Background Although methods of viral attenuation in plasma-derivedclotting-factor concentrates have improved, there is still apossibility that such concentrates may transmit certain blood-borneviruses. For this reason, the use of recombinant DNA-derivedfactor VIII (which is virus-free) to treat hemophilia A hasgenerated considerable interest.
Methods We conducted a multicenter trial in previously untreatedchildren with hemophilia A. They received recombinant factorVIII for all treatment or for prophylaxis and were evaluatedat their respective clinics at intervals of no more than threemonths.
Results Between January 1, 1989, and July 1, 1992, 95 patientswho could be evaluated received recombinant factor VIII. BySeptember 1, 1992, they had received the concentrate exclusivelyfor 2.4 months to 3.5 years (median, 1.5 years). All respondedwell, with no treatment failures. A total of 3315 infusionswere administered; there were three reports of minor adversereactions. Inhibitor antibodies to factor VIII developed in16 of 81 patients tested for them, after a median of nine daysof exposure to factor VIII treatment. Inhibitor titers wereor became low in 9 of the 16 patients despite continued episodictreatment with the concentrate. Inhibitors disappeared completelyin 4 patients and remained at a low level (<10 Bethesda units)in 5 patients receiving episodic treatment.
Conclusions Transient or low levels of inhibitor, as observedin this study, may represent part of the natural history ofhemophilia in infants. In view of the transient nature and lowerconcentration of the inhibitors detected and the generally satisfactoryresponse to treatment, the benefits of recombinant factor VIIIfor the treatment of hemophilia seem to outweigh the risks.
Source Information
From Children's Hospital of Michigan, Detroit (J.M.L.); Mount Sinai Medical School, New York (S.A.); the University of California, Davis (C.F.A.); and the Department of Clinical Research, Miles Inc., Berkeley, Calif. (R.S.S.). Presented in part as an abstract at the 33rd Annual Meeting of the American Society of Hematology, Denver, December 7-10, 1991.The members of the Kogenate Previously Untreated Patient Study Group are listed in the Appendix.
Address reprint requests to Dr. Lusher at Children's Hospital of Michigan, 3901 Beaubien Blvd., Detroit, MI 48201.
Ettinger, R. A., James, E. A., Kwok, W. W., Thompson, A. R., Pratt, K. P.
(2009). Lineages of human T-cell clones, including T helper 17/T helper 1 cells, isolated at different stages of anti-factor VIII immune responses. Blood
114: 1423-1428
[Abstract][Full Text]
Viel, K. R., Ameri, A., Abshire, T. C., Iyer, R. V., Watts, R. G., Lutcher, C., Channell, C., Cole, S. A., Fernstrom, K. M., Nakaya, S., Kasper, C. K., Thompson, A. R., Almasy, L., Howard, T. E.
(2009). Inhibitors of Factor VIII in Black Patients with Hemophilia. NEJM
360: 1618-1627
[Abstract][Full Text]
Peerschke, E. I.B., Castellone, D. D., Ledford-Kraemer, M., Van Cott, E. M., Meijer, P., the NASCOLA Proficiency Testing Committee,
(2009). Laboratory Assessment of Factor VIII Inhibitor Titer: The North American Specialized Coagulation Laboratory Association Experience. Am J Clin Pathol
131: 552-558
[Abstract][Full Text]
Kempton, C. L., White, G. C. II
(2009). How we treat a hemophilia A patient with a factor VIII inhibitor. Blood
113: 11-17
[Abstract][Full Text]
Waters, B., Qadura, M., Burnett, E., Chegeni, R., Labelle, A., Thompson, P., Hough, C., Lillicrap, D.
(2009). Anti-CD3 prevents factor VIII inhibitor development in hemophilia A mice by a regulatory CD4+CD25+-dependent mechanism and by shifting cytokine production to favor a Th1 response. Blood
113: 193-203
[Abstract][Full Text]
Meeks, S. L., Healey, J. F., Parker, E. T., Barrow, R. T., Lollar, P.
(2008). Nonclassical anti-C2 domain antibodies are present in patients with factor VIII inhibitors. Blood
112: 1151-1153
[Abstract][Full Text]
Meeks, S. L., Healey, J. F., Parker, E. T., Barrow, R. T., Lollar, P.
(2007). Antihuman factor VIII C2 domain antibodies in hemophilia A mice recognize a functionally complex continuous spectrum of epitopes dominated by inhibitors of factor VIII activation. Blood
110: 4234-4242
[Abstract][Full Text]
Gouw, S. C., van der Bom, J. G., Auerswald, G., Ettinghausen, C. E., Tedgard, U., van den Berg, H. M., for the CANAL Study group,
(2007). Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood
109: 4693-4697
[Abstract][Full Text]
Goudemand, J., Rothschild, C., Demiguel, V., Vinciguerrat, C., Lambert, T., Chambost, H., Borel-Derlon, A., Claeyssens, S., Laurian, Y., Calvez, T., the members of the FVIII-LFB and Recombinant FVIII,
(2006). Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A. Blood
107: 46-51
[Abstract][Full Text]
Sabatino, D. E., Armstrong, E., Edmonson, S., Liu, Y.-L., Pleimes, M., Schuettrumpf, J., Fitzgerald, J., Herzog, R. W., Arruda, V. R., High, K. A.
(2004). Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene. Blood
104: 2767-2774
[Abstract][Full Text]
Parker, E. T., Healey, J. F., Barrow, R. T., Craddock, H. N., Lollar, P.
(2004). Reduction of the inhibitory antibody response to human factor VIII in hemophilia A mice by mutagenesis of the A2 domain B-cell epitope. Blood
104: 704-710
[Abstract][Full Text]
Fischer, K.-G., Deschler, B., Lubbert, M., Wiestner, A., Weksler, B. B., Schechter, G. P.
(2003). Acquired high-titer factor VIII inhibitor: fatal bleeding despite multimodal treatment including rituximab preceded by multiple plasmaphereses. Blood
101: 3753-3754
[Full Text]
Manno, C. S., Chew, A. J., Hutchison, S., Larson, P. J., Herzog, R. W., Arruda, V. R., Tai, S. J., Ragni, M. V., Thompson, A., Ozelo, M., Couto, L. B., Leonard, D. G. B., Johnson, F. A., McClelland, A., Scallan, C., Skarsgard, E., Flake, A. W., Kay, M. A., High, K. A., Glader, B.
(2003). AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood
101: 2963-2972
[Abstract][Full Text]
Desnick, R. J., Brady, R., Barranger, J., Collins, A. J., Germain, D. P., Goldman, M., Grabowski, G., Packman, S., Wilcox, W. R.
(2003). Fabry Disease, an Under-Recognized Multisystemic Disorder: Expert Recommendations for Diagnosis, Management, and Enzyme Replacement Therapy. ANN INTERN MED
138: 338-346
[Abstract][Full Text]
Jacquemin, M., Vantomme, V., Buhot, C., Lavend'homme, R., Burny, W., Demotte, N., Chaux, P., Peerlinck, K., Vermylen, J., Maillere, B., van der Bruggen, P., Saint-Remy, J.-M.
(2003). CD4+ T-cell clones specific for wild-type factor VIII: a molecular mechanism responsible for a higher incidence of inhibitor formation in mild/moderate hemophilia A. Blood
101: 1351-1358
[Abstract][Full Text]
Doering, C. B., Healey, J. F., Parker, E. T., Barrow, R. T., Lollar, P.
(2002). High Level Expression of Recombinant Porcine Coagulation Factor VIII. J. Biol. Chem.
277: 38345-38349
[Abstract][Full Text]
Villard, S., Piquer, D., Raut, S., Leonetti, J.-P., Saint-Remy, J.-M., Granier, C.
(2002). Low Molecular Weight Peptides Restore the Procoagulant Activity of Factor VIII in the Presence of the Potent Inhibitor Antibody ESH8. J. Biol. Chem.
277: 27232-27239
[Abstract][Full Text]
Mannucci, P. M.
(2002). Ham-Wasserman Lecture : Hemophilia and Related Bleeding Disorders: A Story of Dismay and Success. ASH Education Book
2002: 1-9
[Abstract][Full Text]
Eng, C. M., Guffon, N., Wilcox, W. R., Germain, D. P., Lee, P., Waldek, S., Caplan, L., Linthorst, G. E., Desnick, R. J., the International Collaborative Fabry Disease Stud,
(2001). Safety and Efficacy of Recombinant Human {alpha}-Galactosidase A Replacement Therapy in Fabry's Disease. NEJM
345: 9-16
[Abstract][Full Text]
Mannucci, P. M., Tuddenham, E. G.D.
(2001). The Hemophilias -- From Royal Genes to Gene Therapy. NEJM
344: 1773-1779
[Full Text]
Arruda, V. R., Hagstrom, J. N., Deitch, J., Heiman-Patterson, T., Camire, R. M., Chu, K., Fields, P. A., Herzog, R. W., Couto, L. B., Larson, P. J., High, K. A.
(2001). Posttranslational modifications of recombinant myotube-synthesized human factor IX. Blood
97: 130-138
[Abstract][Full Text]
Moreau, A., Lacroix-Desmazes, S., Stieltjes, N., Saenko, E., Kaveri, S. V., D'Oiron, R., Sultan, Y., Scandella, D., Kazatchkine, M. D.
(2000). Antibodies to the FVIII light chain that neutralize FVIII procoagulant activity are present in plasma of nonresponder patients with severe hemophilia A and in normal polyclonal human IgG. Blood
95: 3435-3441
[Abstract][Full Text]
Hedner, U., Ginsburg, D., Lusher, J. M., High, K. A.
(2000). Congenital Hemorrhagic Disorders: New Insights into the Pathophysiology and Treatment of Hemophilia. ASH Education Book
2000: 241-265
[Abstract][Full Text]
Jacquemin, M., Benhida, A., Peerlinck, K., Desqueper, B., Vander Elst, L., Lavend'homme, R., d'Oiron, R., Schwaab, R., Bakkus, M., Thielemans, K., Gilles, J.-G., Vermylen, J., Saint-Remy, J.-M.
(2000). A human antibody directed to the factor VIII C1 domain inhibits factor VIII cofactor activity and binding to von Willebrand factor. Blood
95: 156-163
[Abstract][Full Text]
Fijnvandraat, K., Celie, P. H.N., Turenhout, E. A.M., ten Cate, J. W., van Mourik, J. A., Mertens, K., Peters, M., Voorberg, J.
(1998). A Human Alloantibody Interferes With Binding of Factor IXa to the Factor VIII Light Chain. Blood
91: 2347-2352
[Abstract][Full Text]
Fijnvandraat, K., Turenhout, E. A.M., van den Brink, E. N., ten Cate, J. W., van Mourik, J. A., Peters, M., Voorberg, J.
(1997). The Missense Mutation Arg593 right-arrow Cys Is Related to Antibody Formation in a Patient With Mild Hemophilia A. Blood
89: 4371-4377
[Abstract][Full Text]
Prescott, R., Nakai, H., Saenko, E. L., Scharrer, I., Nilsson, I. M., Humphries, J. E., Hurst, D., Bray, G., Scandella, D., the Recombinate and Kogenate Study Groups,
(1997). The Inhibitor Antibody Response Is More Complex in Hemophilia A Patients Than in Most Nonhemophiliacs With Factor VIII Autoantibodies. Blood
89: 3663-3671
[Abstract][Full Text]
Tuddenham, E G D, Laffan, M
(1995). Purified factor VIII. BMJ
311: 465-466
[Full Text]
Hoyer, L. W.
(1994). Hemophilia A. NEJM
330: 38-47
[Full Text]
Lozier, J. N., Brinkhous, K. M.
(1994). Gene Therapy and the Hemophilias. JAMA
271: 47-51
[Abstract]
(1993). RECOMBINANT FACTOR VIII APPEARS SAFE AND EFFECTIVE. JWatch General
1993: 4-4
[Full Text]
