Affinage

F5

Coagulation factor V · UniProt P12259

Round 2 corrected
Length
2224 aa
Mass
251.7 kDa
Annotated
2026-04-28
130 papers in source corpus 21 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Coagulation factor V is a large plasma glycoprotein (A1-A2-B-A3-C1-C2 domain architecture) that circulates as an inactive procofactor and, upon thrombin-mediated proteolysis generating noncovalently associated heavy and light chains, becomes Factor Va — the essential nonenzymatic cofactor of the prothrombinase complex (Factor Xa/Factor Va/phospholipid/Ca²⁺) that dramatically accelerates prothrombin conversion to thrombin (PMID:7076681, PMID:3052293). Factor Va is inactivated by activated protein C (APC) through sequential phospholipid-dependent cleavages at Arg506, Arg306, and Arg679, with protein S as cofactor; the FV Leiden mutation (Arg506Gln) impairs this inactivation and is the most common inherited cause of thrombophilia (PMID:7989361, PMID:8164741). Efficient ER-to-Golgi secretion of Factor V requires the LMAN1–MCFD2 calcium-dependent cargo receptor complex, and biallelic loss-of-function mutations in LMAN1 or MCFD2 cause combined Factor V and Factor VIII deficiency (PMID:12717434, PMID:21795745). A naturally occurring splice isoform, FV-Short, forms a high-affinity trimolecular complex with TFPIα and protein S that synergistically inhibits Factor Xa, establishing an anticoagulant threshold whose dysregulation underlies the East Texas bleeding disorder (PMID:36746318, PMID:33773040).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1982 High

    Establishing how Factor V is converted to its active cofactor form resolved the long-standing question of how a single-chain procofactor gains catalytic relevance: thrombin generates a heavy chain (D fragment) and light chain (F1F2 doublet) whose noncovalent association reconstitutes cofactor activity.

    Evidence Purification of human FV; SDS-PAGE of thrombin cleavage products; reconstitution of cofactor activity from isolated fragments

    PMID:7076681

    Open questions at the time
    • Precise thrombin cleavage sites on the procofactor were not mapped at single-residue resolution
    • Contribution of individual domains to prothrombinase assembly was not defined
  2. 1987 High

    Determination of the complete primary structure of Factor V revealed its A1-A2-B-A3-C1-C2 domain architecture and homology to Factor VIII and ceruloplasmin, providing the structural framework for interpreting all subsequent mutagenesis and disease-mutation studies.

    Evidence Full-length cDNA cloning from human fetal liver library with sequence analysis

    PMID:3110773

    Open questions at the time
    • No three-dimensional structure was available
    • Function of the large, heavily glycosylated B domain remained unclear
  3. 1988 High

    Reconstitution of the prothrombinase and intrinsic Xase complexes demonstrated that Factor Va is the critical nonenzymatic cofactor that dramatically accelerates thrombin generation, and that APC limits coagulation by proteolytically inactivating both Factor Va and Factor VIIIa.

    Evidence Biochemical reconstitution of coagulation enzyme complexes with kinetic analysis

    PMID:2538457 PMID:3052293

    Open questions at the time
    • APC cleavage sites on FVa were not yet mapped
    • The role of protein S as APC cofactor was not molecularly defined
  4. 1994 High

    Mapping APC cleavage sites at Arg506, Arg306, and Arg679 — and the near-simultaneous discovery that the Arg506Gln (FV Leiden) mutation causes APC resistance and familial thrombophilia — established the molecular basis of the predominant inherited thrombotic risk factor and the obligate sequential inactivation pathway of Factor Va.

    Evidence In vitro APC cleavage assays with purified FVa and phospholipid vesicles; family linkage study and DNA sequencing in thrombophilia kindreds; APC resistance assays

    PMID:7911873 PMID:7989361 PMID:8164741

    Open questions at the time
    • Structural basis of APC–FVa interaction was not resolved
    • Whether protein S specifically redirects APC cleavage hierarchy was not yet shown
  5. 1998 Medium

    Identification of a second APC-site mutation (Arg306Thr, FV Cambridge) in a thrombophilic patient confirmed that Arg306 is a physiologically important APC cleavage site independent of Arg506.

    Evidence F5 gene sequencing in APC-resistant patients lacking FV Leiden; clinical phenotyping

    PMID:9454742

    Open questions at the time
    • Only a single kindred was described
    • Relative contribution of Arg306 versus Arg506 cleavage to overall FVa inactivation was not quantified
  6. 2002 High

    Recombinant expression of FV Cambridge and FV Hong Kong variants demonstrated that Arg306 mutations produce intermediate APC resistance and that protein S rescues near-complete inactivation by stimulating cleavage at Arg679, quantifying the protein S contribution to the alternative inactivation pathway.

    Evidence Recombinant FV variant expression; APC inactivation kinetics ± protein S; FVIIIa degradation assays

    PMID:12091344

    Open questions at the time
    • Structural basis of protein S stimulation of Arg679 cleavage was unknown
    • In vivo relevance of the Arg679 cleavage site was not tested
  7. 2003 High

    Discovery that MCFD2 and LMAN1 form a calcium-dependent cargo receptor complex required for ER-to-Golgi transport of both Factor V and Factor VIII explained the molecular basis of combined F5F8 deficiency and identified the secretory pathway mechanism for FV.

    Evidence Mutation screening of F5F8D patients; co-immunoprecipitation of MCFD2–LMAN1; subcellular localization by immunofluorescence

    PMID:12717434

    Open questions at the time
    • Direct binding of LMAN1–MCFD2 to FV cargo had not been reconstituted
    • Whether the complex recognizes FV glycans or polypeptide determinants was unresolved
  8. 2011 High

    LMAN1 knockout mice confirmed in vivo that LMAN1 is required for efficient FV (and FVIII) secretion, though the ~50% reduction was milder than in human F5F8D patients, suggesting partial redundancy or species differences in the secretory pathway.

    Evidence Lman1−/− mouse model; plasma FV/FVIII and platelet FV measurement; electron microscopy of hepatocyte ER

    PMID:21795745

    Open questions at the time
    • Identity of any redundant ER-to-Golgi cargo receptor for FV was unknown
    • Platelet-specific FV trafficking mechanism was not defined
  9. 2013 High

    Crystal structures of the LMAN1 carbohydrate recognition domain bound to mannobiose defined how LMAN1 recognizes high-mannose glycans on FV/FVIII cargo, and mutagenesis identified critical residues (His178, Gly251/252); Ca²⁺-dependent binding suggested compartmental Ca²⁺ gradients regulate cargo release.

    Evidence X-ray crystallography of LMAN1-CRD with mannobiose; site-directed mutagenesis; Ca²⁺ titration binding assays

    PMID:23709226

    Open questions at the time
    • No structure of the full LMAN1–MCFD2–FV ternary complex
    • Which specific glycan sites on FV are recognized was not determined
  10. 2021 High

    Discovery of FV-Short as a naturally occurring splice isoform and identification of cis-regulatory elements in F5 exon 13 that control alternative splicing at East Texas splice sites established a previously unrecognized regulatory layer linking F5 mRNA processing to circulating TFPIα levels and anticoagulant capacity.

    Evidence Patient plasma analysis; F5 cDNA sequencing of the F5-Atlanta deletion; heterologous expression recapitulating alternative splicing

    PMID:33605529 PMID:33773040

    Open questions at the time
    • Trans-acting splicing regulators controlling FV-Short production were not identified
    • Quantitative contribution of FV-Short to normal hemostatic balance in healthy individuals was not established
  11. 2023 High

    Demonstration that FV-Short, protein S, and TFPIα form a high-affinity trimolecular complex that synergistically inhibits Factor Xa revealed a dual procoagulant/anticoagulant role for Factor V and explained the bleeding phenotype of the East Texas disorder.

    Evidence Binding affinity measurements; functional TFPIα inhibition assays; patient plasma characterization

    PMID:36746318

    Open questions at the time
    • Structural basis of the FV-Short/protein S/TFPIα complex is unresolved
    • Whether therapeutic modulation of FV-Short splicing can rebalance hemostasis is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the three-dimensional structure of intact Factor Va in the prothrombinase complex, the identity of trans-acting regulators of FV-Short alternative splicing, and the structural determinants that allow Factor V to switch between procoagulant cofactor (in prothrombinase) and anticoagulant cofactor (for APC and as FV-Short/TFPIα complex) roles.
  • No high-resolution structure of FVa within the prothrombinase complex
  • Trans-acting regulators of FV-Short splicing unknown
  • Molecular basis of FV dual procoagulant/anticoagulant switching unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0008289 lipid binding 2
Localization
GO:0005576 extracellular region 5 GO:0005783 endoplasmic reticulum 4 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-109582 Hemostasis 10 R-HSA-1643685 Disease 4 R-HSA-9609507 Protein localization 4
Partners
F10F2LMAN1MCFD2PROCPROS1TFPI
Complex memberships
FV-Short/TFPIα/protein S anticoagulant complexProthrombinase complex (FXa/FVa/phospholipid/Ca²⁺)

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 Complete cDNA cloning of human Factor V revealed a 2224-amino-acid single-chain protein with a domain structure A1-A2-B-A3-C1-C2 (triplicated A domains homologous to Factor VIII and ceruloplasmin, duplicated C domains, and a large B domain containing 35+ tandem 9-amino-acid repeats with 37 potential N-linked glycosylation sites, 25 in the B domain). cDNA cloning and sequence analysis of human fetal liver library; direct amino acid sequence comparison with Factor VIII and ceruloplasmin Proceedings of the National Academy of Sciences of the United States of America High 3110773
1982 Thrombin activates single-chain Factor V (Mr ~330,000) by limited proteolysis, generating Factor Va with 25–30-fold higher cofactor activity. Activation produces fragments D (105 kDa) and F1F2 (71–74 kDa doublet) held by noncovalent interactions, plus two activation peptides (E and C1); reconstitution of D and F1F2 restores cofactor activity, establishing that these two fragments constitute the biologically active cofactor. Purification of human Factor V; SDS-PAGE analysis of thrombin cleavage products; reconstitution experiments with isolated fragments; NH2-terminal sequencing The Journal of biological chemistry High 7076681
1988 Factor Va functions as an essential nonenzymatic cofactor in the prothrombinase complex (Factor Xa + Factor Va on phospholipid membranes) and in the intrinsic Xase complex, dramatically accelerating thrombin generation; Factor V is activated by thrombin and inactivated by activated protein C (APC), which cleaves cofactors Va and VIIIa to limit clot formation. Biochemical reconstitution of coagulation enzyme complexes; kinetic analysis; review synthesizing multiple experimental studies Annual review of biochemistry High 3052293
1989 Activated protein C (APC), formed on the endothelial cell surface when thrombin binds thrombomodulin, proteolytically inactivates Factor Va by cleavage, with protein S serving as a nonenzymatic APC cofactor; intact Factor V also serves as an APC cofactor in the inactivation pathway. Biochemical characterization of protein C activation on endothelial surfaces; proteolysis assays of Factor Va inactivation; identification of protein S cofactor requirement The Journal of biological chemistry High 2538457
1994 APC inactivates Factor Va by sequential proteolytic cleavages at Arg506, Arg306, and Arg679 on the heavy chain; cleavage at Arg506 precedes and is required for cleavage at Arg306 and Arg679; inactivation (>90% loss of cofactor activity) only occurs efficiently in the presence of phospholipid membranes (phosphatidylserine/phosphatidylcholine vesicles); in the absence of membrane, Factor Va retains ~80% activity even after APC cleavage at Arg506. In vitro APC cleavage assays of purified human Factor V and Factor Va; SDS-PAGE fragment identification; cofactor activity assays with and without phospholipid vesicles The Journal of biological chemistry High 7989361
1994 The phenotype of APC resistance is caused by a single point mutation in the Factor V gene (G→A at nucleotide 1691, predicting Arg506Gln substitution), producing FV Leiden (FV Q506), which is activated normally by thrombin or Factor Xa but is impaired in inactivation by APC; the allelic frequency is ~2% in the Dutch population. Family linkage study; DNA sequencing of Factor V gene; functional assays of APC resistance in plasma Nature High 8164741
1994 Linkage analysis in a family with thrombophilia showed 100% cosegregation of Factor V gene polymorphisms with APC resistance, and identified the Arg506Gln point mutation in the APC cleavage site as the cause; purified Factor V expressed an anticoagulant activity that corrected APC resistance in plasma, establishing Factor V as an APC cofactor. RFLP linkage analysis in familial thrombophilia kindred; Factor V gene sequencing; purified Factor V cofactor activity assay Lancet High 7911873
1998 A second APC cleavage site mutation in Factor V, Arg306→Thr (Factor V Cambridge), causes APC resistance and thrombosis, confirming the physiological importance of the Arg306 APC cleavage site in regulation of the prothrombinase complex. Sequencing of Factor V gene in patients with APC resistance lacking FV Leiden; clinical phenotyping; exclusion of other APC resistance causes Blood Medium 9454742
2000 The R2 haplotype of the Factor V gene (containing the 4070G variant) is associated with an altered ratio of two functionally distinct FV plasma isoforms: carriers of the Ala2194Gly variant (C2 domain) show a relative increase of the more thrombogenic, more glycosylated FV isoform (FV1) versus FV2, suggesting that differential glycosylation (determined by C2 domain sequence) modulates FV isoform distribution and thrombotic risk. Molecular genetics (sequencing of R2 homozygotes); chromatographic separation of FV1 and FV2 isoforms; biochemical characterization in plasma Thrombosis and haemostasis Medium 10744138
2002 Recombinant Factor V Cambridge (Arg306Thr) and FV Hong Kong (Arg306Gly) both produce intermediate APC resistance patterns (between wild-type and FV Leiden). In the absence of protein S, APC causes only partial inactivation of these FVa variants. In the presence of protein S, both variants are nearly completely inactivated through stimulation of cleavage at Arg679. Both variants show slightly impaired APC cofactor activity in FVIIIa degradation assays. Recombinant expression of FV variants; APC inactivation kinetics assays with and without protein S; FVIIIa degradation assays Blood High 12091344
2003 MCFD2 (an EF-hand domain protein) mutations cause combined Factor V and Factor VIII deficiency (F5F8D) with a phenotype indistinguishable from LMAN1 mutations. MCFD2 is localized to the ERGIC through a direct, calcium-dependent interaction with LMAN1, and the MCFD2-LMAN1 complex forms a specific cargo receptor for ER-to-Golgi transport of Factor V and Factor VIII. Mutation screening of F5F8D patients; subcellular localization by immunofluorescence; Co-IP demonstrating MCFD2-LMAN1 calcium-dependent interaction; genetic analysis Nature genetics High 12717434
2003 Coinheritance of FV Leiden in a patient with severe FVII deficiency (FVII Lazio) increases thrombin generation, particularly in the presence of APC, explaining a milder bleeding phenotype. Experiments with purified FV or FV Leiden reconstituted into doubly-deficient plasma confirmed that FV Leiden generates more FXa and thrombin than normal FV due to APC resistance of FVa Leiden. Thrombin generation assays in patient plasma; FXa and FVa generation assays; reconstitution with purified normal FV vs. FV Leiden in doubly-deficient plasma Blood High 12881304
2009 Combined FV and FVIII deficiency (F5F8D) is caused by mutations in LMAN1 or MCFD2, which encode a calcium-dependent heteromeric cargo receptor complex that cycles between the ER and ERGIC. Missense mutations in MCFD2 EF-hand domains abolish interaction with LMAN1. MCFD2 mutations generally cause lower FV and FVIII levels than LMAN1 mutations. The LMAN1-MCFD2 complex acts as a cargo receptor for ER-to-Golgi transport of both FV and FVIII. Review synthesizing genetic and biochemical studies; EF-hand domain mutation analysis; LMAN1-MCFD2 interaction studies British journal of haematology High 19183188
2011 LMAN1-deficient (Lman1−/−) mice exhibit ~50% reduction in plasma FV, plasma FVIII, and platelet FV levels, confirming LMAN1 as a cargo receptor required for efficient ER-to-Golgi transport of FV. The reduction is less severe than in human F5F8D patients (5–30%), suggesting partial redundancy or strain-dependent effects. ER in Lman1−/− hepatocytes is slightly distended with accumulation of α1-antitrypsin and GRP78. Lman1 knockout mouse model; plasma FV and FVIII level measurement; platelet FV measurement; electron microscopy of hepatocytes; in vitro COPII vesicle formation assay Blood High 21795745
2011 A homozygous deep-intronic F5 mutation (IVS8 +268A→G) causes inclusion of a pseudo-exon with an in-frame stop codon in F5 mRNA, resulting in severe FV deficiency with undetectable FV activity in plasma and platelets. This patient showed no thrombin generation in platelet-rich plasma triggered with 1–50 pM tissue factor, demonstrating that platelet FV is essential for thrombin generation support in PRP. F5 gene sequencing; RT-PCR/cDNA analysis of aberrant splicing; prothrombinase-based FV activity assay; thrombin generation in PRP; Western blotting for FV antigen in platelets Journal of thrombosis and haemostasis High 21320286
2013 Crystal structures of the LMAN1 carbohydrate recognition domain (CRD) bound to Man-α-1,2-Man (terminal moiety of high-mannose glycans) reveal the central mannose-binding site; mutagenesis identifies His178 and Gly251/252 as critical for FV/FVIII cargo binding. Mannobiose binding is relatively pH-independent in the ER-to-Golgi range but sensitive to lowered Ca2+ concentrations, suggesting that compartmental Ca2+ changes regulate glycoprotein cargo binding and release from the LMAN1·MCFD2 complex. X-ray crystallography of LMAN1-CRD with mannobiose; site-directed mutagenesis; in vitro carbohydrate binding assays; Ca2+ titration experiments The Journal of biological chemistry High 23709226
2014 An apparently synonymous F5 variant (c.1281C>G in exon 8) activates a cryptic donor splice site and abolishes an exonic splicing enhancer, causing half of the patient's F5 mRNA to lack the last 18 nucleotides of exon 8. The aberrantly spliced mRNA encodes a putative FV protein lacking amino acids 427–432 that is poorly secreted and nonfunctional when expressed in COS-1 cells. A mutation-specific morpholino antisense oligonucleotide partially corrects the splicing defect. F5 gene sequencing; RT-PCR/cDNA analysis; F5 minigene assay; bioinformatics splice site prediction; COS-1 cell expression of mutant protein; morpholino antisense oligonucleotide correction Haemophilia High 25470420
2021 A novel FV missense mutation Ala2086Asp (FV Besançon) in the C2 domain favors a 'closed conformation' predicting impaired phospholipid binding, causes markedly decreased FV secretion, and paradoxically induces a hypercoagulable/thrombotic state in an FV-deficient patient. Recombinant FVa Besançon shows slightly unfavorable kinetics of prothrombin activation (Km, Vmax) but a lower rate of APC-catalyzed inactivation in the presence of protein S, abolishing FV APC-cofactor activity. Patient clinical characterization; F5 gene sequencing; recombinant FV Besançon expression; thrombin generation assays in platelet-poor and platelet-rich plasma; APC resistance testing; prothrombinase kinetics with diluted plasma reconstituted with recombinant FVa; TFPI antigen/activity measurement Journal of thrombosis and haemostasis High 33605529
2021 A novel heterozygous 832-bp deletion within F5 exon 13 (F5-Atlanta) enhances alternative splicing at East Texas (ET) splice sites within exon 13, producing a FV-Short isoform with a truncated B domain. This alternatively spliced transcript markedly elevates circulating total and free TFPIα levels. The findings establish that cis-acting regulatory sequences within F5 exon 13 control alternative splicing at ET splice sites and thereby regulate circulating FV-Short and TFPIα levels. Patient plasma analysis (TFPI levels, FV isoform sizing); F5 cDNA sequencing; heterologous expression in mammalian cells to recapitulate alternative splicing Journal of thrombosis and haemostasis High 33773040
2023 FV-Short, a naturally occurring splice isoform of Factor V with a truncated B domain, binds TFPIα with high affinity. Together with protein S, FV-Short forms a high-affinity trimolecular complex (FV-Short/protein S/TFPIα) that synergistically stimulates the FXa-inhibitory activity of TFPIα, functioning as a natural anticoagulant threshold mechanism. In the East Texas bleeding disorder, this complex is elevated ~10-fold, explaining the bleeding phenotype. Synthesis of experimental findings on FV-Short discovery; binding affinity measurements; functional TFPIα inhibition assays; patient plasma characterization Journal of thrombosis and haemostasis High 36746318
2004 Three F5 gene mutations were identified in two Chinese pedigrees with inherited FV deficiency: (i) homozygous IVS8 -2A>G (splicing mutation) that abolishes the canonical splice acceptor site and activates a cryptic acceptor 24 bp upstream, inserting 8 extra amino acids into FV; (ii) heterozygous 2238-9del AG (frameshift, exon 13, introducing premature stop at AA 689); and (iii) heterozygous G6410T (exon 23, missense Gly2079Val). PCR amplification and sequencing of all 25 F5 exons; RT-PCR/cDNA analysis of aberrant mRNA from patient lymphocytes Haemophilia Medium 15086325

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 3563 8164741
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1999 Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature genetics 1381 10391209
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1989 The roles of protein C and thrombomodulin in the regulation of blood coagulation. The Journal of biological chemistry 927 2538457
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
1988 Assembly of a functional immunoglobulin Fv fragment in Escherichia coli. Science (New York, N.Y.) 795 3285470
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2004 The human plasma proteome: a nonredundant list developed by combination of four separate sources. Molecular & cellular proteomics : MCP 658 14718574
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1988 Cofactor proteins in the assembly and expression of blood clotting enzyme complexes. Annual review of biochemistry 534 3052293
1990 A comparison of strategies to stabilize immunoglobulin Fv-fragments. Biochemistry 429 2110478
2008 Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. Journal of thrombosis and haemostasis : JTH 427 18248600
1994 Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet (London, England) 419 7911873
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1987 Complete cDNA and derived amino acid sequence of human factor V. Proceedings of the National Academy of Sciences of the United States of America 398 3110773
2010 Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation 389 20351233
2003 The dynamics of thrombin formation. Arteriosclerosis, thrombosis, and vascular biology 387 12524220
2005 Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. Journal of proteome research 350 16335952
1994 The mechanism of inactivation of human factor V and human factor Va by activated protein C. The Journal of biological chemistry 347 7989361
2009 Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study. The Lancet. Neurology 315 19783216
2004 Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Archives of neurology 313 15534175
1996 Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv. Molecular immunology 286 9171898
2001 Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism. Thrombosis and haemostasis 261 11583312
2000 Mutations in coagulation factors in women with unexplained late fetal loss. The New England journal of medicine 250 11018168
1990 Small rearrangements in structures of Fv and Fab fragments of antibody D1.3 on antigen binding. Nature 249 2215663
2009 Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach. Blood 245 19278955
1982 Thrombin-catalyzed activation of human coagulation factor V. The Journal of biological chemistry 244 7076681
1998 Factor V Cambridge: a new mutation (Arg306-->Thr) associated with resistance to activated protein C. Blood 239 9454742
2003 Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex. Nature genetics 234 12717434
2000 Symptomatic ischemic stroke in full-term neonates : role of acquired and genetic prothrombotic risk factors. Stroke 224 11022077
2014 Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive dataset. Journal of proteomics 218 24769233
2007 Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. British journal of haematology 217 17897305
1999 Activated protein C resistance (FV:Q506) and pregnancy. Thrombosis and haemostasis 178 10235434
2009 Toward high-resolution homology modeling of antibody Fv regions and application to antibody-antigen docking. Proteins 159 19062174
1995 Redox state of single chain Fv fragments targeted to the endoplasmic reticulum, cytosol and mitochondria. Bio/technology (Nature Publishing Company) 141 9636285
2006 Isolation of anti-CD22 Fv with high affinity by Fv display on human cells. Proceedings of the National Academy of Sciences of the United States of America 139 16763048
2002 Gene therapy for cancer using single-chain Fv fragments specific for 4-1BB. Nature medicine 125 11927939
1996 Engineering antibody Fv fragments for cancer detection and therapy: disulfide-stabilized Fv fragments. Nature biotechnology 122 9631086
2001 Expression of single-chain Fv-Fc fusions in Pichia pastoris. Journal of immunological methods 107 11292488
2008 Selectivity for grasp in local field potential and single neuron activity recorded simultaneously from M1 and F5 in the awake macaque monkey. The Journal of neuroscience : the official journal of the Society for Neuroscience 93 18945904
1989 Fv-4 resistance gene: a truncated endogenous murine leukemia virus with ecotropic interference properties. Journal of virology 92 2555565
2002 Functional characterization of recombinant FV Hong Kong and FV Cambridge. Blood 88 12091344
1988 Expression of an antibody Fv fragment in myeloma cells. Journal of molecular biology 85 3210233
2006 Stabilizing and destabilizing effects of phenylalanine --> F5-phenylalanine mutations on the folding of a small protein. Journal of the American Chemical Society 79 17165695
1992 Three-dimensional structure of an Fv from a human IgM immunoglobulin. Journal of molecular biology 76 1447781
2010 Recombinant Fv-Hsp70 protein mediates neuroprotection after focal cerebral ischemia in rats. Stroke 67 20075343
1996 Resistance to activated protein C, the FV:Q506 allele, and venous thrombosis. Annals of hematology 57 8624369
1994 Sequencing and modeling of anti-DNA immunoglobulin Fv domains. Comparison with crystal structures. The Journal of biological chemistry 57 8106407
1999 Domain interactions in antibody Fv and scFv fragments: effects on unfolding kinetics and equilibria. FEBS letters 55 10622716
1996 Antibody engineering of recombinant Fv immunotoxins for improved targeting of cancer: disulfide-stabilized Fv immunotoxins. Clinical cancer research : an official journal of the American Association for Cancer Research 54 9816166
1977 Genetic studies of the Fv-1 locus of mice: linkage with Gpd-1 in recombinant inbred lines. Journal of virology 54 196096
2000 Mutations in the R2 FV gene affect the ratio between the two FV isoforms in plasma. Thrombosis and haemostasis 53 10744138
1999 Expression and characterization of bispecific single-chain Fv fragments produced in transgenic plants. European journal of biochemistry 53 10411643
1996 Crystal structure of an Fv-Fv idiotope-anti-idiotope complex at 1.9 A resolution. Journal of molecular biology 51 8950273
1994 Mammalian expression and secretion of functional single-chain Fv molecules. The Journal of biological chemistry 49 7929344
2009 Recent developments in the understanding of the combined deficiency of FV and FVIII. British journal of haematology 48 19183188
1993 A bacterially expressed single-chain Fv construct from the 2B4 T-cell receptor. Proceedings of the National Academy of Sciences of the United States of America 47 8387198
1968 Deoxyribonucleic acid synthesis in FV-3-infected mammalian cells. Journal of virology 46 5749374
2011 Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin. Blood 44 21795745
1999 Fluobodies: green fluorescent single-chain Fv fusion proteins. Journal of immunological methods 44 10594359
1995 Disulfide stabilization of antibody Fv: computer predictions and experimental evaluation. Protein engineering 43 8869646
2013 Structural characterization of carbohydrate binding by LMAN1 protein provides new insight into the endoplasmic reticulum export of factors V (FV) and VIII (FVIII). The Journal of biological chemistry 42 23709226
1993 Protein Fv produced during vital hepatitis is a novel activator of human basophils and mast cells. Journal of immunology (Baltimore, Md. : 1950) 42 7693815
2008 Combined FV and FVIII deficiency. Haemophilia : the official journal of the World Federation of Hemophilia 41 19141160
1997 Molecular cloning, expression, and characterization of a functional single-chain Fv antibody to the mycotoxin zearalenone. Applied and environmental microbiology 39 8979354
1992 Production of stable anti-digoxin Fv in Escherichia coli. Molecular immunology 39 1528194
1981 Fv-1 host restriction of Friend leukemia virus: analysis of unintegrated proviral DNA. Journal of virology 38 7288927
2014 Increased coagulation activity and genetic polymorphisms in the F5, F10 and EPCR genes are associated with breast cancer: a case-control study. BMC cancer 37 25407022
2013 Clostridium botulinum strain Af84 contains three neurotoxin gene clusters: bont/A2, bont/F4 and bont/F5. PloS one 37 23637798
2003 Coinheritance of Factor V (FV) Leiden enhances thrombin formation and is associated with a mild bleeding phenotype in patients homozygous for the FVII 9726+5G>A (FVII Lazio) mutation. Blood 37 12881304
1997 Female gender and resistance to activated protein C (FV:Q506) as potential risk factors for thrombosis after elective hip arthroplasty. Thrombosis and haemostasis 36 9308742
2011 Homozygous F5 deep-intronic splicing mutation resulting in severe factor V deficiency and undetectable thrombin generation in platelet-rich plasma. Journal of thrombosis and haemostasis : JTH 35 21320286
1997 Direct T cell activation by chimeric single chain Fv-Syk promotes Syk-Cbl association and Cbl phosphorylation. The Journal of biological chemistry 35 9079685
1993 Bacterial expression of a single-chain Fv fragment which efficiently protects the acetylcholine receptor against antigenic modulation caused by myasthenic antibodies. European journal of immunology 35 8344344
2004 Immunosuppressive properties of anti-CD3 single-chain Fv and diabody. Journal of immunological methods 33 14871540
2001 Structure of an anti-blood group A Fv and improvement of its binding affinity without loss of specificity. The Journal of biological chemistry 31 11679577
1996 Single-chain Fv radioimmunotargeting. The quarterly journal of nuclear medicine : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR) 31 8961808
2018 Influence of c-Src on hypoxic resistance to paclitaxel in human ovarian cancer cells and reversal of FV-429. Cell death & disease 30 29324735
1993 Expression, purification and characterization of B72.3 Fv fragments. The Biochemical journal 30 8457200
2011 Single-chain Fv-based anti-HIV proteins: potential and limitations. Journal of virology 29 22013046
1994 On the interaction between single chain Fv antibodies and bacterial immunoglobulin-binding proteins. Journal of immunological methods 29 7822821
1985 Cellular site and mode of Fv-2 gene action. Cell 29 3855388
2003 Activated protein C resistance (FV(Leiden)) and thrombosis: factor V mutations causing hypercoagulable states. Hematology/oncology clinics of North America 28 12627662
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