Sickle Cell Anemia

SICKLE CELL ANEMIA

Sickle cell anemia is a severe hemolytic anemia that results from inheritance of the sickle hemoglobin gene. This gene causes the hemoglobin molecule to be defective. The sickle hemoglobin (HbS) acquires a crystal-like formation when exposed to low oxygen tension. The oxygen level in venous blood can be low enough to cause this change; consequently, the RBC contain-ing (HbS) loses its round, very pliable, biconcave disk shape and becomes deformed, rigid, and sickle-shaped (Fig. 33-5). These long, rigid RBCs can adhere to the endothelium of small ves-sels; when they pile up against each other, blood flow to a re-gion or an organ may be reduced (Hoffman, et al., 2000). If ischemia or infarction results, the patient may have pain, swelling, and fever. The sickling process takes time; if the RBC is again exposed to adequate amounts of oxygen (eg, when it travels through the pulmonary circulation) before the mem-brane becomes too rigid, it can revert to a normal shape. For this reason, the “sickling crises” are intermittent. Cold can aggravate

the sickling process, because vasoconstriction slows the blood flow. Oxygen delivery can also be impaired by an increased blood viscosity, with or without occlusion due to adhesion of sickled cells; in this situation, the effects are seen in larger ves-sels, such as arterioles.

The HbS gene is inherited in people of African descent and to a lesser extent in people from the Middle East, the Mediter-ranean area, and aboriginal tribes in India. Sickle cell anemia is the most severe form of sickle cell disease. Less severe forms in-clude sickle cell hemoglobin C (SC) disease, sickle cell hemo-globin D (SD) disease, and sickle cell beta-thalassemia. The clinical manifestations and management are the same as for sickle cell anemia. The term sickle cell trait refers to the carrier state for SC diseases; it is the most benign type of SC disease, in that less than 50% of the hemoglobin within an RBC is HbS. However, in terms of genetic counseling, it is still an important condition. If two people with sickle cell trait have children, the children may inherit two abnormal genes. These children will produce only HbS and therefore will have sickle cell anemia.

Clinical Manifestations

Symptoms of sickle cell anemia vary and are only somewhat based on the amount of HbS. Symptoms and complications result from chronic hemolysis or thrombosis. The sickled RBCs have a short-ened life span. Patients are always anemic, usually with hemoglo-bin values of 7 to 10 g/dL. Jaundice is characteristic and is usually obvious in the sclerae. The bone marrow expands in childhood in a compensatory effort to offset the anemia, sometimes leading to enlargement of the bones of the face and skull. The chronic ane-mia is associated with tachycardia, cardiac murmurs, and often an enlarged heart (cardiomegaly). Dysrhythmias and heart failure may occur in adults.

Virtually any organ may be affected by thrombosis, but the pri-mary sites involve those areas with slowed circulation, such as the spleen, lungs, and central nervous system. All the tissues and or-gans are constantly vulnerable to microcirculatory interruptions by the sickling process and therefore are susceptible to hypoxic damage or true ischemic necrosis. Patients with sickle cell anemia are unusually susceptible to infection, particularly pneumonia and osteomyelitis. Complications of sickle cell anemia include infec-tion, stroke, renal failure, impotence, heart failure, and pulmonary hypertension. Table 33-4 summarizes the complications resulting from sickle cell anemia.

SICKLE CELL CRISIS

There are three types of sickle cell crisis in the adult population. The most common is the very painful sickle crisis, which results from tissue hypoxia and necrosis due to inadequate blood flow to a specific region of tissue or organ. Aplastic crisis results from in-fection with the human parvovirus. The hemoglobin level falls rapidly and the marrow cannot compensate, as evidenced by an absence of reticulocytes. Sequestration crisis results when other or-gans pool the sickled cells. Although the spleen is the most com-mon organ responsible for sequestration in children, by 10 years of age most children with sickle cell anemia have had a splenic in-farction and the spleen is then no longer functional (autosplenec-tomy). In adults, the common organs involved in sequestration are the liver and, more seriously, the lungs.

ACUTE CHEST SYNDROME

Acute chest syndrome is manifested by a rapidly falling hemoglo-bin level, tachycardia, fever, and bilateral infiltrates seen on the chest x-ray. These signs often mimic infection; in fact, recent studies have identified infection as a major cause of acute chest syndrome (Vichinsky, et al., 2000). Another common cause is pulmonary fat embolism. Increased secretory phospholipase A₂ concentration has been identified as a predictor of impending acute chest syndrome; the increased amounts of free fatty acids can cause increased permeability of the pulmonary endothelium and leakage of the pulmonary capillaries. Although this syndrome is potentially lethal, prompt intervention can result in a favorable outcome.

Assessment and Diagnostic Findings

The patient with sickle cell trait usually has a normal hemoglobin level, a normal hematocrit, and a normal blood smear. In contrast, the patient with sickle cell anemia has a low hematocrit and sick-led cells on the smear. The diagnosis is confirmed by hemoglobin electrophoresis.

Prognosis

Patients with sickle cell anemia are usually diagnosed in child-hood, because they become anemic in infancy and begin to have sickle cell crises at 1 or 2 years of age. Some children die in the first years of life, typically from infection, but the use of antibiotics and parent teaching have greatly improved the outcomes for these chil-dren. However, with current management strategies, the average life expectancy is still suboptimal, at 42 years. Young adults are often forced to live with multiple, often severe, complications from their disease. In some patients, the symptoms and compli-cations diminish by 30 years of age; these patients live into the sixth decade or longer. At this time, there is no way to predict which patients will fall into this subgroup.

Medical Management

Treatment for sickle cell anemia is the focus of continued research (Steinberg, 1999). Many trials of medications that have antisick-ling properties are being conducted, as is research using antiadhe-sion treatment for vasoocclusive crises. However, aside from the equally important aggressive management of symptoms and com-plications, currently there are only three primary treatment modalities for sickle cell diseases: BMT, hydroxyurea, and long-term RBC transfusion.

BMT offers the potential for cure for this disease. However, this treatment modality is available to only a small subset of the patient population, because of either the lack of a compatible donor or the severe organ (eg, renal, liver, lung) damage already present in the patient.

PHARMACOLOGIC THERAPY

Hydroxyurea (Hydrea), a chemotherapy agent, has been shown to be effective in increasing hemoglobin F levels in patients with sickle cell anemia, thereby decreasing the permanent formation of sickled cells. Patients who receive hydroxyurea appear to have fewer painful episodes of sickle cell crisis, a lower incidence of acute chest syndrome, and less need for transfusions (Ferster et al., 2001). However, whether hydroxyurea can prevent or reverse ac-tual organ damage remains unknown. Side effects of hydroxyurea include chronic suppression of WBC formation, teratogenesis, and potential for later development of a malignancy. Patient re-sponse to the medication varies significantly. The incidence and severity of side effects are also highly variable within a dose range. Some patients have toxicity when receiving a very small dose (5 mg/kg per day), whereas others have little toxicity with a much higher dose (35 mg/kg per day). More research is needed to iden-tify specific patient subgroups that are more likely to respond to this medication.

TRANSFUSION THERAPY

Chronic transfusions with RBCs have been shown to be highly ef-fective in several situations: in an acute exacerbation of anemia (eg, aplastic crisis), in the prevention of severe complications from anesthesia and surgery, and in improving the response to infection (when it results in exacerbated anemia) (Ohene-Frempong, 2001). Chronic transfusions have also been shown to be effective in di-minishing episodes of sickle cell crisis in pregnant women; how-ever, these transfusions have not been shown to improve fetal survival. Transfusion therapy may be effective in preventing com-plications from sickle cell disease. Although controversial, some data support the use of chronic transfusions in patients with cere-bral ischemic injury (as seen on magnetic resonance imaging [MRI] or Doppler studies) to prevent more severe injury (eg, CVA). More than 50% of asymptomatic patients have some cerebral ischemia documented by MRI. In a recent study (Adams, 2000), chronic transfusion with RBCs resulted in a 90% reduction of stroke in children at risk for this complication, as demonstrated by elevated blood viscosity on transcranial Doppler ultrasonography. Transfu-sions may also be useful in the management of severe cases of acute chest syndrome.

The risk of complications from transfusion is important to con-sider. These risks include iron overload, which necessitates chronic chelation therapy (see MDS Nursing Management); poor venous access, which necessitates a vascular access device (and its attendant risk for infection or thrombosis); infections (hepatitis, human immunodeficiency virus [HIV]); and alloimmunization from re-peated transfusions. Another complication from transfusion is the increased viscosity of blood before the concentration of hemoglo-bin S is reduced. Exchange transfusion (in which the patient’s own blood is removed and replaced via transfusion) may be performed to diminish the risk of increasing the viscosity excessively; the ob-jective is to reduce the hematocrit to less than 30%, with transfu-sions supplying more than 80% of the patient’s blood volume. Finally, it is important to consider the significant financial cost of an aggressive transfusion and chelation program.

Patients with sickle cell anemia require daily folic acid replace-ments to maintain the supply required for increased erythropoiesis from hemolysis. Infections must be treated promptly with appro-priate antibiotics; infection remains a major cause of death in these patients.

Acute chest syndrome is managed by prompt initiation of an-tibiotic therapy. Incentive spirometry has been shown to decrease the incidence of pulmonary complications significantly. In severe cases, bronchoscopy may be required to identify the source of pulmonary disease. Fluid restriction may be more beneficial than aggressive hydration. Corticosteroids may also be useful. Trans-fusions reverse the hypoxia and decrease the level of secretory phospholipase A₂. Pulmonary function should be monitored reg-ularly to detect pulmonary hypertension early, when therapy (hydroxyurea, transfusions, or transplantation) may have a posi-tive impact.

Because repeated blood transfusions are necessary, patients may develop multiple autoantibodies, making cross-matching difficult. In this patient population, a hemolytic transfusion reaction (see later discussion) may mimic the signs and symptoms of a sickle cell cri-sis. The classic distinguishing factor is that, with a hemolytic trans-fusion reaction, the patient becomes more anemic after being transfused. These patients need very close observation. Further transfusion is avoided if possible until the hemolytic process abates. If possible, the patient is supported with corticosteroids (Pred-nisone), intravenous immunoglobulin (IVIG; Gammagard, Sando-globulin, Venoglobulin), and erythropoietin (Epogen, Procrit).

SUPPORTIVE THERAPY

Supportive care is equally important. A significant issue is pain management. The incidence of painful sickle cell crises is highly variable; many patients have pain on a daily basis. The severity of the pain may not be enough to cause the patient to seek assistance from health care providers but severe enough to interfere with the ability to work and function within the family. Acute pain episodes tend to be self-limited, lasting hours to days. If the patient cannot manage the pain at home, intervention is frequently sought in the acute care setting, usually at an urgent care facility or emergency department. Adequate hydration is important during a painful sickling episode. Oral hydration is acceptable if the patient can maintain adequate amounts of fluids; intravenous hydration with dextrose 5% in water (D5W) or dextrose 5% in 0.25 normal saline solution (3 L/m²/24 hours) is usually required for sickle crisis. Sup-plemental oxygen may also be needed.

The use of medication to relieve pain is important. Aspirin is very useful in diminishing mild to moderate pain; it also diminishes inflamma-tion and potential thrombosis (due to its ability to diminish platelet adhesion). Nonsteroidal anti-inflammatory drugs (NSAIDs) are useful for moderate pain or in combination with opioid analgesics. Although no tolerance develops with NSAIDs, a “ceiling effect” does develop whereby an increase in dosage does not increase anal-gesia. NSAID use must be carefully monitored, because these med-ications can precipitate renal dysfunction. When opioid analgesics are used, morphine is the medication of choice for acute pain. Patient-controlled analgesia is frequently used.

Chronic pain increases in incidence as the patient ages. Here, the pain is caused by complications from the sickling, such as avascular necrosis of the hip. With chronic pain management, the principal goal is to maximize functioning; pain may not be com-pletely eliminated without sacrificing function. This concept may be difficult for patients to accept; they may need repeated expla-nations and support from nonjudgmental health care providers. Nonpharmacologic approaches to pain management are crucial in this setting. Examples include physical and occupational therapy, physiotherapy (including the use of heat, massage, and exercise), cognitive and behavioral intervention (including distraction, relaxation, and motivational therapy), and support groups.

Working with patients who have multiple episodes of severe pain can be challenging. It is important for health care providers to realize that patients with sickle cell disease must face a lifelong experience with severe and unpredictable pain. Such pain is dis-ruptive to the person’s level of functioning, including social func-tioning, and may result in a feeling of helplessness. Patients with inadequate social support systems may have more difficulty cop-ing with chronic pain.