Recombinant factor XIII prophylaxis is safe and effective in young children with congenital factor XIII-A deficiency: international phase 3b trial results.

Essentials Prophylaxis is the standard of care for congenital factor XIII-A (FXIII-A) deficiency. Six children with FXIII-A deficiency received once-monthly prophylaxis with recombinant FXIII-A. Prophylaxis was well tolerated and no anti-FXIII antibodies were detected. Prophylaxis was effective with an annualized bleeding rate of zero. SUMMARY: Background Factor XIII deficiency is a rare, severe congenital bleeding disorder. Monthly prophylaxis with recombinant FXIII A-Subunit (rFXIII) has demonstrated favorable safety and efficacy in patients aged ≥ 6 years, and may similarly benefit younger children. Objective To evaluate the long-term safety and efficacy of rFXIII in children aged < 6 years with congenital FXIII A-subunit deficiency. Patients/methods Six children, who had previously completed a single-dose pharmacokinetic trial of rFXIII, received 35 IU kg-1 rFXIII every 28 days (± 2 days) for a minimum of 52 weeks, and were evaluated for bleeding and adverse events. The Berichrom FXIII activity assay was used to monitor FXIII activity. Results The children, three girls and three boys, had an average age of 3.0 years (range: 1-4 years) at enrollment. The total treatment duration was 1.8-3.5 years, giving a total of 16.6 patient-years. No antibody development, thromboembolic events or allergic reactions occurred. There were 93 mild and seven moderate adverse events. Two adverse events (lymphopenia and gastroenteritis) were reported as probably or possibly related to rFXIII in two children. Two serious adverse events, unrelated to rFXIII, were reported in a single child, each related to head injury, and neither resulting in intracranial hemorrhage. The geometric mean FXIII activity trough was 0.19 IU mL-1 . No bleeding episodes requiring treatment with an FXIII-containing hemostatic agent occurred during the trial; thus, the annualized bleeding rate was 0. Conclusions Consistent with data from older age groups, prophylaxis with rFXIII appears to be safe and effective in young children with congenital FXIII A-subunit deficiency.

Pharmacokinetic characterization of recombinant factor XIII (FXIII)-A2 across age groups in patients with FXIII A-subunit congenital deficiency.

Three trials investigated the pharmacokinetics (PK) of recombinant factor XIII (rFXIII) A-subunit. To compare the PK characteristics of rFXIII among trials and different age groups of patients. Dosing with rFXIII 35 IU kg(-1) every 4th week. Blood samples for PK assessments were collected regularly throughout the dosing interval from a total of 68 individual patients with FXIII congenital deficiency. The mean PK parameters were similar across the three age groups, and for the three trials, as well as constant over time based on results from patients participating in both mentor 1 and mentor 2 trials. The geometric mean half-life ranged from 11.6 to 15.0 days, and the trough FXIII activity levels ranged from 0.15 to 0.21 IU mL(-1) . The population PK model identified body weight as a statistically significant covariate influencing clearance (CL) and volume of distribution (Vd ), with a similar increase in both parameters with increased body weight. The half-life was not affected by body weight. Gender (females vs. males) and age category (paediatric vs. adult) did not affect CL. The PK profile of rFXIII, after dosing with 35 IU kg(-1) of rFXIII, was independent of age and comparable between trials and FXIII trough activity levels were constant. Despite rather large individual variation in the maximal FXIII activity levels, all individual mean trough activity levels were above 0.1 IU mL(-1) during the entire duration of the trials. The results support that monthly dosing with 35 IU kg(-1) of rFXIII to patients with FXIII A-subunit deficiency, regardless of age, is adequate for prophylaxis.

The PFA-100 ® does not predict delta-granule platelet storage pool deficiencies.

There are no published reports investigating the ability of the platelet function analyzer (PFA-100(®) ) to detect the presence of delta-granule platelet storage pool deficiencies (δ-PSPD), a common mild bleeding disorder. Prior studies of the PFA-100(®) and congenital platelet disorders have been limited by small numbers of patients with a variety of disorders. We examined PFA-100(®) results in a large paediatric patient population diagnosed specifically with δ-PSPD, and determined the relationship between PFA-100(®) and platelet electron microscopy (the gold standard for diagnosis). This study is a retrospective review of patients <19 years of age diagnosed with δ-PSPD at Nationwide Children's Hospital from 2008 to 2010. To examine the correlation between PFA-100(®) and average number of granules per platelet we used Spearman's Rho as a non-parametric measure of dependence. A total of 105 patients diagnosed with δ-PSPD were included, of which 99 patients underwent PFA-100(®) testing. Of those tested 46% had at least one abnormal closure time, whereas 16% had abnormal results for both cartridges. We found no statistical correlation between C-EPI closure time and average number of granules per platelet (ρ= -0.0095, P-value = 0.9328), nor between C-ADP closure time and the average number of granules (ρ = 0.0315, P-value = 0.7798). The PFA-100(®), a widely used screening test for suspected bleeding disorders, did not correlate with presence or severity of δ-PSPD as determined by platelet electron microscopy. When evaluating patients with suspected bleeding disorders, PFA-100(®) alone cannot be used to rule out the presence of a δ-PSPD.