eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Sickle Cell Anemia

Author: Ariel Distenfeld, MD, Clinical Professor, Department of Medicine, New York University School of Medicine
Coauthor(s): Ulrich Woermann, MD, Consulting Staff, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland
Contributor Information and Disclosures

Updated: Aug 26, 2009

Introduction

Background

Sickle cell disease (SCD) and its variants are genetic disorders of mutant hemoglobins (Hb). The most common form found in North America is homozygous Hb S disease, first described by Herrick in 1910. Morbidity, frequency of crisis, degree of anemia, and the organ systems involved vary considerably from individual to individual.

Pathophysiology

Hb S arises from a mutation substituting thymine for adenine in the sixth codon of the beta-chain gene, GAG to GTG. This causes coding of valine instead of glutamate in position 6 of the Hb beta chain. The resulting Hb has the physical properties of forming polymers under deoxy conditions. It also exhibits changes in solubility and molecular stability. These properties are responsible for the profound clinical expressions of the sickling syndromes.

• Oxygen tension
  • Polymer formation occurs only in the deoxy state.
  • If oxygen is present, the liquid state prevails.
• Concentration of hemoglobin S
  • The normal cellular Hb concentration is 30 g/dL.
  • Gelation of Hb S occurs at concentrations greater than 20.8 g/dL.
• The presence of other hemoglobins
  • Normal adult hemoglobin (Hb A) and fetal hemoglobin (Hb F) have an inhibitory effect on gelation.
  • These and other Hb interactions affect the severity of clinical syndromes. Hb SS produces a more severe disease than sickle cell Hb C (Hb SC), Hb SD, Hb SO Arab, and Hb with one normal and one sickle allele (Hb SA).

When red blood cells (RBCs) containing homozygous Hb S are exposed to deoxy conditions, the sickling process begins. A slow and gradual polymer formation ensues. Electron microscopy reveals a parallel array of filaments. Repeated and prolonged sickling involves the membrane; the RBC assumes the characteristic sickled shape.

• After recurrent episodes of sickling, membrane damage occurs and the cells are no longer capable of resuming the biconcave shape upon reoxygenation. Thus, they become irreversibly sickled cells (ISCs). From 5-50% of RBCs permanently remain in the sickled shape.
• When RBCs sickle, they gain Na⁺ and lose K⁺. Membrane permeability to Ca⁺⁺ increases, possibly due, in part, to impairment in the Ca⁺⁺ pump that is dependent on adenosine triphosphatase (ATPase). The intracellular Ca⁺⁺ concentration is 4 times the reference level. The membrane becomes more rigid, possibly due to changes in cytoskeletal protein interactions; however, these changes are not found consistently. Also, whether calcium is responsible for membrane rigidity is not clear.
• Membrane vesicle formation occurs, and the lipid bilayer is perturbed. The outer leaflet has increased amounts of phosphatidyl ethanolamine and contains phosphatidyl serine. The latter may play a role as a contributor to thrombosis, acting as a catalyst for plasma clotting factors. Membrane rigidity can be reversed in vitro by replacing Hb S with Hb A, suggesting that Hb S interacts with the cell membrane.
• Sickle cells express very late antigen (VLA)-4 on the surface. VLA-4 interacts with the endothelial cell adhesive molecule, vascular cell adhesive molecule (VCAM)-1. VCAM-1 is upregulated by hypoxia and inhibited by nitric oxide. Hypoxia also decreases nitric oxide production, thereby adding to the adhesion of sickle cells to the vascular endothelium. Nitric oxide is a vasodilator. Free Hb is an avid scavenger of nitric oxide. Because of the continuing active hemolysis, there is free Hb in the plasma, and it scavenges nitric oxide. This makes it less available and contributes to vasoconstriction.
• Sickle RBCs adhere to endothelium because of increased stickiness. The endothelium participates in this process as do neutrophils, which also express increased levels of adhesive molecules.
• Deformable sickle cells express CD18 and adhere abnormally to endothelium up to 10 times more than normal cells, while ISCs do not. As paradoxical as it might seem, individuals who produce large numbers of ISCs have fewer vasoocclusive crises than those with more deformable RBCs.
• Sickle cells also adhere to macrophages. This property may contribute to erythrophagocytosis and the hemolytic process. The microvascular perfusion at the level of the prearterioles is influenced by RBCs containing Hb S polymers. This occurs at arterial oxygen saturation, before any morphologic change is apparent.
• Hemolysis is a constant finding in sickle cell syndromes. Approximately one third of RBCs undergo intravascular hemolysis, possibly due to loss of membrane filaments during oxygenation and deoxygenation. The remainder hemolyze by erythrophagocytosis by macrophages. This process can be partially modified by Fc (crystallizable fragment) blockade, suggesting that the process can be mediated by immune mechanisms.
• Sickle RBCs have increased immunoglobulin G (IgG) on the cell surface. Vasoocclusive crisis is often triggered by infection. Levels of fibrinogen and fibronectin and the D-dimer are elevated in these patients. Plasma clotting factors likely participate in the microthrombi in the prearterioles.
• These physiological changes result in a disease with the following cardinal signs: (1) hemolytic anemia, (2) painful vasoocclusive crisis, and (3) multiple organ damage with microinfarcts, including heart, skeleton, spleen, and central nervous system.

Frequency

United States

The sickle gene is present in approximately 8% of black Americans. The expected incidence of sickle cell anemia in the United States is 1 in 625 persons at birth. The actual prevalence is less because of early mortality. More than 2 million people in the United States, nearly all of them of African American ancestry, carry the sickle gene. More than 30,000 patients have homozygous Hb S disease.

International

In several sections of Africa, the prevalence of sickle cell trait (heterozygote) is as high as 30%.

Mortality/Morbidity

• SCD diagnosis is suggested with the typical clinical picture of chronic hemolytic anemia and vasoocclusive crisis. It is confirmed when the presence of homozygous Hb S is demonstrated by electrophoresis. This test documents Hb SS, Hb SC, or Hb S-beta+ thalassemia, as common examples. Patients with Hb SA are heterozygous carriers and essentially are asymptomatic. Morbidity is highly variable in patients with SCD, partly depending on the level of Hb F. Nearly all individuals with the condition are affected to some degree and experience multiple organ system involvement. Vasoocclusive crisis and chronic pain are associated with considerable economic loss and disability.
• Mortality is high, especially in the early childhood years. Since the introduction of widespread penicillin prophylaxis and pneumococcal vaccination, a marked reduction has been observed in childhood deaths. The leading cause of death is acute chest syndrome. Based on data from the cooperative study of the SCD group in 1995, the life expectancy is 42 years for males and 48 years for females. Median survival is approaching 50 years, which is considerably less than life expectancy for African Americans who do not have SCD.
• In Africa, available mortality data are sporadic and incomplete. Many children are not diagnosed, especially in rural areas, and death is often attributed to malaria or other comorbid conditions.

Race

SCD is present mostly in blacks. It also is found, with much less frequency, in eastern Mediterranean and Middle East populations.

Sex

The male-to-female ratio is 1:1.

Age

SCD is a lifelong condition. It first manifests in the second half of the first year of life and persists for the entire lifespan.

Clinical

History

The presenting symptoms of SCD involve pain and anemia.

• SCD usually manifests early in childhood.
  • For the first 6 months of life, infants are protected largely by elevated levels of Hb F; soon thereafter, the condition becomes evident.
  • The following 3 prognostic factors have been identified as predictors of an adverse outcome: (1) dactylitis in infants younger than 1 year, (2) Hb level of less than 7 g/dL, and (3) leukocytosis in the absence of infection.
• The most common clinical picture during adult life is vasoocclusive crisis.
  • The crisis begins suddenly, sometimes as a consequence of infection or temperature change, such as an air-conditioned environment during a hot summer day. However, often, no precipitating cause can be identified.
  • Severe deep pain is present in the extremities, involving long bones. The abdomen is affected with severe pain resembling acute abdomen. The face also may be involved. Pain may be accompanied by fever, malaise, and leukocytosis. The person in crisis is in extreme discomfort.
  • The crisis may last several hours to several days and terminate as abruptly as it began.
• Approximately half the individuals with homozygous Hb S disease experience vasoocclusive crisis.
  • The frequency of crisis is extremely variable. Some have as many as 6 or more episodes annually, whereas others may have episodes only at great intervals or none at all.
  • Each individual typically has a consistent pattern for crisis frequency.
• Many individuals with Hb S disease experience chronic low-level pain, mainly in bones and joints. Intermittent vasoocclusive crisis may be superimposed, or chronic low-level pain may be the only expression of the disease.
• Anemia is universally present.
  • It is chronic and hemolytic in nature and usually very well tolerated.
  • While patients with an Hb level of 6-7 g/dL who are able to participate in the activities of daily life in a normal fashion are not uncommon, their tolerance for exercise and exertion tends to be very limited.
  • Anemia may be complicated with megaloblastic changes secondary to folate deficiency. These result from increased RBC turnover and folate utilization. Periodic bouts of hyperhemolysis may occur.
  • A serious complication is the aplastic crisis.
    • This is caused by infection with the Parvovirus B-19 (B19V). The virus infects RBC progenitors in bone marrow, resulting in cessation of erythropoiesis.
    • Coupled with greatly shortened RBC lifespan, usually 10-20 days, a very rapid drop in Hb occurs.
    • The condition is self-limited, with bone marrow recovery occurring in 7-10 days, followed by brisk reticulocytosis.
• During childhood and adolescence, the disease is associated with growth retardation, delayed sexual maturation, and being underweight. Over a 2-year period, Rhodes et al assessed preadolescent children with homozygous sickle cell anemia to determine a correlation between the causes of impaired growth and maturation with metabolic and hematologic factors during puberty in these children.⁸⁴ Height, weight, body mass index, and body composition changes were longitudinally and compared between the groups and with Z scores based on US growth charts.The investigators found children with sickle cell anemia progressed more slowly through puberty than healthy control children. Affected pubertal males were shorter and had significantly slower height growth than their unaffected counterparts, with a decline in height over time; however, the annual weight increases didn't differ between the 2 groups of males.⁸⁴ In addition, the mean fat free mass increments in affected males and females were significantly less than those of the control children. Overall, Rhodes et al demonstrated children with sickle cell anemia have growth delays during puberty and the decreased growth velocity is independently associated with decreased Hb concentration and increased total energy expenditure.⁸⁴ Several other processes also occur at this time.

• The spleen enlarges in the latter part of the first year of life.
  • Occasionally, it undergoes a sudden very painful enlargement due to pooling of large numbers of sickled cells. This phenomenon is known as splenic sequestration crisis.
  • The spleen undergoes repeated infarction, aided by low pH and low oxygen tension in the sinusoids and splenic cords.
  • Even while enlarged, its function is impaired, as evidenced by its failure to take up particulate matter such as technetium during nuclear scanning.
  • Over time, the spleen becomes fibrotic and shrinks. This is, in fact, an autosplenectomy.
  • The nonfunctional spleen is a major contributor to the immune deficiency that exists in these individuals. Failure of opsonization and an inability to deal with infective encapsulated microorganisms, particularly Streptococcus pneumoniae, ensue.
• Pneumococcal infections are common in childhood.
  • During adult life, infections with gram-negative organisms, especially Salmonella, predominate.
  • Of special concern is the frequent occurrence of Salmonella osteomyelitis in areas of bone weakened by infarction.
• Another problem occurring in infancy is hand-foot syndrome.
  • This is a dactylitis presenting as painful swelling of the dorsum of the hand and foot.
  • Cortical thinning and destruction of the metacarpal and metatarsal bones appear on radiographs 3-5 weeks after the swelling begins.
  • Leukocytosis or erythema does not accompany the swelling.
• The acute chest syndrome consists of chest pain, fever, tachypnea, leukocytosis, and pulmonary infiltrates.
  • This is a medical emergency and must be treated immediately.
  • It probably begins with infarction of ribs, leading to chest splinting and atelectasis.
  • Fat embolism, resulting from bone marrow infarction, plays an important etiological role in the pathogenesis of this syndrome.
  • If not attended to promptly, it may lead to acute respiratory distress syndrome (ARDS).
• Central nervous system involvement is one of the most devastating aspects of SCD.
  • It is most prevalent in childhood and adolescence.
  • The most severe manifestation is stroke, resulting in varying degrees of neurological deficit. The stroke is mostly thrombotic, but it may also be hemorrhagic.
  • Vigorous diagnostic and therapeutic efforts may have a beneficial impact on the outcome of this condition. All children with SCD should be screened with transcranial Doppler. Those in whom increased velocity is found should be considered for chronic transfusion therapy, maintaining the level of Hb S at 30% or less. The specific cut off point depends on the method used and is lower for duplex Doppler.
• The heart is involved due to chronic anemia and microinfarcts.
  • Hemolysis and blood transfusion lead to hemosiderin deposition in the myocardium.
  • Both ventricles and the left atrium are all dilated.
  • Usually, a systolic murmur is present, with wide radiation over the precordium.
• Chronic hemolysis with hyperbilirubinemia is associated with the formation of bile stones. Cholelithiasis may be asymptomatic or result in acute cholecystitis, requiring surgical intervention. In addition, a hepatopathy may be present.
• Repeated infarction of joints, bones, and growth plates leads to aseptic necrosis, especially in weightbearing areas such as the femur. This complication is associated with chronic pain and disability and may require changes in employment and lifestyle.
• Blood in the pulmonary circulation is deoxygenated, resulting in a high degree of polymer formation.
  • The lungs develop areas of microinfarction. The resulting areas that lack oxygenation aggravate the sickling process.
  • Pulmonary hypertension may develop. This may be due in part to the depletion of nitric oxide. Various studies have found that more than 40% of adults with SCD have pulmonary hypertension that worsens with age.
• The kidneys lose concentrating capacity.
  • Isosthenuria results in a large loss of water, further contributing to dehydration in these patients. Renal failure may ensue, usually preceded by proteinuria.
  • Nephrotic syndrome is uncommon but may occur.
• Paraorbital facial infarction may result in ptosis.
  • Retinal vascular changes also occur.
  • A proliferative retinitis is common in Hb SC disease and may lead to loss of vision.
• Leg ulcers are a chronic painful problem. They result from minor injury to the area around the malleoli. Because of relatively poor circulation, compounded by sickling and microinfarcts, healing is delayed and infection is established.
• Priapism is a serious complication and tends to occur repeatedly. When it is prolonged, it may lead to impotence.
• Pregnancy represents a special area of concern. The high rate of fetal loss is due to spontaneous abortion. Placenta previa and abruption are common due to hypoxia and placental infarction. At birth, the infant often is premature or has low birth weight.

Physical

• Physical findings are not specific.
  • Scleral icterus is present, and, upon ophthalmoscopic examination of the conjunctiva with the +40 lens, abnormal or corkscrew-shaped blood vessels may be seen.
  • The mucous membranes are pale.
  • A systolic murmur may be heard over the entire precordium.
  • In childhood, splenomegaly is present, although this is not present in adults due to autosplenectomy. In adulthood, leg ulcers may be found over the malleoli.

Causes

• SCD originated in West Africa, where it has the highest prevalence.
  • It also is present to a lesser extent in India and the Mediterranean region.
  • DNA polymorphism of the beta S gene suggests that it arose from 5 separate mutations, 4 in Africa and 1 in India and the Middle East.
    • The most common of these is an allele found in Benin in West Africa.
    • The other haplotypes are found in Senegal and Bantu, Africa, as well as in India and the Middle East.
• The Hb S gene, when present in homozygous form, is an undesirable mutation, so a selective advantage in the heterozygous form must account for its high prevalence and persistence.
  • Malaria is possibly the selecting agent because a concordance exists between the prevalence of malaria and Hb S. Sickling might protect a person from malaria by either of the following:
    • Accelerating sickling so that parasitized cells are removed
    • Making it more difficult for the parasite to metabolize or to enter the sickled cell
  • While children with sickle cell trait Hb SA seem to have a milder form of falciparum malaria, those with homozygous Hb S have a severe form that is associated with very high mortality rate.

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