A S van Velzen1, C L Eckhardt1, M Peters1, F W G Leebeek2, C Escuriola-Ettingshausen3, C Hermans4, R Keenan5, J Astermark6, C Male7, K Peerlinck8, S le Cessie9, J G van der Bom10, K Fijnvandraat1. 1. Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands. 2. Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands. 3. HZRM, Haemophilia Centre Rhine Main, Frankfurt-Moerfelden, Moerfelden-Walldorf, Germany. 4. Haemostasis and Thrombosis Unit, Division of Haematology, St-Luc University Hospital, Brussels, Belgium. 5. Liverpool Paediatric Haemophilia Centre, Haematology Treatment Centre, Alderhey Childrens Hospital, Liverpool, UK. 6. Centre for Thrombosis and Haemostasis, Lund University, Skåne University Hospital Malmö, Malmo, Sweden. 7. Universitätsklinik für Kinder- und Jugendheilkunde, Medical University of Vienna, Vienna, Austria. 8. Department of Vascular Medicine and Haemostasis, University of Leuven, Leuven, Belgium. 9. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands. 10. Center for Clinical Transfusion Research, Sanquin Research and Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
Abstract
Essentials Research suggests that intensive treatment episodes may increase the risk to develop inhibitors. We performed an international nested case-control study with 298 non-severe hemophilia A patients. Surgery and a high dose of factor VIII concentrate were associated with increased inhibitor risk. Physicians need to review arguments for factor VIII dose and elective surgery extra critically. SUMMARY: Background Inhibitor development is a major complication of treatment with factor VIII concentrates in hemophilia. Findings from studies among severe hemophilia A patients suggest that intensive treatment episodes increase the risk of developing inhibitors. Objectives We set out to assess whether intensive treatment is also associated with an increased risk of inhibitor development among non-severe hemophilia A patients. Patients/Methods We performed a nested case-control study. A total of 75 inhibitor patients (cases) and 223 control patients were selected from 2709 non-severe hemophilia A patients (FVIII:C, 2-40%) of the INSIGHT cohort study. Cases and controls were matched for date of birth and cumulative number of exposure days (EDs) to FVIII concentrates. Conditional logistic regression was used to calculate both unadjusted and adjusted odds ratios (aOR); the latter were adjusted for a priori specified confounders. Results Peak treatment of 5 or 10 consecutive EDs did not increase inhibitor risk (aOR, 1.0; 95% confidence interval (CI), 0.4-2.5; and aOR, 1.8; CI, 0.6-5.5, respectively). Both surgical intervention (aOR, 4.2; CI, 1.7-10.3) and a high mean dose (> 45 IU kg-1 /ED) of FVIII concentrate (aOR, 7.5; CI, 1.6-35.6) were associated with an increased inhibitor risk. Conclusions Our findings suggest that high-dose FVIII treatment and surgery increase the risk of inhibitor development in non-severe hemophilia A. Together with the notion that non-severe hemophilia A patients are at a lifelong risk of inhibitor development, we suggest that in the future physicians will review the arguments for the FVIII dose and elective surgery extra critically.
Essentials Research suggests that intensive treatment episodes may increase the risk to develop inhibitors. We performed an international nested case-control study with 298 non-severe hemophilia Apatients. Surgery and a high dose of factor VIII concentrate were associated with increased inhibitor risk. Physicians need to review arguments for factor VIII dose and elective surgery extra critically. SUMMARY: Background Inhibitor development is a major complication of treatment with factor VIII concentrates in hemophilia. Findings from studies among severe hemophilia Apatients suggest that intensive treatment episodes increase the risk of developing inhibitors. Objectives We set out to assess whether intensive treatment is also associated with an increased risk of inhibitor development among non-severe hemophilia Apatients. Patients/Methods We performed a nested case-control study. A total of 75 inhibitor patients (cases) and 223 control patients were selected from 2709 non-severe hemophilia Apatients (FVIII:C, 2-40%) of the INSIGHT cohort study. Cases and controls were matched for date of birth and cumulative number of exposure days (EDs) to FVIII concentrates. Conditional logistic regression was used to calculate both unadjusted and adjusted odds ratios (aOR); the latter were adjusted for a priori specified confounders. Results Peak treatment of 5 or 10 consecutive EDs did not increase inhibitor risk (aOR, 1.0; 95% confidence interval (CI), 0.4-2.5; and aOR, 1.8; CI, 0.6-5.5, respectively). Both surgical intervention (aOR, 4.2; CI, 1.7-10.3) and a high mean dose (> 45 IU kg-1 /ED) of FVIII concentrate (aOR, 7.5; CI, 1.6-35.6) were associated with an increased inhibitor risk. Conclusions Our findings suggest that high-dose FVIII treatment and surgery increase the risk of inhibitor development in non-severe hemophilia A. Together with the notion that non-severe hemophilia Apatients are at a lifelong risk of inhibitor development, we suggest that in the future physicians will review the arguments for the FVIII dose and elective surgery extra critically.
Authors: P L F Giangrande; C Hermans; B O'Mahony; P de Kleijn; M Bedford; A Batorova; J Blatný; K Jansone Journal: Orphanet J Rare Dis Date: 2018-04-27 Impact factor: 4.123
Authors: A Abdi; M R Bordbar; S Hassan; F R Rosendaal; J G van der Bom; J Voorberg; K Fijnvandraat; S C Gouw Journal: Front Immunol Date: 2020-05-07 Impact factor: 7.561
Authors: Alice S van Velzen; Corien L Eckhardt; Marjolein Peters; Johannes Oldenburg; Marjon Cnossen; Ri Liesner; Massimo Morfini; Giancarlo Castaman; Simon McRae; Johanna G van der Bom; Karin Fijnvandraat Journal: Br J Haematol Date: 2020-03-22 Impact factor: 6.998