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766 Part VI: The Erythrocyte Chapter 49: Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities 767

by two enzymes: adenosine kinase, which phosphorylates adenosine to Plasma tocopherol and zinc levels are low. 114–116 Serum ferritin is
adenosine monophosphate and adenosine deaminase, which converts increased, especially in iron overloaded patients. Elevated brain natri-
adenosine to inosine. Adenosine signals through four different recep- uretic peptide is seen in patients with pulmonary hypertension (PH)
tors that have differing functions. Signaling via the A R expressed on and congestive heart failure. Morphologically, classic sickle red cells
2A
most leukocyte and platelets results in an antiinflammatory effect; how- are seen on blood film examination, and the marrow shows erythroid
ever, signaling via the A R was shown to cause priapism in SCD mice hyperplasia.
2B
via hypoxia-inducible factor (HIF)-1–mediated decrease of phosphodi- Sickle cell anemia can be accurately diagnosed with
esterase 5. Signaling via A R also leads to increased 2,3-BPG in red cells high-performance liquid chromatography (HPLC) and isoelectric
2B
causing decreased oxygen binding affinity of Hb, which promotes sick- focusing. Rapid methods, such as solubility testing and sickling
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ling. Pegylated adenosine deaminase treatment of sickle mice resulted of red cells using sodium metabisulfite, are less-reliable tests. Poly-
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in decreased hemolysis and hypoxia reoxygenation injury. 94,95 merase chain reaction is the method of choice for prenatal diagnosis.
0
No HbA is found in patients with HbSS, HbSC, or HbSβ diseases. Vary-
SICKLE CELL TRAIT ing amounts of HbA (depending on the severity of the β-thalassemia
+
Inheritance of only one HbS allele is termed sickle cell trait (HbAS). An mutation) are found in HbS–β -thalassemia subjects.
estimated 300 million people carry the trait worldwide. The percent-
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age of HbA is always higher (~60 percent) than HbS (~40 percent) in COURSE AND PROGNOSIS
sickle cell trait. Mortality from SCD in the United States has declined since 1968, coin-
HbAS is considered a generally asymptomatic state with HbA in ciding with the introduction of pneumococcal polyvalent conjugate 7
the cell preventing sickling except in the most unusual circumstances. (PVC7) vaccine. Comparison of mortality rates between 1979 to 1998
HbAS cells sickle at O tension of approximately 15 torr. 97 and 1999 to 2009 showed a 61 percent decrease in infants, 67 percent
2
Plasma myeloperoxidase and red cell sickling have been reported to in children ages 1 to 4 years, and 35 percent decrease in children ages 5
increase during exercise with fluid restriction in HbAS subjects. Plasma to 19 years. Transition from pediatric to adult medical care showed an
98
levels of VCAM-1 are higher in HbAS subjects and remain elevated fol- increased mortality trend with similar rises in rates during the decades
lowing exercise compared to normal controls or HbAS with concomitant of comparison. Average life expectancy of patients with HbSS disease
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α-thalassemia, which is suggestive of subtle microcirculatory dysfunc- in the United States is 42 and 48 years for males and females, respec-
tion in this population. Skeletal muscle capillary structures are different tively. In Jamaica, the population has a median survival of 53 years
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in HbAS subjects compared to controls. There is a 30-fold increased risk and 58 years for men and women, respectively, with 44 percent of indi-
of sudden death in black army recruits with HbAS. Although con- viduals born prior to 1943 still living as of 2009. As the sickle cell
100
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troversial, in 2009 the National Collegiate Athletic Association recom- population ages, causes of death change from an infectious etiology to
mended mandatory testing for HbAS for all its student athletes. 101 those related to end-organ damage, such as renal failure.
Renal abnormalities are among the most common manifestations
of HbAS. Anoxia, hyperosmolarity, and low pH of the renal medulla
predisposes to sickling. Microscopic or gross hematuria from renal CLINICAL FEATURES AND MANAGEMENT
papillary necrosis is usually painless. Renal neoplasm or stones should The reader is referred to the National Institutes of Health, National
be excluded in those with persistent gross hematuria. Isosthenuria may Heart, Lung and Blood Institute’s guidelines from 2002 for an exten-
be seen in and may contribute to exercise induced rhabdomyolysis and sive review on the topic; revised guidelines were released in the fall of
sudden death. Renal medullary carcinoma is a rare but serious com- 2014 at http://www.nhlbi.nih.gov/health-pro/guidelines/sickle-cell-dis-
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plication of HbAS. Risk of urinary tract infection is higher in females ease-guidelines/. General approaches to SCD management and pain
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with HbAS, especially during pregnancy. End-stage renal disease occurs management are described separately (Table 49–2).
at an earlier age for HbAS patients with polycystic kidney disease and
HbAS may contribute to erythropoietin resistance. 103
Splenic infarction occurs under extreme environmental conditions Sickle Cell Crises
in persons with HbAS; most resolve spontaneously. 104,105 Caution and The typical course for a sickle cell patient is that of periods of relatively
immediate intervention is also warranted in those HbAS individuals normal functioning despite chronic anemia and ongoing vasoocclusion,
who develop traumatic hyphema. The risk of venous thromboembo- punctuated by periods of increased pain, and serial changes in various
106
lism is increased twofold in HbAS subjects compared to those without laboratory parameters that is termed “a sickle cell crisis.” Crises have
the trait. The risk appears to be greater for pulmonary embolism than typically been classified as VOEs, aplastic crises, sequestration crises,
for deep vein thrombosis. 101,105 HbAS patients do not have increased and hyperhemolytic crises.
perioperative morbidity or mortality. The life span of patients with Vasoocclusive Crises The hallmark of SCD is the VOE. It is the
HbAS is normal. 107 most common clinical manifestation but occurs with varying frequency
in different individuals. It results from increasing vasoocclusion caus-
ing tissue hypoxia, which manifests as pain. Vasoocclusion may affect
LABORATORY FEATURES any tissue, but patients typically have pain in the chest, lower back, and
Sickle cell anemia is characterized by a laboratory profile of evidence of extremities. Abdominal pain may mimic acute abdomen from other
hemolytic anemia with increases in lactate dehydrogenase (LDH), indi- causes. Different patients display different patterns of painful sites
rect bilirubin, reticulocyte count, and a decrease in serum haptoglobin. during a VOE, but each patient’s recurrences usually mimic the same
Anemia is usually normochromic, normocytic with a steady-state Hb pattern of pain. Fever is often present, even in the absence of infec-
level between 5 and 11 g/dL. 1,108 The red cell density is increased with a tion. Episodes may be precipitated by dehydration, infection, and cold
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normal mean cell Hb concentration (MCHC). Serum erythropoietin weather although in about most cases no precipitating factor is found. 124
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level is decreased relative to the degree of anemia. Elevated neutrophil Figure 49–7 illustrates the phases of VOEs. Crises requir-
110
and platelet levels are observed even in asymptomatic patients reflective ing readmission within 1 week occur in approximately 20 percent of
of persistent low-grade inflammation. 111–113 patients after hospital discharge. 125

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