Factor VIII Hydrolysis Mediated by Anti-Factor VIII Autoantibodies in Acquired Hemophilia1

Acquired hemophilia is a rare hemorrhagic disorder caused by the spontaneous appearance of inhibitory autoantibodies directed against endogenous coagulation factor VIII (FVIII). Inhibitory Abs also arise in patients with congenital hemophilia A as alloantibodies directed to therapeutic FVIII. Both autoimmune and alloimmune inhibitors neutralize FVIII by steric hindrance. We have described FVIII-hydrolyzing IgG in 50% of inhibitor-positive patients with severe hemophilia A that inactivate therapeutic FVIII. In this study, we investigated the presence of autoimmune FVIII-hydrolyzing IgG in patients with acquired hemophilia. Pooled IgG from healthy donors demonstrated moderate FVIII-hydrolyzing activity (56 ± 26 μmol/min/mol). Purified IgG from 21 of 45 patients with acquired hemophilia demonstrated FVIII hydrolysis rates (mean 219 ± 94 μmol/min/mol) significantly greater than that of control IgG. Three of four patients followed over the course of the disease had rates of FVIII hydrolysis that co-evolved with inhibitory titers in plasma, suggesting that IgG-mediated FVIII hydrolysis participates, in part, in FVIII inactivation. The present work extends the scope of the diseases associated with FVIII proteolysis and points toward the importance of FVIII as a key target substrate for hydrolytic immunoglobulins. Our data suggest that elevated levels of FVIII-hydrolyzing IgG in acquired hemophilia result from the exacerbation of a physiological catalytic immune response.

[1]  T. Baglin,et al.  Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation. , 2007, Blood.

[2]  S. Kaveri,et al.  Catalytic IgG from Patients with Hemophilia A Inactivate Therapeutic Factor VIII1 , 2006, The Journal of Immunology.

[3]  O. M. Durova,et al.  Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Sylvie Villard,et al.  Anti-factor VIII antibodies , 2005, Thrombosis and Haemostasis.

[5]  G. Mariani,et al.  Acquired hemophilia A: A concise review , 2005, American journal of hematology.

[6]  S. Kaveri,et al.  High levels of catalytic antibodies correlate with favorable outcome in sepsis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Y. Nishiyama,et al.  Broadly Distributed Chemical Reactivity of Natural Antibodies Expressed in Coordination with Specific Antigen Binding Activity* , 2003, Journal of Biological Chemistry.

[8]  O. Favorova,et al.  Amylolytic activity of IgM and IgG antibodies from patients with multiple sclerosis. , 2003, Immunology letters.

[9]  O. M. Durova,et al.  Catalytic antibodies in clinical and experimental pathology: human and mouse models. , 2002, Journal of immunological methods.

[10]  S. Kaveri,et al.  The prevalence of proteolytic antibodies against factor VIII in hemophilia A. , 2002, The New England journal of medicine.

[11]  S. Karpatkin,et al.  Complement-Independent, Peroxide-Induced Antibody Lysis of Platelets in HIV-1-Related Immune Thrombocytopenia , 2001, Cell.

[12]  E G Tuddenham,et al.  The hemophilias--from royal genes to gene therapy. , 2001, The New England journal of medicine.

[13]  O. Favorova,et al.  Catalytic heterogeneity of polyclonal DNA-hydrolyzing antibodies from the sera of patients with multiple sclerosis. , 2001, Immunology letters.

[14]  I. Scharrer,et al.  In hemophilia A and autoantibody inhibitor patients: the factor VIII A2 domain and light chain are most immunogenic. , 2001, Thrombosis research.

[15]  Kessler Cm.  Acquired factor VIII autoantibody inhibitors: current concepts and potential therapeutic strategies for the future. , 2000 .

[16]  K N Houk,et al.  Evolution of shape complementarity and catalytic efficiency from a primordial antibody template. , 1999, Science.

[17]  M. Sun,et al.  Innate antibody catalysis. , 1999, Molecular immunology.

[18]  H. Debat,et al.  A possible role of catalytic antibodies in metabolism. , 1999, Immunology today.

[19]  S. Kaveri,et al.  Catalytic activity of antibodies against factor VIII in patients with hemophilia A , 1999, Nature Medicine.

[20]  M. Shima,et al.  Some human inhibitor antibodies interfere with factor VIII binding to factor IX. , 1998, Blood.

[21]  P. Schultz,et al.  Immunological origins of binding and catalysis in a Diels-Alderase antibody. , 1998, Science.

[22]  R. Lerner,et al.  Making chemistry selectable by linking it to infectivity. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Peter G. Schultz,et al.  The interplay between binding energy and catalysis in the evolution of a catalytic antibody , 1997, Nature.

[24]  S. Hinrichs,et al.  Characterization of thyroglobulin-directed and polyreactive catalytic antibodies in autoimmune disease. , 1997, Journal of immunology.

[25]  G. Kobbe,et al.  Acquired factor VIII inhibitors in nonhemophilic patients , 1997, Annals of Hematology.

[26]  G. E. Gilbert,et al.  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* , 1996, The Journal of Biological Chemistry.

[27]  F. Stevens,et al.  Natural Catalytic Antibodies: Peptide-hydrolyzing Activities of Bence Jones Proteins and VL Fragment (*) , 1995, The Journal of Biological Chemistry.

[28]  M. Kazatchkine,et al.  Catalytic Activity of Anti‐Thyroglobulin Antibodies a , 1995, Journal of immunology.

[29]  Dan S. Tawfik,et al.  Unexpectedly high occurrence of catalytic antibodies in MRL/lpr and SJL mice immunized with a transition-state analog: is there a linkage to autoimmunity? , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[30]  C. Kessler,et al.  Use of porcine factor VIII in the treatment of patients with acquired hemophilia. , 1993, Blood.

[31]  M. Shima,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 , 1993, Thrombosis and Haemostasis.

[32]  D. Green.  Cytotoxic suppression of acquired factor VIII:C inhibitors. , 1991, The American journal of medicine.

[33]  B. Halliwell.  Reactive oxygen species in living systems: source, biochemistry, and role in human disease. , 1991, The American journal of medicine.

[34]  L. Hoyer,et al.  Molecular basis of factor VIII inhibition by human antibodies. Antibodies that bind to the factor VIII light chain prevent the interaction of factor VIII with phospholipid. , 1989, The Journal of clinical investigation.

[35]  J. Ware,et al.  Identification of a F.VIII epitope recognized by a human hemophilic inhibitor. , 1989, Blood.

[36]  C. Fulcher,et al.  Immunoblot analysis shows changes in factor VIII inhibitor chain specificity in factor VIII inhibitor patients over time. , 1988, Blood.

[37]  R. Houghten,et al.  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. , 1988, The Journal of clinical investigation.

[38]  C. Fulcher,et al.  FVIII inhibitor IgG subclass and FVIII polypeptide specificity determined by immunoblotting. , 1987, Blood.

[39]  K. Lechner,et al.  A Survey of 215 Non-Hemophilic Patients with Inhibitors to Factor VIII , 1981, Thrombosis and Haemostasis.

[40]  S. Shapiro.  The immunologic character of acquired inhibitors of antihemophilic globulin (factor 8) and the kinetics of their interaction with factor 8. , 1967, The Journal of clinical investigation.

[41]  C. Kessler.  Acquired factor VIII autoantibody inhibitors: current concepts and potential therapeutic strategies for the future. , 2000, Haematologica.

[42]  D. Green,et al.  A More Uniform Measurement of Factor VIII Inhibitors , 1975, Thrombosis and Haemostasis.