Sickle Cell Disease

GENERAL PRINCIPLES

• SCD is a group of hereditary Hgb disorders in which Hgb undergoes a sickle shape transformation under conditions of deoxygenation.

• The most common are homozygous sickle cell anemia (Hgb SS) or other double-heterozygous conditions (Hgb SC, Hgb S-#946;⁰, or Hgb S-#946;⁺ thalassemia).

• Newborn screening programs for hemoglobinopathies are available throughout the US and identify most patients in infancy.

• In the US, the incidence of SCD is approximately 1 in 625 births.

• Sickle cell trait is present in 7%-8% of African Americans. It is generally considered to be a benign carrier state, but high-altitude hypoxia is associated with splenic infarction, whereas intense physical exertion has been associated with sudden death and rhabdomyolysis.

• Sickle cell trait has been associated with an increased risk of pulmonary embolism, proteinuria, and CKD. Minimizing other risk factors for kidney disease is likely to benefit patients at risk.

DIAGNOSIS

Diagnostic Testing

• Hgb analysis by high-pressure liquid chromatography is commonly used and distinguishes most hemoglobinopathies.

• Laboratory abnormalities include anemia (mean Hgb in SCD, 8 g#8725;dL), reticulocytosis (3%-15%), indirect hyperbilirubinemia, elevated LDH, and decreased or absent haptoglobin. Leukocytosis (10,000-20,000#8725;#956;L) and thrombocytosis (gt;450,000#8725;#956;L) are common because of enhanced stimulation of the marrow compartment and autosplenectomy.

• Peripheral smear shows sickle-shaped RBCs, target cells (particularly in Hgb SC and Hgb S-#946; thalassemia), and Howell-Jolly bodies, indicative of functional asplenism.

Clinical Presentation

• Clinical presentation of SCD is heterogeneous and is dependent on the type and degree of hemoglobinopathy. The most common clinical manifestations of SCD result from hemolysis and#8725;or vascular occlusions.

• Vasoocclusive complications (VOCs) result from polymerization of deoxygenated Hgb S. These polymerized RBCs assume the classic sickle shape and develop a marked loss of deformability, leading to vasoocclusion.

î Acute painful episodes (“sickle cell pain crisis”)

#9632; Sickle cell pain crisis is the most common VOC and manifestation of SCD.

#9632; Pain is typically in the long bones, back, chest, and abdomen.

#9632; Precipitating factors can include stress, infection, dehydration, alcohol, and weather. However, a majority of cases have no identifiable trigger.

#9632; Higher levels of Hgb F seem to be protective against VOC.

î Acute chest syndrome (ACS) is a life-threatening emergency that occurs when there is irreversible occlusion of the pulmonary microvasculature. The diagnosis is based on a pulmonary infiltrate involving at least one complete segment and one of the following: fever, hypoxemia, tachypnea, respiratory failure, chest pain, or wheezing. ACS precipitated by pulmonary fat emboli as the inciting event may be more severe and associated with other organ dysfunction, including stroke.

î Priapism often presents in adolescence and may result in impotence.

î Retinopathy is caused by chronic vasoocclusion of the retina, which causes proliferative retinopathy and may lead to complications including vitreous hemorrhage and retinal detachment.

î Functional asplenia results from recurrent splenic infarcts due to sickling and eventually results in the loss of splenic function. The majority of cases occur before the age of 1 year. Functional asplenia places patients at higher risk of infection, especially with encapsulated organisms.

î Avascular necrosis (AVN) is the result of infarction of bone trabeculae and occurs most commonly in the femoral and humeral heads. Up to 50% of adults affected by SCD can manifest AVN, which is a leading cause of pain and disability.

• Hemolytic complications

î Cholelithiasis is present in gt;80% of patients and is primarily due to bilirubin stones.

î Leg ulceration occurring at the ankle is often chronic and recurring.

î Pulmonary hypertension has been linked to several hemolytic disorders and can occur in up to 60% of patients with SCD. The American Society of Hematology 2019 evidence-based guidelines for SCD recommend considering screening echocardiography that symptomatic patients and those with tricuspid regurgitant jet velocity gt;2.5 m/s should proceed with a right-sided heart catheterization for confirmation of diagnosis.¹⁰ The pathophysiology is unclear but may be the result of nitric oxide depletion.

• Renal medulla infarction is the result of repeated occlusion of renal medullary capillaries, resulting in CKD in many patients. This can lead to isosthenuria (inability to concentrate urine) and hematuria, predisposing patients to dehydration and thus increasing the risk of VOC.

• Neurologic complications occur in up to 25% of patients with SCD by the age of 45 years and include cerebrovascular events (transient ischemic attacks, ischemic stroke, cerebral hemorrhage), seizure, and sensory hearing loss.¹¹ Ischemic stroke is felt to result from recurrent endothelial injury from hemolysis and vasoocclusion, resulting in intimal hyperplasia with large artery vasculopathy. High cerebral flow rate (gt;200 cm/s) detected by transcranial Doppler has been associated with increased risk of stroke in children. This risk is greatly reduced by routine transfusion or exchange therapy. “Silent strokes” are those without obvious neurological symptoms—affect one in three children and at least one in two adults with SCD. They cause cognitive impairment and are risk factors for future strokes. The American Society of Hematology recommends at least a one-time MRI screening to detect silent cerebral infarcts in adults with HbSS or HbS#946;⁰ thalassemia.¹²

• Infections typically occur in tissues susceptible to vasoocclusive infarcts (i.e., lungs, bone, kidney).

• Aplastic “crisis” occurs when there is a transient interruption of erythropoiesis due to an inciting event causing a sudden decrease in Hgb with a very low reticulocyte count. The most common etiology in children with SCD is parvovirus B19 infection. Folate deficiency has also been suspected in some cases.

• Pregnancy in a patient with sickle cell anemia should be considered high risk and is associated with an increase in both maternal and fetal complications. Maternal complications include an increased risk of VOC, ACS, and infections.¹³ Fetal complications include preterm delivery, low birth weight, and increased risk of stillbirth.

TREATMENT

• Acute painful episodes. Management of acute painful episodes consists of rehydration, evaluation for and management of infections, analgesia, and if needed, antipyretic and empiric antibiotic therapy.

î Opioids are typically used and are effectively administered by a patient-controlled analgesia pump, allowing the patient to self-administer medication within a set limit of infusions (lockout interval) and basal rate. Morphine or hydromorphone are the commonly used opioids for moderate or severe pain and the doses vary considerably from patient to patient.

î Transfusion therapy has no proven role in the treatment of uncomplicated vasoocclusive crises unless a symptomatic anemia is present or other complications occur.

î Supplemental oxygen does not benefit an acute pain crisis unless hypoxia is present.

• ACS. Multimodal treatment includes adequate analgesia, volume resuscitation, supplemental oxygen and incentive spirometry, and blood transfusion. It is unclear whether exchange transfusion is superior to simple RBC transfusion; however, it is standard practice to perform exchange transfusion for moderate to severe cases, whereas simple transfusion to gt;10 g/dL for mild cases may be sufficient.

• Priapism is initially treated with hydration and analgesia. Persistent erections for more than 24 hours may require transfusion therapy or surgical drainage.

• AVN management consists of local heat, analgesics, and avoidance of weight bearing. Hip and shoulder arthroplasty are often effective at decreasing symptoms and improving function.

• Cholelithiasis. Induced acute cholecystitis should be treated medically with antibiotics followed by cholecystectomy when the attack subsides. Elective cholecystectomy for asymptomatic gallstones is controversial.

• Leg ulcers should be treated with rest, leg elevation, and intensive local care. Wet to dry dressings should be applied three to four times per day. A zinc oxide-impregnated bandage (Unna boot), changed weekly for 3-4 weeks, can be used for nonhealing or more extensive ulcers.

• There is no standard therapy for treatment of pulmonary hypertension in SCD and clinically effective therapy remains elusive.¹⁴

• Acute stroke should be managed based on current standards. Long-term transfusions to maintain the Hgb S concentration to lt;30% for at least 5 years significantly reduce the incidence of recurrence.

• Patients with suspected aplastic crisis require hospitalization. Therapy includes folic acid, 5 mg/d, as well as RBC transfusions until recovery.

• Iron chelation therapy is used to treat iron overload in patients with transfusion-related iron overload similar to that described for thalassemia.

• Emerging therapies for potentially curative options for SCD include hematopoietic SCT, although its use is restricted by the high cost, toxicity, and limited availability of suitable donors. Less-toxic conditioning regimens and the use of alternative sources of donor cells have improved transplant success. However, SCT may be superseded by investigational gene therapy and gene editing approaches using either addition of a helpful gene encoding an antisickling #946; globin or a gene knockdown/editing of globin regulatory elements, to partially reverse the normal Hgb switching from fetal to adult Hgb.

Risk Modification

• Dehydration and hypoxia should be avoided because they may precipitate or exacerbate irreversible sickling.

• Folic acid (1 mg PO daily) is administered to patients with SCD because of chronic hemolysis.

• Hydroxyurea (15-35 mg/kg PO daily) has been shown to increase levels of Hgb F and significantly decrease the frequency of VOC and ACS in adults with SCD.¹⁵ In practice, the dose is increased until the ANCs are between 2000 and 4000#8725;#956;L.

• L-glutamine (0.3 g/kg PO twice daily) recently became available for the prevention of VOC and may

be incorporated into preventative care with or without concomitant hydroxyurea.¹⁶

• Crizanlizumab, a P-selectin inhibitor given as an infusion, was recently approved after showing significantly lower frequency of sickle cell-related pain crises in patients receiving this therapy, with or without hydroxyurea.¹⁷

• Voxelotor, an HbS polymerization inhibitor, is another recently approved agent shown to significantly increase Hgb levels and reduce markers of hemolysis in patients with SCD and anemia.¹⁸

• Antimicrobial prophylaxis with penicillin VK, 125 mg PO bid to age 3 years and then 250 mg PO bid until age 5 years, is effective at reducing risk of infection. Patients who are allergic to penicillin should receive erythromycin 10 mg/kg PO bid. Prophylaxis should be stopped at age 5 years to avoid development of resistant organisms.

• Immunizations against the usual childhood illnesses should be given to children with SCD, including hepatitis B vaccine. After 2 years of age, a polyvalent pneumococcal vaccine should be administered. Yearly influenza vaccine is recommended.

• Ophthalmologic examinations are recommended yearly in adults because of the high incidence of proliferative retinopathy.

• Preoperative optimization. Local and regional anesthesia can be used without special precautions. Care should be taken to avoid volume depletion, hypoxia, and hypernatremia. For surgery with general anesthesia, RBC transfusions to increase the Hgb to 10 g/dL is as effective as more aggressive thresholds to decrease postoperative complications and more effective than withholding preoperative transfusions.¹⁹