Similar bleeding phenotype in young children with haemophilia A or B: a cohort study

The bleeding phenotype has been suggested to differ between haemophilia A and B. More knowledge on the bleeding phenotype at initiation of treatment is important to optimize patient care. The aim of this study was to investigate the severity of the bleeding phenotype and the variation in bleeding in children with severe or moderate haemophilia A and B. Consecutive, previously untreated patients with severe or moderate haemophilia A and B (factor VIII or IX activity <0.01 or 0.01–0.05 IU mL^?1 respectively) born between January 1st 2000 and January 1st 2010 were included. Primary outcome was severity of bleeding tendency. Secondary outcome was variation in bleeding pattern. A total of 582 patients with severe haemophilia A and 76 with severe haemophilia B did not differ in age at first exposure to clotting factor (0.81 vs. 0.88 years, P = 0.20), age at first bleed (0.82 vs. 0.88 years, P = 0.36), and age at first joint bleed (1.18 vs. 1.20 years, P = 0.59). Patients with moderate haemophilia were older compared to patients with severe haemophilia. In patients with moderate haemophilia there were no clear differences between haemophilia A and B. Severity and variation in bleeding phenotype are similar during the early stage of treatment in patients with severe and moderate haemophilia A and B respectively. The findings imply that children with haemophilia B should be observed and treated as vigilantly as those with haemophilia A.     

Break‐through bleeding in relation to pharmacokinetics of Factor VIII in paediatric patients with severe haemophilia A

Introduction

As the pharmacokinetics (PK) of factor VIII (FVIII) is individualized in children with haemophilia A (HA), PK parameters may be indicators of patients' bleeding phenotype and instruction for their personalized replacement program.

Aim

The aim of this study was to investigate the possible relationship between PK/FVIII level and bleeding frequency in Chinese paediatric patients with severe (HA).

Methods

A total of 24 patients were enrolled in Beijing Children's Hospital from February to October 2015, all of whom were given 50 IU/kg of FVIII concentrates after a 72‐hours washout period. Samples' activities (FVIII:C) were tested at 5 time points, using WinNonlin software for PK testing, and then the individual half‐life(t_1/2) and the time (h) of FVIII concentrations <1 IU/dL within a week during prophylaxis were calculated. Baseline and the annual bleeding rate (ABR), annual joint bleeding rate (AJBR) were recorded and analyzed.

Results

The mean t_1/2 of FVIII was 10.20 ± 2.72 hours and the mean time of FVIII <1 IU/dL in 1 week was 44.7 hours (?38.56 to 102.33 hours). A significant relationship between t_1/2 of FVIII and ABR₀/AJBR₀ (baseline bleeding) was found (R² = 0.75 and 0.62, P < .001). Besides, baseline and the annual bleeding rate during prophylactic treatment of haemophilia had a positive correlation with the time (hours) of FVIII <1 IU/dL in 1 week (R² = 0.67 and 0.52, P < .001).

Conclusion

t_1/2 was an important indicator to prevent bleeding in severe HA; the frequency of bleeding will be reduced with the increased of t_1/2 of FVIII. The data also demonstrates that increasing the time with a FVIII<1 IU/dL is associated with an increased rate of bleeding during prophylaxis.     

Lifelong prophylaxis in a large cohort of adult patients with severe haemophilia: a beneficial effect on orthopaedic outcome and quality of life

Background: In the 1950s, Sweden initiated prophylaxis as a lifelong treatment for haemophilia. It was the first country to do so. Objectives: To describe and evaluate dosing and outcome of prophylactic treatment in a large cohort of adult people with severe haemophilia who have been using prophylaxis most of their lives. Methods: Eighty‐one patients born between 1932 and1992 were divided into two groups (Group A started prophylaxis at the age of ≤ 3 yr; Group B at three or more years of age) and evaluated retrospectively. Outcome was evaluated using the Hemophilia Joint Health Score (HJHS) and SF‐36, a measure of quality of life. Results: The median number of joint bleeds per year was 0 in both study groups; however, the annual number of joint bleeds during the final 3 yr of observation was higher in group B than in group A (P < 0.006). Twenty‐five of 30 patients in group A and 27/51 patients in group B had no joint bleeds in that period. Group A had significantly better joint outcomes than group B. Patients in group A experienced better physical and social health than those in group B. Conclusions: This follow‐up has provided for the first time more extensive and detailed information regarding the practice of prophylactic treatment in a large cohort of adults with severe haemophilia. The present study confirms that early start of prophylaxis continuing throughout the lifespan has been successful in virtually eliminating joint bleeds, preserving a close to normal joint status, and keeping patients healthy and able to live normal lives.     

Goal Attainment Scaling for haemophilia (GAS‐Hēm): testing the feasibility of a new patient‐centric outcome measure in people with haemophilia

Introduction

To address the need for a patient‐reported outcome that can measure clinically and personally meaningful change in people with haemophilia (PwH) on prophylaxis, an approach based on Goal Attainment Scaling (GAS) was developed: the GAS‐Hēm.

Aim

To establish real‐world feasibility of GAS‐Hēm in PwH.

Methods

Patients aged 5‐65 years were enroled from four North American centres for a 12‐week study. The primary outcome was the proportion of participants who completed GAS‐Hēm interviews at baseline, 6 and 12 weeks. GAS‐Hēm scores were obtained by subject‐ and clinician‐rated goal attainment at Weeks 6 and 12, and compared with quality of life (QoL) measures and annualized bleed rate (ABR) for construct validity. Goals were evaluated qualitatively for content validity. Responsiveness was calculated using standardized response means (SRM).

Results

Forty‐two participants set 63 goals. Participants preferred to define (37/63) their own goals or further individualize (23/63) from the GAS‐Hēm menu. Thirty of the 37 self‐defined goals were matched to goals on the GAS‐Hēm menu. The most common goal areas were: weight, exercise and nutrition (n = 17); leisure activities (n = 8); and joint problems (n = 7). Both participant‐ and clinician‐rated GAS‐Hēm scores at 6 weeks (n = 40) and 12 weeks (n = 41) demonstrated satisfactory goal attainment (SRM [subject‐rated] at 12 weeks for adult and paediatric groups was 1.25 and 1.16, respectively). Correlations of GAS‐Hēm scores with QoL measures and ABR were uniformly small.

Conclusion

GAS‐Hēm was feasible and tapped constructs not captured by ABR or QoL measures.     

Trends in bleeding patterns during prophylaxis for severe haemophilia: observations from a series of prospective clinical trials

Summary. Replacement therapy or prophylaxis, has become the standard of care for the treatment of severe haemophilia A. To describe bleeding patterns in children, adolescents and adults on prophylaxis and their observed relationships to times of infusion (during the week and during the day) as well as season of the year. Data from Advate pre‐licensure prospective clinical trials from 145 patients with factor VIII (FVIII) <1%, were used. All patients underwent a 48‐h pharmacokinetic study. The 10–65 year group had ≥75 exposure days on fixed prophylaxis (25–40 IU kg^?1 3–4x per week). Prophylaxis was not fixed but similar for 1–6 year olds. Bleeding patterns were analysed. Overall, 700 bleeds were observed in 110/145 patients. All were treated with prophylaxis, mean dose 108 IU kg^?1 week^?1 in on average 2.9 infusions (1–6 years), 86 IU kg ^?1week^?1 in 2.7 infusions (10–17 years),and 75 IU kg ^?1week^?1 in 2.6 infusions (18–65 years), respectively. On prophylaxis, median total bleeds per year were low at 3.1 for patients aged 1–6 years, 3.3 for those aged 10–17 years and 2.1 for patients aged 18–65 years. Patients aged 1–6 years had predominantly soft tissue bleeds (79%). Incidence of joint bleeding was not associated with season, but was significantly lower in patients who infused FVIII in the mornings: median 0 per year (IQR 0.0–0.4) compared to those who infused later [median 1.8 per year (IQR 0.0–5.2)]. Older patients predominantly experienced joint bleeds (50% and 62%, respectively). More joint bleeds occurred during the summer [43 and 46% respectively, (P < 0.01)]. Bleeding patterns in patients on prophylaxis varied according to age. In addition, the 10–65 year olds showed increased bleeding during the summer. After confirmation in prospective studies, this information may be used to improve tailoring of prophylactic treatment.     

A sensitive venous bleeding model in haemophilia A mice: effects of two recombinant FVIII products (N8 and Advate®)

Summary. Haemostatic effect of compounds for treating haemophilia can be evaluated in various bleeding models in haemophilic mice. However, the doses of factor VIII (FVIII) for normalizing bleeding used in some of these models are reported to be relatively high. The aim of this study was to establish a sensitive venous bleeding model in FVIII knock out (F8‐KO) mice, with the ability to detect effect on bleeding at low plasma FVIII concentrations. We studied the effect of two recombinant FVIII products, N8 and Advate^®, after injury to the saphenous vein. We found that F8‐KO mice treated with increasing doses of either N8 or Advate^® showed a dose‐dependent increase in the number of clot formations and a reduction in both average and maximum bleeding time, as well as in average blood loss. For both compounds, significant effect was found at doses as low as 5 IU kg^?1 when compared with vehicle‐treated F8‐KO mice. Normalization of maximum bleeding time was found at doses equal to or above 10 IU kg^?1 N8 or Advate^®, corresponding to plasma concentrations of approximately 10% of the level in wild type mice. The present study adds a new model to the armamentarium of bleeding models used for evaluation of pro‐coagulant compounds for treatment of haemophilia. Interestingly, the vena saphena model proved to be sensitive towards FVIII in plasma levels that approach the levels preventing bleeding in haemophilia patients, and may, thus, in particular be valuable for testing of new long‐acting variants of e.g. FVIII that are intended for prophylaxis.