Kawasaki Disease (KD) is an acute systemic vasculitis in children. The strongest genetic associat... more Kawasaki Disease (KD) is an acute systemic vasculitis in children. The strongest genetic association with KD found in genome-wide association studies (GWAS), is FCGR2A-H131R (rs1801274). Rs1801274 is located at the FCGR2/3 locus, which contains five highly homologous genes encoding the major receptors for IgG (Fc-gamma receptors, FcγRs). Multiple SNPs and copy number variations (CNVs) at this locus, that are not included in the GWAS, have been associated with susceptibility to various infectious and autoimmune diseases or efficacy of immunotherapy. Because of sequence complexity of this locus, most association studies can only genotype two SNPs (rs1801274 and rs396991). In contrast, with multiplex ligation-dependent probe amplification (MLPA), we detected all eight known functionally relevant SNPs and haplotypes as well as CNV at this locus and could define extensive ethnic variation and linkage disequilibrium (LD) in >1800 healthy subjects. In a fine-mapping follow-up based on b...
Timely recognition of clinical signs and symptoms of sickle cell disease remains of great importa... more Timely recognition of clinical signs and symptoms of sickle cell disease remains of great importance because the neonatal PKU screening program in The Netherlands that was introduced in January 1st 2007 will not reach all children with this disease. Of children that have been diagnosed in the Emma Children's Hospital AMC, Amsterdam, 20% would not have been reached by this new program: immigrant's children born abroad and adopted children. It goes without saying that also in children that have been born in the Netherlands before January 1st 2007 the diagnosis sickle cell disease should be considered in cases of disease-specific clinical symptoms. The initial clinical manifestation of sickle cell disease in children born in the Netherlands is potentially life-threatening in 8% (7/88), e.g. a pneumococcal infection or an acute splenic sequestration. Painful crisis, paleness and jaundice are the most common presenting symptoms. The median age at diagnosis of the group of Amsterd...
Journal of Clinical and Translational Research, 2018
Background: The half-life and mean residence time (MRT) of infused recombinant factor VIII (FVIII... more Background: The half-life and mean residence time (MRT) of infused recombinant factor VIII (FVIII) concentrate are associated with pre-infusion levels of von Willebrand factor (VWF) in severely affected hemophilia A patients. It is currently unknown if individual FVIII concentrate half-life and MRT can be extended by increasing endogenous VWF levels. Aim: Our aim was to evaluate the effect of a 1-deamino-8-D-arginine vasopressin (DDAVP)-induced rise in VWF concentration on the pharmacokinetics of infused FVIII in hemophilia A patients. Methods: Four adult hemophilia A patients participated in this cross-over, placebo-controlled study. Each patient received either intravenous DDAVP or placebo, one hour prior to administration of 50 IU/kg plasma-derived immune-affinity purified FVIII concentrate. Results: The combined administration of DDAVP and FVIII concentrate was well tolerated. The levels of VWF Antigen (Ag) doubled after DDAVP, whereas they remained stable after placebo infusion...
For children with haemophilia, early initiation of prophylaxis is crucial to prevent life‐threate... more For children with haemophilia, early initiation of prophylaxis is crucial to prevent life‐threatening bleeds and maintain joint health throughout life. Options for prophylaxis have recently increased from replacement therapy with standard or extended half‐life coagulation factor products to include other haemostasis products, such as the non‐replacement therapy emicizumab.
Background Hemophilia A is an X-linked inherited bleeding disorder caused by a deficiency of clot... more Background Hemophilia A is an X-linked inherited bleeding disorder caused by a deficiency of clotting factor VIII (FVIII). It is treated by infusion of FVIII clotting factor concentrate with dosing based primarily on bodyweight. Previous studies evaluating perioperative dosing strategies in hemophilia conclude that improvement with regard to consumption of clotting factor concentrates is possible. However, the magnitude and complexity of the problem has not yet been addressed. Moreover, guidelines to optimize treatment have been lacking. Methods In a retrospective multicenter study, we evaluated perioperative management in hemophilia A patients with clotting factor VIII (FVIII) plasma levels below 0.05 IUml-1 by quantification of perioperative infusion of clotting factor concentrate and achieved FVIII plasma levels, while exploring possible modifiers of clotting factor concentrate consumption. Results Data was collected in a total of 198 surgical procedures in 119 patients; 75 adult...
Introduction Approximately 40% of children with a severe form of sickle cell disease (SCD) will d... more Introduction Approximately 40% of children with a severe form of sickle cell disease (SCD) will develop cerebral white matter hyperintensities (WMHs), visible on magnetic resonance imaging (MRI). This may be associated with impaired neurocognitive functioning. It is unknown whether the volume of these WHMs is associated with the degree of neurocognitive dysfunction. Our objective was to investigate the association between volume of WMHs and neurocognitive functioning. Methods We prospectively included children with HbSS or HbS-beta(0)thalassemia aged 8-16 years. Exclusion criteria were prior stroke and chronic blood transfusion therapy. Volume of WMHs was calculated on MRI and patients were ranked by size of WMHs. Neurocognitive function was evaluated by testing intelligence (IQ, intelligence quotient), memory, visuo-motor functioning and executive functioning. Fatigue was measured using a validated questionnaire (Pediatric Quality of Life Inventory Multidimensional Fatigue Scale, P...
The Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benef... more The Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benefit of a prophylactic platelet transfusion threshold of 25 × 109/L compared with 50 × 109/L for major bleeding and/or mortality in preterm neonates (7% absolute-risk reduction). However, some neonates in the trial may have experienced little benefit or even harm from the 25 × 109/L threshold. We wanted to assess this heterogeneity of treatment effect in the PlaNet-2 trial, to investigate whether all preterm neonates benefit from the low threshold. We developed a multivariate logistic regression model in the PlaNet-2 data to predict baseline risk of major bleeding and/or mortality for all 653 neonates. We then ranked the neonates based on their predicted baseline risk and categorized them into 4 risk quartiles. Within these quartiles, we assessed absolute-risk difference between the 50 × 109/L- and 25 × 109/L-threshold groups. A total of 146 neonates died or developed major bleeding. The i...
Background Transfusion of red blood cells (RBC) is a common intervention to treat and prevent com... more Background Transfusion of red blood cells (RBC) is a common intervention to treat and prevent complications in sickle cell disease (SCD). However, frequent transfusions may lead to erythrocyte alloimmunization, thereby complicating donor matching procedures and posing patients at risk for hemolytic transfusion reactions. Little information is available about the risk of alloimmunization of sickle cell patients living in European countries. In the Netherlands extensive matching procedures to prevent alloimmunization were introduced a decade ago, but the effect on alloimmunization has not been evaluated yet. Aims The primary aim of this study is to evaluate the cumulative incidence of first alloantibody formation in a Dutch cohort of transfused SCD patients, and to compare this with a general Dutch RBC-transfused population. In addition, the effect of extended RBC matching protocols on the incidence of alloantibody formation in SCD and potential clinical determinants of alloimmunizati...
4815 Abstract Background: Sickle cell disease (SCD) is a hereditary anemia characterized by chron... more 4815 Abstract Background: Sickle cell disease (SCD) is a hereditary anemia characterized by chronic hemolytic anemia and vaso-occlusive episodes, associated with a high susceptibility for infections and damage to all vital organs. Cardiologic effects of SCD are dilatation and hypertrophy of the left ventricle and pulmonary hypertension. The prevalence of these cardiac complications in children with SCD living in the Netherlands is unknown. The role of hemolysis in this process is still unclear. Therefore, the objectives of this study are: 1) to evaluate the prevalence of cardiac abnormalities in children with SCD living in the Netherlands, 2) to analyse the association between cardiac abnormalities and the severity of anemia and hemolysis. Methods: Cross-sectional study, including 92 children with SCD (genotype HBSS, HBSC or HBS-beta 0) treated at the Emma…
Nederlandse samenvatting: - De ziekte van von Willebrand is de meest voorkomende erfelijke bloedi... more Nederlandse samenvatting: - De ziekte van von Willebrand is de meest voorkomende erfelijke bloedingsziekte en wordt gekenmerkt door slijmvliesbloedingen. - De ziekte van von Willebrand wordt veroorzaakt door een tekort aan of een functioneel afwijkende vorm van von-willebrandfactor. Op grond van de oorzaak onderscheidt men verschillende types met eigen kenmerken en behandelingsopties. - De frequentie en ernst van de bloedingen bij patiënten met de ziekte van von Willebrand wordt sterk bepaald door de concentraties van von-willebrandfactor en factor VIII en door het type van de ziekte. - Van alle volwassen vrouwen met de ziekte van von Willebrand heeft 85% klachten van menorragie; een hoog percentage heeft postpartumbloedingen (37% van alle bevallingen). - Patiënten met de ziekte van von Willebrand hebben een verminderde kwaliteit van leven. - Patiënten met de ziekte van von Willebrand hebben een kleinere kans op arteriële trombose, zoals een hart- of herseninfarct. English summary: ...
Haemophilia : the official journal of the World Federation of Hemophilia, Jan 9, 2015
Joint bleeds (JB) are reported in a minority of patients with von Willebrand disease (VWD) but ma... more Joint bleeds (JB) are reported in a minority of patients with von Willebrand disease (VWD) but may lead to structural joint damage. Prevalence, severity and impact of JB in VWD are largely unknown. The aim of this study was to assess JB prevalence, onset, treatment and impact on health-related quality of life (HR-QoL) and joint integrity in moderate and severe VWD. In the Willebrand in the Netherlands study 804 moderate and severe VWD patients [von Willebrand factor (VWF) activity ≤30U dL(-1) ] completed a questionnaire on occurrence, sites and consequences of JB. To analyse JB number, onset, treatment and impact on joint integrity we additionally performed a patient-control study on medical file data comparing patients with JB to age, gender, factor VIII (FVIII)- and VWF activity matched VWD patients without JB. Of all VWD patients 23% (184/804) self-reported JB. These 184 patients reported joint damage more often (54% vs. 18%, P < 0.001) and had lower HR-QoL (SF36, P < 0.05)...
The ratios between von Willebrand factor propeptide (VWFpp) or FVIII coagulant activity (FVIII:C)... more The ratios between von Willebrand factor propeptide (VWFpp) or FVIII coagulant activity (FVIII:C) and VWF antigen (VWF:Ag) reflect synthesis, secretion and clearance of VWF. We aimed to define the pathophysiology of 658 types 1, 2 and 3 von Willebrand disease (VWD) patients with VWF levels ≤30 U/dL from the "Willebrand in the Netherlands" (WiN-)study using the VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios. We also evaluated the use of VWFpp in the classification and diagnosis of VWD. Based on the ratios, reduced VWF synthesis was observed in 18% (67/380) of type 1 patients and in only 2% (5/240) of type 2 patients. A significant proportion of type 3 patients had detectable VWFpp (14/37, 41%). These patients had a lower bleeding score than type 3 patients with complete absence of both VWF:Ag and VWFpp: 14.0 vs. 19.5, p=0.025. The majority of these patients had missense mutations with rapid VWF clearance, whereas type 3 patients with absence of VWFpp were homozygous for null allele...
Background: The development of neutralizing antibodies (inhibitors) towards factor VIII is a majo... more Background: The development of neutralizing antibodies (inhibitors) towards factor VIII is a major complication in non-severe hemophilia A, profoundly aggravating the bleeding pattern. Identification of high risk patients is hampered by lack of data on the association between factor VIII gene (F8) mutations and the development of inhibitors that take exposure days to therapeutic factor VIII concentrates into account. Aims: To determine the risk of inhibitor development in patients with non-severe hemophilia A and to analyze the association with F8 mutation, taking exposure days to therapeutic factor VIII concentrates into account. Methods: The study population was derived from a source population of 2711 non-severe hemophilia A patients (factor VIII 2-40%), treated in 34 hemophilia treatment centers in Europe and Australia (the INSIGHT consortium). The association between F8 mutation and inhibitor development was assessed in 1112 patients, only recruited from centers that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as time variable. Thus, risk was calculated as the proportion of patients that developed an inhibitor after a certain number of exposure days (e.g. 20 or 50) to therapeutic factor VIII concentrates. Results: During 44,800 exposure days (median 24 exposure days per patient; Inter Quartile Range (IQR), 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval (CI), 4.0-6.6) after a median of 28 exposure days (IQR, 12- 71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5- 8.9) and at 100 exposure days this risk was further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 221 different F8 point mutations 19 were associated with inhibitor development. The inhibitor risk was highest for R593C, D2074G, R2159C and W2229C, reaching 19%, 21%, 39% and 42%, respectively, at 50 exposure days. Conclusion: Among a total of 221 different point mutations, 19 mutations were associated with inhibitor development. Longitudinal analysis revealed that the inhibitor incidence in non-severe hemophilia A patients with certain F8 mutations approaches the incidence observed in patients with severe hemophilia. These results emphasize the importance of F8 genotyping in non-severe hemophilia A. New preventive and therapeutic approaches in this patient group are urgently needed.
Kawasaki Disease (KD) is an acute systemic vasculitis in children. The strongest genetic associat... more Kawasaki Disease (KD) is an acute systemic vasculitis in children. The strongest genetic association with KD found in genome-wide association studies (GWAS), is FCGR2A-H131R (rs1801274). Rs1801274 is located at the FCGR2/3 locus, which contains five highly homologous genes encoding the major receptors for IgG (Fc-gamma receptors, FcγRs). Multiple SNPs and copy number variations (CNVs) at this locus, that are not included in the GWAS, have been associated with susceptibility to various infectious and autoimmune diseases or efficacy of immunotherapy. Because of sequence complexity of this locus, most association studies can only genotype two SNPs (rs1801274 and rs396991). In contrast, with multiplex ligation-dependent probe amplification (MLPA), we detected all eight known functionally relevant SNPs and haplotypes as well as CNV at this locus and could define extensive ethnic variation and linkage disequilibrium (LD) in >1800 healthy subjects. In a fine-mapping follow-up based on b...
Timely recognition of clinical signs and symptoms of sickle cell disease remains of great importa... more Timely recognition of clinical signs and symptoms of sickle cell disease remains of great importance because the neonatal PKU screening program in The Netherlands that was introduced in January 1st 2007 will not reach all children with this disease. Of children that have been diagnosed in the Emma Children's Hospital AMC, Amsterdam, 20% would not have been reached by this new program: immigrant's children born abroad and adopted children. It goes without saying that also in children that have been born in the Netherlands before January 1st 2007 the diagnosis sickle cell disease should be considered in cases of disease-specific clinical symptoms. The initial clinical manifestation of sickle cell disease in children born in the Netherlands is potentially life-threatening in 8% (7/88), e.g. a pneumococcal infection or an acute splenic sequestration. Painful crisis, paleness and jaundice are the most common presenting symptoms. The median age at diagnosis of the group of Amsterd...
Journal of Clinical and Translational Research, 2018
Background: The half-life and mean residence time (MRT) of infused recombinant factor VIII (FVIII... more Background: The half-life and mean residence time (MRT) of infused recombinant factor VIII (FVIII) concentrate are associated with pre-infusion levels of von Willebrand factor (VWF) in severely affected hemophilia A patients. It is currently unknown if individual FVIII concentrate half-life and MRT can be extended by increasing endogenous VWF levels. Aim: Our aim was to evaluate the effect of a 1-deamino-8-D-arginine vasopressin (DDAVP)-induced rise in VWF concentration on the pharmacokinetics of infused FVIII in hemophilia A patients. Methods: Four adult hemophilia A patients participated in this cross-over, placebo-controlled study. Each patient received either intravenous DDAVP or placebo, one hour prior to administration of 50 IU/kg plasma-derived immune-affinity purified FVIII concentrate. Results: The combined administration of DDAVP and FVIII concentrate was well tolerated. The levels of VWF Antigen (Ag) doubled after DDAVP, whereas they remained stable after placebo infusion...
For children with haemophilia, early initiation of prophylaxis is crucial to prevent life‐threate... more For children with haemophilia, early initiation of prophylaxis is crucial to prevent life‐threatening bleeds and maintain joint health throughout life. Options for prophylaxis have recently increased from replacement therapy with standard or extended half‐life coagulation factor products to include other haemostasis products, such as the non‐replacement therapy emicizumab.
Background Hemophilia A is an X-linked inherited bleeding disorder caused by a deficiency of clot... more Background Hemophilia A is an X-linked inherited bleeding disorder caused by a deficiency of clotting factor VIII (FVIII). It is treated by infusion of FVIII clotting factor concentrate with dosing based primarily on bodyweight. Previous studies evaluating perioperative dosing strategies in hemophilia conclude that improvement with regard to consumption of clotting factor concentrates is possible. However, the magnitude and complexity of the problem has not yet been addressed. Moreover, guidelines to optimize treatment have been lacking. Methods In a retrospective multicenter study, we evaluated perioperative management in hemophilia A patients with clotting factor VIII (FVIII) plasma levels below 0.05 IUml-1 by quantification of perioperative infusion of clotting factor concentrate and achieved FVIII plasma levels, while exploring possible modifiers of clotting factor concentrate consumption. Results Data was collected in a total of 198 surgical procedures in 119 patients; 75 adult...
Introduction Approximately 40% of children with a severe form of sickle cell disease (SCD) will d... more Introduction Approximately 40% of children with a severe form of sickle cell disease (SCD) will develop cerebral white matter hyperintensities (WMHs), visible on magnetic resonance imaging (MRI). This may be associated with impaired neurocognitive functioning. It is unknown whether the volume of these WHMs is associated with the degree of neurocognitive dysfunction. Our objective was to investigate the association between volume of WMHs and neurocognitive functioning. Methods We prospectively included children with HbSS or HbS-beta(0)thalassemia aged 8-16 years. Exclusion criteria were prior stroke and chronic blood transfusion therapy. Volume of WMHs was calculated on MRI and patients were ranked by size of WMHs. Neurocognitive function was evaluated by testing intelligence (IQ, intelligence quotient), memory, visuo-motor functioning and executive functioning. Fatigue was measured using a validated questionnaire (Pediatric Quality of Life Inventory Multidimensional Fatigue Scale, P...
The Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benef... more The Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benefit of a prophylactic platelet transfusion threshold of 25 × 109/L compared with 50 × 109/L for major bleeding and/or mortality in preterm neonates (7% absolute-risk reduction). However, some neonates in the trial may have experienced little benefit or even harm from the 25 × 109/L threshold. We wanted to assess this heterogeneity of treatment effect in the PlaNet-2 trial, to investigate whether all preterm neonates benefit from the low threshold. We developed a multivariate logistic regression model in the PlaNet-2 data to predict baseline risk of major bleeding and/or mortality for all 653 neonates. We then ranked the neonates based on their predicted baseline risk and categorized them into 4 risk quartiles. Within these quartiles, we assessed absolute-risk difference between the 50 × 109/L- and 25 × 109/L-threshold groups. A total of 146 neonates died or developed major bleeding. The i...
Background Transfusion of red blood cells (RBC) is a common intervention to treat and prevent com... more Background Transfusion of red blood cells (RBC) is a common intervention to treat and prevent complications in sickle cell disease (SCD). However, frequent transfusions may lead to erythrocyte alloimmunization, thereby complicating donor matching procedures and posing patients at risk for hemolytic transfusion reactions. Little information is available about the risk of alloimmunization of sickle cell patients living in European countries. In the Netherlands extensive matching procedures to prevent alloimmunization were introduced a decade ago, but the effect on alloimmunization has not been evaluated yet. Aims The primary aim of this study is to evaluate the cumulative incidence of first alloantibody formation in a Dutch cohort of transfused SCD patients, and to compare this with a general Dutch RBC-transfused population. In addition, the effect of extended RBC matching protocols on the incidence of alloantibody formation in SCD and potential clinical determinants of alloimmunizati...
4815 Abstract Background: Sickle cell disease (SCD) is a hereditary anemia characterized by chron... more 4815 Abstract Background: Sickle cell disease (SCD) is a hereditary anemia characterized by chronic hemolytic anemia and vaso-occlusive episodes, associated with a high susceptibility for infections and damage to all vital organs. Cardiologic effects of SCD are dilatation and hypertrophy of the left ventricle and pulmonary hypertension. The prevalence of these cardiac complications in children with SCD living in the Netherlands is unknown. The role of hemolysis in this process is still unclear. Therefore, the objectives of this study are: 1) to evaluate the prevalence of cardiac abnormalities in children with SCD living in the Netherlands, 2) to analyse the association between cardiac abnormalities and the severity of anemia and hemolysis. Methods: Cross-sectional study, including 92 children with SCD (genotype HBSS, HBSC or HBS-beta 0) treated at the Emma…
Nederlandse samenvatting: - De ziekte van von Willebrand is de meest voorkomende erfelijke bloedi... more Nederlandse samenvatting: - De ziekte van von Willebrand is de meest voorkomende erfelijke bloedingsziekte en wordt gekenmerkt door slijmvliesbloedingen. - De ziekte van von Willebrand wordt veroorzaakt door een tekort aan of een functioneel afwijkende vorm van von-willebrandfactor. Op grond van de oorzaak onderscheidt men verschillende types met eigen kenmerken en behandelingsopties. - De frequentie en ernst van de bloedingen bij patiënten met de ziekte van von Willebrand wordt sterk bepaald door de concentraties van von-willebrandfactor en factor VIII en door het type van de ziekte. - Van alle volwassen vrouwen met de ziekte van von Willebrand heeft 85% klachten van menorragie; een hoog percentage heeft postpartumbloedingen (37% van alle bevallingen). - Patiënten met de ziekte van von Willebrand hebben een verminderde kwaliteit van leven. - Patiënten met de ziekte van von Willebrand hebben een kleinere kans op arteriële trombose, zoals een hart- of herseninfarct. English summary: ...
Haemophilia : the official journal of the World Federation of Hemophilia, Jan 9, 2015
Joint bleeds (JB) are reported in a minority of patients with von Willebrand disease (VWD) but ma... more Joint bleeds (JB) are reported in a minority of patients with von Willebrand disease (VWD) but may lead to structural joint damage. Prevalence, severity and impact of JB in VWD are largely unknown. The aim of this study was to assess JB prevalence, onset, treatment and impact on health-related quality of life (HR-QoL) and joint integrity in moderate and severe VWD. In the Willebrand in the Netherlands study 804 moderate and severe VWD patients [von Willebrand factor (VWF) activity ≤30U dL(-1) ] completed a questionnaire on occurrence, sites and consequences of JB. To analyse JB number, onset, treatment and impact on joint integrity we additionally performed a patient-control study on medical file data comparing patients with JB to age, gender, factor VIII (FVIII)- and VWF activity matched VWD patients without JB. Of all VWD patients 23% (184/804) self-reported JB. These 184 patients reported joint damage more often (54% vs. 18%, P < 0.001) and had lower HR-QoL (SF36, P < 0.05)...
The ratios between von Willebrand factor propeptide (VWFpp) or FVIII coagulant activity (FVIII:C)... more The ratios between von Willebrand factor propeptide (VWFpp) or FVIII coagulant activity (FVIII:C) and VWF antigen (VWF:Ag) reflect synthesis, secretion and clearance of VWF. We aimed to define the pathophysiology of 658 types 1, 2 and 3 von Willebrand disease (VWD) patients with VWF levels ≤30 U/dL from the "Willebrand in the Netherlands" (WiN-)study using the VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios. We also evaluated the use of VWFpp in the classification and diagnosis of VWD. Based on the ratios, reduced VWF synthesis was observed in 18% (67/380) of type 1 patients and in only 2% (5/240) of type 2 patients. A significant proportion of type 3 patients had detectable VWFpp (14/37, 41%). These patients had a lower bleeding score than type 3 patients with complete absence of both VWF:Ag and VWFpp: 14.0 vs. 19.5, p=0.025. The majority of these patients had missense mutations with rapid VWF clearance, whereas type 3 patients with absence of VWFpp were homozygous for null allele...
Background: The development of neutralizing antibodies (inhibitors) towards factor VIII is a majo... more Background: The development of neutralizing antibodies (inhibitors) towards factor VIII is a major complication in non-severe hemophilia A, profoundly aggravating the bleeding pattern. Identification of high risk patients is hampered by lack of data on the association between factor VIII gene (F8) mutations and the development of inhibitors that take exposure days to therapeutic factor VIII concentrates into account. Aims: To determine the risk of inhibitor development in patients with non-severe hemophilia A and to analyze the association with F8 mutation, taking exposure days to therapeutic factor VIII concentrates into account. Methods: The study population was derived from a source population of 2711 non-severe hemophilia A patients (factor VIII 2-40%), treated in 34 hemophilia treatment centers in Europe and Australia (the INSIGHT consortium). The association between F8 mutation and inhibitor development was assessed in 1112 patients, only recruited from centers that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as time variable. Thus, risk was calculated as the proportion of patients that developed an inhibitor after a certain number of exposure days (e.g. 20 or 50) to therapeutic factor VIII concentrates. Results: During 44,800 exposure days (median 24 exposure days per patient; Inter Quartile Range (IQR), 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval (CI), 4.0-6.6) after a median of 28 exposure days (IQR, 12- 71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5- 8.9) and at 100 exposure days this risk was further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 221 different F8 point mutations 19 were associated with inhibitor development. The inhibitor risk was highest for R593C, D2074G, R2159C and W2229C, reaching 19%, 21%, 39% and 42%, respectively, at 50 exposure days. Conclusion: Among a total of 221 different point mutations, 19 mutations were associated with inhibitor development. Longitudinal analysis revealed that the inhibitor incidence in non-severe hemophilia A patients with certain F8 mutations approaches the incidence observed in patients with severe hemophilia. These results emphasize the importance of F8 genotyping in non-severe hemophilia A. New preventive and therapeutic approaches in this patient group are urgently needed.
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