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Semin Thromb Hemost 2002; 28(3): 309-322
DOI: 10.1055/s-2002-32667
DOI: 10.1055/s-2002-32667
Hemophilia A-From Basic Science to Clinical Practice
Weitere Informationen
Publikationsverlauf
Publikationsdatum:
04. Juli 2002 (online)
ABSTRACT
This article summarizes achievements of basic research and their implementation in clinical treatment of one of the most common inherited bleeding disorders hemophilia A, which is caused by genetic deficiency of coagulation factor VIII (FVIII). We discuss the structure of FVIII, its major interactions in the intrinsic pathway of blood coagulation, and the catabolism of FVIII. We also discuss achievements in the contemporary clinical practice of treatment of hemophilia A. Replacement therapy has substantially improved by development of purification and virus inactivation procedures, allowing preparation of safe and effective therapeutic plasma-derived FVIII concentrates. We give special attention to the principles used in the development of contemporary recombinant FVIII products, which do not inherit a potential risk for viral or prion transmission. Development of FVIII inhibitory antibodies is the major complication of FVIII replacement therapy. We summarize the accumulated knowledge regarding epitopes of FVIII inhibitors and mechanisms by which they inactivate FVIII and discuss approaches to overcome the effects of inhibitors and to prevent their formation by induction of immunotolerance. We also analyze the main concepts and scientific priorities in the gene-therapeutic approach for treatment of hemophilia A.
KEYWORDS
Hemophilia A - factor VIII - replacement therapy - inhibitors - gene therapy
REFERENCES
- 1 Rosner F. Hemophilia in the Talmud and rabbinic writings. Ann Intern Med . 1969; 70 833-837
- 2 Otto J. An account of a hemorrhagic disposition existing in certain families. Med Repos . 1803; 6 1-4
- 3 Brinkhous K. Clotting defect in hemophilia: deficiency in a plasma factor required for platelet utilization. Proc Soc Exp Biol Med . 1947; 66 117
- 4 Hoyer L W. Hemophilia A. N Engl J Med . 1994; 330 38-47
- 5 Arnold W D, Hilgartner M W. Hemophilic arthropathy. Current concepts of pathogenesis and management. J Bone Joint Surg Am . 1977; 59 287-305
- 6 Gilbert M S. Musculoskeletal manifestations of hemophilia. Mt Sinai J Med . 1977; 44 339-358
- 7 Pettersson H, Ahlberg A, Nilsson I M. A radiologic classification of hemophilic arthropathy. Clin Orthop . 1980; 149 153-159
- 8 Nilsson I M, Berntorp E, Lofqvist T, Pettersson H. Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B. J Intern Med . 1992; 232 25-32
- 9 Lofqvist T, Nilsson I M, Berntorp E, Pettersson H. Haemophilia prophylaxis in young patients-a long-term follow-up. J Intern Med . 1997; 241 395-400
- 10 Kreuz W, Escuriola Ettingshausen C, Funk M. Prevention of joint damage in hemophilic children with early prophylaxis. Orthopäde . 1999; 28 341-346
- 11 Fernandez-Palazzi F, Hernandez S R, De Bosch B N, De Saez R A. Hematomas within the iliopsoas muscles in hemophilic patients: the Latin American experience. Clin Orthop . 1996; 328 19-24
- 12 Klinge J, Auberger K, Auerswald G. Prevalence and outcome of intracranial haemorrhage in haemophiliacs-a survey of the paediatric group of the German Society of Thrombosis and Haemostasis (GTH). Eur J Pediatr . 1999; 158(Suppl 3) 162-165
- 13 de Tezanos Pinto M, Fernandez J, Perez Bianco R P. Update of 156 episodes of central nervous system bleeding in hemophiliacs. Haemostasis . 1992; 22 259-267
- 14 Rizza C R, Matthews J M. Management of the haemophilic child. Arch Dis Child . 1972; 47 451-462
- 15 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
- 16 Gilbert G E, Arena A A. Activation of the factor VIIIa-factor IXa enzyme complex of blood coagulation by membranes containing phosphatidyl-L-serine. J Biol Chem . 1996; 271 11120-11125
- 17 Nesheim M E, Pittman D D, Wang J H. The binding of 35S-labeled recombinant factor VIII to activated and unactivated human platelets. J Biol Chem . 1988; 263 16467-16470
- 18 Saenko E L, Shima M, Sarafanov A G. Role of activation of the coagulation factor VIII in interaction with vWF, phospholipid, and functioning within the factor Xase complex. Trends Cardiovasc Med . 1999; 9 185-192
- 19 Fay P J. Regulation of factor VIIIa in the intrinsic factor Xase. Thromb Haemost . 1999; 82 193-200
- 20 Rawala-Sheikh R, Ahmad S S, Ashby B, Walsh P N. Kinetics of coagulation factor X activation by platelet-bound factor IXa. Biochemistry . 1990; 29 2606-2611
- 21 Mann K G. Biochemistry and physiology of blood coagulation. Thromb Haemost . 1999; 82 165-174
- 22 Saenko E L, Scandella D. The acidic region of the light chain and the C2 domain together form a high affinity binding site for von Willebrand factor. J Biol Chem . 1997; 272 18007-18014
- 23 Jacquemin M, Lavend'homme R, Benhida A. A novel cause of mild/moderate hemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Willebrand factor. Blood . 2000; 96 958-965
- 24 Liu M L, Thompson A R. Factor VIII's C1 domain enhances C2 binding of factors IX/IXa, X/Xa and von Willebrand factor (vWF) (Abst). Blood . 2000; 96 489A
- 25 Morfini M, Mannucci P, Tenconi P M. Pharmacokinetics of monoclonally-purified and recombinant factor VIII in patients with severe von Willebrand disease. Thromb Haemost . 1993; 70 270-272
- 26 Schwarz H P, Lenting P J, Binder B. 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
- 27 Regan L M, Fay P J. Cleavage of factor VIII light chain is required for maximal generation of factor VIIIa activity. J Biol Chem . 1995; 270 8546-8552
- 28 Nogami K, Shima M, Hosokawa K. Factor VIII C2 domain contains the thrombin-binding site responsible for thrombin-catalyzed cleavaget Arg1689 . J Biol Chem . 2000; 275 25774-25780
- 29 Nogami K, Shima M, Hosokawa K. Role of factor VIII C2 domain in factor VIII binding to factor Xa. J Biol Chem . 1999; 274 31000-31007
- 30 Saenko E L, Scandella D, Yakhyaev A V, Greco N. Activation of factor VIII by thrombin increases its affinity for binding to synthetic phospholipid membranes and activated platelets. J Biol Chem . 1998; 273 27918-27926
- 31 Foster P A, Fulcher C A, Houghten R A, Zimmerman T S. Synthetic factor VIII peptides with amino acid sequences contained within the C2 domain of factor VIII inhibit factor VIII binding to phosphatidylserine. Blood . 1990; 75 1999-2004
- 32 Saenko E L, Shima M, Rajalakshmi K J, Scandella D. A role for the C2 domain of factor VIII in binding to von Willebrand factor. J Biol Chem . 1994; 269 11601-11605
- 33 Healey J F, Barrow R T, Tamim H M. Residues Glu2181-Val2243 contain a major determinant of the inhibitory epitope in the C2 domain of human factor VIII. Blood . 1998; 92 3701-3709
- 34 Pratt K P, Shen B W, Takeshima K. Structure of the C2 domain of human factor VIII at 1.5 Å resolution. Nature . 1999; 402 439-442
- 35 Barrow R T, Healey J F, Jacquemin M, Saint-Remy J-M, Lollar P. Antigenicity of putative phospholipid membrane-binding residues in factor VIII. Blood . 2001; 97 169-174
- 36 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 the membrane-binding and von Willebrand factor-binding motifs. J Biol Chem . 2002; 277 6374-6381
- 37 Lenting P J, van de Loo H P J-W, Donath S H 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
- 38 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
- 39 Fay P J, Scandella D. Human inhibitor antibodies specific for the factor VIII A2 domain disrupt the interaction between the subunit and factor IXa. J Biol Chem . 1999; 274 29826-29830
- 40 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
- 41 Fay P J, Koshibu K. The A2 subunit of factor VIIIa modulates the active site of factor IXa. J Biol Chem . 1998; 273 19049-19054
- 42 Lollar P, Parker E T, Fay P J. Coagulant properties of hybrid human/porcine factor VIII molecules. J Biol Chem . 1992; 267 23652-23657
- 43 Fay P J, Beattie T L, Regan L M, O'Brien L M, Kaufman R J. Model for the factor VIIIa-dependent decay of the intrinsic factor Xase: role of subunit dissociation and factor IXa-catalyzed proteolysis. J Biol Chem . 1996; 271 6027-6032
- 44 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
- 45 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
- 46 Lenting P, Neels J G, van den Berg M B. The light chain of factor VIII comprises a binding site for low density lipoprotein receptor-related protein. J Biol Chem . 1999; 274 23734-23739
- 47 Turecek P L, Lenting P J, van Mourik A J. Low density lipoprotein receptor-related protein (LRP) mediates the clearance of factor VIII in vWF-deficient mice (Abst). Blood . 1999; 94 647A
- 48 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
- 49 Neels J G, Horn I R, Van den Berg M M B, Pannekoek H, van Zonneveld A-J. Ligand-receptor interactions of the low density lipoprotein receptor-related protein, a multi-ligand endocytic receptor. Fibrinolysis Proteolysis . 1998; 12 219-240
- 50 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
- 51 Ananyeva N, Kouiavskaia D, Shima M, Saenko E. Catabolism of the coagulation factor VIII. Can we prolong lifetime of FVIII in circulation?. Trends Cardiovasc Med . 2001; 11 252-257
- 52 Neels J G, van den Berg M B, Mertens K. Activation of factor IX zymogen results in exposure of a binding site for low-density lipoprotein receptor-related protein. Blood . 2000; 96 3459-3465
- 53 Narita M, Rudolph A E, Miletich J P, Schwartz A L. The low-density lipoprotein receptor-related protein (LRP) mediates clearance of coagulation factor Xa in vivo. Blood . 1998; 91 555-560
- 54 Moestrup S K, Gliemann J, Pallesen G. Distribution of the alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues. Cell Tissue Res . 1992; 269 375-382
- 55 Larsson S A. Life expectancy of Swedish haemophiliacs, 1831-1980. Br J Haematol . 1985; 59 593-602
- 56 Ikkala E, Helske T, Myllyla G. Changes in the life expectancy of patients with severe haemophilia A in Finland in 1930-79. Br J Haematol . 1982; 52 7-12
- 57 Chorba T L, Holman R C, Clarke M J, Evatt B L. Effects of HIV infection on age and cause of death for persons with hemophilia A in the United States. Am J Hematol . 2001; 66 229-240
- 58 Morfini M, Lee M, Messori A. The design and analysis of half-life and recovery studies for factor VIII and factor IX. Factor VIII/Factor IX Scientific and Standardization Committee of the International Society for Thrombosis and Haemostasis. Thromb Haemost . 1991; 66 384-386
- 59 Messori A, Longo G, Morfini M. Multi-variate analysis of factors governing the pharmacokinetics of exogenous factor VIII in haemophiliacs. Eur J Clin Pharmacol . 1988; 35 663-668
- 60 Bray G L, Gomperts E D, Courter S. A multicenter study of recombinant factor VIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood . 1994; 83 2428-2435
- 61 Lusher J M, Arkin S, Abildgaard C F, Schwartz R S. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. Kogenate Previously Untreated Patient Study Group. N Engl J Med . 1993; 328 453-459
- 62 Ragni M V, Winkelstein A, Kingsley L, Spero J A, Lewis J H. 1986 Update of HIV seroprevalence, seroconversion, AIDS incidence and immunologic correlates of HIV infection in patients with hemophilia A and B. Blood . 1987; 70 786-790
- 63 Levy J A, Mitra G A, Wong M F, Mozen M M. Inactivation by wet and dry heat of AIDS-associated retroviruses during factor VIII purification from plasma. Lancet . 1985; 1 1456-1457
- 64 Prince A M, Stephan W, Kotitschke R, Brotman B. Inactivation of hepatitis B and non-A, non-B viruses by combined use of Tween 80, beta-propiolactone, and ultraviolet irradiation. Thromb Haemost . 1983; 50 534-536
- 65 Santagostino E, Mannucci P M, Gringeri A. Transmission of parvovirus B19 by coagulation factor concentrates exposed to 100 degrees C heat after lyophilization. Transfusion . 1997; 37 517-522
- 66 Lee C A, Ironside J W, Bell J E. Retrospective neuropathological review of prion disease in UK haemophilic patients. Thromb Haemost . 1998; 80 909-911
- 67 Evatt B, Austin H, Barnhart E. Surveillance for Creutzfeldt-Jakob disease among persons with hemophilia. Transfusion . 1998; 38 817-820
- 68 Vehar G A, Keyt B, Eaton D. Structure of human factor VIII. Nature . 1984; 312 337-342
- 69 Toole J J, Knopf J L, Wozney J M. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature . 1984; 312 342-347
- 70 Kaufman R J, Pipe S W. Can we improve on nature?. <~>``Super molecules'' of factor VIII. Haemophilia . 1998; 4 370-379
- 71 Schwartz R S, Abildgaard C F, Aledort L M. Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med . 1990; 323 1800-1805
- 72 Addiego J E, Gomperts E, Liu S-L. Treatment of hemophilia A with a highly purified factor VIII concentrate prepared by anti-FVIIIc immunoaffinity chromatography. Thromb Haemost . 1992; 67 19-27
- 73 Abshire T C, Brackmann H H, Scharrer I. Sucrose formulated recombinant human antihemophilic factor VIII is safe and efficacious for treatment of hemophilia A in home therapy-International Kogenate-FS Study Group. Thromb Haemost . 2000; 83 811-816
- 74 Yoshioka A, Shima M, Fukutake K, Takamatsu J, Shirahata A. Safety and efficacy of a new recombinant FVIII formulated with sucrose (rFVIII-FS) in patients with haemophilia A: a long-term, multicentre clinical study in Japan. Haemophilia . 2001; 7 242-249
- 75 Kaufman R J, Wasley L C, Furie B C, Furie B, Shoemaker C B. Expression, purification, and characterization of recombinant gamma-carboxylated factor IX synthesized in Chinese hamster ovary cells. J Biol Chem . 1986; 261 9622-9628
- 76 Griffith M, Kingdon H, Liu S L, Burkart W. In-process controls and characterization of recombinate antihemophilic factor (recombinant). Ann Hematol . 1991; 63 166-171
- 77 Eriksson R K, Fenge C, Lindner-Olsson E. The manufacturing process for B-domain deleted recombinant factor VIII. Semin Hematol . 2001; 38 24-31
- 78 Keppler O T, Horstkorte R, Pawlita M, Schmidt C, Reutter W. Biochemical engineering of the N-acyl side chain of sialic acid: biological implications. Glycobiology . 2001; 11 11R-18R
- 79 Rothschild C, Laurian Y, Satre E P. French previously untreated patients with severe hemophilia A after exposure to recombinant factor VIII: Incidence of inhibitor and evaluation of immune tolerance. Thromb Haemost . 1998; 80 779-783
- 80 Ehrenforth S, Kreuz W, Scharrer I. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet . 1992; 339 594-598
- 81 Schwaab R, Brackmann H H, Meyer C. Haemophilia A: mutation type determines risk of inhibitor formation. Thromb Haemost . 1995; 74 1402-1406
- 82 Vianello F, Radossi P, Tison T. Prevalence of anti-FVIII antibodies in severe haemophilia A patients with inversion of intron 22. Br J Haematol . 1997; 97 807-809
- 83 Kasper C K, Aledort L, Aronson D. Proceedings: a more uniform measurement of factor VIII inhibitors. Thrombosis et Diathesis Haemorrhagica . 1975; 34 869-872
- 84 Dazzi F, Tison T, Vianello F. High incidence of anti-FVIII antibodies against non-coagulant epitopes in haemophilia A patients: a possible role for the half-life of transfused FVIII. Br J Haematol . 1996; 93 688-693
- 85 Klinge J, Auerswald G, Budde U. Detection of all anti-factor VIII antibodies in haemophilia A patients by the Bethesda assay and a more sensitive immunoprecipitation assay. Haemophilia . 2001; 7 26-32
- 86 Kasper C K. Treatment of factor VIII inhibitors. Prog Hemost Thromb . 1989; 9 57-86
- 87 Brettler D B, Forsberg A D, Levine P H. The use of porcine factor VIII concentrate (Hyate:C) in the treatment of patients with inhibitor antibodies to factor VIII. A multicenter US experience. Arch Intern Med . 1989; 149 1381-1385
- 88 Lusher J M, Blatt P M, Penner J A. Autoplex versus proplex: a controlled, double-blind study of effectiveness in acute hemarthroses in hemophiliacs with inhibitors to factor VIII. Blood . 1983; 62 1135-1138
- 89 Sjamsoedin L J, Heijnen L, Mauser-Bunschoten E P. The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII. A double-blind clinical trial. N Engl J Med . 1981; 305 717-721
- 90 Lusher J M, Roberts H R, Davignon G. A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with haemophilia A and B, with and without inhibitors. rFVIIa Study Group. Haemophilia . 1998; 4 790-798
- 91 Macik B G, Lindley C M, Lusher J. Safety and initial clinical efficacy of three dose levels of recombinant activated factor VII (rFVIIa): results of a phase I study. Blood Coagul Fibrinolysis . 1993; 4 521-527
- 92 Lusher J M. Recombinant factor VIIa (NovoSeven) in the treatment of internal bleeding in patients with factor VIII and IX inhibitors. Haemostasis . 1996; 26 124-130
- 93 Lusher J M. Prediction and management of adverse events associated with the use of factor IX complex concentrates. Semin Hematol . 1993; 30 36-40
- 94 Gringeri A, Santagostino E, Mannucci P M. Failure of recombinant activated factor VII during surgery in a hemophiliac with high-titer factor VIII antibody. Haemostasis . 1991; 21 1-4
- 95 Sultan Y, Kazatchkine M D, Maisonneuve P, Nydegger U E. Anti-idiotypic suppression of autoantibodies to factor VIII (antihaemophilic factor) by high-dose intravenous gammaglobulin. Lancet . 1984; 2 765-768
- 96 Wensley R T, Stevens R F, Burn A M, Delamore I W. Plasma exchange and human factor VIII concentrate in managing haemophilia A with factor VIII inhibitors. BMJ . 1980; 281 1388-1389
- 97 Revesz T, Matyus J, Goldschmidt B, Harsanyi V. Control of life-threatening bleeding by combined plasmapheresis and immunosuppressive treatment in a haemophiliac with inhibitors. Arch Dis Child . 1980; 55 641-643
- 98 Oldenburg J, Schwaab R, Brackmann H H. Induction of immune tolerance in haemophilia A inhibitor patients by the ``Bonn Protocol'': predictive parameter for therapy duration and outcome. Vox Sang . 1999; 77 49-54
- 99 Smith M P, Spence K J, Waters E L. Immune tolerance therapy for haemophilia A patients with acquired factor VIII alloantibodies: comprehensive analysis of experience at a single institution. Thromb Haemost . 1999; 81 35-38
- 100 Nilsson I M, Berntorp E, Zettervall O. Induction of split tolerance and clinical cure in high-responding hemophiliacs with factor IX antibodies. Proc Natl Acad Sci USA . 1986; 83 9169-9173
- 101 Mariani G, Scheibel E, Nogao T. Immunetolerance as treatment of alloantibodies to factor VIII in hemophilia. The International Registry of Immunetolerance Protocols. Semin Hematol . 1994; 31 62-64
- 102 Di Michele M D. Immune tolerance: a synopsis of the international experience. Haemophilia . 1998; 4 568-573
- 103 Scandella D, deGraaf Mahoney S, Mattingly M. Epitope mapping of human factor VIII inhibitor antibodies by deletion analysis of factor VIII fragments expressed in Escherichia coli Proc Natl Acad Sci USA . 1988; 85 6152-6156
- 104 Scandella D, Mattingly M, de Graaf S, Fulcher C A. Localization of epitopes for human factor VIII inhibitor antibodies by immunoblotting and antibody neutralization. Blood . 1989; 74 1618-1626
- 105 Scandella D, Gilbert G E, Shima M. Some factor VIII inhibitor antibodies recognize a common epitope corresponding to C2 domain amino acids 2248-2312 which overlap a phospholipid binding site. Blood . 1995; 86 1811-1819
- 106 Koshihara K, Qian J, Lollar P, Hoyer L W. Immunoblot cross-reactivity of factor VIII inhibitors with porcine factor VIII. Blood . 1995; 86 2183-2190
- 107 Healey J F, Lubin I M, Saenko E L. 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
- 108 Zhong D, Saenko E, Scandella D. Some human inhibitor antibodies interfere with factor VIII binding to factor IX. Blood . 1998; 92 136-142
- 109 Fijnvandraat K, Celie P H, Turenhout E A. A human alloantibody interferes with binding of factor IXa to the factor VIII light chain. Blood . 1998; 91 2347-2352
- 110 Foster P A, Fulcher C A, Houghten R A, de Graaf Mahoney S, Zimmerman T S. Localization of the binding regions of a murine monoclonal anti- factor VIII antibody and a human anti-factor VIII alloantibody, both of which inhibit factor VIII procoagulant activity, to amino acid residues threonine351-serine365 of the factor VIII heavy chain. J Clin Invest . 1988; 82 123-128
- 111 Jacquemin M, Pratt K P, Spiegel B. Deletion of residue Ala2201 in the factor VIII C2 domain results in mild haemophilia A and destroys major determinant recognized by factor VIII inhibitor antibodies. Thromb Haemost 2001;(Suppl):(Abst OC194).
- 112 Saenko E L, Scandella D. A mechanism for inhibition of factor VIII binding to phospholipid by von Willebrand factor. J Biol Chem . 1995; 270 13826-13833
- 113 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
- 114 Saenko E L, Shima M, Gilbert G E, Scandella D. Slowed release of thrombin-cleaved factor VIII from von Willebrand factor by a monoclonal and a human antibody is a novel mechanism for factor VIII inhibition. J Biol Chem . 1996; 271 27424-27431
- 115 High K A. Gene transfer as an approach to treating hemophilia. Circ Res . 2001; 88 137-144
- 116 Kay M A, High K. Gene therapy for the hemophilias. Proc Natl Acad Sci USA . 1999; 96 9973-9975
- 117 Connelly S, Mount J, Mauser A. Complete short-term correction of canine hemophilia A by in vivo gene therapy. Blood . 1996; 88 3846-3853
- 118 Connelly S, Andrews J L, Gallo A M. Sustained phenotypic correction of murine hemophilia A by in vivo gene therapy. Blood . 1998; 91 3273-3281
- 119 Balague C, Zhou J, Dai Y. Sustained high-level expression of full-length human factor VIII and restoration of clotting activity in hemophilic mice using a minimal adenovirus vector. Blood . 2000; 95 820-828
- 120 Yang Y, Nunes F A, Berencsi K. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci USA . 1994; 91 4407-4411
- 121 Bristol J A, Gallo-Penn A, Andrews J. Adenovirus-mediated factor VIII gene expression results in attenuated anti-factor VIII-specific immunity in hemophilia A mice compared with factor VIII protein infusion. Hum Gene Ther . 2001; 12 1651-1661
- 122 Park F, Ohashi K, Kay M A. Therapeutic levels of human factor VIII and IX using HIV-1-based lentiviral vectors in mouse liver. Blood . 2000; 96 1173-1176
- 123 Wunsch K., Hauser C AE. Development of a non-viral, non-invasive oral gene transfer system. Biotech Int . 2001; 13 22-23
- 124 Okoli G, Hortelano G, Leong K. Oral delivery of plasmid DNA encoding the factor IX gene (Abst). Mol Ther . 2000; 1 S28