In thalassemia, deficient globin-chain production during erythropoiesis results in anemia. Thalassemia may be further complicated by iron overload (frequently exacerbated by blood transfusion), which induces numerous endocrine diseases, hepatic cirrhosis, cardiac failure and even death. Accumulation of iron in the absence of blood transfusions may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism. To test this hypothesis, we examined erythroblast transcriptome profiles from 15 healthy, nonthalassemic donors. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-beta superfamily, showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 +/- 50 pg/ml. In comparison, individuals with beta-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 +/- 9,600 pg/ml; range 4,800-248,000 pg/ml; P < 0.05) that were positively correlated with the levels of soluble transferrin receptor, erythropoietin and ferritin. Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. These results suggest that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression.
Background
For children with sickle cell anaemia and elevated transcranial Doppler (TCD) flow velocities, regular blood transfusions effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxyurea in this setting is unknown.
Methods
TWiTCH was a multicentre Phase III randomised open label, non-inferiority trial comparing standard treatment (transfusions) to alternative treatment (hydroxyurea) in children with abnormal TCD velocities but no severe vasculopathy. Iron overload was managed with chelation (Standard Arm) and serial phlebotomy (Alternative Arm). The primary study endpoint was the 24-month TCD velocity calculated from a general linear mixed model, with non-inferiority margin = 15 cm/sec.
Findings
Among 121 randomised participants (61 transfusions, 60 hydroxyurea), children on transfusions maintained <30% sickle haemoglobin, while those taking hydroxyurea (mean 27 mg/kg/day) averaged 25% fetal haemoglobin. The first scheduled interim analysis demonstrated non-inferiority, and the sponsor terminated the study. Final model-based TCD velocities (mean ± standard error) on Standard versus Alternative Arm were 143 ± 1.6 and 138 ± 1.6 cm/sec, respectively, with difference (95% CI) = 4.54 (0.10, 8.98), non-inferiority p=8.82 × 10−16 and post-hoc superiority p=0.023. Among 29 new neurological events adjudicated centrally by masked reviewers, no strokes occurred but there were 3 transient ischaemic attacks per arm. Exit brain MRI/MRA revealed no new cerebral infarcts in either arm, but worse vasculopathy in one participant (Standard Arm). Iron burden decreased more in the Alternative Arm, with ferritin difference −1047 ng/mL (−1524, −570), p<0.001 and liver iron difference −4.3 mg Fe/gm dry weight (−6.1, −2.5), p=0.001.
Interpretation
For high-risk children with sickle cell anaemia and abnormal TCD velocities, after four years of transfusions and without severe MRA vasculopathy, hydroxyurea therapy can substitute for chronic transfusions to maintain TCD velocities and help prevent primary stroke.
This is the first multicenter study to show that extended RBC phenotyping can be implemented nationwide. Compared to studies, the alloimmunization rate dropped from 3 percent to 0.5 percent per unit, and hemolytic transfusion reactions dropped by 90 percent. It is recommended that all transfused sickle cell anemia patients be antigen matched for E, C, and Kell. Patients should be closely monitored during transfusions to avoid preventable risks.
We have systematically developed evidence-based guidance to inform plasma transfusion decisions in common clinical scenarios. Data from additional randomized studies will be required to establish more comprehensive and definitive guidelines for plasma transfusion.
BACKGROUND: Blood product transfusions are a valuable health‐care resource. Guidelines for transfusion exist, but variability in their application, particularly in children, remains. The risk factors that threaten transfusion safety are well established, but because their occurrence in children is rare, single‐institution studies have limited utility in determining the rates of occurrence. An epidemiologic approach that investigates blood transfusions in hospitalized children may help improve our understanding of transfused blood products in this vulnerable population.
STUDY DESIGN AND METHODS: This was a nonconcurrent cohort study of pediatric patients not more than 18 years of age hospitalized from 2001 to 2003 at 35 academic children's hospitals that are members of the Pediatric Health Information System (PHIS).
RESULTS: A total of 51,720 (4.8%) pediatric patients received blood product transfusions during the study period. Red blood cells (n = 44,632) and platelets (n = 14,274) were the two most frequently transfused products. The rate of transfusions was highest among children with neutropenia, agranulocytosis, and sickle cell crisis. Asian and American Indian patients had important differences in the rate of blood transfusions and their complications. Resource use in terms of length of stay and costs were higher in patients who received transfusion. Of those patients who received transfusions, 492 (0.95%) experienced a complication from the administered blood product. This accounted for a rate of complications of 10.7 per 1,000 units transfused.
CONCLUSIONS: The administration of blood products to children is a common practice in academic children's hospitals. Complications associated with these transfused products are rare.
Background
Hepatitis E virus (HEV) infection has become relevant to blood transfusion practice because isolated cases of blood transmission have been reported and because HEV has been found to cause chronic infection and severe liver disease in immuno-compromised patients.
Study design and Methods
We tested for IgG and IgM antibodies to the hepatitis E virus (HEV) and for HEV RNA in 1939 unselected volunteer US blood donors. Subsequently, we tested the same parameters in pre- and serial post-transfusion samples from 362 prospectively followed blood recipients to assess transfusion risk.
Results
IgG anti-HEV seroprevalence in the total 1939 donations was 18.8%: 916 of these donations were made in 2006 at which time the seroprevalence was 21.8% and the remaining 1023 donations were in 2012 when the seroprevalence had decreased to 16.0% (p<0.01). A significant (P<0.001) stepwise increase in anti-HEV seroprevalence was seen with increasing age. Eight of 1939 donations (0.4%) tested anti-HEV IgM positive; no donation was HEV RNA positive. Two recipients had an apparent anti-HEV seroconversion, but temporal relationships and linked donor testing showed that these were not transfusion transmitted HEV infections.
Conclusion
No transfusion-transmitted HEV infections were observed in 362 prospectively followed blood recipients despite an anti-HEV seroprevalence among donations exceeding 16%.
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