Affinage

F8

Coagulation factor VIII · UniProt P00451

Length
2351 aa
Mass
267.0 kDa
Annotated
2026-06-09
100 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

F8 encodes coagulation factor VIII (FVIII), a plasma procoagulant cofactor whose biology spans biosynthesis, intracellular trafficking, chaperoned secretion, plasma stabilization, clearance, and immune recognition (PMID:21795745, PMID:30124466). Newly synthesized FVIII exits the ER via the LMAN1-MCFD2 cargo receptor complex, in which MCFD2 is the primary cargo-binding component and LMAN1 acts as a shuttling carrier; loss of this complex causes combined FV/FVIII deficiency and roughly halves plasma FVIII, while N-glycan binding by LMAN1 is dispensable for transport (PMID:19183188, PMID:21795745, PMID:36490287). FVIII is expressed predominantly in liver sinusoidal endothelial cells and in lymphatic endothelium, where co-synthesis with VWF directs it into Weibel-Palade bodies for stimulus-dependent regulated secretion (PMID:30862611, PMID:35950488, PMID:16470522). In plasma, VWF binding shields FVIII and limits its immunogenicity by blocking uptake by dendritic cells and downstream T-cell activation, and the VWF-FVIII complex is cleared through the endothelial scavenger receptor stabilin-2 (PMID:18549909, PMID:30124466). Immune tolerance to FVIII is enforced by PD-L1+ regulatory T cells that ligate PD-1 on FVIII-specific B cells to drive their apoptosis; inhibitory antibodies that arise target distinct epitopes on the 92-kDa and 80-kDa FVIII polypeptides and an immunodominant HLA-DR-restricted T-cell epitope in the C2 region (residues 2194-2213) (PMID:36107620, PMID:2436689, PMID:29444872). F8 output is set transcriptionally by an intron 1 enhancer active in endothelial cells and post-transcriptionally by 3'UTR-targeting miRNAs, and pathogenic exon 19 variants act pleiotropically by simultaneously disrupting mRNA splicing and protein folding/secretion (PMID:33275657, PMID:31785023, PMID:29170251, PMID:34242570).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1987 Medium

    Defined the molecular targets of pathogenic FVIII inhibitors, establishing that inhibitory antibodies recognize distinct FVIII polypeptide domains rather than a single site.

    Evidence Immunoblotting of purified FVIII against inhibitor plasmas with IgG subclass-specific monoclonals

    PMID:2436689

    Open questions at the time
    • Did not map epitopes to specific residues or domains structurally
    • Did not link epitope specificity to clinical inhibitor titer or persistence
  2. 2006 Medium

    Showed that regulated, stimulus-dependent FVIII secretion requires endogenous co-synthesis with VWF, explaining how FVIII enters Weibel-Palade body storage pools.

    Evidence DDAVP-stimulated release and VWF/FVIII co-expression studies in endothelial cells

    PMID:16470522

    Open questions at the time
    • Did not define the in vivo endothelial cell type responsible
    • Trafficking determinants on FVIII directing WPB storage not mapped
  3. 2008 Medium

    Established a mechanistic basis for VWF's immunoprotective effect by showing VWF must bind FVIII to block dendritic-cell uptake and T-cell activation.

    Evidence In vitro DC uptake and T-cell activation assays using VWF and a FVIII-binding-deficient VWF mutant

    PMID:18549909

    Open questions at the time
    • In vitro only; no in vivo immunogenicity confirmation
    • Receptor mediating DC uptake of free FVIII not identified
  4. 2009 Medium

    Identified the LMAN1-MCFD2 cargo receptor as the cause of combined FV/FVIII deficiency, defining a dedicated ER-to-Golgi export pathway for FVIII.

    Evidence Genetic mapping of F5F8D mutations and biochemical/mutational analysis of MCFD2 EF-hand domains (review)

    PMID:19183188

    Open questions at the time
    • Review synthesis rather than primary data
    • Precise FVIII B-domain determinants contacting the receptor not resolved
  5. 2010 Medium

    Demonstrated in a rat model that a single A1-domain point mutation causes hemophilia A via tertiary structure disruption, correctable by FVIII replacement.

    Evidence F8 cDNA sequencing, coagulation activity assays, and recombinant FVIII correction in affected rats

    PMID:20626616

    Open questions at the time
    • Structural disruption inferred, not directly visualized
    • Rat F8 is autosomal, limiting direct comparison to human X-linked locus
  6. 2011 High

    Provided in vivo genetic proof that LMAN1 functions as a FV/FVIII cargo receptor, with deficiency halving plasma factor levels without disrupting COPII vesicle formation.

    Evidence LMAN1-knockout mouse coagulation measurements, in vitro COPII assay, and hepatocyte EM

    PMID:21795745

    Open questions at the time
    • Residual ~50% secretion implies an LMAN1-independent export route
    • Did not separate LMAN1 from MCFD2 contributions
  7. 2013 Medium

    Revealed that mesenchymal stem cells from multiple tissues can express and secrete functional FVIII, broadening the cellular sources of FVIII beyond endothelium.

    Evidence RT-PCR, confocal immunofluorescence, and aPTT/chromogenic functional FVIII assays in MSCs

    PMID:23042590

    Open questions at the time
    • Physiological contribution of MSC-derived FVIII to plasma levels unknown
    • Perinuclear (non-granular) localization mechanism not explained
  8. 2017 High

    Showed that an exon 19 missense mutation is pleiotropic, simultaneously impairing splicing and protein secretion/activity, establishing overlap of the amino-acid and splicing codes in F8.

    Evidence Patient mRNA analysis, minigene splicing assays, lentiviral expression, and antisense U7snRNA rescue

    PMID:29170251

    Open questions at the time
    • Single variant focus; generality across the gene not yet shown
    • Therapeutic feasibility of antisense correction in vivo untested
  9. 2018 High

    Identified stabilin-2 as a clearance and immunoregulatory receptor for the VWF-FVIII complex, linking plasma half-life to endothelial scavenging.

    Evidence Cell internalization assays, STAB2-knockout mouse pharmacokinetics, variant expression, and immunogenicity assays

    PMID:30124466

    Open questions at the time
    • Relative contribution of stabilin-2 versus other clearance receptors not quantified
    • Mechanism linking clearance to reduced immunogenicity incompletely defined
  10. 2018 High

    Mapped an immunodominant HLA-DR-restricted T-cell epitope in the C2 region and showed engineered substitutions reduce immunogenicity while preserving procoagulant activity.

    Evidence Peptide-MHC binding, T-cell clone proliferation with Ala-scan peptides, and recombinant BDD-FVIII activity assays

    PMID:29444872

    Open questions at the time
    • Single epitope; full T-cell epitope repertoire not enumerated
    • Reduced-immunogenicity variants not validated in vivo for tolerance
  11. 2019 Medium

    Defined transcriptional control of F8 by localizing expression to liver sinusoidal endothelial cells under the native promoter and showed Tregs mediate tolerance to FVIII.

    Evidence GFP reporter under native F8 promoter in mice plus Treg depletion in hemophilic mice

    PMID:30862611

    Open questions at the time
    • Treg subset identity left to later work
    • Promoter elements driving LSEC specificity not dissected
  12. 2019 Medium

    Established post-transcriptional regulation of F8 by identifying 3'UTR-targeting miRNAs that suppress FVIII expression.

    Evidence Patient miRNA sequencing plus miRNA overexpression and inhibitor rescue in FVIII-expressing cell lines

    PMID:31785023

    Open questions at the time
    • Only two miRNAs tested; in vivo relevance to plasma FVIII unproven
    • Endogenous regulatory contexts driving these miRNAs unknown
  13. 2019 Medium

    Demonstrated that the FVIII locus itself is a viable site for HDR-based gene correction with functional endothelial FVIII output.

    Evidence CRISPR/Cas9 HDR insertion of B-domain-deleted FVIII in patient iPSCs and differentiation to FVIII-producing endothelial cells

    PMID:30996250

    Open questions at the time
    • In vivo engraftment and durable correction not tested
    • Off-target and integration safety not assessed
  14. 2021 Medium

    Identified an intron 1 transcriptional enhancer whose duplication drives F8 overexpression and thrombophilia, defining a cis-regulatory determinant of FVIII levels.

    Evidence Thrombophilic family genetics, RNA quantification, endothelial luciferase reporter assays, and chromatin accessibility analysis

    PMID:33275657

    Open questions at the time
    • Trans-acting factors binding the enhancer not identified
    • Cosegregation limited to two families
  15. 2021 High

    Generalized the pleiotropy of exon 19 variants across 30 alleles and separated splicing defects from folding/secretion defects using distinct RNA- and protein-targeted rescues.

    Evidence Recombinant expression, minigene assays, engineered U1snRNA splicing rescue, and chaperone-drug secretion rescue across 30 variants

    PMID:34242570

    Open questions at the time
    • Rescue approaches validated in cell models only
    • Variant-specific mechanism assignment may not extend to other exons
  16. 2022 Medium

    Extended the cellular map of FVIII to lymphatic endothelium, showing FVIII/VWF co-localization in WPBs, a reciprocal expression relationship, and shear-stress downregulation.

    Evidence Immunofluorescence, stimulated release assays, and shear-stress exposure across endothelial cell types

    PMID:35950488

    Open questions at the time
    • Physiological contribution of lymphatic endothelium to plasma FVIII unclear
    • Mechanism of reciprocal FVIII/VWF regulation undefined
  17. 2022 High

    Defined a mechanism of natural and acquired tolerance to FVIII via PD-L1+ Tregs that drive PD-1-mediated apoptosis of FVIII-specific B cells, linking tolerance to inhibitor prevention and ITI success.

    Evidence FVIII-deficient and ITI mouse models, Treg flow cytometry, PD-1/PD-L1 blockade, B-cell apoptosis assays, and post-ITI human samples

    PMID:36107620

    Open questions at the time
    • Antigen-specific Treg induction triggers incompletely defined
    • Translation to predictive clinical biomarkers not established
  18. 2023 High

    Resolved the division of labor within the FVIII export receptor, showing MCFD2 is the cargo-binding component while LMAN1 acts as its shuttling carrier and N-glycan binding is dispensable.

    Evidence LMAN1- and MCFD2-deficient HEK293T/HepG2/HCT116 lines with carbohydrate-binding mutant and MCFD2-overexpression rescue assays

    PMID:36490287

    Open questions at the time
    • Structural basis of MCFD2-FVIII cargo recognition not defined
    • Identity of the residual LMAN1-independent secretion route unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How transcriptional (intron 1 enhancer), post-transcriptional (miRNA), trafficking (LMAN1-MCFD2), and immune-tolerance (PD-L1+ Treg) layers are integrated to set physiological FVIII levels in vivo remains unresolved.
  • No unified in vivo model coupling FVIII output, clearance, and tolerance
  • Trans-acting regulators of the F8 enhancer and miRNAs unidentified
  • Structural mechanism of cargo recognition and inhibitor epitope architecture incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 2 GO:0005783 endoplasmic reticulum 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-109582 Hemostasis 2 R-HSA-9609507 Protein localization 2
Partners
LMAN1MCFD2STAB2VWF
Complex memberships
Weibel-Palade body VWF-FVIII complex

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 FVIII inhibitor epitopes map to either the 92-kDa polypeptide (and its 54-kDa/44-kDa thrombin fragments) or the 80-kDa polypeptide (and its 72-kDa thrombin fragment), establishing that inhibitory antibodies target distinct FVIII polypeptide domains. Inhibitors are of restricted polyclonal origin containing IgG-1 and IgG-4 subclasses, with different IgG subclasses showing differential reactivity to specific FVIII polypeptides. Immunoblotting of purified FVIII with inhibitor plasmas; affinity purification and quantitative radial immunodiffusion; monoclonal antibodies specific for IgG subclasses Blood Medium 2436689
2009 Combined deficiency of FV and FVIII (F5F8D) is caused by mutations in LMAN1 or MCFD2, which encode components of an ER-to-Golgi cargo receptor complex. MCFD2 is a calcium-dependent EF-hand domain protein that forms a heteromeric complex with LMAN1; missense mutations in MCFD2 EF-hand domains abolish interaction with LMAN1. The B domain of FVIII is implicated in mediating its interaction with the LMAN1-MCFD2 complex. Genetic mapping of F5F8D mutations; biochemical characterization of LMAN1-MCFD2 complex; mutational analysis of MCFD2 EF-hand domains British journal of haematology Medium 19183188
2011 LMAN1-deficient mice show ~50% reduction in plasma FV and FVIII and platelet FV levels, confirming that the LMAN1-MCFD2 complex functions as an ER-to-Golgi cargo receptor for FV and FVIII. LMAN1 deficiency causes slight ER distension with accumulation of α1-antitrypsin and GRP78 in hepatocytes. LMAN1 deficiency had no effect on COPII-coated vesicle formation in vitro. LMAN1 knockout mouse analysis; plasma coagulation factor measurements; in vitro COPII vesicle formation assay; electron microscopy of hepatocytes; immunoblotting Blood High 21795745
2006 Regulated secretion of FVIII occurs only when there is endogenous synthesis of FVIII together with VWF in endothelial cells, demonstrating that co-synthesis with VWF is required for FVIII storage in regulated secretory pools (Weibel-Palade bodies) and stimulus-dependent release. DDAVP-stimulated release studies in endothelial cells; co-expression analysis of VWF and FVIII Pediatric blood & cancer Medium 16470522
2018 Stabilin-2 (encoded by STAB2) functions as a clearance and immunoregulatory receptor for the VWF-FVIII complex. Stabilin-2-expressing cells bind and internalize human VWF and FVIII in a VWF-dependent manner. Stabilin-2-deficient mice show prolonged human VWF-FVIII half-life. The stabilin-2 variant p.E2377K decreases stabilin-2 expression and impairs VWF endocytosis. Co-infusion of VWF-FVIII with stabilin-2 ligand hyaluronic acid attenuates the immune response to exogenous FVIII. Cell binding and internalization assays; stabilin-2 knockout mouse pharmacokinetic studies; heterologous expression of stabilin-2 variant; immunogenicity assays in STAB2-deficient mice The Journal of clinical investigation High 30124466
2013 Mesenchymal stem cells (MSC) isolated from human lung, liver, brain, and bone marrow express FVIII mRNA and produce functional FVIII protein. In MSC, FVIII protein localizes to the perinuclear region rather than in granules, and functional FVIII is detectable in MSC supernatants and cell lysates. Quantitative RT-PCR; confocal immunofluorescence microscopy with FVIII-specific antibody; functional FVIII measurement by aPTT and chromogenic assays Journal of cellular physiology Medium 23042590
2008 VWF reduces the immunogenicity of FVIII by inhibiting uptake of FVIII by immature dendritic cells and inhibiting activation of FVIII-specific T cells in a dose-dependent manner. Recombinant VWF lacking the FVIII-binding domain did not inhibit T-cell activation, demonstrating that VWF must bind FVIII to exert its immunomodulatory effect. In vitro dendritic cell FVIII uptake assays; T-cell activation assays with VWF and VWF mutant lacking FVIII-binding domain Thrombosis research Medium 18549909
2017 The F8 missense mutation c.6046C>T/p.R2016W in exon 19 exerts pleiotropic effects: it impairs both FVIII secretion (antigen ~11% of wild-type) and activity (~6% of wild-type) and decreases correct mRNA splicing to 70%. Antisense U7snRNA masking the mutated exon 19 region confirmed the presence of a splicing regulatory element. Additional clustered missense mutations (p.G2013R, p.E2018G, p.N2038S) also reduce exon inclusion, demonstrating that the amino acid and splicing codes overlap in this region. Lentiviral vector expression studies; minigene splicing assays; ectopic F8 mRNA analysis from patient samples; antisense U7snRNA rescue experiments; FVIII antigen and activity measurements Haematologica High 29170251
2021 Extensive characterization of 30 F8 exon 19 variants revealed pleiotropic effects on both mRNA splicing and protein biology. A single engineered U1snRNA rescued aberrant mRNA splicing of nine different F8 variants. A chaperone-like drug improved FVIII protein secretion for four missense variants impairing protein folding, establishing that protein folding and secretion are separable from splicing as pathogenic mechanisms. Recombinant expression assays; minigene splicing assays; in silico prediction algorithms; engineered U1snRNA rescue; chaperone drug treatment; FVIII antigen and activity measurement American journal of human genetics High 34242570
2010 A point mutation (Leu176Pro) in the A1 domain of rat FVIII causes hemophilia A by disrupting the tertiary structure of the FVIII molecule. The F8 gene has an autosomal location on chromosome 18 in rats (versus X-linked in mice and humans). Administration of human recombinant FVIII corrects the coagulation abnormality in affected rats. F8 cDNA sequencing to identify causative mutation; coagulation factor activity assays; FVIII replacement correction experiment Journal of thrombosis and haemostasis Medium 20626616
2019 The native F8 promoter drives FVIII expression predominantly in liver sinusoidal endothelial cells, with some expression in hematopoietic organs, as demonstrated by GFP reporter under pF8 in mice. Depletion of regulatory T cells (Tregs) in lentiviral-treated mice allowed formation of anti-FVIII antibodies, indicating that Tregs mediate immune tolerance to FVIII under pF8-driven gene therapy. Lentiviral vector with GFP reporter under native F8 promoter; in vivo GFP expression analysis; FVIII activity measurement; Treg depletion experiments in hemophilic mice Blood advances Medium 30862611
2022 In human lymphatic endothelial cells (hLECs) where FVIII is significantly expressed, FVIII and VWF co-localize in Weibel-Palade bodies (WPBs) and are released together upon stimulation. A reciprocal relationship between FVIII and VWF expression levels exists across endothelial cell types. Exposure to laminar shear stress markedly reduces both FVIII and VWF expression in hLECs. Immunofluorescence microscopy; stimulated release assays; shear stress exposure; RNA and protein quantification across multiple endothelial cell types Journal of thrombosis and haemostasis Medium 35950488
2023 In ER-to-Golgi trafficking of FV and FVIII, MCFD2 is the primary cargo-binding component while LMAN1 serves mainly as a shuttling carrier of MCFD2. LMAN1 with mutations abolishing carbohydrate binding can still partially rescue FV/FVIII secretion, indicating N-glycan binding is not essential for FV/FVIII transport. Overexpression of either wild-type or mutant MCFD2 alone is sufficient to rescue FV/FVIII secretion in LMAN1-deficient cells. LMAN1- and MCFD2-deficient cell lines (HEK293T, HepG2, HCT116); FV/FVIII secretion assays; rescue experiments with LMAN1 carbohydrate-binding mutants and MCFD2 overexpression Blood advances High 36490287
2022 Immune tolerance to FVIII under non-hemophilic conditions is maintained by PD-L1-expressing regulatory T cells (Tregs) that ligate PD-1 on FVIII-specific B cells, causing B cell apoptosis. FVIII-deficient mice lack these Tregs and develop inhibitors. Repetitive FVIII injection in an ITI mouse model induces FVIII-specific PD-L1+ Tregs that re-engage removal of inhibitor-forming B cells. FVIII-specific Tregs upregulate PD-L1 in hemophilia patients after successful ITI. FVIII-deficient mouse model; ITI mouse model with repetitive FVIII injection; Treg characterization by flow cytometry; PD-1/PD-L1 blocking experiments; B cell apoptosis assays; human patient samples post-ITI The Journal of clinical investigation High 36107620
2019 MicroRNAs miR-374b-5p and miR-30c-5p suppress FVIII expression by targeting the 3' UTR of F8 mRNA. Overexpression of miR-374b or miR-30c decreased FVIII expression in cell lines that constitutively express FVIII, while an miR-30c inhibitor partially restored FVIII expression. miRNA sequencing from hemophilia A patients without F8 coding mutations; overexpression of specific miRNAs in FVIII-expressing cell lines; miRNA inhibitor rescue experiment; FVIII expression measurement Transfusion Medium 31785023
2021 A 23.4-kb tandem duplication of the proximal F8 gene (promoter, exon 1, and part of intron 1) causes twofold or greater upregulation of F8 mRNA and extremely elevated FVIII levels (>400%), resulting in severe thrombophilia. A 927-bp region within F8 intron 1 showed >45-fold increased reporter activity in endothelial cells in a luciferase assay, identifying it as a transcriptional enhancer element for F8. Genetic analysis of thrombophilic families; RNA quantification; luciferase reporter assay of intron 1 sequences in endothelial cells; chromatin accessibility (open chromatin signatures) analysis Blood Medium 33275657
2019 CRISPR/Cas9-mediated homology-directed repair can insert a functional B-domain-deleted FVIII gene at the FVIII locus in hemophilia A patient-derived iPSCs at high frequency (81.81%). Endothelial cells differentiated from gene-corrected iPSCs produce functionally active FVIII protein, demonstrating that the FVIII locus is a suitable site for integration and endothelial expression of corrected FVIII. CRISPR/Cas9 HDR gene targeting in patient iPSCs; iPSC differentiation to endothelial cells; FVIII functional activity assay Experimental & molecular medicine Medium 30996250
2018 The FVIII peptide FVIII2194-2213 contains an immunodominant HLA-DRA*01-DRB1*01:01-restricted T-cell epitope. The core binding residues are F2196, M2199, A2201, and S2204. The substitution F2196A abrogates T-cell clone proliferation to the wild-type sequence. B-domain-deleted FVIII proteins with F2196K or M2199A substitutions show reduced immunogenicity while retaining procoagulant activity comparable to wild-type. Peptide-MHC class II binding assays; T-cell proliferation assays with Ala-substituted peptides; recombinant BDD-FVIII protein expression and functional activity measurement; T-cell clone stimulation with recombinant FVIII-C2 domain proteins Blood advances High 29444872

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1987 FVIII inhibitor IgG subclass and FVIII polypeptide specificity determined by immunoblotting. Blood 155 2436689
2016 FVIII-specific human chimeric antigen receptor T-regulatory cells suppress T- and B-cell responses to FVIII. Blood 132 28064157
2011 F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia : the official journal of the World Federation of Hemophilia 111 22103590
2006 Inhibition of TEGDMA and HEMA-induced genotoxicity and cell cycle arrest by N-acetylcysteine. Dental materials : official publication of the Academy of Dental Materials 101 16890983
1999 Conditional stability of the HemA protein (glutamyl-tRNA reductase) regulates heme biosynthesis in Salmonella typhimurium. Journal of bacteriology 87 9973348
1989 Cloning, genetic characterization, and nucleotide sequence of the hemA-prfA operon of Salmonella typhimurium. Journal of bacteriology 85 2544564
2014 HEMA-induced cytotoxicity: oxidative stress, genotoxicity and apoptosis. International endodontic journal 73 24355064
2018 The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity. The Journal of clinical investigation 69 30124466
1989 Isolation, nucleotide sequence, and preliminary characterization of the Escherichia coli K-12 hemA gene. Journal of bacteriology 69 2548996
1990 Cloning and characterization of the hemA region of the Bacillus subtilis chromosome. Journal of bacteriology 59 2110138
2015 Parameters influencing FVIII pharmacokinetics in patients with severe and moderate haemophilia A. Haemophilia : the official journal of the World Federation of Hemophilia 55 25582282
2008 Gene transfer to hemophilia A mice via oral delivery of FVIII-chitosan nanoparticles. Journal of controlled release : official journal of the Controlled Release Society 55 18634839
2004 Antioxidative vitamins decrease cytotoxicity of HEMA and TEGDMA in cultured cell lines. Archives of oral biology 54 14693206
2018 Engineered FVIII-expressing cytotoxic T cells target and kill FVIII-specific B cells in vitro and in vivo. Blood advances 53 30232086
2009 Recent developments in the understanding of the combined deficiency of FV and FVIII. British journal of haematology 48 19183188
2014 Diagnosis and management challenges in patients with mild haemophilia A and discrepant FVIII measurements. Haemophilia : the official journal of the World Federation of Hemophilia 45 24517184
2011 Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin. Blood 44 21795745
1989 Isolation and nucleotide sequence of the hemA gene of Escherichia coli K12. Molecular & general genetics : MGG 44 2664455
2009 Immune response to FVIII in hemophilia A: an overview of risk factors. Clinical reviews in allergy & immunology 42 19148784
2007 Effects of HEMA on type I collagen protein in human gingival fibroblasts. Cell biology and toxicology 42 17486417
2017 Noninvasive detection of F8 int22h-related inversions and sequence variants in maternal plasma of hemophilia carriers. Blood 41 28490568
2008 Combined FV and FVIII deficiency. Haemophilia : the official journal of the World Federation of Hemophilia 41 19141160
2007 HEMA reduces cell proliferation and induces apoptosis in vitro. Dental materials : official publication of the Academy of Dental Materials 40 17920114
1993 G6PD haplotypes spanning Xq28 from F8C to red/green color vision. Genomics 40 8104869
2019 Synthesis and Characterization of Silicone Contact Lenses Based on TRIS-DMA-NVP-HEMA Hydrogels. Polymers 39 31159172
2012 F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort. Haemophilia : the official journal of the World Federation of Hemophilia 39 22958194
2006 Regulated release of VWF and FVIII and the biologic implications. Pediatric blood & cancer 39 16470522
2011 DNA-damage, cell-cycle arrest and apoptosis induced in BEAS-2B cells by 2-hydroxyethyl methacrylate (HEMA). Mutation research 37 21640196
2002 High throughput mutation screening of the factor VIII gene (F8C) in hemophilia A: 37 novel mutations and genotype-phenotype correlation. Human mutation 37 12325022
2010 Immunoglobulin isotypes and functional anti-FVIII antibodies in response to FVIII treatment in Balb/c and C57BL/6 haemophilia A mice. Haemophilia : the official journal of the World Federation of Hemophilia 35 21091850
2005 Adhesive resin and the hydrophilic monomer HEMA induce VEGF expression on dental pulp cells and macrophages. Dental materials : official publication of the Academy of Dental Materials 35 16182358
2020 Electrospun GelMA fibers and p(HEMA) matrix composite for corneal tissue engineering. Materials science & engineering. C, Materials for biological applications 34 33545871
2010 Expression, engineering and characterization of the tumor-targeting heterodimeric immunocytokine F8-IL12. Protein engineering, design & selection : PEDS 34 20551083
2019 Cell Loaded GelMA:HEMA IPN hydrogels for corneal stroma engineering. Journal of materials science. Materials in medicine 32 31811387
2002 The identification and classification of 41 novel mutations in the factor VIII gene (F8C). Human mutation 32 11857744
1987 Recombination between the factor VIII gene and the DXS52 locus gives the most probable genetic order as centromere-fra(X)-DXS15-DXS52-F8C-telomere. American journal of medical genetics 32 3105317
1995 Regulation of the hemA gene during 5-aminolevulinic acid formation in Pseudomonas aeruginosa. Journal of bacteriology 31 7883699
1990 Cloning and expression of a structural gene from Chlorobium vibrioforme that complements the hemA mutation in Escherichia coli. Journal of bacteriology 31 2407729
2015 Assessment of HEMA and TEGDMA induced DNA damage by multiple genotoxicological endpoints in human lymphocytes. Dental materials : official publication of the Academy of Dental Materials 30 26025483
2019 FVIII expression by its native promoter sustains long-term correction avoiding immune response in hemophilic mice. Blood advances 29 30862611
1997 Selectivity of F8-actinomycin D for RNA:DNA hybrids and its anti-leukemia activity. Bioorganic & medicinal chemistry 29 9222513
2017 Clustered F8 missense mutations cause hemophilia A by combined alteration of splicing and protein biosynthesis and activity. Haematologica 28 29170251
2021 Partial F8 gene duplication (factor VIII Padua) associated with high factor VIII levels and familial thrombophilia. Blood 27 33275657
2023 Thermoresponsive Smart Copolymer Coatings Based on P(NIPAM-co-HEMA) and P(OEGMA-co-HEMA) Brushes for Regenerative Medicine. ACS biomaterials science & engineering 26 37874897
2013 Mesenchymal stem cells contribute to endogenous FVIII:c production. Journal of cellular physiology 25 23042590
2008 Effects of TEGDMA and HEMA on the expression of COX-2 and iNOS in cultured murine macrophage cells. Dental materials : official publication of the Academy of Dental Materials 25 18755506
2020 B Cell Depletion Eliminates FVIII Memory B Cells and Enhances AAV8-coF8 Immune Tolerance Induction When Combined With Rapamycin. Frontiers in immunology 24 32670285
2019 Clinical manifestation of hemophilia A in the absence of mutations in the F8 gene that encodes FVIII: role of microRNAs. Transfusion 24 31785023
2018 FVIII proteins with a modified immunodominant T-cell epitope exhibit reduced immunogenicity and normal FVIII activity. Blood advances 24 29444872
2014 Fc-fusion technology and recombinant FVIII and FIX in the management of the hemophilias. Drug design, development and therapy 24 24729686
2013 Characterization of large deletions in the F8 gene using multiple competitive amplification and the genome walking technique. Journal of thrombosis and haemostasis : JTH 24 23551875
2020 The Immune Response to the fVIII Gene Therapy in Preclinical Models. Frontiers in immunology 23 32351497
2019 Restoration of FVIII expression by targeted gene insertion in the FVIII locus in hemophilia A patient-derived iPSCs. Experimental & molecular medicine 23 30996250
1991 Structure and expression of the Chlorobium vibrioforme hemA gene. Archives of microbiology 23 1793335
2023 Comprehensive Analysis of Hemophilia A (CAHEA): Towards Full Characterization of the F8 Gene Variants by Long-Read Sequencing. Thrombosis and haemostasis 22 37285902
2019 Solvent and HEMA Increase Adhesive Toxicity and Cytokine Release from Dental Pulp Cells. Materials (Basel, Switzerland) 22 31461952
1997 Expression of the heme biosynthetic pathway genes hemCD, hemH, hemM, and hemA of Escherichia coli. FEMS microbiology letters 22 8997718
2015 Cell toxicity of 2-hydroxyethyl methacrylate (HEMA): the role of oxidative stress. European journal of oral sciences 21 25968591
2018 F8-IL10: A New Potential Antirheumatic Drug Evaluated by a PET-Guided Translational Approach. Molecular pharmaceutics 20 30550295
2015 The role of previously untreated patient studies in understanding the development of FVIII inhibitors. Haemophilia : the official journal of the World Federation of Hemophilia 20 26315604
2010 WAG-F8(m1Ycb) rats harboring a factor VIII gene mutation provide a new animal model for hemophilia A. Journal of thrombosis and haemostasis : JTH 20 20626616
2009 HEMA down-regulates procollagen alpha1 type I in human gingival fibroblasts. Journal of biomedical materials research. Part A 20 18496863
2015 HEMA but not TEGDMA induces autophagy in human gingival fibroblasts. Frontiers in physiology 19 26483703
1991 Cloning and nucleotide sequence of the hemA gene of Agrobacterium radiobacter. Molecular & general genetics : MGG 19 2034217
2022 Immune tolerance against infused FVIII in hemophilia A is mediated by PD-L1+ Tregs. The Journal of clinical investigation 18 36107620
2007 F8 gene mutation profile and ITT response in a cohort of Italian haemophilia A patients with inhibitors. Haemophilia : the official journal of the World Federation of Hemophilia 18 17610549
2024 Vector integration and fate in the hemophilia dog liver multiple years after AAV-FVIII gene transfer. Blood 17 38452208
2020 Mutation analysis in the F8 gene in 485 families with haemophilia A and prenatal diagnosis in China. Haemophilia : the official journal of the World Federation of Hemophilia 17 33245802
2013 F8 genetic analysis strategies when standard approaches fail. Hamostaseologie 16 24296544
2011 Integration-free and stable expression of FVIII using a human artificial chromosome. Journal of human genetics 16 21833006
2021 Immune Responses to Plasma-Derived Versus Recombinant FVIII Products. Frontiers in immunology 15 33552050
2021 Dissection of pleiotropic effects of variants in and adjacent to F8 exon 19 and rescue of mRNA splicing and protein function. American journal of human genetics 15 34242570
2008 The role of VWF in the immunogenicity of FVIII. Thrombosis research 15 18549909
2023 Structural insights into the assembly and mechanism of mpox virus DNA polymerase complex F8-A22-E4-H5. Molecular cell 14 37995690
2019 The impact of GPIbα on platelet-targeted FVIII gene therapy in hemophilia A mice with pre-existing anti-FVIII immunity. Journal of thrombosis and haemostasis : JTH 14 30609275
2015 Engineering less immunogenic and antigenic FVIII proteins. Cellular immunology 14 26566286
2002 Prevalence of small rearrangements in the factor VIII gene F8C among patients with severe hemophilia A. Human mutation 14 12204009
2022 Heterogeneity and reciprocity of FVIII and VWF expression, and the response to shear stress in cultured human endothelial cells. Journal of thrombosis and haemostasis : JTH 13 35950488
2019 Protection against HEMA-Induced Mitochondrial Injury In Vitro by Nrf2 Activation. Oxidative medicine and cellular longevity 13 31089407
2019 HEMA Effects on Autophagy Mechanism in Human Dental Pulp Stem Cells. Materials (Basel, Switzerland) 13 31315300
2016 Accurate, simple, and inexpensive assays to diagnose F8 gene inversion mutations in hemophilia A patients and carriers. Blood advances 13 29296938
2015 Experimental self-etching HEMA-free adhesive systems: cytotoxicity and degree of conversion. Journal of materials science. Materials in medicine 13 25589203
1988 Cloning of the Rhodobacter capsulatus hemA gene. Journal of bacteriology 13 2842318
2022 Liver gene therapy with intein-mediated F8 trans-splicing corrects mouse haemophilia A. EMBO molecular medicine 12 35491676
2022 Race, ethnicity, F8 variants, and inhibitor risk: analysis of the "My Life Our Future" hemophilia A database. Journal of thrombosis and haemostasis : JTH 12 36696179
2020 Defining the Optimal FVIII Transgene for Placental Cell-Based Gene Therapy to Treat Hemophilia A. Molecular therapy. Methods & clinical development 12 32258210
2019 HEMA 3 Staining: A Simple Alternative for the Assessment of Myoblast Differentiation. Current protocols in stem cell biology 12 31756292
2017 The dental monomer hydroxyethyl methacrylate (HEMA) counteracts lipopolysaccharide-induced IL-1β release-Possible role of glutathione. Toxicology letters 12 28188892
2017 Evaluation of F8-TNF-α in Models of Early and Progressive Metastatic Osteosarcoma. Translational oncology 12 28448958
2015 Complexity and diversity of F8 genetic variations in the 1000 genomes. Journal of thrombosis and haemostasis : JTH 12 26383047
2015 T cell response to FVIII. Cellular immunology 12 26435345
2008 Severe haemophilia A in a female resulting from an inherited gross deletion and a de novo codon deletion in the F8 gene. Haemophilia : the official journal of the World Federation of Hemophilia 12 18665854
2000 Changes in cell phospholipid metabolism in vitro in the presence of HEMA and its degradation products. Dental materials : official publication of the Academy of Dental Materials 12 10831786
2008 Mutational spectrum of F8 gene and prothrombotic gene variants in haemophilia A patients from Southern Italy. Haemophilia : the official journal of the World Federation of Hemophilia 11 18459951
2002 Identification of seven novel mutations of F8C by DHPLC. Human mutation 11 12203998
2023 Separate roles of LMAN1 and MCFD2 in ER-to-Golgi trafficking of FV and FVIII. Blood advances 10 36490287
2023 Current Understanding of Inherited Modifiers of FVIII Pharmacokinetic Variation. Pharmacogenomics and personalized medicine 10 36998673
2021 Role of ADAMTS13, VWF and F8 genes in deep vein thrombosis. PloS one 10 34662354
2014 Characterisation and quantification of F8 transcripts of ten putative splice site mutations. Thrombosis and haemostasis 10 25503412
2003 Long distance PCR in detection of inversion mutations of F8C gene in hemophilia A patients. General physiology and biophysics 10 14699993

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