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762 Part VI: The Erythrocyte Chapter 49: Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities 763

Irving Sherman, while a medical student at Johns Hopkins, showed state Medicaid program estimated a lifetime cost of care of $500,000
that sickled red cells were birefringent under a polarizing microscope per patient with SCD. In this patient population, cost increased with
and that this finding was reversible with oxygenation of the cells. This increasing age, including cost of non-SCD health issues. The majority of
observation ultimately led Linus Pauling to study sickle Hb after being the costs were for inpatient healthcare utilization. 14
advised of this property of sickle cell by William Castle, a noted research Previously, speculation existed as to whether the sickle mutation
hematologist. Indeed, in 1949, Pauling and his colleagues demon- arose once and gained worldwide distribution or whether the mutation
strated electrophoretic differences between Hbs from normal, sickle had arisen independently in different regions of the world. The non-
cell trait, and sickle cell anemia subjects and hypothesized that there random association of restriction endonuclease polymorphisms in the
must be chemical differences, thus establishing sickle cell anemia as the β-globin cluster define the β-globin haplotype. The β-globin gene clus-
first molecular disease described. In the late 1950s, Hunt and Ingram ter yields five distinct haplotypes associated with sickle cell mutations
sequenced the globin peptide and linked the abnormality to a change (Chap. 9). 15–17 Four of the five patterns occur in Africa and are desig-
in the amino acid composition of the β-globin chain (replacement of nated as the Senegal, Benin, Bantu, and Cameroon haplotypes, whereas
18
glutamic acid by valine at residue 6). In 1977, Marotta and coworkers the fifth arose on the Indian subcontinent. These findings indicate that
showed that the corresponding change in codon 6 of the β-globin gene the sickle mutation arose independently at five different times.
was GAG→GTG. The discovery of a variant fragment in HbS versus
HbA during restriction endonuclease mapping of amniotic fluid cells PATHOPHYSIOLOGY
by Y. W. Kan paved the way for antenatal diagnosis of SCD and opened
the way for modern genetics using recombinant DNA technology. 5 The sine qua non of sickle cell anemia is a Glu→Val substitution in the
The history of sickle cell anemia serves as an inspiring reminder sixth amino acid of the β-globin gene. However, the pathophysiologic
of the power of clinical and laboratory observations, and in an era of processes that result in the clinical phenotype extend beyond the red
mechanistic basic science research, serves to highlight the importance cell (Fig. 49–5). There is marked clinical heterogeneity from one patient
of bedside to bench and bench to bedside research integration. 6–9 to another and in the same patient over time. The heterogeneity for
the same genotypic abnormality therefore implies that a multitude of
other factors must contribute to the pathology of sickle cell anemia. The
EPIDEMIOLOGY pathology is now far removed from the simplistic theory of hypoxia-in-
The observation that sickle cell trait may have a survival advantage duced microvascular occlusion. Sickle cell anemia is a chronic inflam-
against some environmental factors was first suggested by Dr. Alan matory state punctuated by acute increase in inflammation wherein the
Raper in East Africa in 1949. Drs. Mackey and Vivarelli suggested that endothelium, neutrophils and monocytes, platelets, coagulation path-
the environmental influence might be malaria. It was subsequently ways, several plasma proteins, adhesion molecules, and derangements
noted that blood from sickle cell trait persons contained less malarial in NO metabolism interact in concert with the abnormality in Hb poly-
parasites and that the sickle trait conferred some protection against merization described several decades ago (Fig. 49–6). Abnormal ade-
malaria in early childhood. Data suggest that sickle trait is maximally nosine signaling and activation of invariant natural killer T (iNKT) cells
protective against severe malaria as opposed to asymptomatic para- have been implicated in disease pathophysiology. Added to that are the
sitemia or mild disease. The mechanism of such a protection has been complex differences in tissue-specific vascular beds and differences in
10
the matter of much debate. Plausible mechanisms include selective sick- various parts of the vasculature in the same organ. Also, variation in
ling of parasitized red blood cells, resulting in more effective removal several genes other than the β-globin gene that modify the milieu in
by the monocyte-macrophage system, and inhibitory effect on parasite which organ damage occurs may play a role.
growth by increased red cell potassium loss, decreased red cell pH, and The pathophysiology of sickle cell anemia is described in separate
increased endothelial adherence of parasitized sickle red cells. sections; however, because no single, dominant pathway explains the
Thus, the prevalence of sickle cell anemia closely mirrors the multitude of manifestations, no single therapeutic modality serves to
worldwide distribution of falciparum malaria; however, as a result of abrogate all of the pathology. Most experiments are in isolation in ani-
migration of peoples to the industrialized Western countries, SCD has mal models or relatively simplistic experimental conditions with few in
become more prevalent in areas where malaria is not endemic. vivo studies in humans and thus do not replicate the complexity of this
The World Health Organization estimated in 2006 that 5 percent of disorder.
the world population carries a gene for a hemoglobinopathy. Sickle cell
anemia is highly prevalent in sub-Saharan and equatorial Africa with Hemoglobin Polymerization
lesser but significant prevalence in the Middle East, India, and the Med- Aggregation of deoxy HbS molecules into polymers occurs when aggre-
iterranean region. Incidence of SCD in sub-Saharan African countries gates reach a thermodynamically critical size. This process is termed
ranges between 1 and 2 percent, which translates into approximately homogenous nucleation, and the smallest aggregate formed that favors
500,000 cases per year. In the Jamaican cohort study, newborn screening polymer growth is called the critical nucleus. 19–24 Addition of sub-
in 100,000 consecutive vaginal deliveries resulted in the finding of sickle sequent deoxy HbS molecules to already formed polymers is termed
cell trait in 10 percent of newborns. 11 heterogenous nucleation, which results in polymer branching. Polymer
In the United States, the Centers for Disease Control and Preven- growth is, therefore, an exponential process wherein there is a delay
tion estimates that sickle cell anemia is present in 1 in 500 livebirths time between presence of deoxy HbS molecules and polymer forma-
among Americans of African descent; 1 in 12 American of African tion. This delay time is inversely proportional to the concentration of
descent have the trait, and approximately 100,000 Americans largely of HbS molecules. Polymer formation alters the rheologic properties of the
African descent live with the disease. In Americans of Hispanic descent, red cell.
the rate of SCD is 1 in 36,000 livebirths. Accurate population statistics The quaternary structure of oxy HbS cannot maintain axial and
of SCD are difficult to obtain in the United States because of a lack of lateral hydrophobic contacts unlike that in the deoxygenated state, thus
standardized data collection and central reporting. 12 explaining the unsickling phenomenon upon reoxygenation. 25–28 The
As of 2002, in the United States, more than one billion dollars sickling process that is initially reversible with oxygenation of deoxy
are spent per year on hospitalizations for SCD. Data from a single HbS eventually leads to the formation of sickle-shaped red cells that
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