Sickle Cell Anemia

Sickle cell anemia is an inherited autosomal condition in which glutamic acid in the sixth position on the p-globin chain is replaced by a valine (Glu6Val). This results in hemoglobin SS in the homozygous state. Sickle cell trait, or hemoglobin AS, is found in 8% to 10% of African Americans in the United States, and sickle cell anemia occurs in about 1 in 400, or about 70,000 individuals. The gene for HbS is prevalent in sub-Saharan Africa. Persons of Mediterranean descent from India or Saudi Arabia have varying but somewhat lower percentages of the carrier state for HbSS. Sickle cell anemia occurs worldwide but predominates in Mediterranean, Saudi Arabian, and Indian populations. This distribution appears to be associated with independent mutations in these regions. People with hemoglobin AS or SS are somewhat protected against malaria because their erythrocytes are resistant to invasion by malarial parasites. If the parasite infects the cell, the rate of sickling increases, causing the cell with the parasite to be removed from the circulation more rapidly.

The pathophysiology of the sickling process is related to the oxygenation of the molecule. When deoxygenated, HbSS tends to polymerize into long, tubelike fibrils. This results in an elongated, rigid cell subject to trapping in the microcirculation, resulting in vaso-occlusive crisis. Hypoxemia, acidosis, dehydration of the RBC, hyperosmolality of the renal medulla, and viral infections can play a role in triggering or accentuating the sickling process. Sickled RBCs are also more adhesive to endothelial cells, activate endothelial cells, and contribute to the interaction between neutrophils and activated endothe-lium in the microvasculature. When the conditions that cause sickling are corrected, the sickle cell may return to a more normal shape and function. However, some sickled RBCs are irreversibly changed, indicating that the membrane cytoskel-eton has been damaged. Irreversibly sickled cells are generally removed in the sinusoidal RES networks, but approximately one-third may be hemolyzed intravascularly. Some degree of anemia has a protective effect in vaso-occlusive crises by helping reduce blood viscosity and deoxygenation, thereby reducing the likelihood of polymerization.

During vaso-occlusive crises, the microvascular capillaries, capillary bed, and veins become occluded. Contributing to this locally are low pH, prolonged capillary transit time, and infection. Increased numbers of sickled RBCs occlude the vessels, which leads to painful ischemia, infarction, and reduced organ function over time. Areas particularly affected include the portal circulation, in which oxygen tension is low; the kidney, in which the renal medulla is hyperosmolar and dehydrates RBCs, increasing mean corpuscular hemoglobin concentration (MCHC); the lungs; and the brain. It is not clear why some patients have severe, frequent episodes and others do not. Avascular necrosis of the bone marrow is usually the cause of severe pain.

Clinical Diagnosis

A patient with sickle cell disease usually has chronic hemoly-sis that results in a moderate anemia, intermittent jaundice, and a marrow with a thinned, bony cortex. Vaso-occlusive episodes and the appearance of Howell-Jolly bodies occur by the time the patient becomes an adult. The presence of Howell-Jolly bodies indicates that the patient has undergone an autoinfarction of the spleen.

The diagnosis of sickle cell disease is easily made by finding sickled cells on the peripheral smear, preparing a sickle cell sample, and carrying out a screening hemoglobin elec-trophoresis, which will confirm the Hb type. For a sickle cell preparation, blood is mixed with 2% sodium metabisulfite, which produces sickling. The proportion of sickled cells is measured initially and then 1 hour later to make the diagnosis. The "gold standard" diagnosis is Hb electrophoresis, which shows the relative amounts of Hb forms.

Patients with long-standing sickle cell anemia may have pain syndromes related to bone marrow vaso-occlusive crises and aseptic necrosis of the femoral head. Bilirubin gallbladder stones occur in 40% to 60% of patients. Hepatic and cardiac complications may also develop. Other associated problems include vascular occlusion in the pulmonary bed, leading to acute chest syndrome. Breakdown of the skin over bony prominences in the lower extremities is common and may lead to chronic, poorly healing ulcers. Papillary necrosis of the kidney may occur and, with age, renal function may decline. In the eye, conditions such as hemorrhage and neo-vascularization may occur. Patients with sickle cell anemia are particularly susceptible to Salmonella infections because of decreased complement activation, and asplenic patients are also subject to an increased likelihood of infection from encapsulated organisms such as Pneumococcus. Patients with sickle cell anemia should be given Pneumovax vaccine to prevent streptococcal pneumonia and sepsis. Haemophilus influenzae infection is responsible for a high percentage of pneumonia cases in sickle cell anemia patients.

Neurologically, patients with sickle cell anemia are subject to cerebrovascular accident (CVA, stroke). Particularly disturbing, children with severe sickle cell anemia will have evidence of multiple small strokes on magnetic resonance imaging (MRI) or computed tomography (CT) of the head by age 10 years. This has been associated with learning impairments in affected children. Aggressive transfusion protocols have been tested to reduce the incidence of this complication, with some success. Thrombosis is more common in children, whereas hemorrhage is more common in adults, possibly because of the occlusion of small vessels in hypoxic situations. Also, sickled cells show increased attraction to the endothelium, causing proliferation of the endothelial intimal surface, which can contribute to vascular occlusion. There is a high rate of recurrent stroke within 3 years of the initial event. Parvovirus infection can also cause pure RBC

aplasia in these patients and lead to a devastating exacerbation of the anemia.

Treatment

Patients with sickle cell anemia should have Hb and Hct maintained at moderately low level to protect against vaso-occlusive complications related to viscosity. Patients with a painful crisis should be put on bed rest, hydrated vigorously, and given oral analgesics. Nonsteroidal anti-inflammatory drugs (NSAIDs), antihistamines, and benzodiazepines may also be helpful. Mild alkalinization of the blood is recommended. Oxygen should be given by nasal cannula or mask to keep the hemoglobin well oxygenated. Parenteral narcotics are rarely necessary, especially if the patient is given large volumes of fluid, oxygen, and oral morphine (or similar preparation) for pain control. Avascular necrosis of the bone marrow causes severe pain, and the patient may require intravenous (IV) narcotics and hydration for pain control.

Treatment with drugs that increase the proportion of fetal hemoglobin (HbF) show promise. Mixed polymers of HbF and HbS do not have the same propensity to sickle as SS tetramers. Azacitidine (5-AZA) increases the proportion of HbF but has significant toxicity. Hydroxyurea increases HbF level, which often results in fewer painful episodes, hospital admissions, and transfusions. The goal is to raise HbF level, if possible, to 20% to 30% of the total hemoglobin. Mortality can be reduced by as much as 40%. Unfortunately, not all patients respond to these types of interventions. Because both are antitumor drugs, azacitidine and hydroxyurea have significant toxicity, such as tumor induction. Gene therapies are being investigated but are not yet successful. In severe situations, allogenic (sibling) bone marrow transplantation has been tried, resulting in an 86% event-free survival at 5 years after transplant (Bhetia and Walters, 2008).

Patients undergoing surgery with general anesthesia are at increased risk of hypoxemia, sickling, and sickle cell crisis. They should be transfused before surgery with packed RBCs to bring the HbA level to 50% or higher. This decreases the likelihood of sickle cell episodes.

Pregnancy increases the risk of vaso-occlusive crisis for the mother. There is a high incidence of fetal loss among women who have sickle cell anemia. Vaso-occlusive episodes in the placenta may result in lower-birth-weight infants or fetal death.

Sickle Cell Trait

Patients with sickle cell trait are heterozygous for the sickle gene and have a much lower likelihood of sickling than those who are homozygous. Most heterozygotes are asymptomatic throughout life. Patients with sickle cell trait, however, may develop complications if put into an extremely hypoxic environment such as high altitude, suffer heat stroke and dehydration, or acquire pulmonary infections.

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