ALBERT

Description: This systematic review was designed to provide more precise effect estimates of inhibitor development for the various types of F8 gene mutations in patients with severe hemophilia A. The primary outcome was inhibitor development and the secondary outcome was high-titer-inhibitor development. A systematic literature search was performed to include cohort studies published in peer-reviewed journals with data on inhibitor incidences in the various F8 gene mutation types and a mutation detection rate of at least 80%. Pooled odds ratios (ORs) of inhibitor development for different types of F8 gene mutations were calculated with intron 22 inversion as the reference. Data were included from 30 studies on 5383 patients, including 1029 inhibitor patients. The inhibitor risk in large deletions and nonsense mutations was higher than in intron 22 inversions (pooled OR = 3.6, 95% confidence interval [95% CI], 2.3-5.7 and OR = 1.4, 95% CI, 1.1-1.8, respectively), the risk in intron 1 inversions and splice-site mutations was equal (pooled OR = 0.9; 95% CI, 0.6-1.5 and OR = 1.0; 95% CI, 0.6-1.5), and the risk in small deletions/insertions and missense mutations was lower (pooled OR = 0.5; 95% CI, 0.4-0.6 and OR = 0.3; 95% CI, 0.2-0.4, respectively). The relative risks for developing high titer inhibitors were similar.

Description: Introduction Inhibitors are considered to be the most serious complication of clotting factor concentrate (CFC) therapy in hemophilia. The incidence of inhibitors in PTPs with severe hemophilia is very low (∼ 1 per 1,000 patient years). Four cases of PTP inhibitors that developed during hospital admissions were observed at the University of North Carolina over a 14-month period during 2011 – 2012. Due to concern about the possible role of the CFC used during hospitalization, further investigation by the CDC was requested. Methods A review of hemophilia-related hospital practices and procedures, along with a medical record review of admissions from January 2008 – November 2012 was conducted to: 1) compare inhibitor incidence trends in the time periods before and after January 2011; and 2) assess patient risk factors and evaluate hospital practices relative to inhibitor occurrence. A case was a person who developed an inhibitor during a hospital admission and non-cases were inpatients with no history of inhibitor development. The prevalence of inhibitor risk factors were compared between cases and non-cases and across time periods. Unadjusted odds ratios were used to compare the prevalence of exposures between cases and non-cases and comparisons of means of continuous risk factors used parametric and non-parametric tests as appropriate. Results A check of the FDA's Adverse Event Reporting System (FAERS) revealed no identified problems of the CFC in question. The medical record review revealed 134 admissions in 49 patients (59 in period 1 and 75 in period 2) during the 5-year period (see Figure). No other cases were found during the review; however, one of the index cases was found to have developed the inhibitor as an outpatient leaving 3 cases and 45 non-cases for study. The cases ranged in age from 23 – 69 years. One had severe and one had moderate hemophilia A, while the third case had combined factor V-VIII deficiency with FV and FVIII levels of 7% and 10%, respectively. Compared to non-cases, cases had elevated odds of: an infection (OR, 95% CL=4.4, 0.3–53), continuous factor infusion (CI) (4.2, 0.04–6.4), at least one non-surgical procedure (3.9, 0.1–80.5), and used the only hospital-available CFC (2.7, 0.1–73) during the admission and a product switch prior to admission (3.5, 0.1–105) and a family history of hemophilia (2.4, 0.1–51). In addition, cases had more hospital admissions (mean 6.6 vs. 2.4, p = 0.002) and more total hospital days (mean 39.6 days vs. 14.8 days. p = 0.05) than non-cases. Finally, cases received a greater total dose of CFC than non-cases (mean 101 IU/kg vs. 69 IU/kg, p = 0.003) during admission. Two hospital practices changed in period two: 1) the method of preparation and administration of CI involved less diluent and, therefore, a more concentrated infusion solution; and 2) the hospital pharmacy stocked only one brand of CFC in period 2 whereas several brands were available in period 1. The latter change increased the proportion of inpatients using a different product than that used as an outpatient (i.e., product switch) during period 2. Compared to inpatients admitted during period 1, those in period 2 were: more likely to receive the only available CFC and to have a product switch during the admission (p 〈 0.001). No difference between time periods was seen in the proportion of patients administered CI (58.8% vs. 56.9%) or who were tested for an inhibitor during admission (25% vs. 22%). Conclusions The investigation results support an increase in incidence of inhibitors among inpatients during period 2 compared to period 1, however, the number of cases was small. Nonetheless, because inhibitors are rare in PTPs, the occurrence of 3 cases in a 14-month period after a 3-year time span with no cases is highly suggestive of an actual increase in occurrence. The apparent increase was unlikely due to enhanced surveillance since rates of inhibitor testing during the two time periods were similar. While the odds ratios for some of the risk factors were elevated, the confidence limits were wide indicative of the lack of study power. Although there was no clear indication of a preventable inciting factor and more investigation is needed, the investigation revealed that this inhibitor cluster occurred in patients who had many complications that required lengthy hospitalizations and intense treatment with CFCs, contributing factors that should be considered in future management of hemophilia patients. Disclosures: No relevant conflicts of interest to declare.

Description: Objective While hemarthrosis contributes to morbidity in males with Hemophilia, less is known about joint destruction in females with FVIII deficiency. Our hypothesis was that females with FVIII deficiency enrolled in the Universal Data Collection (UDC) project had a reduced mean overall joint range of motion (ROM) compared to historic controls from the Normal Joint Study. Methods We employed a cross-sectional study design utilizing the UDC dataset. The overall joint ROM was the sum of the right and left ROM measurements of the five joints (hip, ankle, elbow, knee, shoulder) for the females with FVIII deficiency from the UDC and for healthy females without the deficiency 2-69 years of age from the Normal Joint Study. Females that were very obese (BMI 〉35) were excluded from the Normal Joint Study thus they were excluded from the UDC cohort. Mean overall joint ROM between affected and normal females was assessed for statistical difference using the non-parametric Wilcoxon-rank-sum test. Results were displayed as mean overall ROM with 95% confidence interval (CI) and p-value by age group and factor deficiency. Multivariate linear regression was performed using the General Linear Model (GLM) procedure with the overall joint ROM as the dependent variable and the clinical hemophilia severity as the independent variable adjusting for age, race, body mass index (BMI) and number of joint bleeds reported over the last six months. Summary A total of 522 females were identified with FVIII deficiency; 28% (144/522) of females were removed because of inability to assign factor deficiency type and 14% (75/522) of females were removed due to being very obese (BMI〉35) or outside the age range studied in the Normal Joint Study. Final analysis was performed on 303 females with FVIII deficiency between the ages of 2-69 years for comparison to the control group. As FVIII activity decreased, the mean overall joint range of motion became reduced and in most cases was significantly lower than that of the controls (see table 1). In FVIII deficient females there was a significant (p〈 0.0001) correlation between Hemophilia severity and mean overall joint ROM. Furthermore, using multivariate linear regression analysis, stratifying by age and clinical hemophilia severity and controlling for BMI and race, females with severe (5% and