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.

Effect of in vivo administration of all trans-retinoic acid on the hemopoietic cell populations of the spleen and bone marrow: profound strain differences between A/J and C57BL/6J mice.

All trans-retinoic acid (ATRA) is currently the subject of much interest as a possible anti-tumor therapeutic agent, especially for leukemias. One postulated mechanism for its ameliorative action on tumor growth is via stimulating cells of the immune system and its accessory cells. Mice of the A/J strain have an unusually high frequency of leukemia, whereas C57BL/6J mice rarely develop leukemia, and moreover, unlike A/J mice, have strong resistance to a variety of pathogens. The purpose of the study reported here was twofold: to investigate whether A/J mice have quantitative deficiencies in their specific and nonspecific disease defense mechanisms (lymphoid, granuloid, and monocytoid cells) relative to those of C57BL/6J mice, and if so, whether in vivo administration of an ATRA could quantitatively augment these cells in the major organs housing them: the spleen and the bone marrow. Furthermore, for the lymphoid and granuloid lineages, absolute numbers of precursors and of differentiated (mature) cells also were enumerated. The results indicate that A/J mice have significantly lower numbers of lymphoid, granuloid, and monocytoid--but not erythroid--cells in the spleen and/or bone marrow than do C57BL/6J mice. Also, sensitivity to ATRA was generally more profound in A/J mice than in C57BL/6 mice with respect to several hemopoietic cell lineages. These observations collectively suggest a need for considerable prudence in selection of inbred strains of mice, not only because of the possibility of wide interstrain variations in hemopoietic and immune cell-mediated functions, but also because of potential differences in the responses of various strains of common laboratory mice to pharmacologic agents.