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C H A P T E R 41

PATHOBIOLOGY OF SICKLE CELL DISEASE

Robert P. Hebbel and Gregory M. Vercellotti

Since it was recognized as the “first molecular disease,” sickle cell these define discrete β-locus background haplotypes, referred to as
anemia caused by homozygosity for the mutant sickle beta globin the Senegal, Benin, Bantu, Cameroon, and Arab–India haplotypes
gene has provided the classic paradigm for single-gene disorders. (Fig. 41.2). Each designation refers to an ethnographic region in
Predominant clinical features include hemolytic anemia, episodic which the sickle mutation achieved high gene frequency (typically
painful events, chronic organ deterioration, disparate acute and peaking at 0.10 to 0.15). In most cases, the sickle gene resides on one
chronic complications, and a foreshortened life span. The genesis of of these five major haplotypes.
clinical sickle cell disease is complicated, and an understanding of its
pathophysiology integrates concepts from multiple disciplines,
includes contributions from the red blood cell (RBC) membrane and Origin, Selection, and Dispersion of the Sickle Gene
the vascular wall endothelium, and recognizes the likely participation
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of multiple genetic influences. This chapter addresses the pathophysi- The residence of both β and β alleles on the distinct regional β
ology that underlies the sickle cell disease syndromes described in cluster haplotypes suggests that the sickle mutation arose indepen-
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Chapter 42. dently in the five regions. The β mutation arose only once. Historical
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and biologic data argue that frequency of the β gene greatly expanded
in Africa about 3000 years ago and in South Asia about 4000 years
EARLY YEARS OF SICKLE CELL DISEASE RESEARCH ago, following the introduction of iron tools. That led to adoption
of an agricultural system that promoted both increased human habi-
Sickle disease syndromes were known in folk medicine for centuries tation density and favorable breeding conditions for the mosquito
in parts of Africa, but the eponymous RBC was first reported in vector, Anopheles, which in turn enabled development of endemic
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the medical literature in 1910 when Herrick described a young Plasmodium falciparum. In this context, high fixed β gene frequen-
Grenadian man with recurrent pain, anemia, and sickle-shaped red cies were reached because of a balanced polymorphism, such that
corpuscles in the blood (Fig. 41.1). In 1940, Ham and Castle pos- heterozygotes (HbAS) have an adaptive advantage over either homo-
tulated that sickle disease pathophysiology resulted from a “vicious zygote. Thus the Old World geographic distributions of the sickle
cycle” involving mutually promotive erythrostasis and RBC sickling gene and historical endemic malaria are notably concordant (see Fig.
with adverse viscosity changes. In 1949, Neel validated the Men- 41.2), suggesting that the sickle gene represents “a biologic solution
delian autosomal dominant inheritance of sickle cell anemia, and to a cultural problem.”
Pauling demonstrated presence of an abnormal hemoglobin (Hb) in In hyperendemic areas, falciparum malaria uniformly infects the
patients and carriers. This was followed by observation of the poor young and is the primary cause of death for children with sickle cell
solubility of deoxygenated sickle Hb (HbS) and the reversible sol-gel anemia. However, those with sickle trait are less likely to develop
transformation of HbS solutions. In 1957, Ingram identified the high-level parasitemia or to have severe malaria, an effect largely
underlying amino acid substitution. Thereafter, increasingly detailed exerted early in childhood. At the level of the RBC, this protection
investigations began to reveal the striking complexities of sickle cell reflects steps after initial parasite invasion. One proposed mechanism
disease pathobiology. links protection to the instability of HbS, immune status, and splenic
function. Infection of sickle trait RBCs with P. falciparum leads
sequentially to augmented Hb denaturation, clustering of membrane
GENETIC CONSIDERATIONS protein band 3, attraction of band 3 autoantibody, complement
binding, and enhanced erythrophagocytosis, even of the early ring
Molecular Context forms. Thereby, an accelerated clearance of parasitized RBC by the
spleen could protect those with sickle trait, while HbS homozygotes
The sickle mutation in the HBB gene is a GAG→GTG conversion would lose this protection because of acquiring functional asplenia.
that creates a β 6Glu→Val substitution and thereby forms β globin In synergy with this scenario, presence of HbS (via a different mecha-
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chains. Genes for other β-globin variants are allelic to the β gene nism) impairs microvascular endothelial cytoadherence of infected
and have a codominant impact. Examples include genes for the RBC, thereby diminishing cerebral symptoms and impeding the
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normal β chain (β ), β mutants (e.g., β , β° or β thalassemia), and sequestration that protects parasitized RBC from splenic exposure.
deletional hereditary persistence of fetal Hb (HPFH). Compound The protective benefit of HbAS is lost if there is concurrent alpha
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heterozygosity for β and each one of these results in well-defined thalassemia (which lowers proportion of HbS). Yet, the blunted
clinical syndromes, such as HbAS (i.e., sickle trait), HbSC disease, malarial susceptibility in sickle trait reflects a complex interrelation-
HbS–β-thalassemia, and HbS-HPFH. Eight percent of African ship among the sickle gene, host biology, and environmental factors.
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Americans have a β gene, 3% have β , 1.5% have β-thalassemia, Malarial severity is affected by polymorphisms in nonglobin genes
and 0.1% have HPFH. Among African Americans, about 1 in 600 such as CR1 (complement receptor 1), CD36, TGFB1 (transforming
births results in the homozygous state, sickle cell anemia (HbSS), and growth factor β), and HMOX1 (heme oxygenase 1); a polymorphism
about 1 in 400 results in some form of sickle cell disease, which in TLR4 (toll-like receptor 4) prevalent in sub-Saharan Africa exerts
additionally includes the compound heterozygous variants other than a protective effect. Both carbon monoxide (CO) and nitric oxide
sickle trait. Worldwide, about 75% of sickle cell anemia births now (NO) blunt severity of experimental malaria. And certain microRNA,
occur in sub-Saharan Africa, 15% in India, 5% in the Americans, enriched in HbS-containing RBC, can inhibit P. falciparum growth.
4% in the Eastern Mediterranean, 1% in Europe. Eventually, the sickle gene spread geographically by means of
The HBB gene resides in a cluster of β-like genes within which commerce, migration, and the slave trade. This dispersion has been
are various nonexonic polymorphic sites. Different combinations of tracked by analyses of regional β haplotypes, a biologic marker that
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