The Medline database was searched from 1966 to June, 2004 for specific topics in relation to sickle-cell disease pathophysiology, complications, and treatment. We prioritised articles published in high-quality journals, natural history studies, and randomised controlled trials. Personal knowledge and clinical experience was finally used to complete the picture, where gaps in knowledge still remain.
SeminarSickle-cell disease
Introduction
Knowledge of a disease heralded by painful episodes and leading to early death has existed in Africa for over a century.1 James Herrick,2 a physician and Chaucer scholar, first identified sickle cells in a medical student from Grenada. Several seminal observations related to sickle-cell disease dot the landscape of the first half of the 20th century: Linus Pauling3 showed the abnormal electrophoretic mobility of haemoglobin in an affected individual; Vernon Ingram4 discovered that the defect of the disease was a single aminoacid substitution in the haemoglobin molecule of sickle cells (HbS); Max Perutz,5 who deciphered the structure of haemoglobin, elucidated the molecular basis of its function; and Janet Watson,6 who noted that symptoms appeared in infants only after concentrations of fetal haemoglobin (HbF) had fallen, established the notion of the beneficial effect of HbF on disease manifestations.
Section snippets
Genetic epidemiology of the sickle gene
The sickle gene has a genetic advantage: it protects heterozygous carriers from succumbing to endemic Plasmodium falciparum malaria infection.7 However, with the increased premature death rate of homozygous individuals, the sickle gene is an example of balanced polymorphism.7 Globin haplotypes of the gene are based on a series of restriction-endonuclease-defined polymorphisms in the globin-gene cluster on chromosome 11.8, 9 The βs-globin gene is present on three major distinct African
HbS polymerisation
A single nucleotide substitution (GTG for GAG) in the sixth codon of the β-globin gene results in the substitution of valinefor glutamic acid on the surface of the variant β-globin (βs globin) chain (figure 2A).13 This change allows HbS to polymerise when deoxygenated, since valine can dock with complementary sites on adjacent globin chains. The polymerisation of deoxygenated HbS is the primary indispensable event in the molecular pathogenesis of sickle-cell disease. It is dependent on
Extra-erythrocyte-related pathophysiological changes
Natural history studies and animal data implicate the leucocyte as of major importance in the pathophysiology of sickle-cell disease. Raised white cell counts predict disease severity47 and mortality,48 whereas an increased baseline white cell count is an independent risk factor for acute chest syndrome49 and cerebral infarction.50 The syndromes of acute chest and multiple organ failure have also occurred after administration of myeloid colony stimulating factors.51 Qualitative abnormalities in
Selected acute clinical syndromes
The Cooperative Study of Sickle Cell Disease, formed in 1979 among US institutions, started a new era in clinical sickle-cell research. Another cohort that has provided much clinical information is the Jamaican cohort.
Chronic organ dysfunctions
Neonatal screening and the introduction of prophylactic penicillin in early childhood has reduced mortality to less than 2% by 10 years of age.130 The average lifespan in the USA for men and women with HbSS has increased to 42 and 48 years, compared with ages of 60 and 68 years in those with HbSC disease.48 These changes in life expectancy have shifted the spectrum of clinical problems to an increased focus on chronic organ dysfunction in developed countries. Table 2 describes the salient
Select management issues
Management of sickle-cell disease needs a concerted team effort (panel 6). Fragmented care can be disastrous, since life-threatening complications might not be recognised in time by practitioners unfamiliar with the nuances of acute sickle presentations. Chronic problems could also be left unidentified. To complement another review,132 we will discuss specific management issues, and summarise standard and promising new treatments.
Ion-channel blockers
As discussed earlier, cation homoeostasis is important in sickle pathogenesis (Table 1).23 Combination therapy with additional agents (acting synergistically) merits further consideration.
Antiadhesion and anti-inflammatory treatment: future prospects
Antiadhesion and anti-inflammatory treatments also have potential prospects to ameliorate sickle-cell disease. Since the endothelium is the template on which adhesion occurs, inhibition strategies providing maximum benefit might include the targeting of single molecules (such as P-selectin), that mediate
Search strategy and selection criteria
Conflict of interest statement
We declare that we have no conflict of interest.
References (172)
Sickle-cell anaemia: an explanation for the ancient myth of reincarnation in Nigeria
Lancet
(1983)- et al.
Sickle cell hemoglobin polymerization
Adv Protein Chem
(1990) - et al.
Monoclonal antibodies to αvβ3 (7E3 and LM609) inhibit sickle red blood cell-endothelial interactions induced by platelet-activating factor
Blood
(2000) - et al.
Membrane transport in sickle cell disease
Blood Cells Mol Dis
(2002) Therapeutic strategies for prevention of sickle cell dehydration
Blood Cells Mol Dis
(2001)- et al.
Adhesion of normal and sickle erythrocytes to endothelial monolayer cultures
Blood
(1979) - et al.
Integrin α4 β1 and glycoprotein IV (CD36) are expressed on circulating reticulocytes in sickle cell anemia
Blood
(1993) - et al.
α4β1-integrin expression on sickle reticulocytes: vascular cell adhesion molecule-1-dependent binding to endothelium
Blood
(1993) - et al.
Sickle reticulocytes adhere to VCAM-1
Blood
(1995) - et al.
Vascular cell adhesion molecule-1 is involved in mediating hypoxia-induced sickle red blood cell adherence to endothelium: potential role in sickle cell disease
Blood
(1996)