Original Article
Human Recombinant DNA–Derived Antihemophilic Factor (Factor VIII) in the Treatment of Hemophilia A
N Engl J Med 1990; 323:1800-1805December 27, 1990
- Abstract
- Abstract
Background.
Current treatment of hemophilia A, a hereditary disorder affecting approximately 1 in 10,000 males, relies on plasma-derived factor VIII concentrates. We tested the safety and efficacy of a recombinant factor VIII preparation for the treatment of this disorder.
Methods.
We conducted the investigation in three stages: comparing the pharmacokinetics of plasma-derived and recombinant factor VIII, assessing the efficacy of recombinant factor VIII for home therapy, and assessing its efficacy for major surgical procedures and hemorrhage. A total of 107 subjects with hemophilia, 20 of whom had not been treated previously, enrolled in the investigation.
Results.
The in vivo recovery and elimination half-lives of recombinant factor VIII equaled or exceeded those of plasma-derived factor VIII. Seventy-six subjects participated in a home-treatment program, using recombinant factor VIII for 69 to 807 days (median, 618); home diaries of 56 subjects treated for 5 months were analyzed. Of 540 bleeding episodes, 399 (73.9 percent) required only one treatment with recombinant factor VIII. The projected annual consumption of recombinant factor VIII was similar to that of plasma-derived factor VIII concentrate. Twenty-six subjects received recombinant factor VIII for 22 surgical procedures and 10 serious hemorrhages; hemostasis was excellent in all cases. De novo formation of inhibitors occurred in only 1 of 85 previously treated subjects. Inhibitor antibodies also developed in 6 of 21 children, 20 of whom had not previously been treated; 5 had low levels (≤7.5 Bethesda units) despite continued treatment with recombinant factor VIII. There was no evidence of new formation of antibody to foreign proteins, and recombinant factor VIII was well tolerated.
Conclusions.
Recombinant factor VIII has biologic activity comparable to that of plasma factor VIII and is safe and efficacious for the treatment of hemophilia A. (N Engl J Med 1990; 323:1800–5.)
Media in This Article
Figure 1
In Vivo Clearance Curves after the Administration of Plasma-Derived Factor VIII (●; N = 17) or Recombinant Factor VIII (Δ; N = 17) during Week 1 and after 13 Weeks (□; N = 16) and 25 Weeks (; N = 14) of Home Treatment with Recombinant Factor VIII.
Figure 2
Length of Treatment with Recombinant Factor VIII in 77 Subjects.Article Activity
- Article
HEMOPHILIA A is an X-linked recessive genetic disorder affecting approximately 1 in 10,000 males that is due to a defective or deficient factor VIII molecule, resulting in a hemorrhagic tendency.1 In its most severe form, hemophilia A is a life-threatening, crippling disease. The introduction in the mid-1960s of factor VIII concentrates (antihemophilic factor) derived from plasma made possible effective replacement therapy, resulting in a dramatic increase in both the quality of life and the life expectancy of persons with hemophilia A.2 3 4 However, reliance on plasma as the source of factor VIII resulted in the exposure of patients with hemophilia to alloantigens as well as to transfusion-associated viral diseases, including hepatitis B, delta hepatitis, hepatitis C, and more recently human immunodeficiency virus (HIV) infection.4 5 6 There has therefore been great interest in the use of recombinant technology to develop a method of manufacturing factor VIII for the treatment of hemophilia A, thus obviating the need for reliance on plasma. Factor VIII derived from recombinant DNA (recombinant factor VIII) could be expected to be free of many of the risks associated with current therapy and, in principle, to be available in unlimited supply.
In 1984, two groups simultaneously announced the successful cloning and expression of the factor VIII gene.7 , 8 Factor VIII is one of the largest genes cloned to date, and it is the largest cloned protein currently being used in clinical trials. White et al. have described two subjects who were treated with a recombinant factor VIII concentrate.9 We now report a multicenter clinical study involving 107 subjects with hemophilia A who were treated with another preparation of recombinant factor VIII.
Methods
Subjects
Clinical studies with recombinant factor VIII began in June 1988. All subjects participating in the investigation had hemophilia A. Subjects with known neutralizing antibody to factor VIII on the basis of a Bethesda10 inhibitor assay were excluded from the study, as were subjects requiring steroid therapy, those with other coagulation disorders, and those requiring premedication (e.g., antihistamines) for treatment. Both HIV-seropositive and HIV-seronegative persons were permitted to enroll in the study; however, subjects with clinical evidence of symptomatic HIV disease or absolute CD4+ cell counts below 300 per microliter (measured in one central reference laboratory) were excluded, since progression of disease could interfere with the interpretation of data on safety and efficacy.
The study was approved by the ethics committees of the participating institutions and conducted under Food and Drug Administration guidelines. All subjects or, in the case of minors, their parents or guardians were required to give written informed consent, using a consent form approved by the FDA that detailed the risks and benefits of the study.
Study Design
A total of 107 subjects worldwide enrolled in the study, which was conducted in three stages: comparison of the pharmacokinetics of plasma-derived and recombinant factor VIII (stage 1), assessment of the efficacy and safety of home treatment (stage 2), and assessment of the efficacy and safety of treatment during surgical procedures or for serious hemorrhage (stage 3). Some subjects participated in more than one stage.
Stage 1
After a 72-hour period during which they received no treatment, 17 asymptomatic adults with hemophilia A (16 severe and 1 moderate) received a single intravenous injection of plasma-derived factor VIII (Koate-HS, Cutter Biological, Berkeley, Calif.) at a dose of approximately 50 IU per kilogram of body weight, rounded to the nearest whole vial. Blood samples were drawn before the infusion and 10 and 30 minutes and 1, 2, 4, 6, 12, 24, 30, and 48 hours after the infusion. Plasma samples were frozen within 30 minutes after collection, shipped to the central testing laboratory on dry ice, and stored at −70°C until assayed. The activated partial-thromboplastin time was determined before the infusion and 30 minutes, 4 hours, and 24 hours after the infusion. One to two weeks later, the study was repeated in the same subjects except that recombinant factor VIII was used. The subjects then began a program of inclinic treatment with recombinant factor VIII (20 to 40 IU per kilogram three times a week for four weeks). At the end of the fourth week, the recovery of factor VIII in vivo was measured again. The subjects then proceeded to stage 2 of the investigation (home treatment). The pharmacokinetic study with recombinant factor VIII was repeated during weeks 13 and 25 of the study in 16 and 14 of the original 17 subjects, respectively.
Stage 2
Seventy-six subjects (16 who were continuing from stage 1 and 60 new to the study) participated in a home-treatment program with recombinant factor VIII. The subjects were instructed to follow the same treatment program they had used for plasma-derived factor VIII concentrates. They kept diaries of all the treatments administered and were asked to assess the perceived efficacy of each treatment, using a scale of 0 to 4, with 4 indicating most and 0 least effective. The subjects returned to the clinic at monthly intervals to receive challenge doses of recombinant factor VIII (50 IU per kilogram) for the assessment of its recovery in vivo after 10 minutes. During these visits a Bethesda inhibitor assay was performed,10 and serum samples were obtained for antibody screening by enzyme-linked immunosorbent assay (ELISA). A data base of home-treatment records from 56 consecutive subjects who completed five months of home treatment was analyzed for evidence of the efficacy and safety of treatment.
Stage 3
During stage 3 we assessed the efficacy and safety of recombinant factor VIII for surgical procedures or serious hemorrhage requiring hospitalization. Twenty-six subjects were included in this stage, 9 of whom were new to the study and 17 of whom had been enrolled in stage 1 or 2.
Previously Untreated or Minimally Treated Subjects
Twenty infants and children who had never received plasma-derived factor VIII and one child who had received only a single dose of fresh-frozen plasma were also enrolled in the study. These subjects received only recombinant factor VIII for the treatment of or prophylaxis against bleeding episodes. Inhibitor assays were performed approximately every 12 weeks.
Laboratory Tests
Plasma samples for factor VIII assay were drawn according to standardized techniques; 4.5 ml of venous blood was withdrawn with a disposable needle and plastic syringe, immediately added to 0.5 ml of buffered 3.8 percent sodium citrate in silicon-treated Vacutainer tubes, and mixed. Samples were centrifuged at 4°C for 30 minutes at 10,000 to 15,000×g. The plasma was then transferred into a disposable plastic tube, quick-frozen in a mixture of alcohol and dry ice, and stored at −70°C until assayed.
Plasma factor VIII levels were measured in the research laboratories of Cutter Biological by a one-stage clotting assay based on the activated partial-thromboplastin time11 and expressed as the percentage of factor VIII present in pooled normal human plasma. Plasma samples were stored at −70°C and assayed within 15 minutes of thawing. Control frozen plasma was thawed for assay, and standard dilution curves were prepared for each assay series to ensure internal consistency. Diluted standard, control, and test-sample assays were run in duplicate. The coefficient of variation for 93 factor VIII assays was 7.9 percent. Factor VIII—inhibitor levels were measured at participating institutions by the Bethesda method.10 Antibodies to murine IgG, baby-hamster-kidney protein, and recombinant factor VIII were assayed at Cutter Biological by ELISA and reported as negative, borderline, or positive (expressed as 1+, 2+, or 3+).
Pharmacokinetic Analysis
In vivo decay curves for factor VIII from pharmacokinetic studies were analyzed by model-independent methods (moment analysis)12 to calculate total body clearance (expressed as milliliters per hour per kilogram; the overall rate at which plasma is cleared of factor VIII), the mean residence time (in hours; analogous to the half-life and, by definition, the time it takes for 63.2 percent of factor VIII to be lost), the apparent volume of distribution (expressed as milliliters per kilogram; defined as the ratio between the amount of substance present in the body at any time and the corresponding concentration in plasma), and the elimination half-life (in hours) at steady state as determined from the terminal portion (12, 24, 30, and 48 hours after the infusion) of the log-linear decay curve in vivo.
Incremental in vivo recovery values were calculated from the increase above base line (expressed as a percentage of the normal value for the plasma concentration of factor VIII) 10 minutes after completion of the infusion divided by the amount of factor VIII administered in international units per kilogram. Recovery values for recombinant factor VIII were compared with values for plasma-derived factor VIII by means of a two-tailed paired t-test.
Koate-HS, a commercial lyophilized plasma-derived factor VIII concentrate (heat-treated at 60°C in solution for 10 hours), was used for comparative pharmacokinetic studies. Recombinant factor VIII, an antihemophilic factor produced by recombinant DNA technology, was prepared by Cutter Biological. Human complementary DNA (cDNA) for factor VIII was transfected into an established mammalian cell line (baby-hamster kidney), which then secreted recombinant factor VIII into tissue-culture medium.7 The secreted protein was purified by multiple purification steps, including ion-exchange chromatography and immunoaffinity chromatography with murine monoclonal antibody. Recombinant factor VIII consists of multiple peptides including an 80-kd protein and various extensions of the 90-kd subunit proteins. About 40 percent of the molecule has been sequenced to date, and the results are in 100 percent agreement with the consensus structure sequence predicted from the cDNA. In vivo studies in a canine model of hemophilia A have provided evidence that recombinant factor VIII binds to circulating von Willebrand factor and circulates as a complex.13 Recombinant factor VIII contains trace amounts of hamster protein and murine IgG from the manufacturing process as well as human albumin stabilizer. All lots used in the current investigation had a final concentration of approximately 100 IU of recombinant factor VIII per milliliter. The potency of factor VIII was quantified with a one-stage factor VIII assay based on the activated partial-thromboplastin time, with the use of a concentrate standard (Mega 1, Travenol Laboratories, Glendale, Calif.) calibrated against the World Health Organization Third International Standard.
Results
Stage 1
In vivo clearance curves after the infusion of plasma-derived factor VIII and recombinant factor VIII at weeks 1, 13, and 25 are presented in Figure 1Figure 1
In Vivo Clearance Curves after the Administration of Plasma-Derived Factor VIII (●; N = 17) or Recombinant Factor VIII (Δ; N = 17) during Week 1 and after 13 Weeks (□; N = 16) and 25 Weeks (The results of pharmacokinetic moment analysis are shown in Table 1Table 1
Summary of Pharmacokinetic Moment Analysis.*. The mean residence time and elimination half-life of recombinant factor VIII equaled or exceeded those of plasma factor VIII, whereas the clearance and volume of distribution at steady state for recombinant factor VIII were slightly lower than the values for plasma-derived factor VIII.Stage 2
Seventy-six subjects worldwide enrolled in a program of home treatment with recombinant factor VIII. The median duration of home treatment was 618 days (range, 69 to 807) (Fig. 2Figure 2
Length of Treatment with Recombinant Factor VIII in 77 Subjects.). The five-month home-treatment records of the subgroup of 56 subjects were analyzed for safety and efficacy (Fig. 2). Twenty of the 56 subjects (35.7 percent) were less than 18 years of age. Fifty-two had severe hemophilia A (factor VIII level, <2 percent of normal) and four moderate hemophilia A (factor VIII level, 2 to 5 percent of normal). The mean age was 24.2 years (range, 1 to 72; median, 25). Twenty-two subjects (39.3 percent) were HIV-antibody—seropositive.The mean incremental in vivo recovery values of the challenge doses of recombinant factor VIII (50 IU per kilogram) given at weeks 5, 9, 13, and 25 ranged from 2.49±0.70 to 2.92±0.99 percent per international unit of factor VIII administered per kilogram and were not statistically different. Over a six-month period, the 56 subjects had 540 separate bleeding episodes; 399 (73.9 percent) required only one treatment with recombinant factor VIII. The mean dose used was 26.8±13.4 IU of factor VIII per kilogram. On an efficacy scale of 0 to 4, 72.1 and 12.9 percent of the 459 treatments evaluated by the subjects were given grades of 4 and 3, respectively, with only 8.7, 5.0, and 1.3 percent given grades of 2, 1, and 0. The subjects had an average of 1 bleeding episode every 14.6 days (equivalent to an annual rate of 24.4 episodes) and on the average administered recombinant factor VIII once weekly. On the basis of consumption during five months of home treatment, the mean consumption of recombinant factor VIII concentrate was estimated as 78,234 IU per year (range, 500 to 304,022 IU per year; mean, 1308 IU per kilogram).
Stage 3
Twenty-six subjects (17 from stage 1 or 2 and 9 who were new to the study) received recombinant factor VIII on 32 occasions for major surgical procedures (n = 22) or for in-hospital treatment of serious hemorrhage (n = 10). The surgical procedures consisted of orthopedic surgery, including five joint replacements (10 subjects); dental surgery (2 subjects); cystoscopy (1 subject); ureteral-stone manipulation (1 subject); lithotripsy (1 subject on two occasions); herniorrhaphy (2 subjects); and total laparotomy, correction of aortic stenosis, repair of hypospadias, and repair of ingrown toenail (1 subject each). The following types of serious hemorrhage were treated: gastrointestinal hemorrhage, retroperitoneal bleeding, tonsillar bleeding, and hemarthrosis in one subject each, and bleeding in miscellaneous soft tissues in six subjects. On all 32 occasions, hemostasis was judged to be excellent without need for additional treatment.
Previously Untreated and Minimally Treated Subjects
Twenty previously untreated children with hemophilia received recombinant factor VIII, as did one child who had received only one dose of fresh-frozen plasma at birth. The median age at first treatment with recombinant factor VIII was 9.4 months (range, 3 days to 13 years). The median length of treatment was 238 days (range, 61 to 593).
Immunologic Monitoring of Subjects during Stage 2
During stage 2, 56 subjects who were treated with recombinant factor VIII were monitored for six months by ELISA assays for antibodies to human factor VIII, hamster proteins, and murine proteins. Four subjects had measurable antibodies before therapy was begun, with one subject each reactive to hamster and murine proteins and two reactive to all three antigens. In all four subjects, antibody titers either diminished or remained unchanged over the five-month follow-up period. None of the 52 subjects who had negative base-line studies had any evidence of formation of antibody to factor VIII (by ELISA), murine proteins, or hamster proteins at week 26 of the study, with the exception of Subject 53, who had a weakly positive ELISA as well as a low level of inhibitor detected by Bethesda assay. Western blot analysis showed that this subject had antibody to factor VIII before receiving recombinant factor VIII.
Inhibitor Formation
All 107 subjects were monitored for inhibitor formation by serial Bethesda assays. The length of treatment in previously treated subjects participating in stages 1 and 2 is shown in Figure 2. During the course of the investigation inhibitor antibodies developed in 1 of the 56 subjects enrolled in stage 2, in 1 subject enrolled in stage 3, in 5 previously untreated children, and in the 1 minimally treated child. The clinical characteristics of subjects forming inhibitors are summarized in Table 2Table 2
Characteristics of Subjects in Whom Inhibitor Antibodies Developed during Treatment with Recombinant Factor VIII.. Inhibitor antibodies developed in only 2 of the 86 subjects (Subjects 53 and 309) who had previously been treated with plasma-derived factor VlII concentrates. In one of these, Subject 53, who had a family history of inhibitor formation in three of four relatives with hemophilia, a low-level inhibitor (0.39 Bethesda unit) was found after only one dose of recombinant factor VIII. Retrospective Western blot analysis of his base-line serum sample detected antibody to factor VIII, indicating that inhibitor formation antedated his exposure to recombinant factor VIII. Subject 53 continued to receive recombinant factor VIII (Table 2).Of the six children in whom inhibitor antibodies developed (Table 2), a high-level inhibitor (336 Bethesda units) was found in only one (Subject 66); all others had initial inhibitor levels of less than 7 Bethesda units. Except for Subject 66, all other children in whom inhibitors were detected continued to be treated with recombinant factor VIII, and inhibitor levels subsequently remained at or declined to 1.3 to 7.5 Bethesda units (Table 2).
Adverse Reactions
Home-treatment diaries of the 56 subjects who completed five months of continuous home treatment with recombinant factor VIII were analyzed for adverse reactions. A total of 1734 infusions of recombinant factor VIII were administered, with 18 reports of adverse reactions( 1.0 percent), including an unusual metallic taste in the mouth (one subject on four occasions) accompanied by a burning sensation at the infusion site on one occasion, mild dizziness or lightheadedness (one subject on four occasions), an asymptomatic decrease of 5 to 10 mm Hg in blood pressure (one subject on two occasions and one subject on one occasion), mild localized rash or erythema at the infusion site (four subjects), and dryness of the mouth, chest discomfort, and chest tightness with dyspnea (one subject each). Five of these reactions were of a dubious nature, not thought to be specifically related to the administration of recombinant factor VIII. When these doubtful adverse-reaction reports were excluded, the frequency of adverse reactions was 0.75 percent (13 of 1734 infusions). None of the reactions were judged to be more than mild or moderate, and none caused the discontinuation of therapy.
Three subjects (Subjects 1, 11, and 24) had elevated serum aminotransferase levels during the course of study. In all cases, the abnormalities were determined to antedate entrance into the study and reflected preexisting liver disease. Subject 1 was withdrawn from the study, whereas Subjects 11 and 24 continued to receive recombinant factor VIII.
Discussion
This investigation demonstrates that recombinant factor VIII concentrate is safe and clinically effective for the prevention and treatment of hemorrhage in hemophilia A and that its behavior in vivo is similar to that of plasma-derived factor VIII concentrate. In all cases in which recombinant factor VIII was used for serious hemorrhage or as prophylaxis during major surgical procedures, hemostasis was excellent, and no other types of treatment were required.
An important concern about the use of recombinant factor VIII is its potential immunogenicity. Extensive studies were conducted before recombinant factor VIII was given to humans and indicated that the preparation did not carry any immunogenic determinants that were not present in plasma-derived factor VIII.14 In the current investigation, 56 subjects were studied extensively for the appearance of antibodies, and none had any evidence of an immunologic response to the trace amounts of murine and hamster proteins contained in the preparation.
Approximately 12 to 15 percent of patients with hemophilia who are exposed to plasma-derived factor VIII concentrates form neutralizing inhibitor antibodies at some time in their lives; two thirds of them do so by the age of 20 years.15 , 16 Although there is some evidence for a genetic predisposition,17 the factors that predispose a minority of patients with hemophilia to this complication are unknown. In the current investigation, inhibitor antibodies developed in 8 of 107 subjects treated with recombinant factor VIII: 2 adults, 5 previously untreated children, and 1 child who had received fresh-frozen plasma once. Overall, inhibitors developed in only 2 of 86 study subjects who had previously been treated with plasma-derived factor VIII concentrates. It should be noted, however, that one of these subjects, an adult with a strong family history of inhibitor formation, was subsequently found to have had antibody to factor VIII before treatment with recombinant factor VIII was begun. Thus, de novo inhibitor formation was detected in only 1 of 85 previously treated subjects. This low frequency is consistent with previous studies of patients with hemophilia who received plasma-derived factor VIII concentrates.15 , 16
Inhibitors also developed in 5 of 20 previously untreated children and in 1 child who had previously been treated with fresh-frozen plasma. Some inhibitor formation in this age group was expected, since the risk is especially great among children with hemophilia who are treated before the age of five.16 It is unclear, however, whether the frequency of inhibitor formation observed is greater than that expected. The inhibitor concentrations, with one exception, were low or declined to a low level (≤7.5 Bethesda units) despite continued treatment with recombinant factor VIII; they might not have been detected if the frequency of screening during the study had been lower.16 , 18 The observation of inhibitors at very low levels is distinctly unusual; in a recently completed study with a similar design, involving a monoclonal-antibody—purified plasma-derived factor VIII concentrate, inhibitors were observed in 7 of 39 treated children, but 6 had high-level inhibitors and only 1 had a low-level inhibitor.19 , 20 It is too early to determine whether the low levels of inhibitors observed in the previously untreated subjects receiving recombinant factor VIII will turn out to be clinically important or will be transient; long-term studies of this patient population are now being conducted to address this question.
Supported by a grant from Cutter Biological, Miles Inc.
Presented in part in abstract form at the 12th International Congress on Thrombosis and Haemostasis, Tokyo, Japan, August 1989, and the 31st annual meeting of the American Society of Hematology, Atlanta, December 1989.
*Participants in the Recombinant Factor VIII Study Group are as follows: University of California, Davis: Charles F. Abildgaard, M.D., and Janet Harrison, B.S.; Mount Sinai Medical School, New York: Louis M. Aledort, M.D., Steven Arkin, M.D., Esther Rose, M.D., Stephanie Seremetis, M.D., and Alice Forster, R.N.; University of Wales, Cardiff, United Kingdom: Arthur L. Bloom, M.D., and Justin Harrison, M.D.; University of Bonn, Bonn, Germany: Hans H. Brackmann, M.D., and Johannes E. Egli, M.D.; Memorial Hospital, Worcester, Mass.: Peter H. Levine, M.D., Doreen B. Brettler, M.D., and Ann Forsberg, R.N.; Nara Medical College, Nara, Japan: Hiromu Fukui, M.D., and Akira Yoshioka, M.D.; Tokyo Medical College, Tokyo: Michio Fujimaki, M.D., and Shojiro Ikematsu, M.D. (deceased); Cornell University Medical Center, New York: Margaret W. Hilgartner, M.D.; St. Joseph's Hospital, London, Ont.: Martin J. Inwood, M.D., and Elizabeth Inwood, R.N.; Orthopaedic Hospital, Los Angeles: Carol K. Kasper, M.D., Shelby I. Dietrich, M.D., and Peter Mokary, M.T.; Royal Free Hospital and School of Medicine, London: Peter B.A. Kernoff, M.D., and Paul L. Giangrande, M.D.; Children's Hospital of Michigan, Detroit: Jeanne M. Lusher, M.D., Indira Warrier, M.D., and Maureen O'Connor, R.N.; University of Milan, Milan, Italy: Pier M. Mannucci, M.D., Alessandro Gringeri, M.D., and Loredana Simoni, M.D.; University Hospital, Frankfurt, Germany: Inge Scharrer, M.D., Emel Aygören, M.D., and Wolfhart Kreuz, M.D.; Children's Hospital, Oakland, Calif.: Joseph E. Addiego, Jr., M.D.; Albany Medical College, Albany, N.Y.: Jennifer M. Pearce, M.D.; State University of New York, Syracuse: Thomas Coyle, M.D.; Children's Medical Center, Dayton, Ohio: Leticia P. Valdez, M.D.; and Children's Hospital, Akron, Ohio: Carl E. Krill, M.D.
The following participated in data collection, clinical study coordination, and analysis: Cutter Biological, Miles Inc., Berkeley, Calif: Richard S. Schwartz, M.D., Randy U. Allred, D.P.H., Mary A. MacKenzie, B.S.N., Pat Bailey, R.N., M.S., Cheryl Cox, R.N., M.S., Nazreen Pancham, Harng S. Kuo, Ph.D., Stephen Dyla, Ph.D., Barbara Nielsen, B.A., Ralph H. Rousell, M.D., Stephen Coleman, M.D., and James E. Pennington, M.D.; Bayer, Wuppertal, Germany: Dieter Maruhn, M.D., Peter Eckert, M.D., and Jean Pierre Fallise, M.D.; Tropon, Cologne, Germany: Roswita Neumann, Ph.D.; and Osaka, Japan: Takeyoshi Minaga, M.D.
We are indebted to Melanie Madanat for factor VIII assays, to Robert Bouffard, B.S., for ELISA determinations, and to Julie Emerson for assistance in the preparation of the manuscript.
Source Information
From Cutter Biological, Miles Inc., Berkeley, Calif. (R.S.S., M.A.M., N.P., H.S.K., R.U.A.); the University of California, Davis (C.F.A.); Mount Sinai Medical School, New York (L.M.A., S.A.); the University of Wales. Cardiff, United Kingdom (A.L.B.); the University of Bonn, Bonn, Germany (H.H.B.); Memorial Hospital, Worcester, Mass. (D.B.B., P.H.L.); Nara Medical College, Nara, Japan (H.F.); Cornell University Medical Center, New York (M.W.H.); St. Joseph's Hospital, London, Ont. (M.J.I.); Orthopaedic Hospital, Los Angeles (C.K.K.); Royal Free Hospital and School of Medicine, London (P.B.A.K.); Children's Hospital of Michigan, Detroit (J.M.L.); University of Milan, Milan, Italy (P.M.M.); and University Hospital, Frankfurt, Germany (I.S.). Address reprint requests to Dr. Schwartz at the Department of Clinical Research, Cutter Biological, Miles Inc., 4th and Parker Sts., P.O. Box 1986, Berkeley, CA 94701.
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