Annual Academy of Sickle Cell and Thalassaemia (ASCAT) conference: a summary of the proceedings.

The fourteenth annual ASCAT conference was held 21-23 October 2019. The theme of the conference was 'Sickle Cell and Thalassaemia disorders new treatment horizon; while ensuring patient safety and delivering excellence in routine patient care.' Over the three-day conference, topics on current and novel models of care, advances in bone marrow transplant and gene therapy, as well as the psychosocial aspects of mind, body and health related quality of life were discussed. In addition, blood transfusion, apheresis, iron chelation therapy and acute haemolytic complications were presented. Quality standards in the diagnosis and treatment of sickle cell and thalassaemia were reviewed. Experts from Europe, the United Kingdom, the Middle East, the United States and Africa reported up-to-date scientific data, guides to comprehensive care, and current research into developing cures and advancing current therapy were described. In addition, oral and poster presentations on novel research from all over the world were shown during the conference.

White matter integrity and processing speed in sickle cell anemia.

OBJECTIVE: The purpose of this retrospective cross-sectional study was to investigate whether changes in white matter integrity are related to slower processing speed in sickle cell anemia. METHODS: Thirty-seven patients with silent cerebral infarction, 46 patients with normal MRI, and 32 sibling controls (age range 8-37 years) underwent cognitive assessment using the Wechsler scales and 3-tesla MRI. Tract-based spatial statistics analyses of diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) parameters were performed. RESULTS: Processing speed index (PSI) was lower in patients than controls by 9.34 points (95% confidence interval: 4.635-14.855, p = 0.0003). Full Scale IQ was lower by 4.14 scaled points (95% confidence interval: -1.066 to 9.551, p = 0.1), but this difference was abolished when PSI was included as a covariate (p = 0.18). There were no differences in cognition between patients with and without silent cerebral infarction, and both groups had lower PSI than controls (both p < 0.001). In patients, arterial oxygen content, socioeconomic status, age, and male sex were identified as predictors of PSI, and correlations were found between PSI and DTI scalars (fractional anisotropy r = 0.614, p < 0.00001; r = -0.457, p < 0.00001; mean diffusivity r = -0.341, p = 0.0016; radial diffusivity r = -0.457, p < 0.00001) and NODDI parameters (intracellular volume fraction r = 0.364, p = 0.0007) in widespread regions. CONCLUSION: Our results extend previous reports of impairment that is independent of presence of infarction and may worsen with age. We identify processing speed as a vulnerable domain, with deficits potentially mediating difficulties across other domains, and provide evidence that reduced processing speed is related to the integrity of normal-appearing white matter using microstructure parameters from DTI and NODDI.

Refractory severe immune thrombocytopenia in a twin pregnancy.

A 34-year-old woman presented at 29 weeks gestation of a twin pregnancy, with a platelet count of 1 × 109/l. She was extensively investigated and was subsequently diagnosed with severe immune thrombocytopenia. She did not respond to initial treatment with corticosteroids and intravenous immunoglobulin. She also failed to respond to second-line therapies of Anti-D immunoglobulin, Azathioprine and the thrombopoietin agonist Romiplostim. Her case was further complicated by an episode of obstetric cholestasis possibly related to Azathioprine treatment. She went on to require plasma exchange around the time of an elective Caesarean section which provided temporary improvement in the platelet count and enabled safe delivery. This case highlights some of the challenges faced in the management of patients with severe and refractory immune thrombocytopenia during pregnancy.

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.

The utility of thromboelastography and thrombin generation in assessing the prothrombotic state of adults with sickle cell disease.

INTRODUCTION: Previous studies have suggested a chronic hypercoagulable state in SCD, and that thrombosis also plays a role in the pathophysiology of sickle cell vaso-occlusive pain crises (VOC). Studies looking at thrombin generation have produced conflicting results. In this study we aimed to assess and compare whole blood thromboelastography (TEG) and plasma Calibrated Automated Thrombogram (CAT) in SCD versus healthy controls and in four different SCD subgroups. MATERIALS AND METHODS: In this prospective observational study, TEG and 1pM TF activated CAT assays were performed in citrated blood samples from 77 adult (18-66years old) SCD patients (HbSS and HbSB) and 22 healthy (HbAA) ethnically-matched controls. RESULTS AND CONCLUSIONS: SCD was associated with a prothrombotic state in all TEG parameters. CAT results showed that the upslope of the CAT in SCD displayed a hypercoagulable state with shorter time to peak and higher velocity index, but the downslope was also faster leading to an overall lower endogenous thrombin potential (ETP) compared to healthy controls. TEG subgroup analyses showed that during VOC the prothrombotic state is greater compared to patients on disease ameliorating therapy. CAT did not display statistically significant differences between the SCD subgroups. This study shows that the prothrombotic state in SCD is best displayed with TEG, and suggests the hypercoagulable changes of SCD rely at least in part in the cellular components of blood, which can only be detected in whole blood assays.

Intracranial Aneurysms in Sickle-Cell Disease Are Associated With the Hemoglobin SS Genotype But Not With Moyamoya Syndrome.

BACKGROUND AND PURPOSE: Intracranial aneurysms and aneurysmal subarachnoid hemorrhage may occur more frequently in sickle-cell disease (SCD), and this could be related to the sickle genotype and moyamoya syndrome seen in SCD. METHODS: Records from a total of 1002 patients with SCD attending 2 specialized adult hematologic services were retrospectively reviewed. We analyzed data of a cohort of 767 patients attending 1 SCD clinic between 2002 and 2013 and of 235 patients from the other clinic who have had neurovascular imaging between 2007 and 2014. RESULTS: We identified 4 patients in the cohort who had an aneurysmal subarachnoid hemorrhage during 9063 patient-years. The highest incidence rate was seen among women in the age group 30 to 39 years with the hemoglobin SS (HbSS) genotype (440 per 100 000 patient-years). Unruptured intracranial aneurysms were found in 20 of the 324 patients, who had imaging data; the prevalence was significantly higher in patients with HbSS genotype compared with other sickle genotypes with the highest prevalence (15%) observed in women in the age group 30 to 39 years. Fifty-one HbSS patients had a moyamoya vasculopathy, but only 3 of these had concomitant intracranial aneurysms. CONCLUSIONS: Intracranial aneurysms are common in HbSS SCD. There was also a trend toward more common occurrence of aneurysmal subarachnoid hemorrhage in HbSS; women in the age group 30 to 39 years were most at risk. There was no correlation between the occurrence of intracranial aneurysms and moyamoya syndrome.

Cementless total hip replacements in sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) affects around 80,000 people in the USA and 12,000 in the UK. Up to 40% of patients will get osteonecrosis of the femoral head. Cemented acetabular components yield poor results with the rate of osteolysis ranging from 13.5 to 46%. We report on a consecutive cohort of patients with SCD who underwent uncemented THA with ceramic-on-ceramic (CoC) bearings. METHODS: Since 2002 52 primary THAs were carried out in 40 patients. The average age was 36.1 years (17-54). 48 cases had exchange blood transfusion preoperatively and 3 had top-up transfusions.An S-ROM was used in 47 hips a Solutions stem in 4 hips and an AML in 1. It was necessary to drill the femur during 12 hips. There were 5 intra-operative peri-prosthetic fractures. 2 dislocations were observed. 2 superficial infections were detected. RESULTS: All components have in-grown. There have been no cases of radiographic osteolysis, migration or loosening of the hip with average 5-year (2-10.1) follow-up. CONCLUSIONS: The combination of a multidisciplinary team approach and uncemented implants, with ceramic-on-ceramic bearings used, has made THA in patients with SCD a safe and reliable procedure in our hospital.

Myoepithelial markers are expressed in at least 29% of oestrogen receptor negative invasive breast carcinoma.

Around 20% of invasive breast carcinoma are oestrogen receptor alpha (ER) negative. Theoretically, this negativity could be either due to the result of downregulation of ER expression in the tumour cells, or the result of the tumour being derived from or differentiating towards cells which normally lack that expression. Normal basal, including myoepithelial, cells of the breast are ERnegative. CD10, smooth muscle actin and S100 are markers of these basal cells that can be used for their demonstration in routinely processed sections. This study was aimed at comparing the incidence of positivity for three myoepithelial markers in ER-negative and ER-positive invasive breast carcinoma. We have examined sections of 117 cases of breast carcinoma, including 77 ER-negative and 40 ER-positive cases, for the expression of CD10, smooth muscle actin and S100, using the avidin-biotin complex immunoperoxidase technique. A tumour was considered positive if more than 10% of the tumour cells were positively stained. In all, 36 (47%) ER-negative tumours were positive for one or more of these myoepithelial markers. The percentage of positively stained tumour cells varied between 30 and 100%. Of the 40 ER-positive tumours, only three (8%) were positive; two for S100 and one for actin, with none being positive for CD10. If cases stained only with S100 are excluded, as some of these may represent luminal differentiation, definite myoepithelial differentiation seems to be present in 29% (22/77) of ER-negative tumours as compared with 2.5% (1/40) of ER-positive tumours; a difference which is highly significant (P<0.001). It is suggested that at least 29% of ER-negative invasive breast carcinomas may be derived from or differentiating along the direction of basal nonconventional luminal epithelial breast cells that normally lack the expression of ER but totally or partially express various myoepithelial markers. Such tumours might need a different therapeutic approach.