g(HbF): a genetic model of fetal hemoglobin in sickle cell disease.

Fetal hemoglobin (HbF) is a strong modifier of sickle cell disease (SCD) severity and is associated with 3 common genetic loci. Quantifying the genetic effects of the 3 loci would specifically address the benefits of HbF increases in patients. Here, we have applied statistical methods using the most representative variants: rs1427407 and rs6545816 in BCL11A, rs66650371 (3-bp deletion) and rs9376090 in HMIP-2A, rs9494142 and rs9494145 in HMIP-2B, and rs7482144 (Xmn1-HBG2 in the ß-globin locus) to create g(HbF), a genetic quantitative variable for HbF in SCD. Only patients aged ≥5 years with complete genotype and HbF data were studied. Five hundred eighty-one patients with hemoglobin SS (HbSS) or HbSß0 thalassemia formed the "discovery" cohort. Multiple linear regression modeling rationalized the 7 variants down to 4 markers (rs6545816, rs1427407, rs66650371, and rs7482144) each independently contributing HbF-boosting alleles, together accounting for 21.8% of HbF variability (r2) in the HbSS or HbSß0 patients. The model was replicated with consistent r2 in 2 different cohorts: 27.5% in HbSC patients (N = 186) and 23% in 994 Tanzanian HbSS patients. g(HbF), our 4-variant model, provides a robust approach to account for the genetic component of HbF in SCD and is of potential utility in sickle genetic and clinical studies.

A new diagnosis of acute myeloid leukaemia complicated by peripancreatic tuberculous lymphadenitis.

A 29-year-old woman presented with neutropenic sepsis and was found to have a new diagnosis of acute myeloid leukaemia. Following initiation of induction chemotherapy the patient became increasingly unwell with ongoing sepsis despite broad-spectrum antibiotic treatment. An extensive septic screen failed to identify a source, other than the finding of a peripancreatic mass on imaging. Following the introduction of antituberculous treatment the patient showed signs of clinical improvement and a subsequent biopsy confirmed the mass to be tuberculous lymphadenitis. The patient completed three cycles of combination chemotherapy achieving a complete remission and also successfully completed 12 months of antituberculous treatment.

Use of intravenous immunoglobulin and intravenous methylprednisolone in hyperhaemolysis syndrome in sickle cell disease.

Hyperhaemolysis syndrome (HS), a syndrome in which there is destruction of both donor and recipient red cells after transfusion, is well recognised in patients with sickle cell disease and beta-thalassaemia. It has also been reported in a patient with myelofibrosis. In acute forms of HS, evidence of red cell antibody-mediated haemolysis is lacking, and it has been proposed that the transfused and the patient's own red blood cells were destroyed by hyperactive macrophages. Continuation of transfusion may be lethal as this can further exacerbate haemolysis. We report two cases of HS successfully treated with IVIg and IV methylprednisolone. The cessation of haemolysis following administration of IVIg and IV methylprednisolone supports the view that hyperactive macrophages contribute to the RBC destruction. IVIg and methylprednisolone appear to have a synergistic effect on suppressing the activity of macrophages.