Jp Evans

Platelet and leucocyte activation in childhood sickle cell disease: association with nocturnal hypoxaemia

We hypothesized that vaso‐occlusive events in childhood sickle cell disease (SCD) may relate to inflammatory cell activation as well as interactions between sickle erythrocytes and vascular endothelium. Peripheral blood was examined from 24 children with SCD, of whom 12 had neurological sequelae and seven had frequent painful crises, and 10 control subjects. Platelet (CD62P and CD40L expression) and granulocyte (CD11b expression) activation and levels of platelet–erythrocyte and platelet–granulocyte complexes were determined by flow cytometry. Platelets (P = 0·019), neutrophils (P = 0·02) and monocytes (P = 0·001) were more activated and there were increased platelet–erythrocyte complexes (P = 0·026) in SCD patients compared with controls. Platelet–granulocyte complexes were not raised. There were no differences between the different groups of SCD. As hypoxia activates monocytes, platelets and endothelial cells and causes sickling of SCD erythrocytes, we also investigated 20 SCD patients with overnight pulse oximetry. Minimum overnight saturation correlated with the level of platelet–erythrocyte complexes (Spearmans ρ−0·668, P < 0·02), neutrophil CD11b (Spearmans ρ−0·466, P = 0·038) and monocyte CD11b (Spearmans ρ−0·652, P = 0·002). These findings provide important clues about the mechanism by which SCD patients may become predisposed to vaso‐occlusive events.

Perfusion magnetic resonance abnormalities in patients with sickle cell disease.

Neurological complications are common in sickle cell disease (SCD). However, it is often difficult to relate the clinical presentation to conventional neuroimaging, because subclinical infarction is common and stroke has been described in the absence of large‐vessel disease. We studied 48 patients with SCD aged 4–34 (median 13) years with T2‐weighted, diffusion and perfusion magnetic resonance imaging (MRI) and with MR angiography. Forty‐four underwent transcranial Doppler (TCD). Abnormalities on perfusion imaging were seen in 25 cases, 24 of whom had been symptomatic. The remaining patient had evidence of executive dysfunction and reduced perfusion in the frontal lobes. The perfusion abnormality was larger than the area of infarction in 9 patients and was seen in an arterial distribution with no infarction in a further 9. In 3 patients with transient ischemic attacks, perfusion abnormalities were demonstrated in the absence of any other neuroimaging abnormalities, and perfusion changes were seen in 3 others despite normal MR angiography and TCD. Perfusion abnormalities are associated with neurological symptoms in patients with SCD, whether or not MRI, MR angiography, and TCD are abnormal. It is likely that this technique will guide management in individual patients. Ann Neurol 2001;49:477–485

Mutations of the granulocyte-colony stimulating factor receptor in patients with severe congenital neutropenia are not required for transformation to acute myeloid leukaemia and may be a bystander phenomenon

Point mutations of the granulocyte‐colony stimulating factor receptor (G‐CSFR) resulting in an abnormally truncated receptor have been implicated in the pathogenesis of some cases of severe congenital neutropenia (SCN) and in the transformation of SCN to acute myeloid leukaemia (AML). We report here studies in 11 patients with SCN. No mutations were detected in the one patient who developed AML indicating that development of such mutations is not a prerequisite for transformation. Truncation mutations were detected in a minor percentage of transcripts from two other patients. In one patient the mutation has been constant at a low level (5–10% of total mRNA and 2/40 myeloid colonies) for 2 years. In the other patient the mutation was acquired, remained present at low levels for nearly 3 years and then spontaneously disappeared. Both patients had polyclonal haemopoiesis. We hypothesize that these mutations do not cause SCN, are randomly acquired with the mutant clone being expanded to detectable levels by high levels of exogenous or endogenous G‐CSF, and may disappear by clonal succession. In a pre‐leukaemic marrow the mutated subclone could achieve high levels, but this does not necessarily indicate a primary role of the mutant receptor in the leukaemogenic process.

Kostmann's disease, recombinant HuG-CSF, monosomy 7 and MDS/AML

Summary Monosomy 7 (Mo7) and leukaemia predisposition are associated with Kostmanns disease (KD). The recent introduction of long‐term recombinant HuG‐CSF treatment in patients with KD, whilst showing significant reductions in infectious complications and improved quality of life, might also be associated with an increased risk of developing karyotypic abnormalities, myelodysplasia (MDS) and acute myeloid leukaemia (AML). We describe a case of an identical twin with probable autosomal dominant KD who developed anaemia, Mo7/MDS and AML at 18, 30 and 50 months respectively from starting r‐metHuG‐CSF (filgrastim) treatment. Further patient analyses are required to establish the natural history of KD and to determine what role, if any, filgrastim plays in altering the pathobiology of this disorder.