Intravenous immunoglobulin (IVIG) therapy is associated with rare reports of thromboembolic events and severe hyponatremia. We hypothesized that IVIG therapy may result in hyperproteinemia, increased serum viscosity, and pseudohyponatremia. We conducted a prospective observational study to evaluate the incidence of hyperproteinemia occurring after IVIG therapy and its relationship to serum sodium, viscosity, osmolality, and the serum osmolar gap. Eighteen IVIG infusions at a standard dose of 2 g/kg administered over 2-5 days were evaluated. Serum glucose, sodium, protein, viscosity, osmolality, and a calculated osmolar gap were obtained prior to therapy, 6 hr after the initiation of therapy, 24 hr after the conclusion of therapy, and on post-treatment day 10. Paired t-testing revealed a statistically significant increase in serum protein and viscosity and decrease in serum sodium and calculated osmolality 24 hr after the completion of IVIG therapy. The calculated serum osmolar gap increased insignificantly. In multivariate analysis, hyperproteinemia at the 6-hr time point predicted hyponatremia (P < 0.000), and hyperproteinemia at the 24-hr time point predicted both hyponatremia and increased serum viscosity (P = 0.024). These data demonstrate that increased serum viscosity occurs following IVIG therapy due to hyperproteinemia, and the rare hyponatremia reported is a pseudohyponatremia also due to hyperproteinemia. Am. J. Hematol. 73:97-100, 2003.

We report the clinical, hematologic and molecular data of a child (and his heterozygous parents) with a novel form of ␤-thalassemia intermedia. An eight-year-old boy was referred to our institution for molecular characterization of his ␤-thalassemia defect. He was the only child of non-consanguinous Hispanic parents from Puerto Rico. The boy was well at presentation. He weighed 24.3 kg (50 th -75 th percentile) and was 117 cm tall (10 th -25 th percentile). His physical examination was remarkable only for 6 cm of splenomegaly below the costal margin. He did not appear clinically anemic or jaundiced, nor was there any physical evidence of bone marrow hyperactivity. Both parents had a normal physical examination. Routine hematological studies, which included a complete blood count, hemoglobin electrophoresis, iron studies, and liver function tests, were conducted on the patient and both of his parents. In addition, genomic DNA was isolated from peripheral blood leukocytes using standard procedures. Molecular testing was performed by The DNA Diagnostic Laboratory at Johns Hopkins University Hospital, Baltimore, Maryland. A summary of the hematologic findings is listed (Table I).The father's screening tests (a mild microcytic, hypochromic anemia with normal iron studies and an elevated HbA 2 ) were consistent with ␤-thalassemia trait. Molecular testing identified a single sequence mutation Nt168C→T (␤ o mutation in codon 39) in one of his ␤-globin genes. The mother's screening tests were negative for anemia. However, molecular studies revealed the presence of two sequence changes within a single ␤-globin gene (see below), thereby making her a silent ␤-thalassemia carrier. The child's screening tests (a moderate microcytic, hypochromic anemia with normal iron studies and an elevated HbF) were consistent with a diagnosis of thalassemia intermedia. The results of his molecular studies confirmed the boy had in fact inherited three ␤-globin sequence changes (Nt168C→T, Nt494+129T→C and Nt494+132C→A), all in the heterozygous state. No evidence for ␣-globin mutations were found in any of the three probands.To our knowledge the Nt494+129T→C and Nt494+132C→A have not been reported previously. Both of these changes are just 3Ј to the poly A site of the ␤-globin gene. Their functional significance is not known. Expression studies to quantify mRNA and ␤-globin synthesis are underway. These family studies show that the two novel mutations were inherited together (in cis) from the mother and that both of these changes are in trans to the Nt168 mutation, which was inherited from the father. The new mutations can be added to the list of silent beta-thalassemias, characterized by normal red blood cell indices, normal HbA 2 and HbF levels but with an unbalanced globin chain synthesis [1]. At the time of screening, the boy was yet to require any blood transfusions and had a serum ferritin level of 75 ng/mL.