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Sickle Cell Anemia

Clinical Features

Individuals Hemoglobin S disease usually do not manifest symptoms 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. As erythrocytes emerging from the bone marrow carry increasing amounts of Hb S and proportionally decreasing amounts of Hb F, 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

Acute Events: Characteristics, Management, Prevention
Vasoocclusive Events.

The term "sickle cell crisis" was introduced to describe a recurring attack of pain involving the skeleton, chest, and/or abdomen. Using the term in a broader sense, vaso-occlusive "crises" comprise a variety of syndromes that are typically recurrent and potentially catastrophic. Clinical manifestations are sudden in onset and are directly attributable to obstruction of the microcirculation by intravascular sickling. Usually, there is little or no change in hematologic values. Infections often

Hand-Foot Syndrome.

The initial episode in young children often involves the small bones of the hands and feet (the hand-foot syndrome). By 2 years of age, nearly 50% of Jamaican children and 25% of American children with sickle cell anemia have experienced at least one episode of

Painful Crises.

Typically, after the first few years of age, interruption of blood flow occurs in the larger bones of the extremities, spine, rib cage, and periarticular structures, producing painful crises of the bones and

Central Nervous System Events

Stroke is a catastrophic complication of sickle cell anemia that affects 6 to 17% of children and young adults. Two major syndromes are observed: one results from occlusion of major cerebral

Acute Chest Syndrome.

Characterized by fever, tachypnea, chest pain, increased leukocytosis, and pulmonary infiltrates, pulmonary crises are a frequent cause of morbidity and mortality in patients with sickle cell anemia. Because it may be impossible to determine the relative importance of vascular occlusion and infection in the process in any given


Priapism may occur in the majority of boys with sickle cell disease [313] ; it has a bimodal distribution of age of onset with peaks at 5 to 13 years and 21 to 29 years [314] . It may be initiated during the normal erections of REM sleep and may be associated with physiologic dehydration and

Hematologic Crises.

Hematologic crises, characterized by sudden exaggeration of anemia, are pathogenetically and temporally unrelated to vaso-occlusive crises. If unrecognized or untreated, the decrease in

Aplastic Crises.

These events are the most common of the hematologic complications. The pathogenesis and course of aplastic crises in sickle cell anemia are similar to those of other chronic hemolytic states (see Chapter 41) . Several characteristics are indicative of an infectious basis. The crises are characteristically preceded by or associated with febrile illnesses, several members of families with

Hemolytic Crises (Hyperhemolytic Crises).

Such crises result from a sudden acceleration of the hemolytic process. They have been described in association with hereditary spherocytosis and mycoplasma infection. Although approximately 10% of black male patients with sickle cell anemia have the unstable A-variant of

Megaloblastic Crises.

These crises result from the sudden arrest of erythropoiesis by folate depletion . Chronic erythroid hyperplasia imposes a drain on folate reserves and biochemical evidence of mild folate deficiency can be demonstrated with high frequency in subjects with sickle cell anemia [360] . Megaloblastic crises likely occur when food consumption is interrupted by illness or alcoholism or


Overwhelming infection may be the presenting manifestation of sickle cell anemia in early childhood. Acute infection is one of the most common causes of hospitalization and has been the most frequent cause of death, particularly during the first 3 years of life. S. pneumoniae is the most frequent infecting

Prevention of Infection.

Over the past decade, penicillin prophylaxis has emerged as a success story in the management of sickle cell disease. Two controlled trials, one in Jamaica and the other organized by the National Institutes of Health, led to the widespread acceptance of penicillin prophylaxis as standard therapy [398] [399] . In the latter trial, twice-daily oral penicillin V resulted in an 84% reduction in the incidence of pneumococcal bacteremia in infants less than 36 months of age. Current recommendations are to

Chronic Organ Damage
Growth and Development.

The sickling syndromes profoundly affect growth and development. Growth curves for the height, weight, and

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

Central Nervous System.

As expected, children with a history of overt stroke are characterized by borderline to moderate mental retardation, reduced language function, and problems in adjustment [451] . However, several reports in the past decade also have identified deficits in global and/or specific neuropsychological

Cardiovascular System.

The cardiovascular system is stressed by chronic anemia, recurrent small pulmonary artery occlusions, and myocardial hemosiderosis [459] . Autopsies have revealed that right and left ventricular dilation is common in

Pulmonary System.

Chronic pulmonary disease, presumably related to recurring episodes of infarction and infection, is characterized by a decrease in the radiolucency of the lungs and by moderate to severe impairment of pulmonary function. Typically, the vital capacity and total lung capacity are reduced and

Hepatobiliary and Gastrointestinal Systems.

Liver enlargement is present by 1 year of age and persists to a moderate degree throughout life. Analysis of histologic sections reveals distension of sinusoids with sickled cells, Kupffer cell erythrophagocytosis, and varying degrees of periportal fibrosis and hemosiderin pigment. Sickle cell disease may be associated with disturbances in hepatic function. In adult life,


A variety of defects in renal function have been described [508] , and a number of histologic alterations have been noted [509] [510] . Even in the absence of clinically apparent renal disease, small cortical infarcts of varying ages are evident [511] , hemosiderin is deposited in the epithelium of proximal


A variety of ocular lesions result from stasis and occlusion of the small vessels of the eye by sickled erythrocytes. The prominence of end-arterioles within the retina renders this tissue especially vulnerable to irreversible injury after

Leg Ulcers.

Breakdown of the skin over the malleoli and distal portions of the legs is a recurring problem during adult life (Fig. 51.11) . Stasis of blood in the small vessels supplying these areas presumably interferes with the healing of minor traumatic abrasions. Leg ulcers were observed in 2.5% of sickle cell patients over 10 years of age in North America [555] , but they plague as many as 75% of adults


Prognostic expectations for persons with sickle cell anemia have undergone dramatic change as a result of

New Approaches to Therapy

Activation of Hb F Synthesis.

Reversal of ontogeny with reinstitution of Hb F synthesis is a long-standing objective that appears increasingly attainable. This therapeutic strategy is based on the observation that clinical expression of

Bone Marrow Transplantation.

Bone marrow transplantation has the potential to normalize hemoglobin synthesis in patients with sickle cell anemia. The first transplant was performed in a child with both sickle cell anemia and acute myeloblastic