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Factor VIII inhibitors
Letters to the Editor
greater detail than we have been able to, the frequency of inhibitor development.
Factor VIII inhibitors SiR-Addiego and colleagues (Aug 21, p 462) conclude that recombinant factor VIII has no greater risk of inhibitor formation than do intermediate purity or monoclonal antibody purified products. Unfortunately, in their table 2 they compare non-comparable studies, which differ in the definition of severe haemophilia, time that patients are at risk (number of exposure days), and the diligence of inhibitor surveillance. Each manufacturer of factor VIIII replacement product sets their own definitions and testing frequency interval, and, scientifically based conclusions, with respect to comparability, are therefore practically precluded. In the Monoclate (heattreated,
not
pasteurised Monoclate-P) study
followed for
some
patients
4 years, all patients for at least 12 months, with an average of 22 exposure days in those developing inhibitors. Since the prevalence of inhibitor rises with increasing age at least through the first two decades of life, and only half the inhibitors will develop by age 10 years, I propose that any studies of true risk of inhibitor development must follow the cohort at risk for at least 5 years or 50 exposures to product. Standardisation of a protocol to assess this risk is needed and currently overdue because patient safety may be at were
over
issue. Garrett E Bergman Armour Pharmaceutical Company, PO Box 1200,
Author’s
Collegeville,
PA 19426, USA
reply
SIR-I agree with Bergman that protocols for the management of previously-untreated patients with severe factor VIIIdeficient haemophilia need to be standardised and uniformly applied around the world. Unfortunately, apart from the newer recombinant studies, such an approach to the evaluation of the development of inhibitors has not been used. My colleagues and I attempted to standardise our patient population according to guidelines and criteria as discussed at the 1992 factor VIII and IX sub-committee of the International Society of Thrombosis Hemostasis. As we reported, patients were followed for at least 5 years or the equivalent of 30 exposure days to factor product. Current information indicates that most inhibitors do indeed develop in that time. Contrary to Bergman’s assertion, we did not conclude that recombinant factor VIII causes no greater risk of inhibitor formation than monoclonal antibody purified products. We specifically stated that, "there were too few patients in the monoclonal-derived factor VIII study groups to allow meaningful comparison with our study group", and "because several patients in the monoclonal-derived factor VIII study were exposed to several types of products, no conclusion with regard to a specific level of product purity can be established". We, as others, feel that it is unfortunate that carefully controlled inhibitor trials were not done during studies of monoclonal-antibody-derived product and during other studies over the past two decades. The haemophilia community will be unable to retrace steps and accurately assess, in any
previous
true
Joseph E Addiego Pediatric Medical Center for Northern California, Children’s CA 94609, USA
Hospital Oakland, Oakland,
SiR-Addiego and colleagues’ finding that 28% of previously untreated severe haemophilia patients developed inhibitors after treatment with low and intermediate purity factor VIII concentrates, together with data from other prospective studies,1,2 demonstrate that inhibitor formation in haemophilia is much higher than previously estimated. These reports will probably reduce concern about antibody development in patients treated with high purity products. However, we have recorded a change in inhibitor status after therapy with ultra-pure factor VIII concentrate in a previously treated individual. A 57-year-old man with severe haemophilia A (factor VIII < 1U/dL) had been treated successfully over several years with greater than 105 IU of intermediate-purity factor VIII concentrate 8Y blood products laboratory (Elstree), without inhibitor formation but he developed antibodies to factor VIIII after his first exposure to a monoclonally-purified high-purity product (Monoclate P, Armour). He presented with neck pain and mild limitation of flexion with no neurological deficit. Cervical radiographs showed degenerative changes. In view of the possibility of occult bleeding he was given factor VIII concentrate (8Y). He developed fever, followed by weakness of the right hand and arm, hyporeflexia, and a C4/C5 sensory deficit. Magnetic resonance imaging revealed an anterior extradural cervical abscess with secondary haemorrhage at the C4-C6 level. An inhibitor screen before operation was negative. Haemostasis was achieved successfully during surgery and postoperatively with Monoclate P. He was given an initial bolus followed by continuous infusion of Monoclate P to maintain factor VIII levels at 100 IU/dL. After 7 days we changed to 12 hourly bolus injections. His response was adequate for a further week but then a fall in increments was noted. An inhibitor screen was now positive and he had an antibody titre of 4 Bethesda units to human factor VIII. After further replacement therapy with 8Y, factor VIII levels did not rise and the antibody titre increased to 26 Bethesda units. Treatment with factor VIIIwas therefore stopped but he made a good postoperative recovery. 7 months later he haemorrhaged from two benign gastric ulcers; antibody titre to human factor VIII was 86 Bethesda units and to porcine factor VIII 16 Bethesda units. He continued to have melaena after treatment with an activated prothrombin complex concentrate (FEIBAImmuno) but the bleeding abated after treatment with activated recombinant factor VII (Novo-Nordisk). He had no recurrence of haemorrhage after recombinant VIla was withdrawn. We agree that inhibitors developing in previously untreated individuals on exposure to ultra-pure factor VIII products are likely to be accounted for by the natural history of the treated disorder. However, the formation of high-titre inhibitors on 1109
first exposure to ultra-pure material after many exposures to intermediate purity product have failed to provoke such a response, raises again the question of altered immunogenicity of ultra-high purity concentrates. S Allard, N
Philpott, D H Bevan
Department of Haematology, St George’s Hospital, London SW17 OQT, UK Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-98. Peerlinck K, Arnout J, Gilles JG, et al. A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurised factor VIII concentrate. Thromb Haemostas 1993; 69: 115-18.
1
2
SIR-Addiego et al report a high frequency of inhibitor development in haemophiliacs treated with low-purity and intermediate-purity factor VIII. Determinants of inhibitor development among haemophiliacs might include age, age at diagnosis, and amount and type of clotting factor VIIIinfused. Infection with HIV may also affect inhibitor development.1.22 Data from the Italian registry of haemophilia support this hypothesis. So far, 1366 severe (factor VIII < 2 IU/dL) haemophilia A patients have been tested for antibodies to HIV and for the presence of inhibitor: inhibitor has been reported in 21 % (170/808) of HIV-seronegative haemophiliacs, and in 9% (43/458) of HIV-seropositive haemophiliacs (prevalence odds ratio 27, 95% CI 1 8-3 8, p < 0-001). These results show that the presence of HIV infection may be associated with a significantly low frequency of inhibitor to factor VIII because of the immune down-regulation associated with HIV/AIDS"’ Therefore, reports of the evaluation of the frequency of inhibitor should also include information about HIV serological and clinical status, especially in the studies that tend to evaluate this aspect of haemophiliacs treated with low and intermediate purity factor VIII concentrates, which certainly in the past have transmitted HIV to some haemophiliacs. Alessandro Ghirardini, Nicola Schinaia, Italiano Coagulopatie Congenite
on
behalf of the Gruppo
Laboratory of Epidemiology Biostatistics, National AIDS Operational Centre, Istituto Superiore di Sanitá, 00161 Rome, Italy
Ragni MV, Bontempo FA, Lewis JH. Disappearance of inhibitor to factor VIII in HIV-infected hemophiliacs with progression to AIDS or severe ARC. Transfusion 1989; 29: 447-49. Bray GL, Kroner BL, Arkin S, et al. Loss of high-responder inhibitors in patients with severe hemophilia A and human immunodeficiency virus type 1 infection: a report from the multi-center hemophilia cohort study. Am J Hematol 1993; 42: 375-79.
1
2
and colleagues, in their discussion of their that their data can serve to make meaningful comparisons with the frequency of inhibitor develpment in previously untreated patients given only recombinant or concentrates. From a monoclonal-antibody-purified comparison with the results of previous reports on these ultra-pure products, they conclude that the frequency of inhibitor development in patients treated with recombinant factor VIII is lower than in patients with products of lesser
SiR-Addiego
results,
state
purity. To establish the frequency of inhibitor development associated with a particular factor VIII product, one should study patients who were treated solely with that product. Baseline data for inhibitor development on low-purity products should therefore be obtained from patients who used only one low-purity product. Addiego’s study is not suitable for future comparisons, since several products were used, both between and within patients.
1110
We reported a frequency of 6-3% in a group of 48 patients with severe haemophilia A, analysed in a closely similar way to Addiego’s patients but exclusively treated with locally produced cryoprecipitate.! Guerois et aP showed an identical incidence (3/48) in patients with severe haemophilia A treated only with Innovate (high purity, solvent-detergent treated). Addiego and colleagues compare their results with those of studies on Kogenate and on Recombinate, two recombinant factor VIII preparations, in which frequencies of inhibitor development are 25%3 and 19%,4 respectively. They fail to mention the very short follow-up in these studies. In the Kogenate study, median follow-up was only 9 exposure days in the patients who developed inhibitors, and 7 for those who did not; in the Recombinate study it was 11 exposure days for both groups combined. Since a median implies that half the events occur before, and half after this period, one may expect almost a doubling of the reported number of inhibitor patients once the follow-up is extended. Obviously, these data on recombinant factor VIII are too preliminary to allow these kind of
comparisons. In addition, we have recently demonstrated that a particular intermediate-purity product is clearly immunogenic.s,6 One explanation of the Addiego results could thus be that during the period analysed (1975-85) one or several of their intermediatepurity products was also immunogenic, but that this was not appreciated because this aspect was not systematically studied.
We feel that the statement on the use of these data for future comparisons is erroneous, and that the comparison with ultra-pure products is biased. K Peerlinck, J Vermylen Centre for Molecular and Vascular Biology and Division of Bleeding and Vascular Disorders, University of Leuven, B3000 Leuven, Belgium
F Rosendaal, E Briet Departments of Clinical Epidemiology and Haematology, University of Leiden, Netherlands
Peerlinck K, Rosendaal FR, Vermylen J. Incidence of inhibitor development in a group of young hemophilia A patients treated exclusively with lyophilized cryoprecipitate. Blood 1993; 81: 3332-35. 2 Guérois C, Rothschild C, Laurian Y, et al. Incidence of inhibitors specific for Factors VIII or IX in severe hemophiliacs A and B only treated with very high purity FVIII or FIX concentrates. Thromb Haemostas 1993; 69: 852. 3 Lusher JM, Arkin S, Abildgaard CF, Schwartz RS, and the Kogenate Previously Untreated Patient Study Group. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. N Engl J Med 1993; 328: 453-59. 4 Bray GL, Courter S, Lynes M, Lee M, Gomperts E, and the Recombinate Study Group. Safety, efficacy and inhibitor risk of recombinant factor VIII (RecombinateR) in a cohort of previously untreated patients (PUPs) with severe hemophilia A. Thromb Haemostas 1993; 69: 1205. 5 Peerlinck K, Arnout J, Gilles JG, Saint-Remy JM, Vermylen J. A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurized factor VIII concentrate. Thromb Haemostas 1993; 69: 115-18. 6 Rosendaal FR, Nieuwenhuis HK, van den Berg HM, et al. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Blood 1993; 81: 2180-86. 1
Ammonium in intravenous albumin
preparations SiR-During our research on the pathogenesis of hepatic encephalopathy, we unexpectedly found that intravenous albumin preparations contain a significant amount of ammonium. In an enzymic
assay (glutamate dehydrogenase kit, Boehringer Mannheim) and with the Blood Ammonia Checker II (Kyoto Daiichi Kagaku, Kyoto, Japan),’ ammonium
greater detail than we have been able to, the frequency of inhibitor development.
Factor VIII inhibitors SiR-Addiego and colleagues (Aug 21, p 462) conclude that recombinant factor VIII has no greater risk of inhibitor formation than do intermediate purity or monoclonal antibody purified products. Unfortunately, in their table 2 they compare non-comparable studies, which differ in the definition of severe haemophilia, time that patients are at risk (number of exposure days), and the diligence of inhibitor surveillance. Each manufacturer of factor VIIII replacement product sets their own definitions and testing frequency interval, and, scientifically based conclusions, with respect to comparability, are therefore practically precluded. In the Monoclate (heattreated,
not
pasteurised Monoclate-P) study
followed for
some
patients
4 years, all patients for at least 12 months, with an average of 22 exposure days in those developing inhibitors. Since the prevalence of inhibitor rises with increasing age at least through the first two decades of life, and only half the inhibitors will develop by age 10 years, I propose that any studies of true risk of inhibitor development must follow the cohort at risk for at least 5 years or 50 exposures to product. Standardisation of a protocol to assess this risk is needed and currently overdue because patient safety may be at were
over
issue. Garrett E Bergman Armour Pharmaceutical Company, PO Box 1200,
Author’s
Collegeville,
PA 19426, USA
reply
SIR-I agree with Bergman that protocols for the management of previously-untreated patients with severe factor VIIIdeficient haemophilia need to be standardised and uniformly applied around the world. Unfortunately, apart from the newer recombinant studies, such an approach to the evaluation of the development of inhibitors has not been used. My colleagues and I attempted to standardise our patient population according to guidelines and criteria as discussed at the 1992 factor VIII and IX sub-committee of the International Society of Thrombosis Hemostasis. As we reported, patients were followed for at least 5 years or the equivalent of 30 exposure days to factor product. Current information indicates that most inhibitors do indeed develop in that time. Contrary to Bergman’s assertion, we did not conclude that recombinant factor VIII causes no greater risk of inhibitor formation than monoclonal antibody purified products. We specifically stated that, "there were too few patients in the monoclonal-derived factor VIII study groups to allow meaningful comparison with our study group", and "because several patients in the monoclonal-derived factor VIII study were exposed to several types of products, no conclusion with regard to a specific level of product purity can be established". We, as others, feel that it is unfortunate that carefully controlled inhibitor trials were not done during studies of monoclonal-antibody-derived product and during other studies over the past two decades. The haemophilia community will be unable to retrace steps and accurately assess, in any
previous
true
Joseph E Addiego Pediatric Medical Center for Northern California, Children’s CA 94609, USA
Hospital Oakland, Oakland,
SiR-Addiego and colleagues’ finding that 28% of previously untreated severe haemophilia patients developed inhibitors after treatment with low and intermediate purity factor VIII concentrates, together with data from other prospective studies,1,2 demonstrate that inhibitor formation in haemophilia is much higher than previously estimated. These reports will probably reduce concern about antibody development in patients treated with high purity products. However, we have recorded a change in inhibitor status after therapy with ultra-pure factor VIII concentrate in a previously treated individual. A 57-year-old man with severe haemophilia A (factor VIII < 1U/dL) had been treated successfully over several years with greater than 105 IU of intermediate-purity factor VIII concentrate 8Y blood products laboratory (Elstree), without inhibitor formation but he developed antibodies to factor VIIII after his first exposure to a monoclonally-purified high-purity product (Monoclate P, Armour). He presented with neck pain and mild limitation of flexion with no neurological deficit. Cervical radiographs showed degenerative changes. In view of the possibility of occult bleeding he was given factor VIII concentrate (8Y). He developed fever, followed by weakness of the right hand and arm, hyporeflexia, and a C4/C5 sensory deficit. Magnetic resonance imaging revealed an anterior extradural cervical abscess with secondary haemorrhage at the C4-C6 level. An inhibitor screen before operation was negative. Haemostasis was achieved successfully during surgery and postoperatively with Monoclate P. He was given an initial bolus followed by continuous infusion of Monoclate P to maintain factor VIII levels at 100 IU/dL. After 7 days we changed to 12 hourly bolus injections. His response was adequate for a further week but then a fall in increments was noted. An inhibitor screen was now positive and he had an antibody titre of 4 Bethesda units to human factor VIII. After further replacement therapy with 8Y, factor VIII levels did not rise and the antibody titre increased to 26 Bethesda units. Treatment with factor VIIIwas therefore stopped but he made a good postoperative recovery. 7 months later he haemorrhaged from two benign gastric ulcers; antibody titre to human factor VIII was 86 Bethesda units and to porcine factor VIII 16 Bethesda units. He continued to have melaena after treatment with an activated prothrombin complex concentrate (FEIBAImmuno) but the bleeding abated after treatment with activated recombinant factor VII (Novo-Nordisk). He had no recurrence of haemorrhage after recombinant VIla was withdrawn. We agree that inhibitors developing in previously untreated individuals on exposure to ultra-pure factor VIII products are likely to be accounted for by the natural history of the treated disorder. However, the formation of high-titre inhibitors on 1109
first exposure to ultra-pure material after many exposures to intermediate purity product have failed to provoke such a response, raises again the question of altered immunogenicity of ultra-high purity concentrates. S Allard, N
Philpott, D H Bevan
Department of Haematology, St George’s Hospital, London SW17 OQT, UK Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-98. Peerlinck K, Arnout J, Gilles JG, et al. A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurised factor VIII concentrate. Thromb Haemostas 1993; 69: 115-18.
1
2
SIR-Addiego et al report a high frequency of inhibitor development in haemophiliacs treated with low-purity and intermediate-purity factor VIII. Determinants of inhibitor development among haemophiliacs might include age, age at diagnosis, and amount and type of clotting factor VIIIinfused. Infection with HIV may also affect inhibitor development.1.22 Data from the Italian registry of haemophilia support this hypothesis. So far, 1366 severe (factor VIII < 2 IU/dL) haemophilia A patients have been tested for antibodies to HIV and for the presence of inhibitor: inhibitor has been reported in 21 % (170/808) of HIV-seronegative haemophiliacs, and in 9% (43/458) of HIV-seropositive haemophiliacs (prevalence odds ratio 27, 95% CI 1 8-3 8, p < 0-001). These results show that the presence of HIV infection may be associated with a significantly low frequency of inhibitor to factor VIII because of the immune down-regulation associated with HIV/AIDS"’ Therefore, reports of the evaluation of the frequency of inhibitor should also include information about HIV serological and clinical status, especially in the studies that tend to evaluate this aspect of haemophiliacs treated with low and intermediate purity factor VIII concentrates, which certainly in the past have transmitted HIV to some haemophiliacs. Alessandro Ghirardini, Nicola Schinaia, Italiano Coagulopatie Congenite
on
behalf of the Gruppo
Laboratory of Epidemiology Biostatistics, National AIDS Operational Centre, Istituto Superiore di Sanitá, 00161 Rome, Italy
Ragni MV, Bontempo FA, Lewis JH. Disappearance of inhibitor to factor VIII in HIV-infected hemophiliacs with progression to AIDS or severe ARC. Transfusion 1989; 29: 447-49. Bray GL, Kroner BL, Arkin S, et al. Loss of high-responder inhibitors in patients with severe hemophilia A and human immunodeficiency virus type 1 infection: a report from the multi-center hemophilia cohort study. Am J Hematol 1993; 42: 375-79.
1
2
and colleagues, in their discussion of their that their data can serve to make meaningful comparisons with the frequency of inhibitor develpment in previously untreated patients given only recombinant or concentrates. From a monoclonal-antibody-purified comparison with the results of previous reports on these ultra-pure products, they conclude that the frequency of inhibitor development in patients treated with recombinant factor VIII is lower than in patients with products of lesser
SiR-Addiego
results,
state
purity. To establish the frequency of inhibitor development associated with a particular factor VIII product, one should study patients who were treated solely with that product. Baseline data for inhibitor development on low-purity products should therefore be obtained from patients who used only one low-purity product. Addiego’s study is not suitable for future comparisons, since several products were used, both between and within patients.
1110
We reported a frequency of 6-3% in a group of 48 patients with severe haemophilia A, analysed in a closely similar way to Addiego’s patients but exclusively treated with locally produced cryoprecipitate.! Guerois et aP showed an identical incidence (3/48) in patients with severe haemophilia A treated only with Innovate (high purity, solvent-detergent treated). Addiego and colleagues compare their results with those of studies on Kogenate and on Recombinate, two recombinant factor VIII preparations, in which frequencies of inhibitor development are 25%3 and 19%,4 respectively. They fail to mention the very short follow-up in these studies. In the Kogenate study, median follow-up was only 9 exposure days in the patients who developed inhibitors, and 7 for those who did not; in the Recombinate study it was 11 exposure days for both groups combined. Since a median implies that half the events occur before, and half after this period, one may expect almost a doubling of the reported number of inhibitor patients once the follow-up is extended. Obviously, these data on recombinant factor VIII are too preliminary to allow these kind of
comparisons. In addition, we have recently demonstrated that a particular intermediate-purity product is clearly immunogenic.s,6 One explanation of the Addiego results could thus be that during the period analysed (1975-85) one or several of their intermediatepurity products was also immunogenic, but that this was not appreciated because this aspect was not systematically studied.
We feel that the statement on the use of these data for future comparisons is erroneous, and that the comparison with ultra-pure products is biased. K Peerlinck, J Vermylen Centre for Molecular and Vascular Biology and Division of Bleeding and Vascular Disorders, University of Leuven, B3000 Leuven, Belgium
F Rosendaal, E Briet Departments of Clinical Epidemiology and Haematology, University of Leiden, Netherlands
Peerlinck K, Rosendaal FR, Vermylen J. Incidence of inhibitor development in a group of young hemophilia A patients treated exclusively with lyophilized cryoprecipitate. Blood 1993; 81: 3332-35. 2 Guérois C, Rothschild C, Laurian Y, et al. Incidence of inhibitors specific for Factors VIII or IX in severe hemophiliacs A and B only treated with very high purity FVIII or FIX concentrates. Thromb Haemostas 1993; 69: 852. 3 Lusher JM, Arkin S, Abildgaard CF, Schwartz RS, and the Kogenate Previously Untreated Patient Study Group. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. N Engl J Med 1993; 328: 453-59. 4 Bray GL, Courter S, Lynes M, Lee M, Gomperts E, and the Recombinate Study Group. Safety, efficacy and inhibitor risk of recombinant factor VIII (RecombinateR) in a cohort of previously untreated patients (PUPs) with severe hemophilia A. Thromb Haemostas 1993; 69: 1205. 5 Peerlinck K, Arnout J, Gilles JG, Saint-Remy JM, Vermylen J. A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurized factor VIII concentrate. Thromb Haemostas 1993; 69: 115-18. 6 Rosendaal FR, Nieuwenhuis HK, van den Berg HM, et al. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Blood 1993; 81: 2180-86. 1
Ammonium in intravenous albumin
preparations SiR-During our research on the pathogenesis of hepatic encephalopathy, we unexpectedly found that intravenous albumin preparations contain a significant amount of ammonium. In an enzymic
assay (glutamate dehydrogenase kit, Boehringer Mannheim) and with the Blood Ammonia Checker II (Kyoto Daiichi Kagaku, Kyoto, Japan),’ ammonium