Disease relevance of F8

• The risk of inhibitor development was higher in patients treated with rFVIII than in patients treated with pFVIII, regardless of other risk factors (F8 genotype; nonwhite origin; history of inhibitors in patients with a family history of hemophilia; age at first FVIII infusion) [1].
• Antihemophilic factor concentrate therapy in von Willebrand disease. Dissociation of bleeding-time factor and ristocetin-cofactor activities [2].
• Compared to age- and sex-matched blood donors, thrombosis patients showed a significantly higher plasma FVIII/VWF ratio (median: 1.3 vs. 1.0, p<0.001). uFVIII fraction data were adjusted for VWF residuum [3].
• High factor VIII (FVIII) levels in venous thromboembolism: role of unbound FVIII [3].
• In patients' status post deep-vein thrombosis (DVT), an altered uFVIII fraction and high FVIII levels might be indicative of dysfunctional FVIII regulation [3].

Psychiatry related information on F8

• Logistic regression showed that the risk reduction was only partially dependent of the reduction in FVIII levels [4].
• Physical activity and infusion of adrenalin provoke a rise in FVIII, which can be blocked by a nonselective beta-blockade [5].
• Structural analysis of the FVIII A domain homology model allowed us to identify residues 664 and 1826 as a potential disulfide bond pair [6].

High impact information on F8

• Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. recombinant Factor VIII Study Group [7].
• Pharmacokinetics of recombinant antihemophilic factor [8].
• In addition, either in platelet-rich plasma or suspended in buffer, their platelets were aggregated by unmodified normal human FVIII/VWF without ristocetin [9].
• The form of von Willebrand's disease characterized by a qualitative abnormality of Factor VIII/von Willebrand factor (FVIII/vWF) in plasma has been designated as Type II [10].
• We carried out spliceosome-mediated RNA trans-splicing (SMaRT) to repair mutant FVIII mRNA [11].

Chemical compound and disease context of F8

• Treatment of von Willebrand disease with two plasma antihemophilic factor (AHF) concentrates, cryoprecipitate and glycine-precipitated AHF, was compared [2].
• A deletion of Ala2201 (Del2201) was identified in the FVIII C2 domain of 2 unrelated patients with mild hemophilia A (FVIII:C 11%-33%) [12].
• We conclude that the pathogenesis of hemophilia A in this patient is probably due to an arginine to cysteine substitution at a thrombin cleavage site in the FVIII heavy chain [13].
• Desmopressin (DDAVP), a synthetic analogue of vasopressin has been successfully used in the treatment of type I von Willebrand's disease (VWD), mild factor VIII (FVIII) deficiency and intrinsic platelet function defects (PFDs) for almost three decades [14].
• Hemophilia A is an X-linked recessive disorder resulting from deficiency of Factor VIII (F8C), an important protein in blood coagulation [15].

Biological context of F8

• Two yeast artificial chromosome (YAC) libraries were screened for probes in Xq28, around the gene for coagulation factor VIII (F8) [16].
• Previous transfection studies demonstrated that factor VIII was 10-100-fold less efficiently expressed than the homologous coagulation factor, factor V. To investigate the regulatory mechanisms of FVIII synthesis and secretion, we used the yeast two-hybrid system as an approach to search for proteins that associated with FVIII [17].
• No interference by the international normalized ratio, activated partial thromboplastin time (aPTT), protein S activity, fibrinogen and factor VIII (FVIII) levels, or lupus anticoagulant ratio was detected [18].
• G6PD haplotypes spanning Xq28 from F8C to red/green color vision [19].
• The finding that some G6PD mutations are associated with a particular F8C/G6PD haplotype may be useful for future population studies [20].

Anatomical context of F8

• LMAN1 and MCFD2 form a protein complex that functions as a cargo receptor ferrying FV and FVIII from the endoplasmic reticulum to the Golgi [21].
• In addition, transfection in a glucosidase I-deficient Chinese hamster ovary cell line (Lec23) demonstrated that both degradation and secretion of FVIII were inhibited, with little effect on the secretion of FV [22].
• In cirrhotic tissue enlarged portal veins appeared to overgrow FVIII producing sinusoidal endothelial cells [23].
• This review attempts to sum up current knowledge of the nature and properties of anti-FVIII antibodies, their mechanism of action, their neutralization by anti-idiotypic antibodies, and the role of T cells in FVIII inhibitor formation [24].
• During the last two years, however, a particular effort has been made to better understand their generation, with particular emphasis on the interplay of T cells and B cells specific for FVIII and the generation of anti-FVIII antibodies [24].

Associations of F8 with chemical compounds

• This mutation prevents FVIII binding to a human monoclonal antibody recognizing the C2 domain and inhibiting FVIII binding to VWF and phospholipids [12].
• Evidence that functional subunits of antihemophilic factor (Factor VIII) are linked by noncovalent bonds [25].
• The issue was examined by preparing partially purified AHF from fresh human plasma in the presence of protease inhibitors, including benzamidine, soybean trypsin inhibitor, epsilon-aminocaproic acid, heparin, and hirudin [25].
• To capture the FVIII-VWF-complex, superparamagnetic polystyrene beads with covalently attached streptavidin were coated with biotinylated anti-rabbit Ig and incubated with rabbit anti-human VWF-Ig [3].
• The AHF was prepared by sequential chromatography on solid-phase polyelectrolyte (PE E-5), and on Sepharose CL-4B in the presence of a high concentration of CaCl2 [26].

Physical interactions of F8

• Competition studies using synthetic peptides suggested that LRP binding involves the FVIII-specific region Lys(1804)-Ala(1834) in the A3 domain [27].
• In the present study, we showed that the extracellular ligand-binding domain of LDLR interacts with FVIII in vitro and that binding was inhibited by RAP [28].
• The A2 domain of FVIII significantly increases the affinity and stoichiometry of FVIIIa binding to platelets and contributes to the stability of the FX-activating complex [29].
• Heavy and light chains of FVIII were detected in plasma-derived immune complexes extracted by using protein G Sepharose [30].
• Previous studies identified a 110-amino acid region within the FVIII A1-domain that inhibits its secretion and contains multiple short peptide sequences that have potential to bind immunoglobulin-binding protein (BiP) [31].

Enzymatic interactions of F8

• The der(17) chromosome containing Xq24-Xq28 carries a functional G6PD locus and a deleted F8C allele that lacks exons 1-15 [32].
• In previous reports, plasmin was shown in vitro to inactivate FVIII and cleave the vWF subunit extensively, but to cause only a modest decrease in vWF platelet-agglutinating activity [33].
• Isolex selected CD34+ cells from human G-CSF mobilized peripheral blood cells (PBC) and murine bone marrow were transduced with a retrovirus encoding the B-domain deleted form of human FVIII (BDD-FVIII) [34].

Regulatory relationships of F8

• Addition of hemophilic plasma as a source of vWF did not cause additional improvement, nor did a potent antibody to vWF raised in rabbits inhibit the ability of AHF to shorten the clotting time of vWD plasma [26].
• To address the physiologic role of LRP in regulating plasma FVIII in vivo, we used cre/loxP-mediated conditional LRP- deficient mice (MX1cre(+)LRP(flox/flox)) [35].
• The presence of EGR-FIXa and FX increases both the number and the affinity of binding sites on activated platelets for both FVIII and FVIIIa, emphasizing the validity of a three-receptor model in the assembly of the F-X-activating complex on the platelet surface [29].
• We investigated in case-control studies both biological effects (FVIII levels and activated protein C sensitivity ratio) and clinical associations (venous thromboembolism) of the D1241E change [36].
• In vitro, PPT shortened the clotting time of a high-titre human factor VIII (FVIII) inhibitor plasma in a manner similar to that of the activated prothrombin complex concentrate FEIBA and triggered coagulation in plasma samples in which factor V (FV) is present [37].

Other interactions of F8

• We studied nine bipolar pedigrees (in which there was no male-to-male transmission) in an attempt to detect linkage, using three tightly linked polymorphic DNA loci, DXS15, DXS52 and F8C (factor 8 gene), all of which are closely linked to the CB and glucose 6-phosphate dehydrogenase classic Xq28 markers [38].
• The elevated expression of von Willebrand factor had no effect on the suppression of FVIII secretion by PAHX [17].
• High level of plasma VII VWF was observed in diabetics with proliferative retinopathy while the VII AHF level was within normal limits [39].
• By the use of an FV-dependent prothrombin activator, the assay is not influenced by FVIII concentration or lupus anticoagulants [18].
• In both tests FXa formation plays a major role, as the effect of FVIII and TFPI on the tests seems to be executed via FXa [40].

Analytical, diagnostic and therapeutic context of F8

• DDAVP also increased FVIII and VWF levels but did not normalize the GPIb-dependent VWF functions expressed as RIPA and VWF:RCo [41].
• The F8C/G6PD (coagulation factor VIIIc) haplotype that spans the Xq28 region from the gene for coagulation factor VIIIc to the gene for G6PD was also investigated in Chinese using PCR and restriction enzyme digestion [20].
• Using 2 common polymorphisms in F8 exon 14, we were able to show that the same allele shared by the patient, his mother, and his sister was not detected by reverse transcription-polymerase chain reaction (RT-PCR) from total blood mRNA [42].
• We have purified factor VIII from a patient with moderately severe hemophilia A (FVIII, 4 U/dL; FVIII:Ag, 110 U/dL) and subjected the protein to Western blot analysis after time course activation with thrombin [43].
• Immunoblotting of partially purified FVIII Okayama and normal FVIII showed that thrombin cleavage of the 92 kilodalton (Kd) heavy chain was impaired in the mutant protein [13].

References