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CHAPTER 49 There is considerable heterogeneity in the severity of the disease; the best known

DISORDERS OF modifier of the disease is an elevated level of fetal hemoglobin (HbF), which
exerts a potent antisickling effect. Concomitant α-thalassemia is also a modifier,
HEMOGLOBIN STRUCTURE: which leads to a decrease in hemolysis. There is an interest in nonglobin genetic
modifiers of sickle cell disease. Over the past 3 decades, advances in supportive
SICKLE CELL ANEMIA AND care and implementation of disease-modifying therapies, such as anti–γ to
β-globin switching therapies, which result in increased HbF and less HbS syn-
thesis, and have led to an increase in life expectancy. Hydroxyurea has emerged
RELATED ABNORMALITIES as an effective disease-modifying agent that has been approved by the FDA for
use in adults with sickle cell disease. Although its main mechanism of action
is to enhance HbF production, other effects such as a decrease in neutrophils,
platelets, and decreased expression of adhesion molecules contribute to its
Kavita Natrajan and Abdullah Kutlar
efficacy. Novel antiswitching agents, most notably, DNA methyltransferase 1
inhibitors (5′-azacytidine and decitabine) and histone deacetylase inhibitors
(butyrate derivatives and others) are now in clinical trials. Evolving thera-
SUMMARY pies include antiadhesive therapies to prevent interaction of sickle cells with
microvascular endothelium, antiinflammatory approaches, and modulation of
Hemoglobinopathies are the most common inherited red cell disorders world- hemoglobin–oxygen affinity to prevent sickling. To date, the only curative ther-
wide. Among these disorders, sickle cell syndromes and thalassemias consti- apy remains allogeneic hematopoietic stem cell transplantation.
tute a major public health problem. A glutamic acid to valine substitution at the Sickle trait, the heterozygous state for sickle hemoglobin, affects approxi-
sixth amino acid of the β-globin chain of human hemoglobin (HbA) results in mately 8 percent of Americans of African descent, and with rare exceptions is
formation of sickle hemoglobin (HbS). Sickle cell disease results from homozy- asymptomatic. HbC is associated with target cells and spherocytes in the blood
gosity for this mutation, or from a compound heterozygosity for sickle hemo- film and splenomegaly. HbD disease is essentially asymptomatic. HbE is very
globin and β-thalassemia or another β-globin variant such as HbC, HbD, HbE, or common in Southeast Asia, and because of large population movements from
HbO . The sickle mutation renders the hemoglobin molecule insoluble upon this area, it has become a prevalent hemoglobinopathy in other regions of the
Arab
deoxygenation; thus red blood cells containing deoxy HbS polymer are rigid world. HbE is a thalassemic variant and its coinheritance with β -thalassemia
0
and have impaired rheologic properties. The downstream effects of the sick- mutations can result in severe transfusion-dependent thalassemia major.
ling process include: membrane changes leading to potassium loss and cellular Unstable hemoglobin variants appear as rare, sporadic cases and are charac-
dehydration, interaction of sickle hemoglobin with microvascular endothe- terized by a Heinz body hemolytic anemia. Variants that alter the oxygen affin-
lium, neutrophils, and monocytes, hemolysis, nitric oxide depletion, release of ity of the Hb molecule lead to erythrocytosis (high oxygen affinity variants) or
inflammatory proteins and activation of coagulation. These processes lead to a anemia (low oxygen affinity variants) and are rare causes of these syndromes.
hemolytic anemia, an inflammatory state, painful vasoocclusive episodes, and
damage to multiple organ systems with a resultant shortened life expectancy.
THE STRUCTURE AND FUNCTION OF
NORMAL HEMOGLOBIN
Acronyms and Abbreviations: ACS, acute chest syndrome; ADMA, asymmetric The red protein hemoglobin (Hb) serves to transport oxygen from the
dimethylarginine; AHSCT, allogeneic hematopoietic stem cell transplantation; BMP, lungs to the tissues and carbon dioxide (CO ) from the tissues to the
2
bone morphogenic protein; 2,3-BPG, 2,3-bisphosphoglycerate; CO carbon dioxide; lungs. Hb also binds the physiologically important nitric oxide (NO)
2,
CSSCD, Cooperative Study of Sickle Cell Disease; eNOS, endothelial nitric oxide syn- molecule. The protein has evolved to perform its gas transport functions
thase; Hb, hemoglobin; HbAS, sickle cell trait; HbF, fetal hemoglobin; HbS, sickle in a highly efficient manner. The oxygen affinity of Hb permits nearly
hemoglobin; HbSC, sickle cell–HbC disease; HIF, hypoxia-inducible factor; HLA complete saturation with oxygen in the lungs, as well as efficient oxy-
human leukocyte antigen; HPLC, high-performance liquid chromatography; IL, gen unloading in the tissues because of its sigmoid oxygen dissociation
interleukin; iNKT cells, invariant natural killer T cells; K , potassium; LDH, lactate curve. This curve results from the fact that Hb is a four-subunit, allosteric
+
dehydrogenase; MCHC, mean cell hemoglobin concentration; MCV, mean corpuscu- molecule; its conformation, and hence the oxygen affinity, changes as
lar volume; MPs, microparticles; MRI, magnetic resonance imaging; NO, nitric oxide; each successive molecule of oxygen is bound. Hb also plays an important
NT-pro-BNP, N-terminal pro–brain natriuretic peptide; O , oxygen; P , point at which role in acid–base balance: deoxyhemoglobin binds protons and oxyhe-
2
50
hemoglobin is one-half saturated with oxygen; PCV7, pneumococcal polyvalent moglobin releases protons. Regulation of the oxygen dissociation curve
conjugate 7; PH, pulmonary hypertension; PIGF, placenta growth factor; P , partial to meet the needs of the body is remarkable. Hypoxic tissues become
O2
pressure of oxygen; R state, relaxed oxy; SCD, sickle cell disease; SCT, stem cell trans- acidotic acutely, and the protons released produce a shift in the oxygen
plantation; sPLA , secretory phospholipase A ; STOP, Stroke Prevention Trial in Sickle dissociation curve that enables more oxygen to be delivered to the tissue.
2
2
Cell Disease; T state, tense, deoxy; TCD, transcranial Doppler; TF, tissue factor; TGF-β, However, longer-term acidosis or alkalosis (as occurs at high altitudes)
transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha; UDP, uridine is counteracted by modulation of red cell 2,3-bisphosphoglycerate
diphosphate; UGT1A1, UDP glucuronosyltransferase 1 family; VOE, vasoocclusive epi- (2,3-BPG), serving to decrease hemoglobin–oxygen affinity (Chap. 47).
sode; VTE, venous thromboembolism. Normal mammalian Hbs contain two pairs of related polypeptide
chains: one chain of each pair is α or α-like and the other is non-α (β, γ,

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