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Semin Thromb Hemost 2003; 29(1): 011-022
DOI: 10.1055/s-2003-37935
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Structure and Function of the Factor VIII Gene and Protein

Arthur R. Thompson
  • Puget Sound Blood Center, and Professor, Department of Medicine, University of Washington, Seattle, Washington
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Publikationsdatum:
17. März 2003 (online)

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ABSTRACT

Factor (F) VIII is a large gene located near the terminus of the long arm of the X chromosome. It contains 26 exons that code for a signal peptide and a 2332 amino acid polypeptide with three different types of domains, namely A1-A2-B-A3-C1-C2. The A domains are homologous with each other and those of ceruloplasmin; substitution into the known crystal structure of the copper binding protein produces molecular models. The large, central B domain is highly glycosylated but has a variable sequence, even among FVIIIs from different species. Most of B can be deleted and the resulting recombinant protein has essentially normal survival in circulation and corrects the bleeding tendency in hemophilia A patients. The C domains are similar to each other, and the crystal structure of a recombinant human C2 domain is known, allowing construction of a molecular model of C1. The FVIII protein is secreted as a heterodimer following at least two intracellular cleavages within the B domain. In circulation it is stabilized by binding to von Willebrand factor (vWF) with a plasma half-life of about 10 hours. After specific thrombin cleavages that remove the remainder of the B domain and one of the high-affinity von Willebrand factor binding sites, FVIII becomes heterotrimeric FVIIIa, capable of enhancing intrinsic FX activation by FIXa. Inactivation of FVIIIa occurs by A2 dissociation or by specific cleavages within A1 and A2 by activated protein C. Control of intrinsic FX activation is critical for hemostasis and thrombosis.

KEYWORD

Factor VIII gene - structure and expression - factor VIII protein - domain structure and function - intrinsic factor X activation

REFERENCES

  • 1 Aggeler P M, White S G, Glendening M B. et al . Plasma thromboplastin component (PTC) deficiency: a new disease resembling hemophilia.  Proc Soc Exp Biol Med . 1952;  79 692-694
    CrossrefPubMedGoogle Scholar
  • 2 Shulman I, Smith C H. Hemorrhagic disease in an infant due to deficiency of a previously undescribed clotting factor.  Blood . 1952;  7 794-807
    PubMedGoogle Scholar
  • 3 Biggs R, Douglas A S, Macfarlane R G. et al . Christmas disease: a condition previously mistaken for haemophilia.  BMJ . 1952;  2 1378-1382
    CrossrefPubMedGoogle Scholar
  • 4 Biggs R, Douglas A S. The thromboplastin generation test.  J Clin Pathol . 1953;  6 23-29
    PubMedGoogle Scholar
  • 5 Proctor R R, Rapaport S I. The partial thromboplastin time with kaolin.  Am J Clin Pathol . 1961;  36 212-219
    CrossrefPubMedGoogle Scholar
  • 6 Owen W G, Wagner R H. Antihemophilic factor: separation of an active fragment following dissociation by salts or detergents.  Thrombosis et Diathesis Haemorrhagica . 1972;  27 502-515
    PubMedGoogle Scholar
  • 7 Rick M, Hoyer L. Immunologic properties of antihemophilic factor (AHF, factor VIII). V. Immunologic properties of AHF subunits produced by salt dissociation.  Blood . 1973;  42 737-747
    PubMedGoogle Scholar
  • 8 Cooper H A, Reisner F F, Hall M, Wagner R H. Effects of thrombin treatment in preparations of factor VIII and the Ca+2 dissociated small active fragment.  J Clin Invest . 1975;  56 751-760
    PubMedGoogle Scholar
  • 9 Holmberg L, Ljung R. Purification of FVIII:C by antigen-antibody chromatography.  Thromb Res . 1978;  12 667-675
    CrossrefPubMedGoogle Scholar
  • 10 Tuddenham E GD, Trabold N C, Collins J A, Hoyer L W. The properties of factor VIII coagulant activity prepared by immunoabsorbent chromatography.  J Lab Clin Med . 1979;  93 40-53
    PubMedGoogle Scholar
  • 11 Gitschier J, Wood W I, Goralka T M. et al . Characterization of the human factor VIII gene.  Nature . 1984;  312 326-330
    CrossrefPubMedGoogle Scholar
  • 12 Wood W I, Capon D J, Simonsen C C. et al . Expression of active human factor VIII from recombinant DNA clones.  Nature . 1984;  312 330-337
    CrossrefPubMedGoogle Scholar
  • 13 Toole J J, Knopf J L, Wozney J M. et al . Molecular cloning of a cDNA encoding human antihemophilic factor.  Nature . 1984;  12 342-347
    PubMedGoogle Scholar
  • 14 Kemball-Cook G, Tuddenham E GD, Wacey A I. The factor VIII structure and mutation resource site. HAMSTeRS version 4 (http://europium.  csc.mrc.ac.uk). Nucl Acids Res . 1998;  26 216-219
    CrossrefPubMedGoogle Scholar
  • 15 Pittman D D, Kaufman R J. Site-directed mutagenesis and expression of coagulation factors VIII and V in mammalian cells.  Methods Enzymol . 1993;  222 236-260
    PubMedGoogle Scholar
  • 16 Levinson B, Kenwrick S, Lakich D, Hammonds Jr G, Gitschier J. A transcribed gene in an intron of the human factor VIII gene.  Genomics . 1990;  7 1-11
    CrossrefPubMedGoogle Scholar
  • 17 Levinson B, Kenwrick S, Gamel P, Fisher K, Gitschier J. Evidence for a third transcript from the human factor VIII gene.  Genomics . 1992;  14 585-589
    CrossrefPubMedGoogle Scholar
  • 18 Bagnall R D, Waseem N, Green P M, Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A.  Blood . 2002;  99 168-174
    CrossrefPubMedGoogle Scholar
  • 19 Poustka A, Dietrich A, Langenstein G. et al . Physical map of human Xq27-qter: localizing the region of the fragile X mutation.  Proc Natl Acad Sci USA . 1991;  88 8302-8306
    PubMedGoogle Scholar
  • 20 Freije D, Schlessinger D. A 1.6-Mb contig of yeast artificial chromosomes around the human factor VIII gene reveals three regions homologous to probes for the DXS115 locus and two for the DXYS64 locus.  Am J Hum Genet . 1992;  51 66-80
    PubMedGoogle Scholar
  • 21 Figueiredo M S, Brownlee G G. Cis-acting elements and transcription factors involved in the promoter activity of the human factor VIII gene.  J Biol Chem . 1995;  270 11828-11838
    CrossrefPubMedGoogle Scholar
  • 22 McGlynn L K, Mueller C R, Begbie M, Notley C R, Lillicrap D. Role of the liver-enriched transcription factor hepatocyte nuclear factor 1 in transcriptional regulation of the factor VIII gene.  Mol Cell Biol . 1996;  16 1936-1945
    PubMedGoogle Scholar
  • 23 Begbie M, Mueller C, Lillicrap D. Enhanced binding of HLF/DBP heterodimers represents one mechanism of PAR protein transactivation of the factor VIII and factor IX genes.  DNA Cell Biol . 1999;  18 165-173
    CrossrefPubMedGoogle Scholar
  • 24 Valleix S, Jeanny J-C, Elselvier S. et al . Expression of human F8B, a gene nested within the coagulation factor VIII gene, produces multiple eye defects and developmental alterations in chimeric and transgenic mice.  Hum Mol Genet . 1999;  8 1291-1301
    CrossrefPubMedGoogle Scholar
  • 25 Pittman D D, Alderman E M, Tomkinson K N. et al . Biochemical, immunological and in vivo functional characterization of B-domain-deleted factor VIII.  Blood . 1993;  81 2925-2935
    PubMedGoogle Scholar
  • 26 Bi L, Lawler A M, Antonarakis S E. et al . Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A.  Nat Genet . 1995;  10 119-121
    CrossrefPubMedGoogle Scholar
  • 27 Thompson A R. Molecular biology of the hemophilias.  Prog Hemost Thromb . 1991;  10 175-214
    PubMedGoogle Scholar
  • 28 Lalloz M RA, McVey J H, Pattinson J K, Tuddenham E GD. Haemophilia A diagnosis by analysis of a hypervariable dinucleotide repeat within the factor VIII gene.  Lancet . 1991;  338 207-211
    CrossrefPubMedGoogle Scholar
  • 29 Lalloz M RA, Schwaab R, McVey J H, Michaelides K, Tuddenham E GD. Haemophilia A diagnosis by simultaneous analysis of two variable dinucleotide tandem repeats within the factor VIII gene.  Br J Haematol . 1994;  86 804-809
    CrossrefPubMedGoogle Scholar
  • 30 Bontempo F A, Lewis J H, Gorenc T J. et al . Liver transplantation in hemophilia A.  Blood . 1987;  69 1721-1724
    PubMedGoogle Scholar
  • 31 Zelechowska M G, van Mourik A J, Brodniewicz-Proba T. Ultrastructural localization of factor VIII procoagulant antigen in human liver hepatocytes.  Nature . 1985;  317 729-731
    CrossrefPubMedGoogle Scholar
  • 32 Wion K L, Kelly D, Summerfield J A, Tuddenham E GD, Lawn R M. Distribution of factor VIII mRNA and antigen in human liver and other tissues.  Nature . 1985;  317 726-729
    CrossrefPubMedGoogle Scholar
  • 33 Naylor J A, Green P M, Montandon A J, Rizza C R, Giannelli F. Detection of three novel mutations in two haemophilia A patients by rapid screening of whole essential region of factor VIII gene.  Lancet . 1991;  337 635-639
    CrossrefPubMedGoogle Scholar
  • 34 Hollestelle M J, Thinnes T, Crain K. et al . Tissue distribution of factor VIII gene expression in vivo-a closer look.  Thromb Haemost . 2001;  86 855-861
    PubMedGoogle Scholar
  • 35 Kaufman R J, Wasley L C, Dorner A J. Synthesis, processing, and secretion of recombinant human factor VIII expressed in mammalian cells.  J Biol Chem . 1988;  263 6352-6362
    PubMedGoogle Scholar
  • 36 Dorner A J, Bole D G, Kaufman R J. The relationship of Nlinked glycosylation and heavy chain-binding protein association with the secretion of glycoproteins.  J Cell Biol . 1987;  105 2665-2674
    CrossrefPubMedGoogle Scholar
  • 37 Pipe S W, Morris J A, Shah J, Kaufman R J. Differential interaction of coagulation factor VIII and factor V with protein chaperones calnexin and calreticulin.  J Biol Chem . 1998;  273 8537-8544
    CrossrefPubMedGoogle Scholar
  • 38 Tagliavacca L, Wang Q, Kaufman R J. ATP-dependent dissociation of non-disulfide-linked aggregates of coagulation factor VIII is a rate-limiting step for secretion.  Biochemistry . 2000;  39 1973-1981
    CrossrefPubMedGoogle Scholar
  • 39 Moussalli M, Pipe S W, Hauri H-P. et al . Mannose-dependent endoplasmic reticulum (ER)-Golgi intermediate compartment-53-mediated ER to Golgi trafficking of coagulation factors V and VIII.  J Biol Chem . 1999;  274 32539-32542
    CrossrefPubMedGoogle Scholar
  • 40 Cunningham M A, Pipe S W, Hauri H-P, Kaufman R J. The interaction of coagulation factor VIII with ERGIC-53 requires specific N-linked oligosaccharide structures within the B domain (Abst).  Blood . 2001;  98 705a
    CrossrefPubMedGoogle Scholar
  • 41 Pipe S W, Miao H, Tendulkar R, Kaufman R J. Asparagine-linked glycosylation sites within the B domain of coagulation factor VIII improve secretion efficiency (Abst).  Blood . 2001;  98 705a
    CrossrefPubMedGoogle Scholar
  • 42 Kaufman R J, Pipe S W. Regulation of factor VIII expression and activity by von Willebrand factor.  Thromb Haemost . 1999;  82 201-208
    PubMedGoogle Scholar
  • 43 Siesennop A, Jozwiak M, Rosenberg J B, Montgomery R R. Factor VIII and von Willebrand factor synthesis in adjacent cells-can FVIII be stored with vWF (Abst)?.  Blood . 2001;  98 39a
    PubMedGoogle Scholar
  • 44 Lynch C M, Israel D I, Kaufman R J, Miller A D. Sequences in the coding region of clotting factor VIII act as dominant inhibitors of RNA accumulation and protein production.  Hum Gene Ther . 1993;  4 259-272
    PubMedGoogle Scholar
  • 45 Koerbel D D, Halbert C L, Krumm A, Miller A D. Sequences within the coding regions of clotting factor VIII and CFTR block transcriptional elongation.  Hum Gene Ther . 1995;  6 469-479
    PubMedGoogle Scholar
  • 46 Fallaux F J, Hoeben R C, Cramer S J. et al . The human clotting factor VIII cDNA contains an autonomously replicating sequence consensus- and matrix attachment region-like sequence that binds a nuclear factor, represses heterologous gene expression, and mediates the transcriptional effects of sodium butyrate.  Mol Cell Biol . 1996;  16 4264-4272
    PubMedGoogle Scholar
  • 47 Plantier J L, Rodriguez M H, Enjolras N, Attali O, Negrier C. A factor VIII minigene comprising the truncated intron I of factor IX highly improves the in vitro production of factor VIII.  Thromb Haemost . 2001;  86 596-603
    PubMedGoogle Scholar
  • 48 Vehar G A, Keyt B, Eaton D. et al . Structure of factor VIII.  Nature . 1984;  312 337-342
    CrossrefPubMedGoogle Scholar
  • 49 Elder B, Lakich D, Gitschier J. Sequence of the murine factor VIII cDNA.  Genomics . 1993;  16 374-379
    CrossrefPubMedGoogle Scholar
  • 50 Healey J F, Lubin I M, Lollar P. The cDNA and derived amino acid sequence of porcine factor VIII.  Blood . 1996;  88 4209-4214
    PubMedGoogle Scholar
  • 51 Cameron C, Notley C, Hoyle S. et al . The canine factor VIII cDNA and 5' flanking sequence.  Thromb Haemost . 1998;  79 317-322
    PubMedGoogle Scholar
  • 52 Lollar P, Fay P J, Fass D N. Factor VIII and factor VIIIa.  Methods Enzymol . 1993;  222 128-143
    PubMedGoogle Scholar
  • 53 Pittman D D, Wang J H, Kaufman R J. Identification and functional importance of tyrosine-sulfate residues within recombinant factor VIII.  Biochemistry . 1992;  31 3315-3323
    CrossrefPubMedGoogle Scholar
  • 54 Eaton D, Rodriguez H, Vehar G A. Proteolytic processing of human factor VIII. Correlation of specific cleavages by thrombin, factor Xa, and activated protein C with activation and inactivation of factor VIII coagulant activity.  Biochemistry . 1986;  25 505-512
    CrossrefPubMedGoogle Scholar
  • 55 Foster P A, Fulcher C A, Houghten R A, Zimmerman T S. An immunogenic region within residues Val1670-Glu1684 of the factor VIII light chain induces antibodies which inhibit binding of factor VIII to von Willebrand factor.  J Biol Chem . 1988;  263 5230-5234
    PubMedGoogle Scholar
  • 56 Leyte A, van Schijndel B H, Niehrs C. et al . Sulfation of Tyr1680 of human blood coagulation factor VIII is essential for the interaction of factor VIII with von Willebrand factor.  J Biol Chem . 1991;  266 740-746
    PubMedGoogle Scholar
  • 57 Kane W H, Davie E W. Blood coagulation factor V and factor VIII, structural and functional similarities and their relationship to hemorrhagic and thrombotic disorders.  Blood . 1988;  71 539-555
    PubMedGoogle Scholar
  • 58 Stoylova S S, Lenting P J, Kemball-Cook G, Holzenburg A. Electron crystallography of human blood coagulation factor VIII bound to phospholipid monolayers.  J Biol Chem . 1999;  274 36573-36578
    CrossrefPubMedGoogle Scholar
  • 59 Takeshima K, Fujikawa K. The phospholipid binding property of the C2 domain of human factor VIII (Abst).  Thromb Haemost . 1999;  82(Suppl) 234
    PubMedGoogle Scholar
  • 60 Zaitseva I, Zaitsev V, Card G. et al . The X-ray structure of human serum ceruloplasmin at 3.1 Å: nature of the copper centres.  J Biol Inorg Chem . 1996;  1 15-23
    PubMedGoogle Scholar
  • 61 Pemberton S, Lindley P, Zaitsev V. et al . A molecular model for the triplicated A domains of human factor VIII based on the crystal structure of human ceruloplasmin.  Blood . 1997;  89 2413-2421
    PubMedGoogle Scholar
  • 62 Thompson A R, Murphy M EP, Liu M L. et al . Loss of tolerance to exogenous and endogenous factor VIII in a mild hemophilia A patient with an Arg593 to Cys mutation.  Blood . 1997;  90 1902-1910
    PubMedGoogle Scholar
  • 63 Liu M-L, Murphy M EP, Thompson A R. A domain mutations in 65 hemophilia A families and molecular modeling of dysfunctional factor VIII proteins.  Br J Haematol . 1988;  103 1051-1060
    PubMedGoogle Scholar
  • 64 McMullen B A, Fujikawa K, Davie E W, Hedner U, Ezban M. Location of disulfide bonds and free cysteines in the heavy and light chains of recombinant human factor VIII (antihemophilic factor).  Protein Sci . 1995;  4 740-746
    PubMedGoogle Scholar
  • 65 Tagliavacca L, Moon N, Dunham W R, Kaufman R J. Identification and functional requirement of Cu(I) and its ligands within coagulation factor VIII.  J Biol Chem . 1997;  272 27428-27434
    CrossrefPubMedGoogle Scholar
  • 66 Fay P J, Haidaris P J, Smudzin T M. Reconstruction of factor VIIIa from the isolated A1/A3-C1-C2 dimer and A2 subunit.  J Biol Chem . 1991;  266 8957-8962
    PubMedGoogle Scholar
  • 67 Pipe S W, Saenko E L, Eickhorst A N, Kemball-Cook G, Kaufman R J. Hemophilia A mutations associated with 1-stage/ 2-stage activity discrepancy disrupt protein-protein interactions within the triplicated A domains of thrombin-activated factor VIIIa.  Blood . 2001;  97 685-691
    CrossrefPubMedGoogle Scholar
  • 68 Healey J F, Lubin I M, Nakai H. et al . Residues 484-508 contain a major determinant of the inhibitory epitope in the A2 domain of human factor VIII.  J Biol Chem . 1995;  270 14505-14509
    CrossrefPubMedGoogle Scholar
  • 69 Fay P J, Beattie T, Huggins C F, Regan L M. Factor VIIIa A2 subunit residues 558-565 represent a factor IXa interactive site.  J Biol Chem . 1994;  269 20522-20527
    PubMedGoogle Scholar
  • 70 O'Brien L M, Medved L V, Fay P J. Localization of factor IXa and factor VIIIa interactive sites.  J Biol Chem . 1995;  270 27087-27092
    CrossrefPubMedGoogle Scholar
  • 71 Bajaj S P, Schmidt A E, Mathur A. et al . Factor IXa:factor VIIIa interaction-helix 330-338 of factor IX interacts with residues 558-565 and spatially adjacent regions of the A2 subunit of factor VIIIa.  J Biol Chem . 2001;  276 16302-16309
    CrossrefPubMedGoogle Scholar
  • 72 Lenting P J, van den Loo W J, Donath M J, van Mourik A J, Mertens K. The sequence Glu1811-Lys1818 of human blood coagulation factor VIII comprises a binding site for activated factor IX.  J Biol Chem . 1996;  271 1935-1940
    CrossrefPubMedGoogle Scholar
  • 73 Lapan K A, Fay P J. Localization of a factor X interactive site in the A1 subunit of factor VIIIa.  J Biol Chem . 1997;  272 2082-2088
    CrossrefPubMedGoogle Scholar
  • 74 Lapan K A, Fay P J. Interaction of the A1 subunit of factor VIIIa and the serine protease domain of factor X identified by zero-length cross-linking.  Thromb Haemost . 1998;  80 418-422
    PubMedGoogle Scholar
  • 75 Walker F J, Scandella D, Fay P J. Identification of the binding site for activated protein C on the light chain of factors V and VIII.  J Biol Chem . 1990;  265 1484-1489
    PubMedGoogle Scholar
  • 76 Marquette K A, Pittman D D, Kaufman R J. A 110-amino acid region within the A1-domain of coagulation factor VIII inhibits secretion from mammalian cells.  J Biol Chem . 1995;  270 10297-10303
    CrossrefPubMedGoogle Scholar
  • 77 Swaroop M, Moussalli M, Pipe S W, Kaufman R J. Mutagenesis of a potential immunoglobulin-binding protein-binding site enhances secretion of coagulation factor VIII.  J Biol Chem . 1997;  272 24121-24124
    CrossrefPubMedGoogle Scholar
  • 78 Pratt K P, Shen B W, Takeshima K. et al . Structure of the C2 domain of human factor VIII at 1.5 Å resolution.  Nature . 1999;  402 439-442
    CrossrefPubMedGoogle Scholar
  • 79 Liu M-L, Shen B W, Nakaya S. et al . Hemophilic factor VIII C1 and C2 domain missense mutations and their modeling to the 1.5 angström human C2 domain crystal structure.  Blood . 2000;  96 979-987
    PubMedGoogle Scholar
  • 80 Spiegel P C, Jacquemin M, Saint-Remy J-MR, Stoddard B L, Pratt K P. Structure of a factor VIII C2 domain-immunoglobulin G4κ Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII.  Blood . 2001;  98 13-19
    CrossrefPubMedGoogle Scholar
  • 81 Barrow R T, Healey J F, Gailani D, Scandella D, Lollar P. Reduction of the antigenicity of factor VIII toward complex inhibitory antibody plasmas using multiple-substituted hybrid human/porcine factor VIII molecules.  Blood . 2000;  95 564-568
    PubMedGoogle Scholar
  • 82 Saenko E L, Scandella D. The acidic region of the factor VIII light chain and the C2 domain together form the high affinity binding site for von Willebrand factor.  J Biol Chem . 1997;  272 18007-18014
    CrossrefPubMedGoogle Scholar
  • 83 Nogami K, Shima M, Hosokawa K. et al . The factor VIII C2 domain contains the thrombin binding site responsible for thrombin-catalyzed cleavage at Arg 1689.  J Biol Chem . 2000;  275 25774-25780
    CrossrefPubMedGoogle Scholar
  • 84 Nogami K, Shima M, Hosokawa K. et al . Role of factor VIII C2 domain in factor VIII binding to factor Xa.  J Biol Chem . 1999;  274 31000-31007
    CrossrefPubMedGoogle Scholar
  • 85 Liu M-L, Thompson A R. Factor VIII's C1 domain enhances C2 binding of factors IX/IXa, X/Xa and von Willebrand factor (Abst).  Blood . 2000;  96 489a
    PubMedGoogle Scholar
  • 86 Sandberg H, Almstedt A, Brandt J. et al . Structural and functional characteristics of the B-domain-deleted recombinant factor VIII protein, r-VIII SQ.  Thromb Haemost . 2001;  85 93-100
    PubMedGoogle Scholar
  • 87 Over J, Sixma J J, Bruine M H. et al . Survival of 125 iodine-labeled factor VIII in normals and patients with hemophilia. Observations on the heterogeneity of human factor VIII.  J Clin Invest . 1978;  62 223-234
    PubMedGoogle Scholar
  • 88 Vlot A J, Mauser-Bunschoten E P, Zarkova A G. et al . The half-life of infused factor VIII is shorter in hemophiliac patients with blood group O than in those with blood group A.  Thromb Haemost . 2000;  83 65-69
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 89 Chandler W L, Rogers G M, Sprouse J T, Thompson A R. Elevated hemostatic factor levels as potential risk factors for thrombosis.  Arch Pathol Lab Med . 2002;  126 1405-1414
    PubMedGoogle Scholar
  • 90 Begbie M, Notley C, Tinlin S, Sawyer L, Lillicrap D. The factor VIII acute phase response requires the participation of NFkappaB and C/EBP.  Thromb Haemost . 2000;  84 216-222
    PubMedGoogle Scholar
  • 91 Nilsson I M, Blombäck M, Blombäck B. von Willebrand's disease in Sweden. Its pathogenesis and treatment.  Acta Med Scand . 1959;  164 263-278
    PubMedGoogle Scholar
  • 92 Kaufman R J, Dorner A J, Fass D N. von Willebrand factor elevates plasma factor VIII without induction of factor VIII messenger RNA in the liver.  Blood . 1999;  93 193-197
    PubMedGoogle Scholar
  • 93 Vlot A J, Koppelman S J, van den Berg H M, Bouma B N, Sixma J J. The affinity and stoichiometry of binding human factor VIII to von Willebrand factor.  Blood . 1995;  85 3150-3157
    CrossrefPubMedGoogle Scholar
  • 94 Kamphuisen P W, Lensen R, Houwing-Duistermaat J J. et al . Heritability of elevated factor VIII antigen levels in factor V Leiden families with thrombophilia.  Br J Haematol . 2000;  109 519-522
    CrossrefPubMedGoogle Scholar
  • 95 Kamphuisen P W, Eikenboom J C, Bertina R M. Elevated factor VIII levels and the risk of thrombosis.  Arterioscler Thromb Vasc Biol . 2001;  21 731-738
    CrossrefPubMedGoogle Scholar
  • 96 Köster T, Blann A D, Briet E, Vandenbroucke J P, Rosendaal F R. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis.  Lancet . 1995;  21 152-155
    PubMedGoogle Scholar
  • 97 Kamphuisen P W, Eikenboom J CJ, Rosendaal F R. et al . High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene.  Br J Haematol . 2001;  115 156-158
    CrossrefPubMedGoogle Scholar
  • 98 Lenting P J, Neels J G, van den Berg M B. et al . The light chain of factor VIII comprises a binding site for low density lipoprotein receptor-related protein.  J Biol Chem . 1999;  274 23734-23739
    CrossrefPubMedGoogle Scholar
  • 99 Schwarz H P, Lenting P J, Binder B. et al . Involvement of low-density lipoprotein receptor-related protein (LRP) in the clearance of factor VIII in von Willebrand factor-deficient mice.  Blood . 2000;  95 1703-1708
    PubMedGoogle Scholar
  • 100 Saenko E L, Yakhyaev A V, Mikhailenko I, Strickland D K, Sarafanov A G. Role of the low density lipoprotein-related protein receptor in mediation of factor VIII catabolism.  J Biol Chem . 1999;  274 37685-37692
    CrossrefPubMedGoogle Scholar
  • 101 Sarafanov A G, Ananyeva N M, Shima M, Saenko E L. Cell surface heparan sulfate proteoglycans participate in factor VIII catabolism mediated by low density lipoprotein receptor-related protein.  J Biol Chem . 2001;  276 11970-11979
    CrossrefPubMedGoogle Scholar
  • 102 Wakabayashi H, Koszelak M E, Mastri M, Fay P J. Metal ion-independent association of factor VIII subunits and the roles of calcium and copper ions for cofactor activity and inter-subunit affinity.  Biochemistry . 2001;  40 10293-10300
    CrossrefPubMedGoogle Scholar
  • 103 Rapaport S I, Schiffman S, Patch M J, Ames S B. The importance of activation of antihemophilic globulin and procaccelerin by traces of thrombin in the generation of intrinsic prothrombinase activity.  Blood . 1963;  21 221-236
    PubMedGoogle Scholar
  • 104 Pittman D D, Kaufman R J. Proteolytic requirements for thrombin activation of anti-hemophilic factor (factor VIII).  Proc Natl Acad Sci USA . 1988;  85 2429-2433
    PubMedGoogle Scholar
  • 105 Fay P J, Mastri M, Koszelak M E, Wakabayashi H. Cleavage of factor VIII heavy chain is required for the functional interaction of A2 subunit with factor IXa.  J Biol Chem . 2001;  276 12434-12439
    CrossrefPubMedGoogle Scholar
  • 106 Brandstetter H, Bauer M, Huber R, Lollar P, Bode W. Xray structure of clotting factor IXa: active site and module structure related to Xase activity and hemophilia B.  Proc Natl Acad Sci USA . 1995;  92 9796-9800
    PubMedGoogle Scholar
  • 107 Walker F J, Chavin S I, Fay P J. Inactivation of factor VIII by activated protein C and protein S.  Arch Biochem Biophys . 1987;  252 322-328
    CrossrefPubMedGoogle Scholar
  • 108 Mertens K, Celie P HN, Kolkman J A, Lenting P J. Factor VIII-factor IX interactions: molecular sites involved in enzyme-cofactor complex assembly.  Thromb Haemost . 1999;  82 209-217
    PubMedGoogle Scholar
  • 109 van Dieijen G, Tans G, Rosing J, Hemker H C. The role of phospholipid and factor VIIIa in the activation of bovine factor X.  J Biol Chem . 1981;  256 3433-3442
    PubMedGoogle Scholar
  • 110 Mann K G. Biochemistry and physiology of blood coagulation.  Thromb Haemost . 1999;  82 165-174
    PubMedGoogle Scholar
  • 111 Barrow R T, Healey J F, Jacquemin M G, Saint-Remy J-MR, Lollar P. Antigenicity of putative phospholipid membrane-binding residues in factor VIII.  Blood . 2001;  97 169-174
    CrossrefPubMedGoogle Scholar
  • 112 Gilbert G E, Kaufman R J, Arena A A, Miao H, Pipe S W. Four hydrophobic amino acids of the factor VIII C2 domain are constituents of both membrane-binding and von Willebrand factor-binding motifs.  J Biol Chem . 2002;  277 6374-6381
    CrossrefPubMedGoogle Scholar
  • 113 Ahmad S S, Walsh P N. The role of C2 domain of factor VIII in the assembly of factor-X activating complex on platelet membrane(Abst).  Blood . 2001;  98 706a
    PubMedGoogle Scholar
  • 114 Shima M, Scandella D, Yoshioka A. et al . A factor VIII neutralizing monoclonal antibody and a human inhibitor alloantibody recognizing epitopes in the C2 domain inhibit factor VIII binding to von Willebrand factor and to phosphatidylserine.  Thromb Haemost . 1993;  69 240-246
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 115 Koszelak M E, Huggins C F, Fay P J. Sites in the A2 subunit involved in the interfactor VIIIa interaction.  J Biol Chem . 2000;  275 27137-27144
    PubMedGoogle Scholar
  • 116 Rosenblum M K, Freas J, Mastri M, Fay P J. Cofactor activity associated with the isolated A2 subunit of factor VIIIa is stimulated by a truncated A1 subunit lacking C-terminal residues 337-372 (Abst).  Blood . 2001;  98 38a
    PubMedGoogle Scholar
  • 117 Regan L M, O'Brien L M, Beattie T L. et al . Activated protein C-catalyzed proteolysis of factor VIIIa alters its interactions with factor Xase.  J Biol Chem . 1996;  271 3982-3987
    CrossrefPubMedGoogle Scholar
  • 118 Amano K, Michnick D A, Moussalli M, Kaufman R J. Mutation at either Arg336 or Arg562 in factor VIII is insufficient for complete resistance to activated protein C (APC)-mediated inactivation: implications for the APC resistance test.  Thromb Haemost . 1998;  79 557-563
    PubMedGoogle Scholar
  • 119 Benedict C R, Ryan J, Wolitzky B. et al . Active site-blocked factor IXa prevents intravascular thrombus formation in the coronary vasculature without inhibiting extravascular coagulation in a dog model.  J Clin Invest . 1991;  88 1760-1765
    PubMedGoogle Scholar
  • 120 Feuerstein G Z, Toomey J R, Valocik R. et al . An inhibitory anti-factor IX antibody effectively reduces thrombus formation in a rat model of venous thrombosis.  Thromb Haemost . 1999;  82 1443-1445
    PubMedGoogle Scholar
  • 121 Spanier T B, Chen J M, Oz M C. et al . Selective anticoagulation with active-site blocked factor IXa suggests separate roles for intrinsic and extrinsic coagulation pathways in cardiopulmonary bypass.  J Thorac Cardiovasc Surg . 1998;  116 860-868
    PubMedGoogle Scholar
  • 122 Pipe S W, Kaufman R J. Characterization of a genetically engineered inactivation-resistant coagulation factor VIIIa.  Proc Natl Acad Sci USA . 1997;  94 11851-11856
    CrossrefPubMedGoogle Scholar
  • 123 Barrow R T, Lollar P. Amino acid residues R2215, R2220, and F2196 contribute to the antigenicity of human factor VIII C2 domain toward inhibitory antibodies (Abst).  Blood . 2001;  98 531a
    PubMedGoogle Scholar
  • 124 Qian J, Collins M, Sharpe A H, Hoyer L W. Prevention and treatment of factor VIII inhibitors in murine hemophilia A.  Blood . 2000;  95 1324-1329
    PubMedGoogle Scholar
  • 125 Wu H, Reding M, Qian J. et al . Mechanism of the immune response to human factor VIII in murine hemophilia A.  Thromb Haemost . 2001;  85 125-133
    PubMedGoogle Scholar
  • 126 Parker E T, Craddock H N, Barrow R T, Healey J F, Lollar P. Reduction in the immunogenicity of human FVIII in hemophilia A mice by site-directed mutagenesis of the A2 epitope (Abst).  Blood . 2001;  98 826a
    PubMedGoogle Scholar