Sickle Cell Disease

Introduction

Sickle cell syndromes, which can be divided into sickle cell trait (SCT) and sickle cell disease (SCD), are hereditary conditions characterized by the presence of sickle hemoglobin (HbS) in red blood cells (RBCs).

• SCT is the heterozygous inheritance of one normal β-globin gene producing hemoglobin A (HbA) and one sickle gene producing HbS (HbAS) gene. Individuals with SCT are asymptomatic.
• SCD can be of homozygous or compounded heterozygous inheritance. Homozygous HbS (HbSS) has historically been referred to as sickle cell anemia (SCA).
• Clinical manifestations of SCD are due to impaired circulation, RBC destruction, and stasis of blood flow attributed to disturbances in RBC polymerization and to membrane damage. Additional contributing factors include functional asplenia (and increased risk of bacterial infection), deficient opsonization, and coagulation abnormalities.
• Polymerization allows deoxygenated hemoglobin to exist as a semisolid gel that protrudes into the cell membrane, distorting RBCs into sickle shapes. Sickle-shaped RBCs increase blood viscosity and encourage sludging in the capillaries and small vessels, leading to local tissue hypoxia that accentuates the pathologic process.
• Repeated cycles of sickling, upon deoxygenation, and unsickling, upon oxygenation, damage the RBC membrane and cause irreversible sickling. Rigid, sickled RBCs are easily trapped, resulting in shortened circulatory survival and chronic hemolysis.

Clinical Presentation

Cardinal features of SCD are hemolytic anemia and vasoocclusion. Symptoms are delayed until 4 to 6 months of age when HbS replaces fetal hemoglobin (HbF). Common findings include pain with fever, pneumonia, splenomegaly, and, in infants, pain and swelling of the hands and feet (eg, hand-and-foot syndrome or dactylitis).

• Usual clinical signs and symptoms of SCD include chronic anemia; fever; pallor; arthralgia; scleral icterus; abdominal pain; weakness; anorexia; fatigue; enlarged liver, spleen, and heart; and hematuria.
• Acute complications of SCD include fever and infection (eg, sepsis caused by encapsulated pathogens such as Streptococcus pneumoniae), stroke, acute chest syndrome, and priapism. Acute chest syndrome is characterized by pulmonary infiltration, respiratory symptoms, and equivocal response to antibiotic therapy.
• Sickle cell crisis can be precipitated by infection, dehydration, stresses, and sudden temperature changes. The most common type is vasoocclusive crisis, which is manifested by pain over the involved areas without change in Hb. Aplastic crisis is characterized by acute decrease in Hb with decreased reticulocyte count manifested as fatigue, dyspnea, pallor, and tachycardia. Splenic sequestration crisis is a massive enlargement of the spleen, leading to hypotension, shock, and sudden death in young children. Repeated infarctions lead to autosplenectomy; therefore, incidence declines as adolescence approaches.
• Chronic complications involve many organs and include pulmonary hypertension, bone and joint destruction, ocular problems, cholelithiasis, cardiovascular abnormalities, depression, and hematuria and other renal complications. Children experience delayed growth and sexual maturation.
• Patients with SCT are usually asymptomatic, except for rare painless hematuria.

Diagnosis

• SCD is usually identified by routine neonatal screening programs using isoelectric focusing, high-performance liquid chromatography, or electrophoresis.
• Laboratory findings include low hemoglobin; increased

Treatment

• Goals of Treatment: The goals are to reduce hospitalizations, complications, and mortality.

General Principles

Patients with SCD require lifelong multidisciplinary care. Interventions include general measures, preventive strategies, and treatment of complications and acute crises.

• Routine immunizations plus influenza, meningococcal, and pneumococcal vaccinations are recommended.
• Prophylactic penicillin is recommended until 5 years of age. Beginning at age 2 months or earlier, the dosage is penicillin V potassium, 125 mg orally twice daily until 3 years of age and then 250 mg twice daily until age 5 years, or benzathine penicillin, 600,000 units intramuscularly every 4 weeks from age 6 months to 6 years.
• Folic acid, 1 mg daily, is recommended in adult patients, pregnant women, and patients of all ages with chronic hemolysis.

Fetal Hemoglobin Inducers

• HbF directly effects polymer formation. Increases in HbF correlate with decreased RBC sickling and adhesion. Patients with low HbF levels have more frequent crises and higher mortality.
• Hydroxyurea, a chemotherapeutic agent, has many effects on blood cells, including the stimulation of HbF production. It is indicated for patients with frequent painful episodes, severe symptomatic anemia, acute chest syndrome, or other severe vasoocclusive complications. The starting dose is 15 mg/kg as a single daily dose.
• The use of 5-aza-2-deoxycytidine (decitabine) is being investigated in adults who do not respond to hydroxyurea.
• Chronic transfusions are indicated for primary and secondary stroke prevention in children. Transfusions are usually given every 3 to 4 weeks or as needed to maintain desired HbS levels. The optimal duration is unknown. Risks include alloimmunization, hyperviscosity, viral transmission (requiring hepatitis A and B vaccination), volume and iron overload, and transfusion reactions.
• Allogeneic hematopoietic stem cell transplantation is the only curative therapy for SCD.

Treatment Of Complications

• Educate patients to recognize conditions that require urgent evaluation. Balanced fluid status and oxygen saturation of at least 92% are important to avoid exacerbation during acute illness.
• RBC transfusions are indicated for acute exacerbation of baseline anemia (eg, aplastic crisis, hepatic or splenic sequestration, or severe hemolysis), severe vasoocclusive episodes, and procedures requiring general anesthesia or ionic contrast. Transfusions can be useful in patients with complicated obstetric problems, refractory leg ulcers, or refractory and protracted painful episodes.
• Promptly evaluate fever of 38.5°C (101.3°F) or higher. Empiric antibiotic therapy should provide coverage against encapsulated organisms (eg, ceftriaxone for outpatients and cefotaxime for inpatients).
• Initiate incentive spirometry; appropriate fluid therapy; broad-spectrum antibiotics, including a macrolide or quinolone; and, for hypoxia or acute distress, oxygen therapy in acute chest syndrome. Steroids and nitric oxide are being evaluated.
• Priapism has been treated with analgesics, antianxiety agents, and vasoconstrictors to force blood out of the corpus cavernosum (eg, phenylephrine and epinephrine), and vasodilators to relax smooth muscle (eg, terbutaline and hydralazine).

Treatment Of Sickle Cell Crisis

Treatment of aplastic crisis is primarily supportive. Blood transfusions may be indicated for severe or symptomatic anemia.

• Treatment options for splenic sequestration include observation alone, especially for adults because they tend to have milder episodes; chronic transfusion to delay splenectomy; and splenectomy after a life-threatening crisis, after repetitive episodes, or for chronic hypersplenism.
• Hydration and analgesics are mainstays of treatment for vasoocclusive (painful) crisis. Administer fluids IV or orally at 1 to 1.5 times the maintenance requirement; monitor closely to avoid volume overload. Consider an infectious etiology and initiate empiric therapy if indicated.
• Tailor analgesic therapy to the individual because of the variable frequency and severity of pain. Pain scales should be used to quantify the degree of pain.
• Use nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for mild to moderate pain. Manage mild to moderate pain in the outpatient setting with weak opioids such as codeine or hydrocodone.
• Treat severe pain aggressively with an opioid, such as morphine, hydromorphone, fentanyl, or methadone. Meperidine should be avoided because accumulation of the normeperidine metabolite can cause neurotoxicity, especially in patients with impaired renal function.
• Treat severe pain with an IV opioid titrated to pain relief and then administered on a scheduled basis with as-needed dosing for breakthrough pain. Patient-controlled analgesia is commonly utilized