4 (MK-4) was considered as an adjunct therapy. Following MK-4 supplementation, both patients exhibited improved carboxylation of the non-hepatic VKD proteins MGP and OC ([ Fig. 1 ]). Fig. 1 Patient data Conclusion Here, for the first time we present a treatment protocol for VKCFD1 patients that includes supplementation of Vitamin K1 and additionally MK-4 that improves both, the activity of VKD clotting factors and the γ-carboxylation of non-hematological VKDPs. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-12-25 | Optimizing Surgical Approaches for Patients with Inherited Factor VII Deficiency.
Inherited factor VII deficiency (FVIID) presents a highly variable bleeding phenotype. The weak correlation between plasma FVII levels (FVII:C) and bleeding severity results in diverse management strategies and complicates surgical decision-making.To describe surgical management and bleeding outcomes in patients with FVIID, and to identify key decision-making variables and predictors of surgical bleeding.We conducted a multicenter, retrospective study of 380 surgeries performed in 215 patients with FVIID. Patients were classified by FVII:C levels as mild, moderate, or severe deficiency. Bleeding score (BS) was defined according to ISTH-BAT. Surgeries were categorized as low-moderate risk (LR) or high risk (HR) for bleeding. A decision-tree simulation was performed.Most patients had mild FVIID (76%), and 68% of surgeries were classified as LR. Prophylactic treatment with tranexamic acid (TA) and/or rFVIIa was administered in 42.8% of LR and 62.8% of HR surgeries. Prophylaxis was given to 73.9% of moderate/severe and 41% of mild FVIID patients, especially for HR procedures. FVII:C levels and surgical bleeding risk were key factors that influenced the selection of treatment. The overall bleeding rate was 3.1% (HR: 9%; LR: 0.4%). Most bleeding events occurred in mild FVIID patients with BS ≥3. Our algorithm recommends hemostatic treatment for all moderate/severe, and for mild patients HR surgeries and LR procedures when BS is ≥3.FVII:C levels and surgery type influence prophylactic hemostatic treatment strategies. Patients with mild FVIID, higher BS, and no hemostatic treatment had a greater risk of bleeding. Bleeding score and procedural risk were identified as predictors of surgical bleeding.
2025-11-03 | A 10-year retrospective review of the effectiveness and safety of tranexamic acid in women with inherited bleeding disorders in the peripartum setting
Abstract Background: PPH occurs at a rate of nearly 11% globally and is a major cause of maternal mortality worldwide (Carroli, 2008.) Women with inherited bleeding disorders such as hemophilia carriers and those with von Willebrand disease (VWD) are at a substantially greater risk of postpartum hemorrhage (PPH) (Abdul-Kadir, 2014.) TXA use for treatment of PPH has been shown to reduce major bleeding risk without increasing the risk of thromboembolism in patients (Li, 2017). However, the effects of its prophylactic use in patients with bleeding disorders has not been extensively described. The aim of this study was to investigate the effectiveness and safety of prophylactic TXA use in peripartum patients with inherited bleeding disorders. Methods: A retrospective chart review was conducted for all patients with an inherited bleeding disorder cared for by the Multidisciplinary Clinic for Women with Bleeding Disorders (MCWBD) at St. Michael's Hospital (SMH) between 2014 and 2024. We performed descriptive statistical analysis to summarize findings related to bleeding and thrombotic events in patients treated with TXA in the puerperium. Results: There were 296 total patients managed over the course of pregnancy to labour and delivery in the MCWBD over this 10 year time period. 205 had an inherited bleeding disorder (the remainder had an acquired disorder and were not included in the analysis). The median age of patients was 32 (range 18-42). 32% had von Willebrand's Disease, 17% platelet function disorder, 1% hemophilia A,10% symptomatic hemophilia A or B carrier, 18% Bleeding Disorder of Undetermined Cause and 14% rare single clotting factor deficiency. 61% of patients had vaginal delivery, 39% had a C-section. We had access to complete labour and delivery records for 144 patients to allow for reporting of bleeding events. 95% of patients received TXA at some point during delivery. 68% patients received TXA during and after delivery, 11% received TXA only during delivery and 16% received TXA only after delivery. 31% patients also received an additional hemostatic agent (17% received DDAVP, 15% received factor concentrate -VWF:FVIII, FXI, FVIII, rFVIIa and FIX). 17% of patients experienced postpartum hemorrhage (PPH) and of those 88% had primary PPH. 12% of patients with PPH did not use any TXA prophylactically. Two patients who received TXA experienced a thrombotic event post-partum (2/205, 0.98%). One patient with severe factor VII deficiency developed pulmonary embolism 14 days after delivery during which she was being treated with a tapering regimen of rFVIIa and TXA. She had 3 risk factors for VTE: morbid obesity, varicose veins and heterozygosity for factor V leiden mutation. The other patient developed a superficial venous thrombus 1 day after delivery, she had 2 risk factors for VTE: morbid obesity and varicose veins. Conclusions: This data suggests that TXA is associated with very low risk of thrombosis when used as prophylactic treatment for PPH among patients with inherited bleeding disorders in the puerperium. Under 1% of patients over 10 years experienced a thrombotic event and had two or more risk factors for VTE. In contrast, at least 17% had PPH despite provision of preventative peripartum hemostatic therapy that almost always included TXA. This suggests that on balance, TXA should be provided to patients with inherited bleeding disorders with the goal of PPH prevention but caution should be used in those with 2 or more risk factors for thrombosis. Prospective studies on the use of prophylactic TXA in this setting is warranted.
cell therapies
2025-10-09 | Ex vivo correction of severe coagulation Factor VII deficiency in patient-derived 3D liver organoids.
Coagulation factor (F) VII deficiency is the most frequent among the rare, inherited bleeding disorders and is predominantly caused by missense mutations in the F7 gene. The disease phenotype ranges from asymptomatic cases to extremely severe hemorrhagic forms, requiring prophylactic injections with plasma-derived or recombinant FVII concentrates. In response, we have developed an autologous cell-based approach that corrects the disease-causing mutation in patient- derived induced pluripotent stem cells (iPSC) and generates therapeutic, three-dimensional hepatic organoids (HO). We report the CRISPR-mediated correction of homozygous c.718G>C (p.G240R), a missense mutation associated with a severe, life-threatening bleeding phenotype. The HO contain all liver cell types and exhibit key liver functions, including coagulation factor production. After correction, our data indicate that the patient-derived HO secrete consistent amounts of functional FVII protein, resulting in improved thrombin generation times. These results represent a significant milestone toward the establishment of an autologous cell-based therapy for patients with FVII- and other coagulation factor deficiencies.
2018-02-19 | Selection of Tissue Factor-Deficient Cell Transplants as a Novel Strategy for Improving Hemocompatibility of Human Bone Marrow Stromal Cells
Intravascular transplantation of tissue factor (TF)-bearing cells elicits an instant blood-mediated inflammatory reaction (IBMIR) resulting in thrombotic complications and reduced engraftment.Here we studied the hemocompatibility of commonly used human white adipose tissue (WAT), umbilical cord (UC) and bone marrow stromal cells (BMSC) and devised a possible strategy for safe and efficient stromal cell transplantation.Methods: Stromal cell identity, purity, and TF expression was tested by RTQ-PCR, flow cytometry and immunohistochemistry. Pro-coagulant activity and fibrin clot formation/stabilization was measured In Vitro by viscoelastic rotational plasma-thromboelastometry and in vivo by injecting sorted human stromal cells intravenously into rats.The impact of TF was verified in factor VII-deficient plasma and by sort-depleting TF/CD142 + BMSC.Results: We found significantly less TF expression by a subpopulation of BMSC corresponding to reduced pro-coagulant activity.UC and WAT stroma showed broad TF expression and durable clotting.Higher cell numbers significantly increased clot formation partially dependent on coagulation factor VII. Depleting the TF/CD142 + subpopulation significantly ameliorated BMSC's hemocompatibility without affecting immunomodulation.TF-deficient BMSC did not produce thromboembolism in vivo, comparing favorably to massive intravascular thrombosis induction by TF-expressing stromal cells. Conclusion:We demonstrate that plasma-based thromboelastometry provides a reliable tool to detect pro-coagulant activity of therapeutic cells.Selecting TF-deficient BMSC is a novel strategy for improving cell therapy applicability by reducing cell dose-dependent IBMIR risk.The particularly strong pro-coagulant activity of UC and WAT preparations sounds an additional note of caution regarding uncritical systemic application of stromal cells, particularly from non-hematopoietic extravascular sources.
2015-07-08 | First living-related liver transplant to cure factor VII deficiency.
Abstract Congenital factor VII deficiency is an autosomal recessive serious disorder of blood coagulation with wide genotypic and phenotypic variations. The clinical presentation can vary from asymptomatic patients to patients with major bleedings in severe deficiency (factor VII <1%). Investigations show prolonged PT and low factor VII . Treatment modalities include FFP and repeated recombinant factor VII infusions. We hereby report the first successful LRLT for factor VII deficiency in an infant, the first‐ever youngest baby reported worldwide. A six‐month‐old male child presented with easy bruisability, ecchymotic patches, hematuria, and convulsions. CT of the head showed subdural hemorrhage, which was treated conservatively. He had markedly increased PT (120 s) with normal platelets, and aPTT with factor VII level <1%. Despite the treatment by rFVIIa administration weekly, which was very expensive, he still had repeated life‐threatening bleeding episodes. LRLT was performed with mother as the donor, whose factor VII level was 57%. A factor VII infusion plan for pre‐, intra‐ and postoperative periods was formulated and TEG followed. Postoperatively, his factor VII started increasing from third day and was 38% on 24th day with PT <14 s. He had uneventful intraoperative and postoperative courses. LT is a safe and definite cure for factor VII deficiency.
2015-06-19 | Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency
A child with severe S-adenosylhomocysteine hydrolase (AHCY) deficiency (AHCY c.428A > G, p.Tyr143Cys; c.982 T > G, p.Tyr328Asp) presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy, hepatopathy, and factor VII deficiency. Plasma methionine, S-adenosylmethionine (AdoMet), and S-adenosylhomocysteine (AdoHcy) were markedly elevated and the molar concentration ratio of AdoMet:AdoHcy, believed to regulate a myriad of methyltransferase reactions, was 15% of the control mean. Dietary therapy failed to normalize biochemical markers or alter the AdoMet to AdoHcy molar concentration ratio. At 40 months of age, the proband received a liver segment from a healthy, unrelated living donor. Mean AdoHcy decreased 96% and the AdoMet:AdoHcy concentration ratio improved from 0.52 ± 0.19 to 1.48 ± 0.79 mol:mol (control 4.10 ± 2.11 mol:mol). Blood methionine and AdoMet were normal and stable during 6 months of follow-up on an unrestricted diet. Average calculated tissue methyltransferase activity increased from 43 ± 26% to 60 ± 22%, accompanied by signs of increased transmethylation in vivo. Factor VII activity increased from 12% to 100%. During 6 postoperative months, head growth accelerated 4-fold and the patient made promising gains in gross motor, language, and social skills.
2014-02-28 | Liver transplant for congenital factor VII deficiency
Congenital factor VII (FVII) deficiency is a rare, autosomal recessive bleeding disorder with a spectrum of phenotypes ranging from asymptomatic to life-threatening intra-cranial hemorrhage (ICH). Orthotopic liver transplantation has been described for definitive treatment in a few patients with severe manifestations. We report a patient with congenital FVII deficiency and recurrent ICH, despite twice-weekly prophylaxis with recombinant activated FVII. At 17 months of age, he underwent an orthotopic liver transplant. He is now 1-year post-transplant, on maintenance immunosuppression with no hemorrhage or other complications. Pediatr Blood Cancer 2014; 61:1886–1887. © 2014 Wiley Periodicals, Inc.
gene therapies
2025-08-01 | Molecular Aspects of Rare Coagulation Factor Deficiencies.
Rare coagulation factor deficiencies are inherited disorders affecting factors I, II, V, VII, X, XI, XIII, and combined forms. They mainly present with bleeding symptoms of variable severity. These deficiencies show significant clinical heterogeneity, with no consistent correlation between factor levels and bleeding intensity. Prevalence is higher in populations with high consanguinity rates. Understanding relies on the study of genetic and molecular mechanisms. Diagnosis is based on hemostasis testing, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and factor activity assays. In case of abnormalities, Molecular analysis is undertaken using genomic DNA extracted from peripheral blood samples. Depending on the clinical context and the level of detail required, sequencing is performed using either Sanger sequencing or next-generation sequencing (NGS) platforms, enabling the identification of pathogenic variants responsible for the coagulation disorder. Variant interpretation follows American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines. Large deletions or duplications are assessed via Multiplex Ligation-dependent Probe Amplification (MLPA) or Copy number variations (CNV) analysis. Molecular analysis revealed a wide range of mutations depending on the deficient factor. Missense mutations are the most common, followed by nonsense, splicing, and insertion/deletion mutations. Some mutations prevent factor production, while others alter its structure or secretion. Each mutation type has a distinct impact on the bleeding phenotype. Genetic characterization improves diagnostic accuracy and guides clinical management. Modern molecular tools have enhanced the understanding of these disorders' pathophysiology. A multidisciplinary approach is essential for optimal patient care. Ongoing research is key to developing targeted therapies.
2023-10-01 | OC 07.1 Autologous CRISPR/Cas9 Correction of a Missense Variant from a Patient with Severe, Inherited FVII Deficiency
Background: Coagulation Factor VII (FVII) deficiency is a rare monogenic, bleeding disorder caused by mutations in the F7 gene.We have previously reported two young siblings with dramatically reduced FVII activity and a severe, life-threatening hemorrhagic phenotype, induced by a homozygous c.718G>C missense mutation leading to a glycine-to-arginine substitution at amino acid 240 ( p.G240R).Aims: To correct the p.G240R mutation in patients' cells by combining Induced Pluripotent Stem Cell (iPSC) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 gene editing technology.Methods: Patient-derived Peripheral Blood Mononuclear Cells (PBMCs) were reprogrammed into iPSCs using the non-integrative CytoTune™-iPS 2.0 kit and validated for specific markers via quantitative PCR, immunofluorescence, and tri-lineage differentiation.Different candidate guide RNAs (gRNAs) were generated by IDT™ and Benchling ® designing tools and nucleofected using the Neon™ Transfection System.The on-target efficiency was evaluated by T7 Endonuclease I assay and digital droplet PCR (ddPCR), while correction occurrence via Homology-directed Repair (HDR) was assessed through restriction enzyme, ddPCR and by Sanger sequencing.Written informed consent was obtained.Results: To confirm that iPSCs were successfully reprogrammed, the consistent expression of Sox2, Oct4 and Nanog markers was verified, as well as the absence of KOS, hc-Myc and hKlf4 reprogramming vectors.Trilineage assays validated the differentiation of the iPSCs to definitive endoderm, neuroepithelium and functional cardiomyocytes, corroborated by expression of FoxA2 and Sox17, Pax6 and Sox2, Troponin T2, respectively.The candidate gRNAs showed an on-target efficiency up to 48%.The selected gRNA generated a HDR rate up to 20%.Restriction enzyme studies and Sanger sequencing further confirmed a successful homozygous correction. Conclusion(s):We proved the successful correction of a severe FVII missense variant using gene editing technology, in patients' iPSCs.This completes an important step towards obtaining autologous iPSC-derived liver cells with functional FVII and the development of a novel cell-based therapy for the treatment of FVII deficiency.
2022-01-17 | Novel factor VII gene mutations in six families with hereditary coagulation factor VII deficiency.
Hereditary human coagulation factor VII (FVII) deficiency is an inherited autosomal recessive hemorrhagic disease involving mutations in the F7 gene. The sites and types of F7 mutations may influence the coagulation activities of plasma FVII (FVII: C) and severity of hemorrhage symptoms. However, the specific mutations that impact FVII activity are not completely known. We tested the coagulation functions and plasma activities of FVII in seven patients recruited from six families with hereditary FVII deficiency and sequenced the F7 gene of the patients and their families. Then, we analyzed the genetic information from the six families and predicted the structures of the mutated proteins. In this study, we detected 11 F7 mutations, including four novel mutations, in which the mutations p.Phe84Ser and p.Gly156Cys encoded the Gla and EGF domains of FVII, respectively, while the mutation p.Ser339Leu encoded the recognition site of the enzymatic protein and maintained the conformation of the catalytic domain structure. Meanwhile, the mutation in the 5' untranslated region (UTR) was closely associated with the mRNA regulatory sequence. We have identified novel genetic mutations and performed pedigree analysis that shed light on the pathogenesis of hereditary human coagulation FVII deficiency and may contribute to the development of treatments for this disease.
2018-01-24 | Expanded carrier screening and preimplantation genetic diagnosis in a couple who delivered a baby affected with congenital factor VII deficiency
Preimplantation genetic diagnosis (PGD) is a powerful tool for preventing the transmission of Mendelian disorders from generation to generation. However, PGD only can identify monogenically inherited diseases, but not other potential monogenic pathologies. We aimed to use PGD to deliver a healthy baby without congenital FVII deficiency or other common Mendelian diseases in a couple in which both individuals carried a deleterious mutation in the F7 gene.After both members of the couple were confirmed to be carriers of the F7 gene mutation by Sanger sequencing, expanded carrier screening (ECS) for 623 recessive inheritance diseases was performed to detect pathological mutations in other genes. PGD and preimplantational genetic screening (PGS) were employed to exclude monogenic disorders and aneuploidy for their embryos.ECS using targeted capture sequencing technology revealed that the couple carried the heterozygous disease-causative mutations c.3659C > T (p.Thr1220Ile) and c.3209G > A (p.Arg1070Gln) in the CFTR gene. After PGD and PGS, one of their embryos that was free of congenital FVII deficiency, cystic fibrosis (CF) and aneuploidy was transferred, resulting in the birth of a healthy 3200 g male infant.We successfully implemented PGD for congenital FVII deficiency and PGD after ECS to exclude CF for the first time to the best of our knowledge. Our work significantly improved the reproductive outcome for the couple and provides a clear example of the use of ECS combined with PGD to avoid the delivery of offspring affected not only by identified monogenically inherited diseases but also by other potential monogenic pathologies and aneuploidy.
2017-01-06 | An engineered tale-transcription factor rescues transcription of factor VII impaired by promoter mutations and enhances its endogenous expression in hepatocytes.
Tailored approaches to restore defective transcription responsible for severe diseases have been poorly explored. We tested transcription activator-like effectors fused to an activation domain (TALE-TFs) in a coagulation factor VII (FVII) deficiency model. In this model, the deficiency is caused by the -94C > G or -61T > G mutation, which abrogate the binding of Sp1 or HNF-4 transcription factors. Reporter assays in hepatoma HepG2 cells naturally expressing FVII identified a single TALE-TF (TF4) that, by targeting the region between mutations, specifically trans-activated both the variant (>100-fold) and wild-type (20-40-fold) F7 promoters. Importantly, in the genomic context of transfected HepG2 and transduced primary hepatocytes, TF4 increased F7 mRNA and protein levels (2- to 3-fold) without detectable off-target effects, even for the homologous F10 gene. The ectopic F7 expression in renal HEK293 cells was modestly affected by TF4 or by TALE-TF combinations. These results provide experimental evidence for TALE-TFs as gene-specific tools useful to counteract disease-causing promoter mutations.
proteins
2026-01-22 | Congenital factor VII deficiency as a cause of postpartum hemorrhage: A case report.
Obstetric hemorrhage is one of the leading causes of maternal morbidity and mortality worldwide. However, coagulation disorders as an etiology are rare, with a prevalence of less than 1 %. This report concerns the case of a 24-year-old patient with no previous history of bleeding who presented with postpartum hemorrhage at 38.6 weeks of pregnancy after a normal vaginal delivery. The hemorrhage was refractory to the use of uterotonics and compression maneuvers. In the absence of uterine atony, retained products of conception, or obvious trauma, the possibility of an underlying coagulopathy was considered. Initial studies showed an isolated prolongation of prothrombin time, with activated partial thromboplastin time within normal parameters. A correction test with a normal plasma pool was performed, which showed complete correction of prothrombin time. Specific factor quantification confirmed a severe and isolated factor VII deficiency.
2026-01-19 | Factor VII deficiency is more prevalent than previously reported.
The prevalence of factor (F)VII deficiency is estimated at approximately 1 of 500,000 individuals. However, low FVII activity (FVII:C) is frequently observed in a population of <500,000 in the region of Östergötland, Sweden. To estimate the prevalence and bleeding tendency of adult FVII-deficient patients in Östergötland, Sweden. In this retrospective cross-sectional study, the laboratory information system was used to identify adult patients with at least one FVII:C result ≤ 0.50 kilo International Units per Liter (kIU/L) between January 1, 2017, and December 31, 2022. The most likely cause was established, and in patients with a FVII deficiency, as defined by the Nordic Hemophilia Council (FVII:C < 0.35 kIU/L) or low FVII level (0.35-0.50 kIU/L), the bleeding tendency was evaluated. FVII:C ≤ 0.50 kIU/L was identified in 97 patients residing in Östergötland. Of these, 21 had FVII deficiency, and 39 had low FVII level, corresponding to a prevalence of at least 1 of 17,800 and 1 of 9600 in the adult population in Östergötland, respectively. Patients with FVII deficiency differed significantly from patients with low FVII level in bleeding symptoms (P = .01). Of the FVII-deficient patients, 38% were asymptomatic, while 19% and 24% had experienced minor and major spontaneous bleedings, respectively. The prevalence of FVII deficiency was estimated to be at least 1 of 17,800 adults, which is 28 times higher than the internationally claimed prevalence. Spontaneous bleeding occurred in 43% of these individuals.
2026-01-13 | Congenital Factor VII Deficiency Revealed in the Neonatal Period: A Case Report at CHNEAR
Congenital factor VII deficiency is a rare, autosomal recessive disorder with an estimated prevalence of 1 in 1,000,000. We report the case of a female newborn, born to second-degree consanguineous parents, admitted at 22 days of age for management of a subarachnoid hemorrhage. Hemostasis testing revealed a prothrombin time (PT) of 16%, with a preserved activated partial thromboplastin time (aPTT). Coagulation testing demonstrated an isolated factor VII deficiency. Through this case, we highlight the clinical, biological, and therapeutic characteristics of this anomaly during the neonatal period.
2026-01-10 | Use of Plasma-Derived FVII Concentrate in Surgical Patients with Factor VII Deficiency: A Case Series.
Congenital factor VII (FVII) deficiency is the most common rare hemorrhagic disorder. Acquired FVII deficiency can be isolated or associated with other low coagulation factor levels. FVII levels do not accurately predict a patient's bleeding risk. In the case of surgery, the perioperative management needs to be evaluated on a case-by-case basis, considering the patient's bleeding history and the type of surgery. We present 12 patients with congenital or acquired FVII deficiency and describe the perioperative management with plasma-derived nonactivated FVII (pd-FVII) concentrate. Patients with factor VII deficiency treated with pd-FVII for perioperative hemostasis, between April 2022 and May 2025. We report thirteen procedures in 12 patients (11 males and 1 female; age range: 15-78 years). Two patients were affected by acquired deficiency, and 10 patients presented congenital deficiency. Perioperative prophylaxis with pd-FVII was performed at doses ranging from 20 to 40 IU/kg/dose. Total pd-FVII consumption ranged between 20 and 320 IU/kg. During and after surgery, there were no major bleeding or thrombotic events. In the postoperative period, only one patient presented with hematuria.
2026-01-01 | Procoagulant Activity of a SARS-CoV-2 Nucleocapsid C-Terminal Domain Analog in Factor-Deficient Plasma
This study investigates the procoagulant properties of a synthetic peptide analog derived from the SARS-CoV-2 Nucleocapsid (N) C-terminal domain. The research demonstrates that this specific peptide sequence can bypass standard coagulation pathways to promote fibrin clot formation even in compromised biochemical environments.Key Technical Highlights:Bypass Mechanism: The peptide promotes clot formation in factor-deficient plasma lacking Vitamin K-dependent factors (Factors II, VII, IX, and X).Quantitative Efficacy: Experimental results show a significant reduction in plasma recalcification time, shortening it from $23.74 \pm 0.27$ minutes to $8.442 \pm 6.0395$ minutes ($p = 0.0012$).Structural Target: Focus on the C-terminal domain of the SARS-CoV-2 N protein as a novel template for hemostatic agents.Clinical Significance: Provides a foundation for developing synthetic procoagulants for treating coagulopathies, Vitamin K deficiency, or severe bleeding disorders where traditional factors are absent.
other
2024-08-20 | Cardiovascular disease and thrombosis: Intersections with the immune system, inflammation, and the coagulation system.
The coagulation and immune system, both essential physiological systems in the human body, are intricately interconnected and play a critical role in determining the overall health of patients. These systems collaborate via various shared regulatory pathways, such as the Tissue Factor (TF) Pathway. Immunological cells that express TF and generate pro-inflammatory cytokines have the ability to affect coagulation. Conversely, coagulation factors and processes have a reciprocal effect on immunological responses by stimulating immune cells and regulating their functions. These interconnected pathways play a role in both preserving well-being and contributing to a range of pathological disorders. The close relationship between blood clotting and inflammation in the development of vascular disease has become a central focus of clinical study. This research specifically examines the crucial elements of this interaction within the contexts of cardiovascular disease and acute coronary syndrome. Tissue factor, the primary trigger of the extrinsic coagulation pathway, has a crucial function by inducing a proinflammatory reaction through the activation of coagulation factors. This, in turn, initiates coagulation and subsequent cellular signalling pathways. Protease-activated receptors establish the molecular connection between coagulation and inflammation by interacting with activated clotting factors II, X, and VII. Thrombosis, a condition characterised by the formation of blood clots, is the most dreaded consequence of cardiovascular disorders and a leading cause of death globally. Consequently, it poses a significant challenge to healthcare systems. Antithrombotic treatments efficiently target platelets and the coagulation cascade, but they come with the inherent danger of causing bleeding. Furthermore, antithrombotics are unable to fully eliminate thrombotic events, highlighting a treatment deficiency caused by a third mechanism that has not yet been sufficiently addressed, namely inflammation. Understanding these connections may aid in the development of novel approaches to mitigate the harmful mutual exacerbation of inflammation and coagulation. Gaining a comprehensive understanding of the intricate interaction among these systems is crucial for the management of diseases and the creation of efficacious remedies. Through the examination of these prevalent regulatory systems, we can discover novel therapeutic approaches that specifically target these complex illnesses. This paper provides a thorough examination of the reciprocal relationship between the coagulation and immune systems, emphasising its importance in maintaining health and understanding disease processes. This review examines the interplay between inflammation and thrombosis and its role in the development of thrombotic disorders.
small molecules
2026-06-15 | Perioperative management in a patient with congenital factor VII deficiency following mechanical valve replacement: a case report.
Congenital factor VII deficiency (CFVIID) is a rare hemorrhagic disorder which elevates perioperative bleeding risks. Mechanical prosthesis mandates lifelong anticoagulation, while international normalized ratio (INR) of CFVIID deviates significantly from the normal range which could not accurately reflect the real anticoagulation. Perioperative management for CFVIID patients undergoing mechanical valve replacement are highly challenging, with no clinical guidelines currently available. We reported a 59-year-old CFVIID patient undergoing mechanical valve replacement. Perioperative recombinant activated factor VII (rFVIIa) replacement secured hemostasis. After postoperative cerebral thrombosis, anticoagulation of warfarin was initiated and guided by factor Ⅱ/Ⅹ activity (30-45%) rather than INR. No bleeding or recurrent thrombosis was observed. Perioperative rFVIIa replacement guarantees hemostatic safety for cardiac surgery. Lifelong warfarin anticoagulation is essential for CFVIID patient with mechanical prosthesis. Monitoring factor Ⅱ/Ⅹ activity instead of INR can balance bleeding and thrombosis risks for such cases.
2026-03-22 | Managing heavy menstrual bleeding in adolescents with bleeding disorders: Outcomes from a pragmatic LMIC approach.
Heavy menstrual bleeding (HMB) a common manifestation of bleeding disorders in adolescents contributes to anemia, transfusions, and impaired quality-of-life (QOL). Evidence supporting practical management strategies in resource-limited settings remains limited. This observational study in adolescents with confirmed bleeding disorders with HMB at a tertiary hemophilia treatment centre evaluated menstrual blood loss and QOL after a standard regimen of progesterone, tranexamic acid and iron; blood products or clotting factor concentrates were reserved for refractory bleeding. Twenty adolescents were included (2020-2025); von Willebrand disease (n = 11), chronic immune thrombocytopenia (n = 4), congenital aplastic anemia (n = 3), afibrinogenemia (n = 1), and factor VII deficiency (n = 1). Median PBAC score at presentation was 300 (range 190-500). Eighteen patients (90%) had anemia and prior transfusion exposure. After therapy, median PBAC declined to 100 (range 60-150). Hemoglobin improved steadily and no patient required further red cell transfusion during a median follow-up of four years. Hemostatic products were required only in two patients while on this regimen. Quality-of-life scores improved across physical, emotional, and social domains. A low-cost regimen combining progesterone, antifibrinolytic therapy, and iron effectively controls HMB, corrects anemia, reduces transfusion and factor utilization, and improves QOL in adolescents with bleeding disorders in resource-constrained settings.
2026-02-01 | Vitamin K1 and K2 supplementation in VKCFD1 patients
Introduction Vitamin K dependent clotting factor deficiency type1 (VKCFD1) is a rare congenital disorder caused by mutations in the γ-glutamyl carboxylase ( GGCX ) gene. VKCFD1 patients are homozygous or compound heterozygous. GGCX is essential for the post-translational activation of all vitamin K–dependent proteins (VKDPs), including the coagulation factors II, VII, IX, and X, as well as proteins C, S and Z. In addition, GGCX is required for the activation of VKDPs unrelated to coagulation, such as matrix Gla protein (MGP) and osteocalcin (OC), whose impairment contributes to severe phenotypes, including midfacial hypoplasia and hearing loss. Treatment strategies for VKCFD1 have primarily focused on correcting the coagulation defects through the daily supplementation of phylloquinone (vitamin K₁). Here, we present a therapeutic protocol with supplementation of Vitamin K1 and MK-4, addressing both clotting- and non–clotting-related manifestations in 2 children with VKCFD1. Method Patient 1 is a 3-year-old girl compound heterozygous forc.944G>A (p.Trp315Ter) and c.1A>G, (p.Ala2_Met75del). At 31 weeks of gestation, midface hypoplasia, polyhydramnios and micromelia were noted. Soon after birth, she developed extensive subdural, subarachnoid, and epidural hemorrhages with impending herniation. She has spinal punctiform calcifications. Her atlas arch is hypoplastic without brain stem compression. She shows mild vertebral anomalies. She has hearing loss and relevant pulmonary artery stenosis. Patient 2 is a 4-year-old girl compound heterozygous for c.1616dup (p.His539GlnfsTer8); c.1790C>A (p.Ser597Tyr) and c.1822G>C (p.Glu608Gln). At 32 weeks of gestation, amniocentesis was performed because of facial dysplasia and polyhydramnios. She has a small nasal bridge, hypoplastic alae nasi, protruding forehead, shortned limbs, fingers, atlas arch with narrowing of the craniocervical junction without brainstem compression, mild vertebral anomalies, hearing loss and asymptomatic pulmonary artery stenosis. Plasma uncarboxylated OC (ucOC) was measured using the ELISA kit from Takara (#MK118). Plasma ucMGP levels were determined using the CE-marked chemiluminescent InaKtif MGP assay on the IDS-iSYS system (IDS, Boldon, UK). Results Supplementation with vitamin K₁ (K₁) (10 mg/day) improved activities of vitamin K–dependent (VKD) clotting factors. However, for the non-hematological VKDPs, markedly elevated pathological levels of ucOC and ucMGP were detected in plasma. Therefore, a stepwise increase in the concentration of the vitamin K₂ derivative menaquinone-4 (MK-4) was considered as an adjunct therapy. Following MK-4 supplementation, both patients exhibited improved carboxylation of the non-hepatic VKD proteins MGP and OC ([ Fig. 1 ]). Fig. 1 Patient data Conclusion Here, for the first time we present a treatment protocol for VKCFD1 patients that includes supplementation of Vitamin K1 and additionally MK-4 that improves both, the activity of VKD clotting factors and the γ-carboxylation of non-hematological VKDPs. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-12-25 | Optimizing Surgical Approaches for Patients with Inherited Factor VII Deficiency.
Inherited factor VII deficiency (FVIID) presents a highly variable bleeding phenotype. The weak correlation between plasma FVII levels (FVII:C) and bleeding severity results in diverse management strategies and complicates surgical decision-making.To describe surgical management and bleeding outcomes in patients with FVIID, and to identify key decision-making variables and predictors of surgical bleeding.We conducted a multicenter, retrospective study of 380 surgeries performed in 215 patients with FVIID. Patients were classified by FVII:C levels as mild, moderate, or severe deficiency. Bleeding score (BS) was defined according to ISTH-BAT. Surgeries were categorized as low-moderate risk (LR) or high risk (HR) for bleeding. A decision-tree simulation was performed.Most patients had mild FVIID (76%), and 68% of surgeries were classified as LR. Prophylactic treatment with tranexamic acid (TA) and/or rFVIIa was administered in 42.8% of LR and 62.8% of HR surgeries. Prophylaxis was given to 73.9% of moderate/severe and 41% of mild FVIID patients, especially for HR procedures. FVII:C levels and surgical bleeding risk were key factors that influenced the selection of treatment. The overall bleeding rate was 3.1% (HR: 9%; LR: 0.4%). Most bleeding events occurred in mild FVIID patients with BS ≥3. Our algorithm recommends hemostatic treatment for all moderate/severe, and for mild patients HR surgeries and LR procedures when BS is ≥3.FVII:C levels and surgery type influence prophylactic hemostatic treatment strategies. Patients with mild FVIID, higher BS, and no hemostatic treatment had a greater risk of bleeding. Bleeding score and procedural risk were identified as predictors of surgical bleeding.
2025-11-03 | A 10-year retrospective review of the effectiveness and safety of tranexamic acid in women with inherited bleeding disorders in the peripartum setting
Abstract Background: PPH occurs at a rate of nearly 11% globally and is a major cause of maternal mortality worldwide (Carroli, 2008.) Women with inherited bleeding disorders such as hemophilia carriers and those with von Willebrand disease (VWD) are at a substantially greater risk of postpartum hemorrhage (PPH) (Abdul-Kadir, 2014.) TXA use for treatment of PPH has been shown to reduce major bleeding risk without increasing the risk of thromboembolism in patients (Li, 2017). However, the effects of its prophylactic use in patients with bleeding disorders has not been extensively described. The aim of this study was to investigate the effectiveness and safety of prophylactic TXA use in peripartum patients with inherited bleeding disorders. Methods: A retrospective chart review was conducted for all patients with an inherited bleeding disorder cared for by the Multidisciplinary Clinic for Women with Bleeding Disorders (MCWBD) at St. Michael's Hospital (SMH) between 2014 and 2024. We performed descriptive statistical analysis to summarize findings related to bleeding and thrombotic events in patients treated with TXA in the puerperium. Results: There were 296 total patients managed over the course of pregnancy to labour and delivery in the MCWBD over this 10 year time period. 205 had an inherited bleeding disorder (the remainder had an acquired disorder and were not included in the analysis). The median age of patients was 32 (range 18-42). 32% had von Willebrand's Disease, 17% platelet function disorder, 1% hemophilia A,10% symptomatic hemophilia A or B carrier, 18% Bleeding Disorder of Undetermined Cause and 14% rare single clotting factor deficiency. 61% of patients had vaginal delivery, 39% had a C-section. We had access to complete labour and delivery records for 144 patients to allow for reporting of bleeding events. 95% of patients received TXA at some point during delivery. 68% patients received TXA during and after delivery, 11% received TXA only during delivery and 16% received TXA only after delivery. 31% patients also received an additional hemostatic agent (17% received DDAVP, 15% received factor concentrate -VWF:FVIII, FXI, FVIII, rFVIIa and FIX). 17% of patients experienced postpartum hemorrhage (PPH) and of those 88% had primary PPH. 12% of patients with PPH did not use any TXA prophylactically. Two patients who received TXA experienced a thrombotic event post-partum (2/205, 0.98%). One patient with severe factor VII deficiency developed pulmonary embolism 14 days after delivery during which she was being treated with a tapering regimen of rFVIIa and TXA. She had 3 risk factors for VTE: morbid obesity, varicose veins and heterozygosity for factor V leiden mutation. The other patient developed a superficial venous thrombus 1 day after delivery, she had 2 risk factors for VTE: morbid obesity and varicose veins. Conclusions: This data suggests that TXA is associated with very low risk of thrombosis when used as prophylactic treatment for PPH among patients with inherited bleeding disorders in the puerperium. Under 1% of patients over 10 years experienced a thrombotic event and had two or more risk factors for VTE. In contrast, at least 17% had PPH despite provision of preventative peripartum hemostatic therapy that almost always included TXA. This suggests that on balance, TXA should be provided to patients with inherited bleeding disorders with the goal of PPH prevention but caution should be used in those with 2 or more risk factors for thrombosis. Prospective studies on the use of prophylactic TXA in this setting is warranted.
cell therapies
2025-10-09 | Ex vivo correction of severe coagulation Factor VII deficiency in patient-derived 3D liver organoids.
Coagulation factor (F) VII deficiency is the most frequent among the rare, inherited bleeding disorders and is predominantly caused by missense mutations in the F7 gene. The disease phenotype ranges from asymptomatic cases to extremely severe hemorrhagic forms, requiring prophylactic injections with plasma-derived or recombinant FVII concentrates. In response, we have developed an autologous cell-based approach that corrects the disease-causing mutation in patient- derived induced pluripotent stem cells (iPSC) and generates therapeutic, three-dimensional hepatic organoids (HO). We report the CRISPR-mediated correction of homozygous c.718G>C (p.G240R), a missense mutation associated with a severe, life-threatening bleeding phenotype. The HO contain all liver cell types and exhibit key liver functions, including coagulation factor production. After correction, our data indicate that the patient-derived HO secrete consistent amounts of functional FVII protein, resulting in improved thrombin generation times. These results represent a significant milestone toward the establishment of an autologous cell-based therapy for patients with FVII- and other coagulation factor deficiencies.
2018-02-19 | Selection of Tissue Factor-Deficient Cell Transplants as a Novel Strategy for Improving Hemocompatibility of Human Bone Marrow Stromal Cells
Intravascular transplantation of tissue factor (TF)-bearing cells elicits an instant blood-mediated inflammatory reaction (IBMIR) resulting in thrombotic complications and reduced engraftment.Here we studied the hemocompatibility of commonly used human white adipose tissue (WAT), umbilical cord (UC) and bone marrow stromal cells (BMSC) and devised a possible strategy for safe and efficient stromal cell transplantation.Methods: Stromal cell identity, purity, and TF expression was tested by RTQ-PCR, flow cytometry and immunohistochemistry. Pro-coagulant activity and fibrin clot formation/stabilization was measured In Vitro by viscoelastic rotational plasma-thromboelastometry and in vivo by injecting sorted human stromal cells intravenously into rats.The impact of TF was verified in factor VII-deficient plasma and by sort-depleting TF/CD142 + BMSC.Results: We found significantly less TF expression by a subpopulation of BMSC corresponding to reduced pro-coagulant activity.UC and WAT stroma showed broad TF expression and durable clotting.Higher cell numbers significantly increased clot formation partially dependent on coagulation factor VII. Depleting the TF/CD142 + subpopulation significantly ameliorated BMSC's hemocompatibility without affecting immunomodulation.TF-deficient BMSC did not produce thromboembolism in vivo, comparing favorably to massive intravascular thrombosis induction by TF-expressing stromal cells. Conclusion:We demonstrate that plasma-based thromboelastometry provides a reliable tool to detect pro-coagulant activity of therapeutic cells.Selecting TF-deficient BMSC is a novel strategy for improving cell therapy applicability by reducing cell dose-dependent IBMIR risk.The particularly strong pro-coagulant activity of UC and WAT preparations sounds an additional note of caution regarding uncritical systemic application of stromal cells, particularly from non-hematopoietic extravascular sources.
2015-07-08 | First living-related liver transplant to cure factor VII deficiency.
Abstract Congenital factor VII deficiency is an autosomal recessive serious disorder of blood coagulation with wide genotypic and phenotypic variations. The clinical presentation can vary from asymptomatic patients to patients with major bleedings in severe deficiency (factor VII <1%). Investigations show prolonged PT and low factor VII . Treatment modalities include FFP and repeated recombinant factor VII infusions. We hereby report the first successful LRLT for factor VII deficiency in an infant, the first‐ever youngest baby reported worldwide. A six‐month‐old male child presented with easy bruisability, ecchymotic patches, hematuria, and convulsions. CT of the head showed subdural hemorrhage, which was treated conservatively. He had markedly increased PT (120 s) with normal platelets, and aPTT with factor VII level <1%. Despite the treatment by rFVIIa administration weekly, which was very expensive, he still had repeated life‐threatening bleeding episodes. LRLT was performed with mother as the donor, whose factor VII level was 57%. A factor VII infusion plan for pre‐, intra‐ and postoperative periods was formulated and TEG followed. Postoperatively, his factor VII started increasing from third day and was 38% on 24th day with PT <14 s. He had uneventful intraoperative and postoperative courses. LT is a safe and definite cure for factor VII deficiency.
2015-06-19 | Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency
A child with severe S-adenosylhomocysteine hydrolase (AHCY) deficiency (AHCY c.428A > G, p.Tyr143Cys; c.982 T > G, p.Tyr328Asp) presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy, hepatopathy, and factor VII deficiency. Plasma methionine, S-adenosylmethionine (AdoMet), and S-adenosylhomocysteine (AdoHcy) were markedly elevated and the molar concentration ratio of AdoMet:AdoHcy, believed to regulate a myriad of methyltransferase reactions, was 15% of the control mean. Dietary therapy failed to normalize biochemical markers or alter the AdoMet to AdoHcy molar concentration ratio. At 40 months of age, the proband received a liver segment from a healthy, unrelated living donor. Mean AdoHcy decreased 96% and the AdoMet:AdoHcy concentration ratio improved from 0.52 ± 0.19 to 1.48 ± 0.79 mol:mol (control 4.10 ± 2.11 mol:mol). Blood methionine and AdoMet were normal and stable during 6 months of follow-up on an unrestricted diet. Average calculated tissue methyltransferase activity increased from 43 ± 26% to 60 ± 22%, accompanied by signs of increased transmethylation in vivo. Factor VII activity increased from 12% to 100%. During 6 postoperative months, head growth accelerated 4-fold and the patient made promising gains in gross motor, language, and social skills.
2014-02-28 | Liver transplant for congenital factor VII deficiency
Congenital factor VII (FVII) deficiency is a rare, autosomal recessive bleeding disorder with a spectrum of phenotypes ranging from asymptomatic to life-threatening intra-cranial hemorrhage (ICH). Orthotopic liver transplantation has been described for definitive treatment in a few patients with severe manifestations. We report a patient with congenital FVII deficiency and recurrent ICH, despite twice-weekly prophylaxis with recombinant activated FVII. At 17 months of age, he underwent an orthotopic liver transplant. He is now 1-year post-transplant, on maintenance immunosuppression with no hemorrhage or other complications. Pediatr Blood Cancer 2014; 61:1886–1887. © 2014 Wiley Periodicals, Inc.
gene therapies
2025-08-01 | Molecular Aspects of Rare Coagulation Factor Deficiencies.
Rare coagulation factor deficiencies are inherited disorders affecting factors I, II, V, VII, X, XI, XIII, and combined forms. They mainly present with bleeding symptoms of variable severity. These deficiencies show significant clinical heterogeneity, with no consistent correlation between factor levels and bleeding intensity. Prevalence is higher in populations with high consanguinity rates. Understanding relies on the study of genetic and molecular mechanisms. Diagnosis is based on hemostasis testing, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and factor activity assays. In case of abnormalities, Molecular analysis is undertaken using genomic DNA extracted from peripheral blood samples. Depending on the clinical context and the level of detail required, sequencing is performed using either Sanger sequencing or next-generation sequencing (NGS) platforms, enabling the identification of pathogenic variants responsible for the coagulation disorder. Variant interpretation follows American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines. Large deletions or duplications are assessed via Multiplex Ligation-dependent Probe Amplification (MLPA) or Copy number variations (CNV) analysis. Molecular analysis revealed a wide range of mutations depending on the deficient factor. Missense mutations are the most common, followed by nonsense, splicing, and insertion/deletion mutations. Some mutations prevent factor production, while others alter its structure or secretion. Each mutation type has a distinct impact on the bleeding phenotype. Genetic characterization improves diagnostic accuracy and guides clinical management. Modern molecular tools have enhanced the understanding of these disorders' pathophysiology. A multidisciplinary approach is essential for optimal patient care. Ongoing research is key to developing targeted therapies.
2023-10-01 | OC 07.1 Autologous CRISPR/Cas9 Correction of a Missense Variant from a Patient with Severe, Inherited FVII Deficiency
Background: Coagulation Factor VII (FVII) deficiency is a rare monogenic, bleeding disorder caused by mutations in the F7 gene.We have previously reported two young siblings with dramatically reduced FVII activity and a severe, life-threatening hemorrhagic phenotype, induced by a homozygous c.718G>C missense mutation leading to a glycine-to-arginine substitution at amino acid 240 ( p.G240R).Aims: To correct the p.G240R mutation in patients' cells by combining Induced Pluripotent Stem Cell (iPSC) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 gene editing technology.Methods: Patient-derived Peripheral Blood Mononuclear Cells (PBMCs) were reprogrammed into iPSCs using the non-integrative CytoTune™-iPS 2.0 kit and validated for specific markers via quantitative PCR, immunofluorescence, and tri-lineage differentiation.Different candidate guide RNAs (gRNAs) were generated by IDT™ and Benchling ® designing tools and nucleofected using the Neon™ Transfection System.The on-target efficiency was evaluated by T7 Endonuclease I assay and digital droplet PCR (ddPCR), while correction occurrence via Homology-directed Repair (HDR) was assessed through restriction enzyme, ddPCR and by Sanger sequencing.Written informed consent was obtained.Results: To confirm that iPSCs were successfully reprogrammed, the consistent expression of Sox2, Oct4 and Nanog markers was verified, as well as the absence of KOS, hc-Myc and hKlf4 reprogramming vectors.Trilineage assays validated the differentiation of the iPSCs to definitive endoderm, neuroepithelium and functional cardiomyocytes, corroborated by expression of FoxA2 and Sox17, Pax6 and Sox2, Troponin T2, respectively.The candidate gRNAs showed an on-target efficiency up to 48%.The selected gRNA generated a HDR rate up to 20%.Restriction enzyme studies and Sanger sequencing further confirmed a successful homozygous correction. Conclusion(s):We proved the successful correction of a severe FVII missense variant using gene editing technology, in patients' iPSCs.This completes an important step towards obtaining autologous iPSC-derived liver cells with functional FVII and the development of a novel cell-based therapy for the treatment of FVII deficiency.
2022-01-17 | Novel factor VII gene mutations in six families with hereditary coagulation factor VII deficiency.
Hereditary human coagulation factor VII (FVII) deficiency is an inherited autosomal recessive hemorrhagic disease involving mutations in the F7 gene. The sites and types of F7 mutations may influence the coagulation activities of plasma FVII (FVII: C) and severity of hemorrhage symptoms. However, the specific mutations that impact FVII activity are not completely known. We tested the coagulation functions and plasma activities of FVII in seven patients recruited from six families with hereditary FVII deficiency and sequenced the F7 gene of the patients and their families. Then, we analyzed the genetic information from the six families and predicted the structures of the mutated proteins. In this study, we detected 11 F7 mutations, including four novel mutations, in which the mutations p.Phe84Ser and p.Gly156Cys encoded the Gla and EGF domains of FVII, respectively, while the mutation p.Ser339Leu encoded the recognition site of the enzymatic protein and maintained the conformation of the catalytic domain structure. Meanwhile, the mutation in the 5' untranslated region (UTR) was closely associated with the mRNA regulatory sequence. We have identified novel genetic mutations and performed pedigree analysis that shed light on the pathogenesis of hereditary human coagulation FVII deficiency and may contribute to the development of treatments for this disease.
2018-01-24 | Expanded carrier screening and preimplantation genetic diagnosis in a couple who delivered a baby affected with congenital factor VII deficiency
Preimplantation genetic diagnosis (PGD) is a powerful tool for preventing the transmission of Mendelian disorders from generation to generation. However, PGD only can identify monogenically inherited diseases, but not other potential monogenic pathologies. We aimed to use PGD to deliver a healthy baby without congenital FVII deficiency or other common Mendelian diseases in a couple in which both individuals carried a deleterious mutation in the F7 gene.After both members of the couple were confirmed to be carriers of the F7 gene mutation by Sanger sequencing, expanded carrier screening (ECS) for 623 recessive inheritance diseases was performed to detect pathological mutations in other genes. PGD and preimplantational genetic screening (PGS) were employed to exclude monogenic disorders and aneuploidy for their embryos.ECS using targeted capture sequencing technology revealed that the couple carried the heterozygous disease-causative mutations c.3659C > T (p.Thr1220Ile) and c.3209G > A (p.Arg1070Gln) in the CFTR gene. After PGD and PGS, one of their embryos that was free of congenital FVII deficiency, cystic fibrosis (CF) and aneuploidy was transferred, resulting in the birth of a healthy 3200 g male infant.We successfully implemented PGD for congenital FVII deficiency and PGD after ECS to exclude CF for the first time to the best of our knowledge. Our work significantly improved the reproductive outcome for the couple and provides a clear example of the use of ECS combined with PGD to avoid the delivery of offspring affected not only by identified monogenically inherited diseases but also by other potential monogenic pathologies and aneuploidy.
2017-01-06 | An engineered tale-transcription factor rescues transcription of factor VII impaired by promoter mutations and enhances its endogenous expression in hepatocytes.
Tailored approaches to restore defective transcription responsible for severe diseases have been poorly explored. We tested transcription activator-like effectors fused to an activation domain (TALE-TFs) in a coagulation factor VII (FVII) deficiency model. In this model, the deficiency is caused by the -94C > G or -61T > G mutation, which abrogate the binding of Sp1 or HNF-4 transcription factors. Reporter assays in hepatoma HepG2 cells naturally expressing FVII identified a single TALE-TF (TF4) that, by targeting the region between mutations, specifically trans-activated both the variant (>100-fold) and wild-type (20-40-fold) F7 promoters. Importantly, in the genomic context of transfected HepG2 and transduced primary hepatocytes, TF4 increased F7 mRNA and protein levels (2- to 3-fold) without detectable off-target effects, even for the homologous F10 gene. The ectopic F7 expression in renal HEK293 cells was modestly affected by TF4 or by TALE-TF combinations. These results provide experimental evidence for TALE-TFs as gene-specific tools useful to counteract disease-causing promoter mutations.
proteins
2026-01-22 | Congenital factor VII deficiency as a cause of postpartum hemorrhage: A case report.
Obstetric hemorrhage is one of the leading causes of maternal morbidity and mortality worldwide. However, coagulation disorders as an etiology are rare, with a prevalence of less than 1 %. This report concerns the case of a 24-year-old patient with no previous history of bleeding who presented with postpartum hemorrhage at 38.6 weeks of pregnancy after a normal vaginal delivery. The hemorrhage was refractory to the use of uterotonics and compression maneuvers. In the absence of uterine atony, retained products of conception, or obvious trauma, the possibility of an underlying coagulopathy was considered. Initial studies showed an isolated prolongation of prothrombin time, with activated partial thromboplastin time within normal parameters. A correction test with a normal plasma pool was performed, which showed complete correction of prothrombin time. Specific factor quantification confirmed a severe and isolated factor VII deficiency.
2026-01-19 | Factor VII deficiency is more prevalent than previously reported.
The prevalence of factor (F)VII deficiency is estimated at approximately 1 of 500,000 individuals. However, low FVII activity (FVII:C) is frequently observed in a population of <500,000 in the region of Östergötland, Sweden. To estimate the prevalence and bleeding tendency of adult FVII-deficient patients in Östergötland, Sweden. In this retrospective cross-sectional study, the laboratory information system was used to identify adult patients with at least one FVII:C result ≤ 0.50 kilo International Units per Liter (kIU/L) between January 1, 2017, and December 31, 2022. The most likely cause was established, and in patients with a FVII deficiency, as defined by the Nordic Hemophilia Council (FVII:C < 0.35 kIU/L) or low FVII level (0.35-0.50 kIU/L), the bleeding tendency was evaluated. FVII:C ≤ 0.50 kIU/L was identified in 97 patients residing in Östergötland. Of these, 21 had FVII deficiency, and 39 had low FVII level, corresponding to a prevalence of at least 1 of 17,800 and 1 of 9600 in the adult population in Östergötland, respectively. Patients with FVII deficiency differed significantly from patients with low FVII level in bleeding symptoms (P = .01). Of the FVII-deficient patients, 38% were asymptomatic, while 19% and 24% had experienced minor and major spontaneous bleedings, respectively. The prevalence of FVII deficiency was estimated to be at least 1 of 17,800 adults, which is 28 times higher than the internationally claimed prevalence. Spontaneous bleeding occurred in 43% of these individuals.
2026-01-13 | Congenital Factor VII Deficiency Revealed in the Neonatal Period: A Case Report at CHNEAR
Congenital factor VII deficiency is a rare, autosomal recessive disorder with an estimated prevalence of 1 in 1,000,000. We report the case of a female newborn, born to second-degree consanguineous parents, admitted at 22 days of age for management of a subarachnoid hemorrhage. Hemostasis testing revealed a prothrombin time (PT) of 16%, with a preserved activated partial thromboplastin time (aPTT). Coagulation testing demonstrated an isolated factor VII deficiency. Through this case, we highlight the clinical, biological, and therapeutic characteristics of this anomaly during the neonatal period.
2026-01-10 | Use of Plasma-Derived FVII Concentrate in Surgical Patients with Factor VII Deficiency: A Case Series.
Congenital factor VII (FVII) deficiency is the most common rare hemorrhagic disorder. Acquired FVII deficiency can be isolated or associated with other low coagulation factor levels. FVII levels do not accurately predict a patient's bleeding risk. In the case of surgery, the perioperative management needs to be evaluated on a case-by-case basis, considering the patient's bleeding history and the type of surgery. We present 12 patients with congenital or acquired FVII deficiency and describe the perioperative management with plasma-derived nonactivated FVII (pd-FVII) concentrate. Patients with factor VII deficiency treated with pd-FVII for perioperative hemostasis, between April 2022 and May 2025. We report thirteen procedures in 12 patients (11 males and 1 female; age range: 15-78 years). Two patients were affected by acquired deficiency, and 10 patients presented congenital deficiency. Perioperative prophylaxis with pd-FVII was performed at doses ranging from 20 to 40 IU/kg/dose. Total pd-FVII consumption ranged between 20 and 320 IU/kg. During and after surgery, there were no major bleeding or thrombotic events. In the postoperative period, only one patient presented with hematuria.
2026-01-01 | Procoagulant Activity of a SARS-CoV-2 Nucleocapsid C-Terminal Domain Analog in Factor-Deficient Plasma
This study investigates the procoagulant properties of a synthetic peptide analog derived from the SARS-CoV-2 Nucleocapsid (N) C-terminal domain. The research demonstrates that this specific peptide sequence can bypass standard coagulation pathways to promote fibrin clot formation even in compromised biochemical environments.Key Technical Highlights:Bypass Mechanism: The peptide promotes clot formation in factor-deficient plasma lacking Vitamin K-dependent factors (Factors II, VII, IX, and X).Quantitative Efficacy: Experimental results show a significant reduction in plasma recalcification time, shortening it from $23.74 \pm 0.27$ minutes to $8.442 \pm 6.0395$ minutes ($p = 0.0012$).Structural Target: Focus on the C-terminal domain of the SARS-CoV-2 N protein as a novel template for hemostatic agents.Clinical Significance: Provides a foundation for developing synthetic procoagulants for treating coagulopathies, Vitamin K deficiency, or severe bleeding disorders where traditional factors are absent.
other
2024-08-20 | Cardiovascular disease and thrombosis: Intersections with the immune system, inflammation, and the coagulation system.
The coagulation and immune system, both essential physiological systems in the human body, are intricately interconnected and play a critical role in determining the overall health of patients. These systems collaborate via various shared regulatory pathways, such as the Tissue Factor (TF) Pathway. Immunological cells that express TF and generate pro-inflammatory cytokines have the ability to affect coagulation. Conversely, coagulation factors and processes have a reciprocal effect on immunological responses by stimulating immune cells and regulating their functions. These interconnected pathways play a role in both preserving well-being and contributing to a range of pathological disorders. The close relationship between blood clotting and inflammation in the development of vascular disease has become a central focus of clinical study. This research specifically examines the crucial elements of this interaction within the contexts of cardiovascular disease and acute coronary syndrome. Tissue factor, the primary trigger of the extrinsic coagulation pathway, has a crucial function by inducing a proinflammatory reaction through the activation of coagulation factors. This, in turn, initiates coagulation and subsequent cellular signalling pathways. Protease-activated receptors establish the molecular connection between coagulation and inflammation by interacting with activated clotting factors II, X, and VII. Thrombosis, a condition characterised by the formation of blood clots, is the most dreaded consequence of cardiovascular disorders and a leading cause of death globally. Consequently, it poses a significant challenge to healthcare systems. Antithrombotic treatments efficiently target platelets and the coagulation cascade, but they come with the inherent danger of causing bleeding. Furthermore, antithrombotics are unable to fully eliminate thrombotic events, highlighting a treatment deficiency caused by a third mechanism that has not yet been sufficiently addressed, namely inflammation. Understanding these connections may aid in the development of novel approaches to mitigate the harmful mutual exacerbation of inflammation and coagulation. Gaining a comprehensive understanding of the intricate interaction among these systems is crucial for the management of diseases and the creation of efficacious remedies. Through the examination of these prevalent regulatory systems, we can discover novel therapeutic approaches that specifically target these complex illnesses. This paper provides a thorough examination of the reciprocal relationship between the coagulation and immune systems, emphasising its importance in maintaining health and understanding disease processes. This review examines the interplay between inflammation and thrombosis and its role in the development of thrombotic disorders.
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Drug Discovery Landscape
9 orphan drug designations for Congenital factor VII deficiency, including 2 approved therapies.
9 orphan drug designations for Congenital factor VII deficiency, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Humanised IgG4 monoclonal antibody against activated protein C | antibodies | EMA | 2026-06-19 | — | Parexel International (IRL) Limited |
Humanised IgG4 monoclonal antibody against activated protein C | antibodies | EMA | 2026-06-19 | — | Parexel International (IRL) Limited |
Marzeptacog alfa (activated) | proteins | FDA | 2021-09-27 | — | USWM Development Co., LLC |
Adeno-associated viral vector serotype 8 containing the human factor VII gene | gene therapies | EMA | 2015-01-15 | — | UCL Research Limited |
Recombinant factor VIIa modified with three terminal repeats derived from the ß chain of human chorionic gonadotropin | proteins | EMA | 2014-08-22 | — | Eirgen Pharma Limited |
Recombinant fusion protein linking coagulation factor VIIa with albumin | proteins | EMA | 2013-10-07 | — | CSL Behring GmbH |
recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP) | proteins | FDA | 2013-05-06 | — | CSL Behring |
Coagulation factor VIIa (recombinant) [NovoSeven] | proteins | FDA | 2004-09-10 | 2005-07-11 | Novo Nordisk, Inc. |
Coagulation factor VIIa (recombinant) [NovoSeven] | proteins | FDA | 2004-09-10 | 2005-07-11 | Novo Nordisk, Inc. |
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