We did a careful search of the scientific literature in English up to July, 2016, using the terms “sickle cell”, “hydroxyurea or hydroxycarbamide”, “transfusions”, “transcranial Doppler”, and “alloimmunization”; we also reviewed the 2014 National Heart, Lung, and Blood Institute (NHLBI) evidence-based guidelines. We searched through ClinicalTrials.gov for all open trials identified as “sickle cell”, “hydroxyurea”, and “open or recruiting”. We identified and reviewed all published phase 3 trials
SeminarSickle cell disease
Introduction
Sickle cell disease is familiar to physicians but the term is actually a misnomer, since it refers not to a single disease but rather to a collection of inherited blood disorders that feature the propensity for erythrocytes to change into crescent or so-called sickle shapes. This characteristic morphology is akin to the common agricultural cutting tool bearing the same name. The condition is well-recognised in many African tribal cultures by distinct names such as chwechweechwe, ahututuo, or nuidudui, which are onomatopoeic and reflect the painful symptoms and cries from affected patients. Additional names such as kibeka or malari ya mifupa ina pasuka describe signs and symptoms, such as large spleen or broken bones. Perhaps the most sobering name is ako kufa lobi, which translates loosely to “he will die tomorrow”. Although sickle cell is a common phrase among Anglophones, “drepanocytose” from Greek drepane (sickle) or “anemia falciforme” from Latin falcicula (sickle or false shape) are common in Europe and used throughout Francophone and Lusophone Africa.
Health and survival of children with sickle cell disease have improved considerably with the advent of newborn screening, penicillin prophylaxis, pneumococcal immunisation, and education about disease complications. Unfortunately, the average projected lifespan of affected adults has not improved beyond the fifth decade,1 although wider use of hydroxycarbamide and newer therapeutic approaches offer hope for decreased mortality and improved health-related quality of life. Sadly, sickle cell disease in low-resource countries carries a bleak prognosis, especially in sub-Saharan Africa, where it is associated with high early childhood mortality.
This Seminar does not provide an encyclopaedic or exhaustive summary of the history, pathophysiology, and management of sickle cell disease; readers are referred to recent summaries,2, 3 and National Heart, Lung, and Blood Institute Evidence-Based Guidelines.4 Instead, we offer a concise review of clinically relevant issues including current treatments, new advances, novel therapies, areas of controversy, and assessment of the global disease burden. We attempt to document exciting developments in the field reflecting activity and interest by academic institutions, pharmaceutical industries, biotechnology companies, and governments. We predict the near future will provide a long overdue paradigm shift with unprecedented opportunities for prolonged and improved life for people with sickle cell disease.
Section snippets
Diagnosis
Sickle cell disease is caused by the inheritance of abnormal beta-globin alleles carrying the sickle mutation on the HBB gene (Glu6Val, βS). The most common and severe form is homozygous HbSS (sickle cell anaemia) with inheritance of βS from both parents, which permits formation of the pathological sickle haemoglobin tetramer (α2βS2, HbS). Other forms of sickle cell disease include compound heterozygous conditions, such as haemoglobin C (HbC) with HbS (HbSC), HbS with β-thalassaemia (HbS/β0
Pathophysiology
In sickle cell disease, erythrocytes undergo rapid but reversible shape change on deoxygenation, and intracellular polymerisation of the abnormal HbS molecule stretches the normal flexible biconcave shape into an elongated rigid form. Sickled erythrocytes cause vaso-occlusion together with many other cellular and plasma factors and abnormal endothelial interactions (figure 1), leading to a broad range of acute and chronic clinical complications caused by repeated ischaemia and inflammation.
Transfusions
The mainstay of treatment for sickle cell disease is erythrocyte transfusions, with more than 90% of adults receiving at least one transfusion in their lifetimes.14 Transfusions are given acutely for immediate benefits, such as increased oxygen-carrying capacity and improved blood flow, using the simple transfusion technique. Chronic transfusions help prevent long-term complications by replacing rigid sickled erythrocytes with normal deformable cells and by suppressing formation of sickled
Global burden of disease
Despite progress to optimise clinical care and expand therapy for sickle cell disease, most observations and research have originated from patients living in North America, UK, or the rest of Europe. However, the worldwide burden is much greater in lower-resource settings and especially in sub-Saharan Africa. According to a published estimate,102 in 2010 there were 312 302 newborns born with HbSS (IQR 294 307–329 729) and over half of these were born in Nigeria, DR Congo, and India. The
Universal TCD screening
Stroke is a devastating clinical complication of sickle cell disease that leaves permanent motor, cognitive, and psychological deficits. TCD measures the maximum time-averaged mean velocity (TAMV) of blood flow in the intra-cranial arteries, and identifies children with abnormal velocities (≥200 cm/s) at highest risk of developing stroke.118 TCD does not identify moya-moya disease or aneurysms; for this reason TCD screening in adults, using adapted TAMV thresholds, should be combined with brain
Role of haemolysis
Much controversy exists about the respective roles of vaso-occlusion and haemolysis in the pathophysiology of sickle cell disease complications. Two sub-phenotypes have been proposed, associating markers of haemolysis with specific clinical complications in contrast with complications related to sickling, vaso-occlusion, and viscosity.135 The mechanism of haemolysis-associated complications is nitric oxide (NO) depletion following intravascular haemolysis, with plasma free haemoglobin directly
Conclusions
Observational studies investigating the pathophysiology of sickle cell disease and its complications have documented the serious morbidity and early mortality of this inherited blood disorder. Interventional research trials have shown the efficacy of transfusions and hydroxycarbamide. We are now entering an exciting era when improved neonatal screening, effective infection prophylaxis, prevention of neurological complications, and early hydroxycarbamide therapy offer the chance to alter the
Search strategy and selection criteria
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