Decreased Mortality From Intracranial Hemorrhage In Pediatric Patients With Hemophilia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 208-208
Author(s):  
Char Witmer
Keyword(s):  
Cohort Study ◽  
Mortality Rate ◽  
Intracranial Hemorrhage ◽  
Pediatric Patients ◽  
Hemophilia A ◽  
Interquartile Range ◽  
Administrative Database ◽  
Severe Hemophilia ◽  
Entire Cohort ◽  
Mortality Estimates

Introduction and Objective Intracranial hemorrhage (ICH) is one of the most significant bleeding complications in hemophilia with a reported 20% mortality rate. A recent study from the Centers for Disease Control and Prevention Universal Data Collection project demonstrated that prophylaxis in patients with severe hemophilia reduced the risk of intracranial hemorrhage but mortality remained high (19.6 %). However 95% of those ICH deaths occurred in subjects over 20 years of age. This was in contrast to prior studies that demonstrated much higher mortality rates in children. Additional studies are needed to confirm this shift in the age distribution of ICH mortality. The objective of this study was to determine the mortality rate from ICH in pediatric patients with hemophilia admitted to US tertiary care hospitals. Patients and methods This retrospective multicenter cohort study utilized data from 43 free-standing children’s hospitals that contribute data to the Pediatric Health Information System administrative database. Subjects were male, less than 21 years of age, with an International Classification of Diseases (ICD-9) diagnostic code for hemophilia A or B, with an admission between 1/1/2002-12/31/2011. ICD-9 discharge codes were used to identify admissions during which an ICH was diagnosed. Subjects were classified as having an inhibitor if they received bypassing agents (either FEIBA or recombinant factor VIIa). Summary statistics include frequencies and percentages for categorical variables and median and interquartile range for continuous variables. Odds ratios (OR) with 95% confidence intervals were calculated using multivariable logistic regression to evaluate the strength of association between mortality and the presence of ICH, an inhibitor and hemophilia type (A versus B). Result During the 10 year study period there were a total of 8,325 admissions in 3,133 individual male subjects with either hemophilia A or B. 80% (2,506) of the subjects had hemophilia A and 14.4% (451) had an inhibitor. The median number of admissions per subject was 1 (interquartile range 1-3). Overall mortality for the entire cohort was low at 0.7% (21 deaths). There were a total of 327 admissions with ICD-9 codes for ICH in 265 (8.5%) subjects. 12.8% (34) of subjects had more than 1 ICH event during the study period. The median age for ICH was 2.2 (interquartile range 0.6-7.3) years. The ICH mortality rate was 1.8% (6 deaths). This represents an 11 fold decrease from prior ICH mortality estimates of 20%. 50% (3) of subjects who died from ICH had an inhibitor. For the entire cohort, mortality was associated with the presence of ICH (5.6 OR (2.3-14)) and the presence of an inhibitor (3.1 OR (1.2-7.8)). Conclusion This retrospective cohort study utilizing an inpatient pediatric administrative database confirms that mortality from ICH in pediatric patients is significantly reduced from prior studies. In this cohort, mortality from ICH was quite low (1.8%), representing an 11 fold decrease from previous mortality estimates. Potential reasons for this reduction include the routine use of prophylaxis in pediatric patients with severe hemophilia, increased availability of factor concentrates and aggressive management of patients with hemophilia and suspected ICH. Disclosures: No relevant conflicts of interest to declare.

Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6367-6370 ◽  
Author(s):  
Charles R.M. Hay ◽  
Ben Palmer ◽  
Elizabeth Chalmers ◽  
Ri Liesner ◽  
Rhona Maclean ◽  
...  
Keyword(s):  
United Kingdom ◽  
Factor Viii ◽  
Hemophilia A ◽  
Interquartile Range ◽  
Severe Hemophilia ◽  
The United Kingdom ◽  
Potential Risk Factors ◽  
History Of ◽  
Previously Treated Patients ◽  
Adjusted Incidence

Abstract The age-adjusted incidence of new factor VIII inhibitors was analyzed in all United Kingdom patients with severe hemophilia A between 1990 and 2009. Three hundred fifteen new inhibitors were reported to the National Hemophilia Database in 2528 patients with severe hemophilia who were followed up for a median (interquartile range) of 12 (4-19) years. One hundred sixty (51%) of these arose in patients ≥ 5 years of age after a median (interquartile range) of 6 (4-11) years' follow-up. The incidence of new inhibitors was 64.29 per 1000 treatment-years in patients < 5 years of age and 5.31 per 1000 treatment-years at age 10-49 years, rising significantly (P = .01) to 10.49 per 1000 treatment-years in patients more than 60 years of age. Factor VIII inhibitors arise in patients with hemophilia A throughout life with a bimodal risk, being greatest in early childhood and in old age. HIV was associated with significantly fewer new inhibitors. The inhibitor incidence rate ratio in HIV-seropositive patients was 0.32 times that observed in HIV-seronegative patients (P < .001). Further study is required to explore the natural history of later-onset factor VIII inhibitors and to investigate other potential risk factors for inhibitor development in previously treated patients.

Target Joint Bleeding in Pediatric Patients with Hemophilia Α Receiving Twice Weekly Prophylaxis with a Pegylated Full-Length Recombinant Factor VIII with Extended Half-Life

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3778-3778
Author(s):  
Amy L. Dunn ◽  
Alexis A. Thompson ◽  
Werner Engl ◽  
Marlies Sharkhawy ◽  
Brigitt E. Abbuehl
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Pediatric Patients ◽  
Hemophilia A ◽  
Point Estimate ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
The Mean

Abstract Introduction: Patients with hemophilia A are at risk for acute bleeding which may affect muscles and other soft tissues but characteristically involves joints. Prophylaxis with factor VIII (FVIII) is the optimal treatment to prevent bleeding into joints and, when begun at a young age, may prevent arthropathy. BAX 8551, a polyethylene glycol (peg)ylated, full-length, recombinant FVIII built on ADVATE2, demonstrated extended half-life, efficacy, and safety for prophylaxis and treatment of bleeding in patients with severe hemophilia A. Methods: A phase 3, prospective, uncontrolled, multicenter study was performed in pediatric patients with severe hemophilia A without history of inhibitors. To be eligible, patients aged <6 years had to have ≥50, those aged 6 to <12 years ≥150 previous exposure days (EDs) to FVIII. Patients received twice weekly infusions of 50 ±10 IU/kg of BAX 855 over a period of 6 months or ≥50 EDs. The prevalence of target joints, defined as a single joint with ≥3 spontaneous bleeding episodes in any consecutive 6-month period, was assessed at baseline. Annualized rates of target joint bleeds and the course of target joints were evaluated by age (<6 and 6 to <12 years). The study was performed in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Results:Sixty-six patients were treated with a mean (SD) BAX 855 dose of 51.1 (5.5) IU/kg at a mean (SD) frequency of 1.8 (0.2) infusions/week. Fourteen of 66 patients (21.2%), 3/32 (9.4%) in the younger and 11/34 (32.4%) in the older cohort, had a total of 23 target joints at screening. The number of target joint bleeds decreased during a mean (SD) of 48.5 (7.7; median: 49.0) prophylactic EDs/patient. Five of 66 (7.6%) patients had at least 1 target joint bleed, 1/32 (3.1%) in the younger and 4/34 (11.8%) in the older cohort. The point estimate for the mean (95% CI) annualized rate of target joint bleeds was 0 (0 - infinity; median: 0) compared to an annualized rate of all joint bleeds of 1.1 (0.6 - 1.9; median: 0) and an annualized rate of all bleeds of 3.0 (2.2 - 4.2; median: 2.0) (Table 1). The point estimate for the mean (95% CI) annualized bleeding rate (ABR) in 52 patients without target joints was 2.9 (2.0 - 4.2; median: 2.0) and was similar in 14 patients with target joints at screening at 3.5 (1.9 - 6.6; median: 2.1). In the younger cohort, the ABR was lower in patients with than those without target joints. However, the number of patients <6 years with target joints (N = 3) was too small to draw any conclusions (Table 1). During BAX 855 prophylaxis, no new target joints developed in any patient. Ten of 14 patients had at least 1 target joint revert to a non-target joint. In 8 of these 10 patients, 4 with 1 and 4 with 2 target joints, all target joints resolved. Conclusions:These results suggest that twice weekly infusion of BAX 855 is effective in the prevention of bleeding into target joints and may revert target to non-target joints in pediatric patients with severe hemophilia A. 1BAX 855 (Baxalta US Inc., now part of Shire) is licensed in the US and Japan under the trade name ADYNOVATE. 2ADVATE is a trade mark of Baxalta US Inc., now part of Shire. Disclosures Dunn: NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Pfizer: Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta (now part of Shire): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Research Funding. Thompson:Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding. Engl:Shire: Employment, Equity Ownership. Sharkhawy:Baxalta (now part of Shire): Employment. Abbuehl:Baxalta (now part of Shire): Employment.

Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4693-4697 ◽  
Author(s):  
Samantha C. Gouw ◽  
Johanna G. van der Bom ◽  
Günter Auerswald ◽  
Carmen Escuriola Ettinghausen ◽  
Ulf Tedgård ◽  
...  
Keyword(s):  
Cohort Study ◽  
Factor Viii ◽  
Hemophilia A ◽  
High Titer ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Von Willebrand ◽  
Relationship Of ◽  
Viii Product

Abstract It has been suggested that plasma-derived factor VIII products induce fewer inhibitors than recombinant factor VIII products. We investigated the relationship of factor VIII product type and switching between factor VIII products with the risk to develop inhibitors. This multicenter retrospective cohort study included 316 patients with severe hemophilia A born between 1990 and 2000. The outcome was clinically relevant inhibitor development, defined as the occurrence of at least 2 positive inhibitor titers with decreased recovery. The risk of inhibitor development was not clearly lower in plasma-derived compared with recombinant factor VIII products (relative risk [RR], 0.8; 95% confidence interval [CI], 0.5-1.3). Among high-titer inhibitors, the possible reduction in risk was even less pronounced (RR, 0.9; CI, 0.5-1.5). Plasma-derived products with considerable quantities of von Willebrand factor (VWF) carried the same risk for inhibitor development as recombinant factor VIII products (RR, 1.0; CI, 0.6-1.6). Switching between factor VIII products did not increase the risk for inhibitors (RR, 1.1; CI, 0.6-1.8). In conclusion, our findings support neither the notion that plasma-derived factor VIII products with considerable concentrations of VWF confer a lower risk to develop inhibitory antibodies than recombinant factor VIII products, nor that switching between factor VIII product brands increases inhibitor risks in previously untreated patients with severe hemophilia A.

scholarly journals All-Cause and Inhibitor-Related Mortality in Non-Severe Hemophilia Α Patients in the United States

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 902-902 ◽  
Author(s):  
Ming Y. Lim ◽  
Dunlei Cheng ◽  
Christine L. Kempton ◽  
Nigel S. Key
Keyword(s):  
United States ◽  
At Risk ◽  
Mortality Rate ◽  
Hemophilia A ◽  
The United States ◽  
Severe Hemophilia ◽  
All Cause Mortality ◽  
Related Mortality ◽  
Observation Period

Introduction: The majority of published studies evaluating inhibitors have focused mainly on patients with severe hemophilia A. In non-severe hemophilia A (NSHA) patients, the development of inhibitors can have a profound clinical impact, with major bleeding complications similar to that of patients with severe or acquired hemophilia. Yet, epidemiological data on inhibitors in NSHA patients, specifically mortality, is scarce and currently limited to the European and Australian cohort [Eckhardt CL, et al. J Thromb Haemost. 2015 Jul;13(7):1217-251]. Objectives: To determine the all-cause and inhibitor-related mortality in NSHA patients in the United States using the ATHNdataset Methods: Subjects and study design The ATHNdataset is a 'limited dataset' as defined under the United States Health Insurance Portability and Accountability Act (HIPAA) to be free of protected health information, with data collection by more than 130 hemophilia treatment centers (HTC) across the United States. It includes patients with congenital bleeding disorders in the United States who have authorized the sharing of their demographic and clinical information for research. Data collection and definitions The ATHNdataset was queried on December 31, 2018 to extract the following information on NSHA patients: Patient demographics, inhibitor status, date of death, and primary cause of death. The presence of inhibitors was defined as: (i) ≥ 2 positive Bethesda inhibitor assay titers of ≥ 1.0 BU/mL; or (ii) a decrease in plasma FVIII coagulant activity (FVIII:C) to at least 50% of baseline activity and/or spontaneous bleeding symptoms in patients with inhibitor titers between 0.6 and 1.0 BU/mL. Patients who had a negative inhibitor history or have never been tested for FVIII inhibitors were classified as negative for inhibitors. Statistical analyses The person-year mortality rate was calculated as the ratio of the number of deaths to the number of person-years at risk, presented as rates per 1000 person-years. Person-years at risk was calculated for each patient as the time between the start of the observation period (January 1, 2010 or date of birth for patients who are born later) and the end of the observation period (date of death, loss-to follow-up or December 31, 2018). Patients who were deceased or lost to follow-up before January 1, 2010 were not included in the analysis. Inhibitor person-years at risk for inhibitor patients was calculated from January 1, 2010 if the first positive inhibitor test occurred prior to January 1, 2010 or from the date of the first positive inhibitor test that occurred during the observation period until the end of the observation period. Inhibitor-related death was attributed to all patients who had a positive inhibitor history. Mortality rates were compared between inhibitor and non-inhibitor patients using z- test. Results: Between 1/1/2010 and 12/31/2018, the ATHNdataset included 6,606 NSHA patients who were born between 1920 and 2018. Patients were observed for a total of 56,064 person-years. 85.57% (n = 5,653) of these patients were observed for the full nine years. The average follow-up time per patient was almost 8.5 years. Inhibitors developed in 171 (2.59%) NSHA patients. The median age for inhibitor development was 13 years (IQR, 6 - 37 years) and the mean age was 22 years. Demographics characteristics of the patients are listed in Table 1. All-cause mortality At the end of follow-up, there was a total of 136 deaths in the NSHA population, occurring at a median age of 63 years (IQR, 51 - 75 years). The overall all-cause mortality rate was 2.43 per 1,000 person-years (95% CI: 2.02 - 2.83). The most common primary cause of death was cancer (n=27, 19.9%) (Table 2). Inhibitor-related mortality Three deaths were associated with inhibitors. Inhibitor-related mortality rate was 2.40 per 1,000 person-years, whereas among the never inhibitor group, the mortality rate was 2.44 per 1,000 person-years (p = 0.790). Mortality risk ratio between inhibitor and never inhibitor was 0.98 (95% CI: 0.31 - 3.08). Conclusion: In NSHA patients, the development of inhibitors occurred at a relatively early age and was not associated with increased mortality. Disclosures Kempton: Novo Nordisk: Research Funding; Octapharma: Honoraria; Genentech: Honoraria; Spark Therapeutics: Honoraria. Key:Uniqure BV: Research Funding.

scholarly journals Aggressive Neuroblastoma in a Pediatric Patient with Severe Hemophilia A

2021 ◽  
Vol 13 (1) ◽  
pp. 125-130
Author(s):  
Lidia Costa ◽  
Maria Eduarda Couto ◽  
Juliana Moutinho ◽  
Ana Maia Ferreira ◽  
Emilia Costa ◽  
...  
Keyword(s):  
Pediatric Patient ◽  
Rare Case ◽  
Pediatric Patients ◽  
Hemophilia A ◽  
Negative Impact ◽  
Severe Hemophilia ◽  
Hemorrhagic Complications ◽  
Extensive Information

Despite the extensive information regarding hemophilia’s hemorrhagic complications, the literature on cancer in hemophilia is scarce, especially in pediatric patients. Many uncertainties remain concerning diagnosis and workup. We report a rare case of two severe diseases (neuroblastoma and hemophilia A (HA)) concomitantly present in the same pediatric patient. We highlight that the diagnosis of severe HA did not have a negative impact on the patient’s oncologic course. This case also illustrates the significance of the cooperation among different specialties and hospitals when caring for the same patient.

Pharmacokinetic study of Kovaltry in thirty‐five pediatric patients aged <12 years with severe hemophilia A

Haemophilia ◽  
2021 ◽  
Author(s):  
Kun Huang ◽  
Yingzi Zhen ◽  
Gang Li ◽  
Xinyi Wu ◽  
Runhui Wu ◽  
...  
Keyword(s):  
Pharmacokinetic Study ◽  
Pediatric Patients ◽  
Hemophilia A ◽  
Severe Hemophilia

scholarly journals Every 2 Weeks or Every 4 Weeks Subcutaneous Injection of Emicizumab in Pediatric Patients with Severe Hemophilia A without Inhibitors: A Multi-Center, Open-Label Study in Japan (HOHOEMI Study)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1186-1186 ◽  
Author(s):  
Midori Shima ◽  
Keiji Nogami ◽  
Sayaka Nagami ◽  
Seitaro Yoshida ◽  
Koichiro Yoneyama ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Interim Analysis ◽  
Research Funding ◽  
Pediatric Patients ◽  
Hemophilia A ◽  
Bispecific Antibodies ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Favorable Safety ◽  
Cutoff Date

Abstract Introduction: Emicizumab is a novel, subcutaneously injectable, recombinant humanized bispecific monoclonal antibody which mimics the function of activated coagulation factor VIII. Due to its mechanism of action and lack of sequence homology, emicizumab is not expected to induce or be affected by anti-factor VIII (FVIII) antibodies (inhibitors). Emicizumab once-weekly dosing has been approved for hemophilia A patients with inhibitors of all ages in several countries. A clinically meaningful prophylactic effect and favorable safety of emicizumab given every 2 weeks (Q2W) and every 4 weeks (Q4W) in adult/adolescent patients has been demonstrate in HAVEN3 study (NCT02847637) and HAVEN4 study (NCT03020160). This is the first report to assess emicizumab prophylaxis in pediatric patients without inhibitors including a patient previously untreated with FVIII. Methods: The present study (JapicCTI-173710) enrolled Japanese patients aged <12 years with hemophilia A without inhibitors. Patients received a loading dose of 3 mg/kg weekly for the first 4 doses, followed by a maintenance dose of 3 mg/kg Q2W or 6 mg/kg Q4W. This interim analysis was performed after at least 6 patients in each dosing cohort had completed at least 12 weeks of treatment with emicizumab prophylaxis. Results: A total of 13 male patients were enrolled in 2 cohorts. The numbers of patients aged 0 - < 2, 2 - < 6, and 6 - < 12 years were 1, 2, and 3 in the Q2W cohort and 2, 2, and 3 in the Q4W cohort. All patients had been previously treated with FVIII prophylaxis except for 1 patient aged 4 months in the Q4W cohort who was previously untreated. As of the data cutoff date of March 14, 2018, the medians (range) of treatment duration were 21 (18.3 - 22.1) and 16 (4.3 - 16.6) weeks in the Q2W and Q4W cohorts, respectively. The interim analysis results showed a clinically meaningful effect of emicizumab prophylaxis with the Q2W and Q4W regimens. As of the data cutoff date, 3/6 patients in the Q2W cohort and 5/7 patients including 1 patient previously untreated with FVIII in the Q4W cohort experienced no treated bleeds. There were no treated spontaneous bleeds and a total of 6 treated bleeds were traumatic. Two out of them were treated joint bleeds. Model-based annualized bleeding rates for treated bleeds with FVIII products under emicizumab prophylaxis were 1.6 (95% CI, 0.60 to 4.25) and 1.0 (95% CI, 0.25 to 4.06) in the Q2W and Q4W cohorts, respectively. All 13 patients experienced at least 1 adverse event (AE) and a total of 78 AEs were reported. There were no AEs that were grade 3 or higher, serious, led to withdrawal from treatment, or resulted in dose modification or interruption. None of the AEs were considered related to emicizumab. Neither thromboembolic events, thrombotic microangiopathy, systemic hypersensitivity reactions, nor local injection site reactions were reported. The most frequent AEs were contusion in 10 (76.9%) patients, excoriation and nasopharyngitis in 4 (30.8%) patients each, and ligament sprain and influenza in 3 (23.1%) patients each. The emicizumab exposures observed in this study were within the observed variability in preceding studies. No effects of age or body weight on emicizumab exposure were evident. Conclusions: This interim analysis results suggested clinically meaningful efficacy and favorable safety of the emicizumab Q2W and Q4W regimens in patients aged <12 years with severe hemophilia A without inhibitors. This suggests that it should be appropriate to apply the same dosing regimens of emicizumab for pediatric patients without inhibitors and other patient populations of hemophilia A. The updated results of primary analysis after completing at least 24 weeks on emicizumab treatment will be presented at the meeting. Disclosures Shima: Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees. Nogami:Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau. Nagami:Chugai Pharmaceutical Co., Ltd: Employment, Equity Ownership. Yoshida:Chugai Pharmaceutical Co., Ltd: Employment. Yoneyama:Chugai Pharmaceutical Co., Ltd: Employment, Patents & Royalties: Anti-FIXa/X bispecific antibodies . Ishiguro:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Suzuki:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Taki:Chugai Pharmaceutical Co., Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4648-4654 ◽  
Author(s):  
Samantha C. Gouw ◽  
Johanna G. van der Bom ◽  
H. Marijke van den Berg
Keyword(s):  
Cohort Study ◽  
Neutralizing Antibodies ◽  
Hemophilia A ◽  
High Titer ◽  
Early Age ◽  
Severe Hemophilia ◽  
Concerted Action ◽  
Inhibitor Development ◽  
Related Risk ◽  
The Relationship

Abstract The CANAL Study (Concerted Action on Neutralizing Antibodies in severe hemophilia A) was designed to describe the relationship between treatment characteristics and inhibitor development in previously untreated patients with severe hemophilia A. This multicenter retrospective cohort study investigated 366 consecutive patients born between 1990 and 2000. The outcome was clinically relevant inhibitor development, defined as the occurrence of at least 2 positive inhibitor titers combined with a decreased recovery. Eighty-seven (24%) patients developed inhibitors (69 high titer [19%]). The incidence of inhibitors appeared to be associated with age at first treatment, decreasing from 41% for those treated within the first month of age to 18% in those treated after 18 months; after adjustment for treatment intensity, this association largely disappeared. Surgical procedures and peak treatment moments at start of treatment increased inhibitor risk (relative risk [RR], 3.7; 95% confidence interval [CI], 2.0-7.1; and RR, 3.3; CI, 2.1-5.3, respectively). Regular prophylaxis was associated with a 60% lower risk than on-demand treatment (RR, 0.4; CI, 0.2-0.8). Our findings suggest that the previously reported associated between an early age at first exposure and the risk of inhibitor development is largely explained by early, intensive treatment. The latter appears to be an independent risk factor for inhibitor development. In addition, early, regular prophylaxis may protect patients with hemophilia against the development of inhibitors.

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