Summary. Inherited factor XIII (FXIII) deficiency is a rare bleeding disorder that can present with umbilical bleeding during the neonatal period, delayed soft tissue bruising, mucosal bleeding and life-threatening intracranial haemorrhage. FXIII deficiency has also been associated with poor wound healing and recurrent miscarriages. FXIII plays an integral role in haemostasis by catalysing the crosslinking of fibrin, platelet membrane and matrix proteins throughout thrombus formation, thus stabilizing the blood clot. The molecular basis of FXIII deficiency is characterized by a high degree of heterogeneity, which contributes to the different clinical manifestations of the disease. There have been more than 60 FXIII mutations identified in the current literature. In addition, single nucleotide polymorphisms have been described, some of which have been shown to affect FXIII activity, contributing further to the heterogeneity in patient presentation and severity of clinical symptoms. Although there is a lifelong risk of bleeding, the prognosis is excellent when current prophylactic treatment is available using cryoprecipitate or plasma-derived FXIII concentrate.

BackgroundTreatment of chronic severe pediatric ITP is not well studied. In a phase 1/2 12–16-week study, 15/17 romiplostim-treated patients achieved platelet counts ≥50 × 109/L, and romiplostim treatment was well tolerated. In a subsequent open-label extension (≤109 weeks), 20/22 patients received romiplostim; all achieved platelet counts >50 × 109/L. Twelve patients continued in a second extension (≤127 weeks). Longitudinal data from start of romiplostim treatment through the two extensions were evaluated to investigate the safety and efficacy of long-term romiplostim treatment in chronic severe pediatric ITP.ProcedurePatients received weekly subcutaneous romiplostim, adjusted by 1 µg/kg/week to maintain platelet counts (50–200 × 109/L, maximum dose 10 µg/kg). Bone marrow examinations were not required.ResultsAt baseline, patients were median age 10.0 years; median ITP duration 2.4 years; median platelet count 13 × 109/L; 73% were male; and 36% had prior splenectomy. Median romiplostim treatment duration was 167 weeks (Q1, Q3: 78,227 weeks), and median average weekly dose was 5.4 µg/kg (Q1, Q3: 4.3, 8.0 µg/kg). Seven patients discontinued treatment: four withdrew consent, two were noncompliant, and one received alternative therapy. None withdrew because of adverse events (AEs). After the first 12 weeks, median platelet counts remained >50 × 109/L. Eight (36.4%) patients received rescue medication, and 14 (63.6%) used concurrent ITP therapy. Seven patients (31.8%) reported serious AEs, and two (9.1%) reported life-threatening AEs (both thrombocytopenia); there were no serious AEs attributed to treatment and no fatalities.ConclusionsLong-term romiplostim treatment in this small cohort increased and maintained platelet counts for over 4 years in children with ITP with good tolerability and without significant toxicity. Pediatr Blood Cancer 2015;62:208–213. © 2014. The Authors. Pediatr Blood & Cancer published by Wiley Periodicals, Inc.

Hereditary spherocytosis (HS) is the most common red blood cell (RBC) membrane disorder causing hereditary hemolytic anemia. Patients with HS have defects in the genes coding for ankyrin ( ANK1 ), band 3 ( SLC4A1 ), protein 4.2 ( EPB42 ), and α ( SPTA1 ) or β-spectrin ( SPTB ). Severe recessive HS is most commonly due to biallelic SPTA1 mutations. α-spectrin is produced in excess in normal erythroid cells, therefore SPTA1 -associated HS ensues with mutations causing significant decrease of normal protein expression from both alleles. In this study, we systematically compared genetic, rheological, and protein expression data to the varying clinical presentation in eleven patients with SPTA1 -associated HS. The phenotype of HS in this group of patients ranged from moderately severe to severe transfusion-dependent anemia and up to hydrops fetalis which is typically fatal if transfusions are not initiated before term delivery. The pathogenicity of the mutations could be corroborated by reduced SPTA1 mRNA expression in the patients’ reticulocytes. The disease severity correlated to the level of α-spectrin protein in their RBC cytoskeleton but was also affected by other factors. Patients carrying the low expression α LEPRA allele in trans to a null SPTA1 mutation were not all transfusion dependent and their anemia improved or resolved with partial or total splenectomy, respectively. In contrast, patients with near-complete or complete α-spectrin deficiency have a history of having been salvaged from fatal hydrops fetalis , either because they were born prematurely and started transfusions early or because they had intrauterine transfusions. They have suboptimal reticulocytosis or reticulocytopenia and remain transfusion dependent even after splenectomy; these patients require either lifetime transfusions and iron chelation or stem cell transplant. Comprehensive genetic and phenotypic evaluation is critical to provide accurate diagnosis in patients with SPTA1 -associated HS and guide toward appropriate management.