Banu Kaya

Cervical carotid artery disease in sickle cell anemia: clinical and radiological features

Cervical internal carotid artery (cICA) occlusion is a recognized cause of acute ischemic stroke (AIS) in sickle cell disease (SCD), but the associated clinical and radiologic features are not well described. We reviewed data on cervical magnetic resonance angiography (cMRA) performed prospectively in 67 patients (55 children) for indications including transcranial Doppler (TCD) abnormalities, AIS, or previous AIS. cICA lesions were seen in 10 (15%) patients, including 4 of 7 patients presenting with AIS, and appear to have been missed on first presentation in 4 of 10 patients with previous AIS. Radiologic features in 7 patients were consistent with dissection. In 2 patients, there was strong clinical and radiologic evidence for thromboembolic AIS, and this was also considered possible in 4 other patients. Three of the 4 AIS patients were anticoagulated acutely, and the nontreated patient had recurrent, probably thromboembolic, AIS. TCD findings were variable, but in 4 patients there were high velocities in the cerebral vessels contralateral to the cICA stenosis. We suggest that all patients with AIS should have cMRA during acute evaluation to identify cICA occlusions that may require anticoagulation. Routine screening of children with SCD should also include evaluation of neck vessels by carotid Doppler followed by cMRA if a cervical vascular lesion is suspected.

A comparison of chronic manual and automated red blood cell exchange transfusion in sickle cell disease patients.

Chronic transfusion is one of the few effective means for treating or preventing the multisystem complications in sickle cell disease (SCD). Red blood cell (RBC) exchange transfusion (RBCX) is often preferred over simple transfusion because it rapidly reduces sickle haemoglobin (HbS) without raising final haematocrit (Hct), and there is some evidence that it may further reduce the risk of subsequent stroke (Hulbert et al, 2006). With new indications emerging (Casella et al, 2010), it is imperative that effective means of chronic transfusion to maintain appropriate haematological and clinical targets are identified. Some centres advocate the use of manual RBCX, where patients undergo sequential phlebotomies and transfusions at each session as it is a less resource-intensive procedure than automated RBCX. Proponents of automated RBCX argue that it is achieves haematological targets quickly and more consistently. However, no observational or controlled studies comparing automated with manual RBCX in either the paediatric or the adult setting have been reported. This study examined whether adult SCD patients on manual RBCX differ from those on automated RBCX in their ability to achieve pre-defined haematological targets, rate of complications, blood usage and clinical outcome over a 1-year period. This retrospective observational cohort study was conducted as part of a quality assurance audit between 1 May, 2011 and 30 April, 2012 at two SCD comprehensive care centres in London, United Kingdom. Subjects were included if they had a confirmed diagnosis of SCD, received regular RBCX (>1 session) between 1 May 2011 and 30 April 2012 and were aged >16 years. Bart’s Health NHS Trust (BHT) performs manual RBCX while Guy’s and St. Thomas NHS Trust (GSTT) performs automated RBCX exclusively. Both institutions adhere to the same clinical standards of comprehensive care (Olujohungbe, 2008), indications for chronic transfusion and pre-RBCX HbS targets (Table SI). All RBC units are provided by the UK National Blood Service [average packed RBC Hct (pRBC) 0 6]0, leucodepleted, HbS negative, ≤7 d old, phenotypically matched (for D, C/c, E/e, Kell antigens) and antigen-negative for any known alloantibodies. A total of 51 subjects, totalling 401 RBCX sessions and 38 8 patient-years of observation, were included. Table I summarizes the patient demographics and baseline characteristics. The distribution of the pre-RBCX HbS/SC fraction was found to be highly variable both within and between subjects (Fig 1). Although the mean pre-RBCX HbS/SC fraction was not significantly different between the two cohorts (P = 0 212), a greater proportion of subjects in the automated RBCX cohort were able to consistently achieve the pre-RBCX HbS/SC target compared to the manual RBCX cohort (P = 0 048). After adjusting for the prescribed preRBCX HbS/SC target, the Mantel-Haenszel Odds Ratio (OR) estimate for not attaining target because manual RBCX was employed was 4 72 [95% confidence interval (CI): 0 89– 25 20]. On multivariate logistic regression, only older age was associated with a higher likelihood of consistently achieving the pre-RBCX HbS/SC target (OR 1 12, P = 0 012). There was no significant difference in the median post-RBCX haematocrit (P = 0 931). Automated RBCX utilized more pRBC in both the volume (P < 0 0001) and units (P < 0 0001) but required half the time (P < 0 0001) and was performed less frequently (P = 0 001) than manual RBCX (Table I). Treatment failure, defined as a SCD-related complication that the RBCX was intended to prevent, did not occur in any subjects within the defined observation period, with the exception of pain. No significant difference in adverse event rates was observed (Table I, P = 0 7953). The majority of the adverse events in the manual RBCX cohort were termination of RBCX procedure due to poor intravenous access, blocked line or port, while the majority of the adverse events in the automated RBCX cohort were attributed to dizziness or hypotension. In this first systematic comparison of two RBCX methods, a higher proportion of the automated RBCX cohort was able to consistently achieve the prescribed pre-RBCX HbS/SC target while utilizing less time than the manual RBCX cohort. However, a large number of subjects in both cohorts were not able to achieve their prescribed target. Published literature has shown that the ability to achieve the requisite pre-RBCX HbS/ SC target can be quite variable (Aygun et al, 2012; Ware & Helms, 2012). The evidence for the chosen pre-RBCX HbS/SC target of <30% was largely derived from the STOP (Stroke Prevention in Sickle Cell Anaemia) and STOP2 trials (Adams et al, 1998; Adams & Brambilla, 2005), the SWiTCH (Stroke With Transfusions Changing to Hydroxyurea) trial (Ware & Helms, 2012) and retrospective data (Pegelow et al, 1995). Indications without the support of randomized controlled trials (RCTs) were largely drawn from retrospective cohort studies (Cohen et al, 1992; Miller et al, 1992) or expert opinion. Performing a larger volume manual RBCX may improve the pre-RBCX HbS/SC but will present a formidable challenge as the duration of the RBCX session will be lengthened beyond 4 h and will increase the risk of hypotension and syncope. The major advantage of automated RBCX is that it can circumvent all of the above issues and optimization of outcomes can be correspondence

Deferasirox for iron chelation in multitransfused children with sickle cell disease; long-term experience in the East London clinical haemoglobinopathy network.

Deferasirox (DFX) has been licensed for iron chelation in patients with sickle cell disease (SCD), but there is limited data on its long‐term efficacy and safety in children.

Combination-therapy with concurrent deferoxamine and deferiprone is effective in treating resistant cardiac iron-loading in aceruloplasminaemia.

peroxycyclophosphamide is inhibited by fludarabine and clofarabine. Clinical Cancer Research, 7, 3580–3589. Zhang, F., Zhang, L., Jing, L., Zhou, K., Wang, H., Peng, G., Li, Y., Li, Y., Li, J., Ye, L., Shi, L., Fan, H., Zhao, X., Chu, Y., Hao, Y. & Wang, J. (2013) High-dose cyclophosphamide compared with antithymocyte globulin for treatment of acquired severe aplastic anemia. Experimental Hematology, 41, 328–334.

Optimal Manual Exchange Transfusion Protocol for Sickle Cell Disease: A Retrospective Comparison of Two Comprehensive Care Centers in the United Kingdom and Canada

Abstract Chronic red blood cell (RBC) transfusion is employed for a wide range of sickle cell disease complications, ranging from primary and secondary stroke prophylaxis to prevention of painful vaso-occlusive episodes. Currently different methods are employed by centers for chronic transfusion that include simple, automated and partial manual RBC exchange transfusion. A retrospective cohort study of two different manual RBC exchange transfusion methods was conducted between two comprehensive care centers in Toronto, ON, Canada and London, United Kingdom in 19 and 21 sickle cell disease adults, respectively. London used a weight-based protocol, while Toronto used a unit-based method. Our results indicated that sickle cell disease patients utilizing a weight-based method are more often unable to achieve the prescribed Hb S (HBB: c.20A > T) target compared to the unit-based method (90.0 vs. 53.0% in the weight-based and unit-based methods, respectively, p = 0.0123). On multivariable logistic regression, none of the covariates examined was found to influence the ability to achieve the prescribed Hb S target after accounting for the exchange transfusion method. Mean interval of exchange sessions, session duration, total units of packed RBC, volume of blood used by body weight each year, the mean post exchange hematocrit [or packed cell volume (PCV)] and ferritin change were similar in both cohorts. In conclusion, the unit-based method was more effective at maintaining the prescribed Hb S target.

Extracorporeal membrane oxygenation for the treatment of adult sickle cell acute chest syndrome

Sickle cell disease (SCD) is a hereditary haemoglobinopathy that results in polymerization of haemoglobin molecules and subsequent vaso-occlusion. A common cause of death in adults is acute chest syndrome (AChS) with resulting hypoxemic respiratory failure. Veno-venous extracorporeal membrane oxygenation (VV-ECMO) has been used successfully in acutely reversible respiratory failure when conventional mechanical ventilation has been unable to adequately oxygenate and ventilate in a lung-protective fashion. We present an adult SCD patient with severe respiratory failure due to AChS, successfully treated with VV-ECMO. We also discuss some of the technical challenges and considerations when using ECMO in the SCD patient.

Transcranial Doppler Screening in a Regional Care Network for Sickle Cell Disease in the United Kingdom.

The risk of stroke in children screened with transcranial Doppler ultrasound in the United Kingdom is not known. We evaluated a clinician-led program using a risk assessment modified from the STOP protocol. High-risk classification included abnormal velocities in the anterior cerebral artery, and single abnormal scan if initial velocity >220 cm/s (high abnormal) or if preceded by at least 2 conditional scans. In total, 1653 scans were performed in 542 children, followed for 2235 patient-years. Fifty-eight (10.7%) high-risk subjects were identified, including 18 (31%) with high abnormal, and 15 (26%) with previous conditional scans. In 2 (3%), abnormal velocity was restricted to the anterior cerebral artery. The estimated proportion of children at high risk, scanned before 6 years of age was >20%. There were 4 cases of acute ischemic stroke (AIS) and 2 of acute hemorrhagic stroke. The incidence of all stroke, AIS, and acute hemorrhagic stroke were 0.27, 0.18, and 0.09 per 100 patient-years, respectively. The proportion of children at high risk is higher than most previous estimates, partly as a result of our modified risk assessment. About 2 children per 1000 screened with transcranial Doppler ultrasound progress to AIS.

Guidelines for the use of hydroxycarbamide in children and adults with sickle cell disease: A British Society for Haematology Guideline

Department of Paediatric Haematology and Oncology, Oxford Children’s Hospital, Oxford University Hospital NHS Trust, Oxford, Department of Paediatric Haematology and Oncology, Royal London Hospitals, Barts Health NHS Trust, London, Department of Haematology, Sandwell and West Birmingham NHS Trust, West Bromwich, Department of Paediatric Haematology, Alderhey Children’s Hospital NHS Trust, Liverpool, Department of Clinical Psychology, Imperial College Healthcare NHS Trust, London, Department of Haematology, Milton Keynes Hospital NHS Trust, Milton Keynes, and Department of Haematology, Guys and St Thomas’s NHS Foundation Trust, London, UK

Pseudoxanthoma elasticum‐like syndrome in a patient with sickle cell anaemia

A 32-year-old woman with sickle cell anaemia presented with soft tissue swelling in both axillae and excess skin folds in the neck. These were non-tender with no palpable lymph nodes and breast examination was normal. Ultrasound examination found both axillae to be diffusely echogenic, consistent with fatty tissue. Following dermatological review, the appearances were felt to be consistent with keratoma elasticum. Retinal examination revealed bilateral angioid streaks and a diagnosis of pseudoxanthoma elasticum (PXE)-like syndrome was made. This patient had started monthly blood transfusions 4 years previously for worsening symptomatic anaemia and recurrent painful crises. She had developed iron loading with a peak serum ferritin of 6000 lg/l and a T2* magnetic resonance imaging (MRI) scan of the liver demonstrated severe iron loading (T2* of 1Æ36 ms–10Æ3 mg/g DW). She struggled with iron chelation therapy but remains on deferoxamine 2 g three times a week. Angioid streaks are a well recognised association of sickle cell disease (SCD). However, whilst PXE-like syndrome has been reported frequently in patients with b thalassaemia, the link with SCD is less well known. It is thought that the PXE-like syndrome seen in these chronic haemolytic disorders represents an acquired form, which is milder than hereditary PXE and which increases in frequency with age. Free radical-mediated oxidative damage to elastic tissue secondary to haemolysis is implicated. It is likely that the added insult from iron overload explains why more cases are seen in patients with b thalassaemia than in other chronic haemolytic disorders. We predict that, as patients with SCD live longer and increasing numbers undergo regular blood transfusions, it is likely that more cases of the PXE-like syndrome will be seen. Routine follow-up of these patients should include careful skin inspection and annual retinal examination.

Optimizing the care model for an uncomplicated acute pain episode in sickle cell disease

The pathophysiology, clinical presentation, and natural history of acute pain in sickle cell disease are unique and require a disease-centered approach that also applies general principles of acute and chronic pain management. The majority of acute pain episodes are managed at home without the need to access health care. The long-term consequences of poorly treated acute pain include chronic pain, adverse effects of chronic opioid usage, psychological maladjustment, poor quality of life, and excessive health care utilization. There is no standard protocol for management of an acute pain crisis in either the hospital or the community. The assumptions that severe acute pain must be managed in the hospital with parenteral opioids and that strong opioids are needed for home management of pain need to be questioned. Pain management in the emergency department often does not meet acceptable standards, while chronic use of strong opioids is likely to result in opioid-induced hyperalgesia, exacerbation of chronic pain symptoms, and opioid dependency. We suggest that an integrated approach is needed to control the underlying condition, modify psychological responses, optimize social support, and ensure that health care services provide safe, effective, and prompt treatment of acute pain and appropriate management of chronic pain. This integrated approach should begin at an early age and continue through the adolescent, transition, and adult phases of the care model.