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Factor VIII inhibitor treatment with high doses of F VIII
THROMBOSIS RESEARCH 34; 533-539, 1984 0049-3848/84 $3.00 + .OO Printed in the USA. Copyright (c) 1984 Pergamon Press Ltd. All rights reserved.
FACTOR VIII INHIBITOR TREATMENT WITH HIGH DOSES OF F VIII
Stener Stenbjerg, J@rgen Ingerslev and Eva Zachariae Coagulation Laboratory, Department of Clinical Immunology, and Department of Rheumatology, University Hospital Aarhus, DK 8000 Denmark Aarhus C.,
(Received 28.12.1983; Accepted in revised form 2.4.1984 by Editor L.W. Hoyer)
ABSTRACT A hemophilic patient with F VIII inhibitor was treated with intermittent F VIII infusions of 40 - 50 units per kg bodyweight per week. Although the inhibitor declined during treatment, an anamnestic response was recorded on two occasions. A continuous high dose F VIII regimen of 200 units per kg per day resulted in reduction of the inhibitor concentration to less than 1 unit per ml. No anamnestic response was seen after a later exposure to intensive F VIII therapy.
INTRCDUCTION The presence of F VIII inhibitors in hemophilic patients pose a serious problem in the management of bleeding episodes. Out of a total of 133 patients with hemophilia A registered at our center, 14 patients (9.8%) have developed an inhibitor. All inhibitor patients belong to the sub-group of 63 patients with severe hemophilia (F VIII activity less than 1% of normal), and constitute 20.6% of the latter group. Three inhibitor patients seem to belong to a low responder group in that only sporadic bursts of low titer inhibitor have been recorded. Such patients are wellmanaged withadjusteddoses of F VIII concentrate. The majority of inhibitor patients (80% in our series) present with high titered inhibitors and a typical anamnestic response after challenge with F VIII. The treatment of these patients calls for differential measures according to the inhibitor level at the time of treatment. Key Words: F VIII, F VIII inhibitor, 533
Hemophilia A
534
FACTOR VIII INHIBITOR TREATMENT
vo1.34, No.6
Prophylactic treatment with F VIII is obviously impossible unless the patient belongs to the low responder group. In the present case we treated a high responder patient with high doses of F VIII in an endeavour to induce a low responder state or a state of immunotolerance to F VIII. CASE HISTORY An 11 year old boy with severe hemophilia A and blood group type 0 developed an inhibitor of F VIII ten years ago, with levels of 50 - loo BU and a typical anamnestic response after challenge with F VIII concentrate. He has suffered frequent bleedings in major joints and has received numerous infusions of activated concentrates and/or F VIII. Although activated concentrates (FEIBA, IMMUNO or AUTOPLEX, Hyland) seemed to induct hemostasis during acute bleeding episodes, there was progressive destruction of affected joints clinically and radiologically.
MATERIALS
AND METHODS
Five lots of Hematrate (Hemofil) purchased from the Hyland Company were applied during the high dose phase. The activated concentrate FEIBA was obtained from IMMUNO, Vienna. Lately six different lots of heat treated Hematrate (Hemofil-T) and numerous lots of lyophilized, pooled cryoprecipitate have been used. F VIII coagulant activity (F VIII:C) was determined by a one stage technique using Automated APTT reagent (General Diagnostics, USA) andsubstrate plasma from a patient with severe hemophilia A and undetectable levels of F VIII:C. F VIII:C inhibitor was measured by incubation of test material from the patient with a F VIII concentrate for 2 hours at 37 C. (1). After incubation, residual F VIII:C in the mixture was determined. The inhibitor units were calculated so that one unit of inhibitor neutralized one unit (i.u.) of F VIII:C. One inhibitor unit is approximately equal to 2 Bethesda units (BU) (2). F VIII:CAg was quantitated by a micro-Elisa technique employing horseradish peroxidase conjugated F(ab')2 from a hemophilic patient with a high titer inhibitor (3). Venous blood was obtained weekly during the high dose period to estimate F VIII:C before, lo minutes, and one hour after the morning infusion. F VIII inhibitor was estimated only in the prein(ASAT) and creatinine fusion sample. Aspartate-aminotranspherase were monitored regularly.
RESULTS Low dose F VIII (approximately 40 units/kg bodyweight per week in equal doses on Mondays, Wednesdays, and Fridays) was started in June 1979 after treatment of a major bleeding with F VIII concentrate (5000 units) caused an anamnestic rise (by day 5) of the inhibitor (Fig. 1). Seven months later a new large bleeding necessitated infusion of similar amounts of F VIII concentrate.
vo1.34, No.6
FACTOR VIII INHIBITOR TREATMENT
535
FIG 1 Course of F VIII inhibitor during low dose intermittent and high dose continuous F VIII infusion scheme. One inhibitor unit is equal to approximately 2 Bethesda units. F VIII dosage (units/kg bw) is indicated under the inhibitor curve.
A second anamnestic response by day 5 was recorded. The low dose regimen was continued at 50 u/kg per week (equal doses on Mondays, Wednesdays, and Fridays). During the next 2 years the inhibitor slowly decreased to 1 - 3 u/ml plasma. At that point it was believed that the inhibitor would not drop to levels that allowed for prophylactic treatment with F VIII. By April 1982 a high dose F VIII scheme was adopted (loo units of F VIII concentrate/kg every 12 hours (8 a.m. and 8 p.m.). After a third anamnestic response the inhibitor declined steadily during the following months. F VIII:C was first detected (0.03 u/ml plasma) in the lo minute post infusion sample on the 64th day of high dose treatment. After 8 months of treatment the inhibitor had dropped below 0.5 u/ml plasma. The treatment was then adjusted to 50 - 75 units of F VIII/kg every 12 hours. At this stage three courses of immunosuppressive treatment were given (cyclophosphamide lo
536
FACTOR VIII INHIBITOR TREATMENT
vo1.34, No.6
mg/kg/day
and prednisone 3 mg/kg/day for 4 days). Four months later the dose of F VIII was reduced to 30 - 50 units/kg/day, injected as a single dose at 8 a.m. After approximately 9 months of high dose F VIII treatment the inhibitor had fallen to 0.2 The recovery of F VIII rose from less than 1% 0.3 u/ml plasma. to a maximum of 42% in the lo minute post infusion sample. During the initial phase of high dose therapy FEIBA was infused sporadically to treat bleeding episodes. A total of 28.000 units of FEIBA was used during the first three months. Since then no activated concentrate has been used. The patient fractured his right tibia in June 1983. This called for intensive prophylaxis with F VIII (75 units/kg every 12 hours) for 3 weeks. The inhibitor did not rise during this period of intensive treatment with F VIII. FVlll:C/
Fig. 2
FVIII:CAg IU/ml
1.0
F VIII:C (0) and F VII: CAg (0) in plasma samples from inhibitor patient (Oct. 83) before and after a single dose of F VIII (30 u/kg bw).
0.5
0.01
1
6
12
24
HOURS
At present the patient is receiving one daily infusion of 30 units of F VIII/kg. The high purity concentrate has been substituted by intermediate purity (Kryobulin, IMMUNO) or cryoprecipitate to reduce the costs of treatment. The morning level of F VIII:C is 0.02 - 0.03 u/ml plasma prior to infusion. The recovery of F VIII lo minutes after infusion is approximately 40%.'F VIII:C and F VIII:CAg studies of the patient's plasma during a 24 hour period after a single infusion of 30 u/kg of F VIII (Fig. 2) indicate that the F VIII:C level remains above 0.01 u/ml plasma for almost 24 hours and that the two entities are eliminated in parallel with a T of approximately 5 hours. The recovery of F VIII:CAg is higher50than that of F VIII:C. This agrees with the in vitro finding of excess F VIII:CAg to F VIII:C in the F VIII
vo1.34, No.6
FACTOR VIII INHIBITOR TREATMENT
concentrate used. ASAT and serum creatinine the normal range throughout the treatment.
537
have remained within
DISCUSSION
In 1979 Sultan and collaborators (4) reported that frequent small doses of F VIII given to two inhibitor patients resulted in a steady fall in inhibitor level and an abscence of anamnestic response. Later similar results have been observed by ourselves (5) and Rizza & Matthews (6). In the present patient we noticed that although the inhibitor declined during low dose therapy (patient JLTO in (8)1, an anamnestic response was seen on two occasions when large amounts of F VIII were infused to neutralize the circulating inhibitor to establish measurable levels of F VIII:C. A few years earlier Brackmann & Gormsen (7) described a successful treatment of one F VIII inhibitor patient with massive F VIII and FEIBA infusion. In their case the inhibitor seemed to be completely eradicated after 3 months of continuous therapy. Similar results were obtained in larger series of 17 high responder inhibitor patients and 19 low responder patients (8). In our patient the high dose phase resulted in a third anamnestic response followed by a state of steadily declining inhibitor level. Our protocol differed from that recommended by Brackmann and colleagues in that FEIBA was only given when a bleeding necessitated treatment. However, several inhibitor patients have been reported to respond well to F VIII infusions alone (9) (lo). Our results are similar to those communicated by White et al (9) who treated a high responder patient with F VIII alone. As in our case their patient had persisting low levels of inhibitor while anamnestic responses to F VIII were avoided even under periodical intensive F VIII substitution for surgery. Since inhibitor levels are estimated in plasma samples obtained 12 hours after the latest F VIII infusion, we cannot be sure that the inhibitor might not rise to a higher level, if the patient was left untreated for a period of time. Immunosuppressive therapy was introduced when the inhibitor had declined to very low levels. It was hoped that this would further reduce or eliminate the inhibitor, but the level remained at 0.2 - 0.3 u/ml plasma. From a clinical point of view our patient has improved dramatically by not having missed any days in school due to bleedings and by being able to improve his muscular build to a state where he can take part in most activities offered to his age group. During the last 12 months his plasma volume has increased by 60% indicating an intensivation of growth. Joint movements have improved markedly due to physical training which previously was impossible due to frequent bleedings. If the high dose F VIII treatment had induced a general paralysis of the immune system, one would expect that the concentration of immunoglobulins directed against other antigens than F VIII:CAg might also be reduced. We therefore followed the titer of isoagglutinins (anti-A and anti-B! and found no appreciable change during the treatment. Like White et al (9) we find it necessary to evaluate the cost of the inhibitor treatment. In our patient we have infused a total of 1.925 Mio units of F VIII, which at a cost of 31 US cents
538
FACTOR VIII INHIBITOR TREATMENT
vo1.34, No.6
/u (including 22% VAT) amounts to approximately 605.000 US$, an amount that is almost identical to the cost reported by White et al (9).
ACKNOWLEDGEMENT G. Krog, B. 0rum, I. Carlsen, S. Aggergaard and S. Christiansen are thanked for excellent technical assistance. The work was supported in part by the Danish Blood Donors' Foundation and Nordisk Insulin Foundation.
REFERENCES 1.
STENBJERG, S., and JQ)RGENSEN, J. Resistance to activated F IX concentrate (FEIBA). Stand J Haematol. 18, 421-426, 1977.
2.
KASPER, C.K., ALEDORT, L.M., COUNTS, k-B., EDSON, J-R., FRATANTONI, J., GREEN, D., HAMPTON, J.W., HILGARTNER, M.W., LAZERSON, J., LEVINE, P-H., McMILLAN, C.W., POOL, J.G., SHAPIRO, S.S., SHULMAN, N-R., VAN EUS, J. A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh, -34, 869-871, 1975.
3.
INGERSLEV, J. and STENBJERG,
4.
SULTAN, Y., MAISONNEUVE, P., PARQUET-GERNEZ, A., and GOUDEMAND, M. Immune tolerance to F VIII induced in hemophilic patients with inhibitor to F VIII. Proceedings from the XIII Int. Congr. of !qorld Hemophilia Society, (Abstract) 98-99, 1979.
4.
STENBJERG, S., JP)RGENSEN, J., TAURIS, P., and SKOTTUN, T. Low dose factor VIII for the treatment of hemophilia with inhibitors. In: Activated prothrombin Complex Concentrates. G. Mariani, M.A. Russo and F. Mandelli (eds.) New York: Praeger Publishers, 1982, 206-212.
6.
RIZZA, C.R., MATTHEWS, J.M. Effect of frequent factor VIII replacement on the level of factor VIII antibodies in haemophiliacs. Br. J. Haemat. 52, 13-24, 1982.
7.
BRACKMANN, H.H., and GORMSEN, J. Massive factor-VIII infusion in hazmophiliac with factor-VIII inhibitor, high responder. Lancet, 2, 933, 1977.
8.
BRACKMANN, H.H. The treatment of inhibitors against factor VIII by continuous treatment of factor VIII - and activated prothrombin complex concentrates. In: Activated Prothrombin Complex Concentrates. G. Mariani, M.A. Russo and F. Mandelli (eds.) New York: Praeger Publishers, 1982, pp. 194-205.
S.
(Method to be published).
vo1.34, No.6
9.
10.
FACTOR VIII INHIBITOR TREATMENT
539
WHITE, G-C., TAYLOR, R.E., BLATT, P.M., ROBERTS, H.R. Treatment of a high titer anti-factor-VIII antibody by continuous factor VIII administration: Report of a case. -_ Blood, 62, 141145, 1983. GORMSEN, J., DALSGAARD-NIELSEN, J. High doses of factor VIII in haemophiliacs with inhibitors, high responders. Presented at the XIV Congress of the World Federation of Hemophilia, San Jose, CR, 1981 (abstr. l-9).
FACTOR VIII INHIBITOR TREATMENT WITH HIGH DOSES OF F VIII
Stener Stenbjerg, J@rgen Ingerslev and Eva Zachariae Coagulation Laboratory, Department of Clinical Immunology, and Department of Rheumatology, University Hospital Aarhus, DK 8000 Denmark Aarhus C.,
(Received 28.12.1983; Accepted in revised form 2.4.1984 by Editor L.W. Hoyer)
ABSTRACT A hemophilic patient with F VIII inhibitor was treated with intermittent F VIII infusions of 40 - 50 units per kg bodyweight per week. Although the inhibitor declined during treatment, an anamnestic response was recorded on two occasions. A continuous high dose F VIII regimen of 200 units per kg per day resulted in reduction of the inhibitor concentration to less than 1 unit per ml. No anamnestic response was seen after a later exposure to intensive F VIII therapy.
INTRCDUCTION The presence of F VIII inhibitors in hemophilic patients pose a serious problem in the management of bleeding episodes. Out of a total of 133 patients with hemophilia A registered at our center, 14 patients (9.8%) have developed an inhibitor. All inhibitor patients belong to the sub-group of 63 patients with severe hemophilia (F VIII activity less than 1% of normal), and constitute 20.6% of the latter group. Three inhibitor patients seem to belong to a low responder group in that only sporadic bursts of low titer inhibitor have been recorded. Such patients are wellmanaged withadjusteddoses of F VIII concentrate. The majority of inhibitor patients (80% in our series) present with high titered inhibitors and a typical anamnestic response after challenge with F VIII. The treatment of these patients calls for differential measures according to the inhibitor level at the time of treatment. Key Words: F VIII, F VIII inhibitor, 533
Hemophilia A
534
FACTOR VIII INHIBITOR TREATMENT
vo1.34, No.6
Prophylactic treatment with F VIII is obviously impossible unless the patient belongs to the low responder group. In the present case we treated a high responder patient with high doses of F VIII in an endeavour to induce a low responder state or a state of immunotolerance to F VIII. CASE HISTORY An 11 year old boy with severe hemophilia A and blood group type 0 developed an inhibitor of F VIII ten years ago, with levels of 50 - loo BU and a typical anamnestic response after challenge with F VIII concentrate. He has suffered frequent bleedings in major joints and has received numerous infusions of activated concentrates and/or F VIII. Although activated concentrates (FEIBA, IMMUNO or AUTOPLEX, Hyland) seemed to induct hemostasis during acute bleeding episodes, there was progressive destruction of affected joints clinically and radiologically.
MATERIALS
AND METHODS
Five lots of Hematrate (Hemofil) purchased from the Hyland Company were applied during the high dose phase. The activated concentrate FEIBA was obtained from IMMUNO, Vienna. Lately six different lots of heat treated Hematrate (Hemofil-T) and numerous lots of lyophilized, pooled cryoprecipitate have been used. F VIII coagulant activity (F VIII:C) was determined by a one stage technique using Automated APTT reagent (General Diagnostics, USA) andsubstrate plasma from a patient with severe hemophilia A and undetectable levels of F VIII:C. F VIII:C inhibitor was measured by incubation of test material from the patient with a F VIII concentrate for 2 hours at 37 C. (1). After incubation, residual F VIII:C in the mixture was determined. The inhibitor units were calculated so that one unit of inhibitor neutralized one unit (i.u.) of F VIII:C. One inhibitor unit is approximately equal to 2 Bethesda units (BU) (2). F VIII:CAg was quantitated by a micro-Elisa technique employing horseradish peroxidase conjugated F(ab')2 from a hemophilic patient with a high titer inhibitor (3). Venous blood was obtained weekly during the high dose period to estimate F VIII:C before, lo minutes, and one hour after the morning infusion. F VIII inhibitor was estimated only in the prein(ASAT) and creatinine fusion sample. Aspartate-aminotranspherase were monitored regularly.
RESULTS Low dose F VIII (approximately 40 units/kg bodyweight per week in equal doses on Mondays, Wednesdays, and Fridays) was started in June 1979 after treatment of a major bleeding with F VIII concentrate (5000 units) caused an anamnestic rise (by day 5) of the inhibitor (Fig. 1). Seven months later a new large bleeding necessitated infusion of similar amounts of F VIII concentrate.
vo1.34, No.6
FACTOR VIII INHIBITOR TREATMENT
535
FIG 1 Course of F VIII inhibitor during low dose intermittent and high dose continuous F VIII infusion scheme. One inhibitor unit is equal to approximately 2 Bethesda units. F VIII dosage (units/kg bw) is indicated under the inhibitor curve.
A second anamnestic response by day 5 was recorded. The low dose regimen was continued at 50 u/kg per week (equal doses on Mondays, Wednesdays, and Fridays). During the next 2 years the inhibitor slowly decreased to 1 - 3 u/ml plasma. At that point it was believed that the inhibitor would not drop to levels that allowed for prophylactic treatment with F VIII. By April 1982 a high dose F VIII scheme was adopted (loo units of F VIII concentrate/kg every 12 hours (8 a.m. and 8 p.m.). After a third anamnestic response the inhibitor declined steadily during the following months. F VIII:C was first detected (0.03 u/ml plasma) in the lo minute post infusion sample on the 64th day of high dose treatment. After 8 months of treatment the inhibitor had dropped below 0.5 u/ml plasma. The treatment was then adjusted to 50 - 75 units of F VIII/kg every 12 hours. At this stage three courses of immunosuppressive treatment were given (cyclophosphamide lo
536
FACTOR VIII INHIBITOR TREATMENT
vo1.34, No.6
mg/kg/day
and prednisone 3 mg/kg/day for 4 days). Four months later the dose of F VIII was reduced to 30 - 50 units/kg/day, injected as a single dose at 8 a.m. After approximately 9 months of high dose F VIII treatment the inhibitor had fallen to 0.2 The recovery of F VIII rose from less than 1% 0.3 u/ml plasma. to a maximum of 42% in the lo minute post infusion sample. During the initial phase of high dose therapy FEIBA was infused sporadically to treat bleeding episodes. A total of 28.000 units of FEIBA was used during the first three months. Since then no activated concentrate has been used. The patient fractured his right tibia in June 1983. This called for intensive prophylaxis with F VIII (75 units/kg every 12 hours) for 3 weeks. The inhibitor did not rise during this period of intensive treatment with F VIII. FVlll:C/
Fig. 2
FVIII:CAg IU/ml
1.0
F VIII:C (0) and F VII: CAg (0) in plasma samples from inhibitor patient (Oct. 83) before and after a single dose of F VIII (30 u/kg bw).
0.5
0.01
1
6
12
24
HOURS
At present the patient is receiving one daily infusion of 30 units of F VIII/kg. The high purity concentrate has been substituted by intermediate purity (Kryobulin, IMMUNO) or cryoprecipitate to reduce the costs of treatment. The morning level of F VIII:C is 0.02 - 0.03 u/ml plasma prior to infusion. The recovery of F VIII lo minutes after infusion is approximately 40%.'F VIII:C and F VIII:CAg studies of the patient's plasma during a 24 hour period after a single infusion of 30 u/kg of F VIII (Fig. 2) indicate that the F VIII:C level remains above 0.01 u/ml plasma for almost 24 hours and that the two entities are eliminated in parallel with a T of approximately 5 hours. The recovery of F VIII:CAg is higher50than that of F VIII:C. This agrees with the in vitro finding of excess F VIII:CAg to F VIII:C in the F VIII
vo1.34, No.6
FACTOR VIII INHIBITOR TREATMENT
concentrate used. ASAT and serum creatinine the normal range throughout the treatment.
537
have remained within
DISCUSSION
In 1979 Sultan and collaborators (4) reported that frequent small doses of F VIII given to two inhibitor patients resulted in a steady fall in inhibitor level and an abscence of anamnestic response. Later similar results have been observed by ourselves (5) and Rizza & Matthews (6). In the present patient we noticed that although the inhibitor declined during low dose therapy (patient JLTO in (8)1, an anamnestic response was seen on two occasions when large amounts of F VIII were infused to neutralize the circulating inhibitor to establish measurable levels of F VIII:C. A few years earlier Brackmann & Gormsen (7) described a successful treatment of one F VIII inhibitor patient with massive F VIII and FEIBA infusion. In their case the inhibitor seemed to be completely eradicated after 3 months of continuous therapy. Similar results were obtained in larger series of 17 high responder inhibitor patients and 19 low responder patients (8). In our patient the high dose phase resulted in a third anamnestic response followed by a state of steadily declining inhibitor level. Our protocol differed from that recommended by Brackmann and colleagues in that FEIBA was only given when a bleeding necessitated treatment. However, several inhibitor patients have been reported to respond well to F VIII infusions alone (9) (lo). Our results are similar to those communicated by White et al (9) who treated a high responder patient with F VIII alone. As in our case their patient had persisting low levels of inhibitor while anamnestic responses to F VIII were avoided even under periodical intensive F VIII substitution for surgery. Since inhibitor levels are estimated in plasma samples obtained 12 hours after the latest F VIII infusion, we cannot be sure that the inhibitor might not rise to a higher level, if the patient was left untreated for a period of time. Immunosuppressive therapy was introduced when the inhibitor had declined to very low levels. It was hoped that this would further reduce or eliminate the inhibitor, but the level remained at 0.2 - 0.3 u/ml plasma. From a clinical point of view our patient has improved dramatically by not having missed any days in school due to bleedings and by being able to improve his muscular build to a state where he can take part in most activities offered to his age group. During the last 12 months his plasma volume has increased by 60% indicating an intensivation of growth. Joint movements have improved markedly due to physical training which previously was impossible due to frequent bleedings. If the high dose F VIII treatment had induced a general paralysis of the immune system, one would expect that the concentration of immunoglobulins directed against other antigens than F VIII:CAg might also be reduced. We therefore followed the titer of isoagglutinins (anti-A and anti-B! and found no appreciable change during the treatment. Like White et al (9) we find it necessary to evaluate the cost of the inhibitor treatment. In our patient we have infused a total of 1.925 Mio units of F VIII, which at a cost of 31 US cents
538
FACTOR VIII INHIBITOR TREATMENT
vo1.34, No.6
/u (including 22% VAT) amounts to approximately 605.000 US$, an amount that is almost identical to the cost reported by White et al (9).
ACKNOWLEDGEMENT G. Krog, B. 0rum, I. Carlsen, S. Aggergaard and S. Christiansen are thanked for excellent technical assistance. The work was supported in part by the Danish Blood Donors' Foundation and Nordisk Insulin Foundation.
REFERENCES 1.
STENBJERG, S., and JQ)RGENSEN, J. Resistance to activated F IX concentrate (FEIBA). Stand J Haematol. 18, 421-426, 1977.
2.
KASPER, C.K., ALEDORT, L.M., COUNTS, k-B., EDSON, J-R., FRATANTONI, J., GREEN, D., HAMPTON, J.W., HILGARTNER, M.W., LAZERSON, J., LEVINE, P-H., McMILLAN, C.W., POOL, J.G., SHAPIRO, S.S., SHULMAN, N-R., VAN EUS, J. A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh, -34, 869-871, 1975.
3.
INGERSLEV, J. and STENBJERG,
4.
SULTAN, Y., MAISONNEUVE, P., PARQUET-GERNEZ, A., and GOUDEMAND, M. Immune tolerance to F VIII induced in hemophilic patients with inhibitor to F VIII. Proceedings from the XIII Int. Congr. of !qorld Hemophilia Society, (Abstract) 98-99, 1979.
4.
STENBJERG, S., JP)RGENSEN, J., TAURIS, P., and SKOTTUN, T. Low dose factor VIII for the treatment of hemophilia with inhibitors. In: Activated prothrombin Complex Concentrates. G. Mariani, M.A. Russo and F. Mandelli (eds.) New York: Praeger Publishers, 1982, 206-212.
6.
RIZZA, C.R., MATTHEWS, J.M. Effect of frequent factor VIII replacement on the level of factor VIII antibodies in haemophiliacs. Br. J. Haemat. 52, 13-24, 1982.
7.
BRACKMANN, H.H., and GORMSEN, J. Massive factor-VIII infusion in hazmophiliac with factor-VIII inhibitor, high responder. Lancet, 2, 933, 1977.
8.
BRACKMANN, H.H. The treatment of inhibitors against factor VIII by continuous treatment of factor VIII - and activated prothrombin complex concentrates. In: Activated Prothrombin Complex Concentrates. G. Mariani, M.A. Russo and F. Mandelli (eds.) New York: Praeger Publishers, 1982, pp. 194-205.
S.
(Method to be published).
vo1.34, No.6
9.
10.
FACTOR VIII INHIBITOR TREATMENT
539
WHITE, G-C., TAYLOR, R.E., BLATT, P.M., ROBERTS, H.R. Treatment of a high titer anti-factor-VIII antibody by continuous factor VIII administration: Report of a case. -_ Blood, 62, 141145, 1983. GORMSEN, J., DALSGAARD-NIELSEN, J. High doses of factor VIII in haemophiliacs with inhibitors, high responders. Presented at the XIV Congress of the World Federation of Hemophilia, San Jose, CR, 1981 (abstr. l-9).