Sickle Cell Anemia and Other Sickling Syndromes

Sickle Cell Anemia and Other Sickling Syndromes

Jane S. Hankins

Winfred C. Wang

This chapter discusses hemoglobin (Hb) variants that cause alterations in erythrocyte morphology and rheology. Hb S, or sickle Hb, is a variant Hb of tremendous clinical importance due to its high prevalence and worldwide distribution. Homozygous Hb SS (sickle cell anemia) alone is the most common heritable hematologic disease affecting humans.

Long before they were recognized in the Western hemisphere, sickling disorders were known in Africa by onomatopoeic names denoting the recurrent, unrelenting, and painful nature of the crises.1, 2 Although symptoms of sickle cell anemia (SCA) could be traced in one Ghanaian family to the year 1670,3 disorders of Hb synthesis went unrecognized by the scientific community until 1910, when Herrick, a Chicago cardiologist, recorded observations made during investigation of anemia in a 20-year-old West Indian student.4 Herrick’s report led not only to the recognition of hundreds of abnormalities of Hb synthesis, but also to a series of remarkable scientific advances involving protein chemistry, molecular biology, physiology, and genetics. The term sickle cell anemia was first used in 1922, when it was recognized that a common African ancestry was present in all initial cases described.5 In 1949, Linus Pauling and collaborators demonstrated for the first time that an abnormal protein could be causally linked to a disease.6 A historical review has been published summarizing the major developments related to sickle cell disease in the first 100 years since the disease’s description.7

The genetic basis for Hb synthesis is discussed in Chapter 22. Each major hemoglobinopathy occurs in both a heterozygous and a homozygous form. In the heterozygous state, red cells contain both normal adult Hb (Hb A) and the variant Hb. Because they rarely have phenotypic expressions of clinical significance, heterozygotes are said to have the trait for that abnormality, for example, sickle cell trait. In the homozygous state, Hb A is totally lacking, and clinical manifestations are of variable severity; individuals so affected have SCA. In addition, disease may result from the combination of two variant hemoglobins or from a variant Hb and an interacting thalassemia gene. These doubly heterozygous states are designated by both aberrant gene products, such as Hb SC disease or Hb S/β-thalassemia. The term sickle cell disease is used in a generic sense to refer to all of the sickling syndromes, although the compound heterozygous HbS/β0-thalassemia is commonly classified as SCA, due to phenotypic similarity to HbSS.


Hb S, so-called because of the sickle shape it imparts to deoxygenated red cells, is responsible for a wide spectrum of disorders that vary with respect to degree of anemia, frequency of crises, extent of organ injury, and duration of survival. Some of the sickling syndromes lack significant pathologic potential, but they are easily confused with clinically aggressive disorders on the basis of laboratory evaluation; consequently, precision in diagnosis is essential both to proper clinical management and to meaningful genetic counseling.

The highest prevalence of Hb S in the world is in sub-Saharan Africa, followed by the Arabian and Indian subcontinents. It occurs with lower frequency in the rest of the world as the result of voluntary or forced population migration from high prevalence areas. Results of studies of DNA polymorphisms linked to the βS gene suggest that it arose from three independent mutations in tropical Africa.8, 9 The most common βS chromosome is found in Benin and central West Africa. A second haplotype is prevalent in Senegal and the African West Coast, and a third haplotype is seen in the Central African Republic (Bantu-speaking Africa). The same three haplotypes are associated with the βS gene in black Americans and Jamaicans.10 The Hb S gene in the eastern province of Saudi Arabia and in Central India is associated with a different DNA structure that is not encountered in Africa and probably represents a fourth independent occurrence of the sickle cell mutation.9 Only the Benin and Senegal haplotypes are prevalent among North Africans, Greeks, and Italians, suggesting that the βS mutation spread to the Mediterranean basin from West Africa.10, 11 In some parts of Africa, as many as 25% of the population have sickle cell trait, whereas in the United States,12, 13 Latin America, and the Caribbean,14 the prevalence of the sickle gene varies from approximately 2% to 8% (Table 33.1). In the United States, the expected incidence of SCA (Hb SS) at birth is 1 in 625. Taking into account recent trends of decreased mortality among children, approximately 100,000 cases of sickle cell disease would be expected among African Americans in the United States.15

Before this century, most individuals with SCA died before the age of reproduction. Without selective advantage to Hb S trait, the sickle gene would have been eliminated. The most widely accepted theory to account for the remarkable stability of the sickle gene in Africa is that of balanced polymorphism.16, 17 Recognition that sickle cell trait has its highest prevalence in areas that are hyperendemic for malaria suggested that Hb S afforded selective protection against lethal forms of malaria (Fig. 33.1).18 Preferential sickling of parasitized cells has been observed in the blood of children with sickle cell trait and malaria.17 Selective removal of sickled cells from the circulation probably reduces the degree of parasitemia and substantially limits the infectious process.


Clinical Features

The clinical features of SCA result more from the vaso-occlusive consequences of sickle cells than from the anemia itself. These features may be divided into those that characteristically are acute and episodic and those that are chronic and often progressive. Although signs and symptoms attributed to Hb S have been observed in early infancy,172 affected individuals char-acteristically are asymptomatic until the second half of the first year of life. The lack of clinical expression of the Hb SS genotype during fetal and early postnatal life is explained by the production of a sufficient quantity of Hb F to limit clinically important sickling. Because erythrocytes contain increasing amounts of Hb S and proportionally decreasing amounts of Hb F over the first several months of life, the conditions for sickling under physiologic conditions gradually are met. Prospective studies of affected infants followed from birth indicate a close temporal relationship between the postnatal decline in Hb F and evolution of anemia.173, 174, 175, 176 Mild hemolytic anemia is apparent by 10 to 12 weeks of age (Fig. 33.5).176, 177

Clinical features change with age. In the first year of life splenomegaly (usually noted after 6 months of age), dactylitis, and ACS are commonly seen.173 Loss of function of the spleen has been documented as early as 5 months of age,176, 178 and death from overwhelming infection is an increased risk before 12 months of age.175 The first vaso-occlusive episode is experienced before 4 years of age by the majority,175 but not until late childhood or adulthood by a few. During adolescent and especially young adult years, organ dysfunction (e.g., renal, pulmonary, cardiac, and hepatic dysfunction) becomes more prevalent and, in older adults frequently causes mortality.143, 179

The Cooperative Study of Sickle Cell Disease and the Jamaican Cohort Study, the two largest prospective sickle cell cohorts to date, have generated information regarding the “natural history” of sickle cell disease in thousands of pediatric and adult patients. More recently, the Dallas Cohort has offered important data about survival and risk factors in sickle cell disease.180

Compound heterozygote states, such as Hb SC and Hb Sβ+-thalassemia, can exhibit any of the clinical features seen in Hb SS, but often do so with lesser frequency and severity. Hb Sβ0-thalassemia has a very similar phenotype to Hb SS, and is often considered together with Hb SS in the literature, sometimes with both conditions being referred to as SCA. The term sickle cell disease is used to describe all clinically significant genotypes that involve Hb S.

Chronic Organ Damage

Growth and Development

The sickling syndromes profoundly affect growth and development. Growth curves for the height, weight, and sexual development of children with SCA were constructed in the 1980s to permit the identification of individuals whose growth delay was greater than what could be accounted for by the hemoglobinopathy (Fig. 33.7).431, 432 Although normal at birth, the heights and weights of children with SCA were significantly delayed by 2 years of age.431, 432, 433 The growth curves maintain a relatively normal configuration but deviate progressively from the normal curves. Increases in velocity of adolescent height and weight growth occur later, and the magnitude of the growth spurt is substantially less than in healthy children. Puberty also is delayed. Menarche occurs 2 to 3 years later than in the general population (median age, 14.0 to 15.5 years),434 and Tanner stage V is not achieved until the median ages of 17.3 and 17.6 years for girls and boys, respectively.432 As in normal subjects, progression through Tanner stages is orderly and appropriate for bone age, and the age of menarche correlates closely with age and weight. By adulthood, both men and women with sickle cell disease appear to acquire normal or near-normal heights, but their mean weights are still lower than those of controls.432 Investigations in small numbers of subjects show that growth hormone, thyroid hormone, adrenocorticotropic hormone and cortisol levels, and pituitary responses to growth-hormone-releasing factor are normal.435 Transient hypogonadism may occur in adolescence. The normal relationship of puberty and growth pattern seen in most patients suggests that the delay in skeletal maturation represents constitutional delay rather than gonadal or pituitary failure.432

FIGURE 33.7. Height and weight (mean, ±1 standard deviation) of American boys and girls with sickle cell anemia (SCA) compared with National Center for Health Statistics growth percentiles. From Phebus CK, Gloninger MF, Maciak BJ. Growth patterns by age and sex in children with sickle cell disease. J Pediatr 1984;105:28, with permission.

Low weight appears to be the most critical variable influencing differences in physical maturation among the sickling syndromes.432 The basis for delay in weight gain is not fully understood, although it has been hypothesized that chronic hemolysis leads to a state of high protein turnover and increased basal metabolic requirements.436 Recent studies have shown that decreased growth velocity in children with SCA was independently associated with decreased Hb concentration and increased total resting energy expenditure (REE).437 REE measured by indirect calorimetry is 15% to 20% greater in Hb SS patients.436, 438, 439 Increased whole-body protein breakdown and protein synthesis may be related to increased bone turnover.440 Prepubertal children with sickle cell disease do not compensate for their higher resting energy expenditure by increasing their energy intake, measured by weighing all food consumed during a 3-day period.441 Furthermore, caloric intake is significantly decreased at the time of an admission for acute illness, contributing to an overall energy deficit.442 When body composition of children and adolescents with sickle cell disease is measured by bioelectrical impedance analysis, male subjects have significantly lower fatfree mass and body fat compared with controls.443 Response to nasogastric dietary supplementation has been reported.444

Other studies have suggested increased requirements for zinc, folate, riboflavin, vitamin B6, ascorbate, and the fat-soluble vitamins A and E, but consistent correlations between deficiencies and growth retardation have not been established.438, 445, 446, 447 A relationship between zinc deficiency and hypogonadism in adults with SCA has been suggested.448 Defective growth hormone secretion, decreased insulinlike growth factor-1, and partial resistance to growth hormone in short children with sickle cell disease were reported.449, 450

Bones and Joints

In addition to the acute episodes of skeletal pain described previously, chronic and progressive destruction of the bones and joints may take place in the absence of clearly defined episodes of pain. The most prominent changes evolve slowly from the cumulative effect of recurrent small episodes of ischemia or infarction within the spongiosa of bone. Radiographs of the long bones of adults show a mottled strandlike increase in density randomly distributed within the medullary region (Fig. 33.8). These irregular areas of increased density are produced by new bone laid down on devitalized trabeculae.451 Because the bone is weakened during the early stages of repair, weight bearing may collapse the femoral head, producing the clinical and radiologic features of osteonecrosis, which affects patients with all the genotypes of sickle cell disease but occurs most often in those with Hb SS and α-thalassemia (4.5 cases/100 patient-years).452 The overall prevalence of osteonecrosis of the hip in persons with sickle cell disease is approximately 10%, but it occurs in 50% in those >35 years of age.452 The prevalence of osteonecrosis of the humoral head is approximately one half as much.453 Typically, the pain from osteonecrosis of the hip begins insidiously, is brought on by walking or quick movements, and is localized to the groin or buttock. After several months, radiographs may show areas of increased density mixed with areas of increased lucency, followed by the appearance of a “crescent sign,” segmental collapse, molding of the femoral head, loss of joint space, involvement of the acetabulum, and complete degeneration of the joint. When osteonecrosis occurs in the femoral capital epiphysis before closure, healing with minimal destruction may occur. However, long-term follow-up shows that in the majority of cases, the hip is painful and permanently damaged.454 Because weight bearing is not required of the shoulder joint, the prognosis of osteonecrosis of the humeral head is substantially better. Only ˜20% of patients have pain or limited range of movement at the time of diagnosis,453 but functional abnormalities of the shoulder may be a long-term consequence in adults.455

FIGURE 33.8. Sickle cell anemia. A: Femur. The cortex is thinned, and the normal bony architecture is disturbed. Adjoining small areas of translucency are areas of sclerosis. B: Tibia and fibula. Marked thinning of the cortex of the bones as well as periosteal reaction and disarrangement of the trabeculae. The latter changes and the extensive coarseness of the cortical layers suggest the bone is involved from within.

Avoidance of weight bearing in the early phases of bone necrosis may permit sufficient repair to preserve reasonable joint function. More often, however, the deformity is progressively crippling. Total hip replacement is usually recommended for the painful hip in stage III or IV or for restoration of joint movement, if this is desired. However, the prognosis for hip replacement has been suboptimal, with a 30% chance that arthroplasty will require revision within 4 to 5 years.456, 457 For stage I and II osteonecrosis, core decompression, in which a core of cancellous bone ˜8 mm in diameter is removed from the neck and head of the femur through an incision in the lateral cortex, has been of benefit.458, 459 In a prospective randomized trial, physical therapy alone appeared to be as effective as hip core decompression followed by physical therapy, improving hip function and postponing the need for additional surgical intervention at a mean of 3 years after treatment.460 Grafting with autologous bone marrow obtained from the iliac crest is a possible new option for osteonecrosis of the hip.461 This technique, which is currently investigational, appears most effective in the early stages of osteonecrosis, before subchondral collapse has occurred, and provides progenitor cells to the proximal femur which stimulate bone remodeling.

Another characteristic bone change develops in the vertebral column of some individuals during the second decade of life. Recurrent infarcts of the main vertebral arteries lead to ischemic damage of the central portion of the vertebral body growth plates. Because the outer portion of the plates is supplied by numerous apophyseal arteries, vertebral growth is irregular, producing a “fish-mouth” deformity in which symmetric cuplike depressions are confined to the central three fifths of the vertebral plates.462 Other skeletal changes result from expansion of medullary cavities owing to long-standing erythroid hyperplasia. Radiographs of the skull show a thickening of the diplöe and thinning of the outer table of the calvaria in the frontal and parietal regions. Gnathopathy (prominent maxillary overbite) may result from overgrowth of maxillary bone and frequently leads to significant malocclusion.463

Low bone mass density (osteopenia and osteoporosis) has been recognized in adults and more recently in children.209, 464 and has been associated with the severity of hemolysis.465 Vitamin D replacement in those cases of vitamin D deficiency has been reported to offer salutary effects on bone mass density.466

Joints may be affected by avascular necrosis of adjacent bone.467 The joint effusion, pain, fever, and leukocytosis accompanying such infarcts make differentiation from septic arthritis difficult. Numerous neutrophils and sickled erythrocytes are found in the joint fluid.468 Less commonly, joint disease is related to infection,469 gout,470 or synovial hemosiderosis. Adults may have deformities of the hands and feet with shortening of the digits, the remote sequelae of dactylitis during early childhood.471

Cognitive Function

Multiple studies have reported deficits in global and specific neuropsychologic functioning in school-aged children with sickle cell disease when compared with their siblings or healthy children.472, 473, 474 Children with SCA who have experienced an overt stroke have significant cognitive impairment, reduced language function, and problems in adjustment.475 Diminished performance has been noted in the areas of visual-motor integration, attention and concentration, arithmetic, memory, and reading. Similarly to children, adults with SCA have poorer cognitive performance when compared with healthy controls, even without a history of prior stroke.476 Significant areas of deficit in adults with SCA were in working memory, processing speed, and measures of executive function.

MRI data from several studies investigating the central nervous system of children with Hb SS without a history of overt stroke show a prevalence of SCI varying from 11% to 37%.284, 285, 477, 478 Data from the CSSCD gathered over a 10-year period of follow-up of school-aged children with Hb SS indicated that those with SCI had significantly lower scores for math and reading achievement, full-scale intelligence quotient (IQ), verbal IQ, and performance IQ, when compared with individuals with normal MRI of the brain.472 However, even in children with normal MRI findings, the scores for verbal IQ and math achievement declined with increasing age.479 A meta-analysis of 17 reports of cognitive functioning in children concluded that sickle cell disease is associated with detrimental effects even in the absence of cerebral infarction on MRI.480 Direct effects of sickle cell disease on brain function or indirect effects of chronic illness may be important. A multi-institutional study from France in which children with sickle cell disease were compared to sibling controls reported impaired cognitive function in patients both with a history of stroke and with SCI.481 In addition, a hematocrit <20% and a platelet count >500 × 109/L were independent risk factors for cognitive deficiency. Patients with infarction in the frontal lobe differed from their peers in measures of attention, executive function, and memory.482, 483 In another study, children with SCI had twice the rate of school difficulties as those without infarcts, including poor educational attainment, defined as repeating a grade in school because of lack of educational progress, a requirement for special educational services, or both.484

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Oct 21, 2016 | Posted by in HEMATOLOGY | Comments Off on Sickle Cell Anemia and Other Sickling Syndromes

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