What is sickle cell anemia? pathogenesis, morphology, and clinical features.

Sickle Cell Anemia

Hemoglobinopathies are a group of hereditary disorders caused by inherited mutations that lead to structural abnormalities in hemoglobin. Sickle cell anemia, the prototypic hemoglobinopathy, is caused by a mutation in B-globin that creates hemoglobin (HLS). Numerous other hemoglobinopathies have been described, but these are infrequent and beyond the scope of this discussion.

Sickle cell anemia is the most common familial hemolytic anemia. In parts of Africa where malaria is endemic, the gene frequency approaches 30% as a result of a protective effect against Plasmodium falciparum malaria. In the United States, approximately 8% of blacks are heterozygous HbS carriers, and about 1 in 600 have sickle cell anemia.

Pathogenesis

• Sickle cell anemia is caused by a single amino acid substitution in β-globin that results in a tendency for deoxygenated HbS to self-associate into polymers.

• Normal hemoglobins are tetramers composed of two pairs of similar chains. On average, the normal adult red cell contains:

  • 96% HbA (α2β2)

  • 3% HbA2 (0282)

  • 1% fetal Hb (HbF, 22)

• In patients with sickle cell anemia, HbA is completely replaced by HbS, whereas in heterozygous carriers, only about half is replaced.

• HbS differs from HbA by having a valine residue instead of a glutamate residue at the 6th amino acid position in β-globin.

• On deoxygenation, HbS molecules undergo a conformational change that allows polymers to form via intermolecular contacts involving the abnormal valine residue.

• These polymers distort the red cell, which assumes an elongated crescentic or sickle shape.

• The sickling of red cells initially is reversible on reoxygenation.

• However, membrane distortion produced by each sickling episode leads to an influx of calcium, which causes the loss of potassium and water and also damages the membrane skeleton.

• With time, this cumulative damage creates irreversibly sickled cells that rapidly undergo hemolysis.

Three factors are particularly important in determining whether clinically significant polymerization of HbS occurs in patients:

1. The intracellular levels of hemoglobins other than Hbs:

   • In heterozygotes approximately 40% of Hb is HbS and the remainder is HbA, which interacts only weakly with deoxygenated HbS.

   • Because HbA greatly retards HbS polymerization, the red cells of HbS heterozygotes have little tendency to sickle in vivo.

   • Such persons are said to have sickle cell trait.

   • Similarly, because fetal hemoglobin (HbF) interacts weakly with HbS, newborns with sickle cell anemia do not manifest the disease until HbF falls to adult levels, generally around the age of 5 to 6 months.

   • Hemoglobin C (HbC), another mutant B-globin, has a lysine residue instead of the normal glutamic acid residue at position 6.

   • About 2.3% of American blacks are heterozygous carriers of HbC, and about 1 in 1250 newborns are compound HBC/HbS heterozygotes.

   • HbC has a great tendency to aggregate with HbS than does HbA, and as a result HbS/HbC compound heterozygotes have a symptomatic sickling disorder called HSC disease

2. The intracellular concentration of Hbs:

   • The polymerization of deoxygenated Hb5 is strongly concentration-dependent.

   • Thus, red cell dehydration, which increases the Hb concentration, facilitates sickling.

   • Conversely, the coexistence of α-thalassemia, which decreases the Hb concentration, reduces sickling.

3. The time required for red cells to pass through the microvasculature:

   • The normal transit times of red cells through capillary beds are too short for significant polymerization of deoxygenated HbS to occur.

   • Hence, the tissues that are most susceptible to obstruction by sickling are those in which blood flow is normally sluggish, such as the spleen and the bone marrow.

   • However, sickling may occur in other microvascular beds in the face of factors that retard the passage of red cells, particularly inflammation.

   • Recall that inflammation slows blood flow by increasing the adhesion of leukocytes and red cells to endothelium and by inducing the exudation of fluid through leaky vessels.

   • In addition, sickle red cells have a greater tendency than normal red cells to adhere to endothelial cells, apparently because repeated bouts of sickling cause membrane damage that makes the red cells sticky.

   • These factors conspire to prolong the transit times of sickle red cells, increasing the probability of clinically significant sickling.

• The sickling of red cells has two major pathologic consequences:

  1. Chronic, moderately severe hemolytic anemia, produced by red cell membrane damage

  2. Vascular obstructions, which result in ischemic tissue damage and pain crises.

• The mean life span of red cells in sickle cell anemia averages only 20 days (one-sixth of normal), and the severity of the hemolysis correlates with the fraction of irreversibly sickled cells that are present in the blood.

• Vasoocclusion, by contrast, does not correlate with the number of irreversibly sickled cells and instead appears to result from superimposed factors such as infection, inflammation, dehydration, and acidosis, all of which enhance the tendency of red cells to sickle within the microvasculature.

Morphology

The anatomic alterations in sickle cell anemia stem from:

1. Severe chronic hemolytic anemia

2. Increased breakdown of heme to bilirubin

3. Microvascular obstructions, which provoke tissue ischemia and infarction.

• In peripheral smears, elongated, spindled, or boat-shaped irreversibly sickled red cells are evident.

• Both the anemia and the vascular stasis lead to hypoxia-induced fatty changes in the heart, liver, and renal tubules.

• There is a compensatory hyperplasia of erythroid progenitors in the marrow.

• The cellular proliferation in the marrow often causes bone resorption and secondary new bone formation, resulting in prominent cheekbones and changes in the skull resembling a "crewcut" in radiographs.

• Extramedullary hematopoiesis may appear in the liver and spleen.

• In children there is moderate splenomegaly (splenic weight up to 500 g) due to red pulp congestion caused by entrapment of sickled red cells.

• However, chronic splenic erythrostasis produces hypoxic damage and infarcts, which with time reduce the spleen to a useless nubbin of fibrous tissue.

• This process, referred to as autosplenectomy, is complete by adulthood.

• Vascular congestion, thrombosis, and infarction can affect any organ, including the bones, liver, kidney, retina, brain, lung, and skin.

• The bone marrow is particularly prone to ischemia because of its sluggish blood flow and high rate of metabolism.

• Priapism, another frequent problem, can lead to penile fibrosis and erectile dysfunction.

• As with the other hemolytic anemias, hemosiderosis and pigment gallstones are common.

Clinical Features

• From its onset, the disease runs an unremitting course punctuated by sudden crises.

• Homozygous sickle cell disease usually is asymptomatic until 6 months of age when the shift from HbF to HbS is complete.

• The anemia is moderate to severe; most patients have hematocrits of 18% to 30% (normal range, 38%-48%).

The chronic hemolysis is associated with hyperbilirubinemia and compensatory reticulocytosis. Much more serious are vasoocculusive crises, which are characteristically associated with pain and often lead to tissue damage and significant morbidity and mortality. Among the most common and serious of these vasoocclusive crises are the following:

• Hand-foot syndrome, resulting from infarction of bones in the hands and feet, is the most common presenting symptom in young children.

• Acute chest syndrome, in which sluggish blood flow in inflamed lung (e.g., an area of pneumonia) leads to sickling within hypoxemic pulmonary beds. This exacerbates pulmonary dysfunction, creating a vicious circle of worsening pulmonary and systemic hypoxemia, sickling, and vasoocclusion. Acute chest syndrome may also be triggered by fat emboli emanating from infarcted bone.

• Stroke, which sometimes occurs in the setting of the acute chest syndrome. Stroke and the acute chest syndrome are the two leading causes of ischemia-related death.

• Proliferative retinopathy, a consequence of vasoocclusions in the eye that can lead to loss of visual acuity and blindness.

Another acute event:

• Aplastic crisis, is caused by a sudden decrease in red cell production. As in hereditary spherocytosis, this usually is triggered by the infection of erythroblasts by parvovirus B19 and, although severe, is self-limited.

In addition to these crises:

• Patients with sickle cell disease are prone to infections.

• Both children and adults with sickle cell disease are functionally asplenic, making them susceptible to infections caused by encapsulated bacteria, such as pneumococci.

• In adults the basis for "hyposplenism" is autoinfarction.

• In the earlier childhood phase of splenic enlargement, congestion caused by trapped sickled red cells apparently interferes with bacterial sequestration and killing; hence, even children with enlarged spleens are at risk for the development of fatal septicemia.

• Patients with sickle cell disease also are predisposed to Salmonella osteomyelitis, possibly in part because of poorly understood acquired defects in complement function.

• In homozygous sickle cell disease, irreversibly sickled red cells are seen in routine peripheral blood smears.

• In sickle cell trait, sickling can be induced in vitro by exposing cells to marked hypoxia.

• The diagnosis is confirmed by electrophoretic demonstration of HbS.

• Prenatal diagnosis of sickle cell anemia can be performed by analyzing fetal DNA obtained by amniocentesis or biopsy of chorionic villi.

• The clinical course of sickle cell disease is highly variable.

• As a result of improvements in supportive care, an increasing number of patients are surviving into adulthood.

• Approximately 50% of patients now survive beyond the fifth decade.

• Of particular importance is prophylactic treatment with penicillin to prevent pneumococcal infections, especially in children younger than age 5.

• A mainstay of therapy is hydroxyurea, a "gentle" inhibitor of DNA synthesis.

• Hydroxyurea reduces pain crises and lessens the anemia through several effects, including:

  1. An increase in levels of HbF

  2. An anti-inflammatory effect because of the inhibition of white cell production

  3. An increase in red cell size; which lowers the intracellular hemoglobin concentration

  4. Its metabolism to NO, a potent vasodilator and inhibitor of platelet aggregation.

• Encouraging results also have been obtained with allogeneic bone marrow transplantation, which is potentially curative.