Internal and External Determinants of Bleeding Patterns on Prophylaxis for Severe Haemophilia A.
Authors: Fischer Kathelijn , Collins Peter , Astermark Jan , Blanchette Victor S. , Bjorkman Sven , Oh Myungshin , Schroth Phillip , Fritsch Sandor , Casey Kathleen M. , Spotts Gerald , Ewenstein Bruce M. 
Published: October 2019

Abstract
To optimise bleeding control in severe haemophiliacs on prophylaxis, treatment should be individualised, considering patient-related and external determinants. Independent effects of both determinants were assessed using data from Advate pre-licensure trials. Data from 148 patients with FVIII<1% were analysed. All had a 48-hr PK study and were followed prospectively on prophylaxis. The 10–65y group was treated for 75 exposure days on fixed prophylaxis (25–40 IU/kg 3–4 times/wk), after which prophylaxis could be modified. Prophylaxis was not fixed for the 1-6y group. Bleeds defined as events requiring FVIII. Seasonal bleeding rate adjusted for age and time with FVIII activity <1%, as well as age and adherence to frequency of infusions, was analysed by multivariate regression with a negative binomial model. Median total annual bleed rates were 3.1, 3.3, and 2.1 for children, adolescents, and adults. 740 bleeds in 76 subjects (10–65y) on standard prophylaxis and 39 subjects (1–6y) on any prophylaxis were analysed (table). Median prophylactic dose varied with age (100 to 83 IU/kg/wk) with a mean of 2.8 infusions/wk. Adherence to prophylactic dose was high and did not differ among age groups. Adherence to frequency was lower in older patients (p < 0.004). Half-life was shorter and weekly time below 1% was highest in the 1–6y group. Bleeding rates on prophylaxis were low. Bleeding patterns and determinants varied according to age. Patients 1–6y had predominantly soft tissue bleeds. Bleeding was dependent on adherence to frequency of infusions or time below 1% FVIII. Bleeding was not dependent on season adjusted for either of these two factors. Patients aged 10–65y predominantly experienced joint bleeds. Bleeding was dependent on adherence to frequency of infusions or time below 1% FVIII. Bleeding adjusted for adherence to frequency of dose or time below 1% FVIII was different for season (p <0.0032). Bleeding rate appeared to be higher in the summer, lower in the winter, and most likely represents variation in physical activity during these times. Bleeding patterns vary according to age, even with prophylaxis. Breakthrough bleeding in patients aged 1–6y was dependent on time < 1% FVIII and adherence, but not season. The apparent effects of season, time below 1% FVIII activity, and adherence to frequency of infusions in patients 10–65y support the need for individual tailoring of prophylaxis according to activity and bleeding pattern (external factors) as well as the internal factor of pharmacokinetics.
1–6y 10–17y 18–65y N=39 N=39 N=37 |------------- Median (P25, P75) ----------------| Follow up (days) 396 (269, 455) 294 (265, 336) 305 (268, 341) Adherence to prophylactic dose (% of infusions) 100 (75,100) 99 (81,100) 99 (89,100) Adherence to frequency of prophylaxis (% of time) 86 (70,98) 78 (62,83) 70 (50,87) FVIII half life (hrs) 9.3 (8.0,10.7) 10.4 (9.3,12.4) 11.6 (10.4,13.6) Time below 1% FVIII (hrs/wk) 29 (8,45) 20 (9,30) 12(6,26) Joint bleeds (%) 0 (0,33) 50 (14,88) 72 (24,100) Bleeds in Jun–Aug (%) 25 (0,44) 29 (0,50) 33 (8,55)