Major Impact of Underweight and Overweight On Factor VIII Dosing in 201 Patients with Severe Haemophilia A Treated with Advate, Kogenate or Refacto AF/Xyntha
Authors: Severine Henrard , Niko Speybroeck , Hermans Cedric R. 
Published: October 2019

Abstract
Abstract 626

Introduction:
The treatment of hemophilia A (HA) requires infusions of factor VIII (FVIII) concentrates. The number of FVIII units infused in order to obtain a specific circulating FVIII level is calculated with the formula: [body weight (BW) (kg) × desired FVIII increase (%)]/2, with the assumption that each unit of FVIII infused per kg of BW increases the circulating FVIII level by 2 %. The aim of the present study was to evaluate the impact of several morphometrical parameters (BW, body mass index (BMI), fat mass index (FMI), difference between BW and ideal BW, height), age and type of coagulation factor concentrate on the FVIII recovery in a large group of patients with severe haemophilia who had previously taken part in pharmacokinetic studies using Advate®, Kogenate FS® or ReFacto AF/Xyntha®.

Methods:
A total of 201 adults (> 18 yr) with severe HA carefully selected from 8 clinical trials using three recombinant FVIII concentrates were included in the analysis (Fig. 1). The FVIII recovery was calculated using the maximum FVIII concentration measured at 15 or 30 minutes after infusion. Regression tree (RT) was used to identify predictors of FVIII recovery. RT-based models are non-linear and non-parametric alternatives to linear models for regression problems. Continuous variables were compared using the Kruskal-Wallis test.

Results:
The median FVIII recovery was 2.16 for all patients and was significantly different between the 3 coagulation factor groups in univariate analysis. However, the BW, difference between BW and IBW, BMI and FMI were also significantly different between coagulation factor groups. In multivariate analysis, 5 groups were created by RT (Fig. 2 and Fig. 3): patients with a BMI < 20.3 kg/m2 (Group 2; Median FVIII recovery: 1.60), patients with a BMI between 20.3 and 29.5 kg/m2 (Group 4; Median FVIII recovery: 2.14) and patients with a BMI ≥ 29.6 kg/m2 (Group 5; Median FVIII recovery: 2.70). Group 1 and group 3 were made up of 2 outlier patients. The FVIII recovery was significantly different between group 2, group 4 and group 5 (P<0.001) (Fig. 2 and Fig. 3). The random forest associated with this RT shows that the age and the type of coagulation factor concentrate had no influence on FVIII recovery.

Conclusions:
The type of coagulation factor concentrate first emerged as a univariate predictor of FVIII recovery in our study. It later appeared to have no influence in the multivariate model, as opposed to the BMI which emerged as the strongest predictor of FVIII recovery. These results are consistent with previous crossover studies which have demonstrated comparable FVIII recovery of different concentrates (Haemophilia 2007;13:124–30, Haemophilia 2009;15(4):869–80). Our findings also support that dose calculation of FVIII to reach a specific FVIII target level should be adapted in underweight and overweight patients. Taking the ideal BW instead of the actual BW in the dose calculation should be implemented since only a small fraction of FVIII distributes outside the vascular system.

Disclosures:
No relevant conflicts of interest to declare.