Sickle Cell Disease (SCD) is an inherited condition that occurs due to the presence of hemoglobin S, which affects the shape of erythrocytes. The gene defect that leads to hemoglobin S formation is a single nucleotide polymorphism of the beta globin gene (located on chromosome 11) that causes the substitution of glutamic acid for valine at the position 6.
The screening of newborns is the most common way to diagnose infants with SCD and it is routine in many countries. A blood sample may be obtained by heel stick or cord blood, and the sample is then tested with electrophoresis, high performance liquid chromatography (HPLC) or thin-layer isoelectric focusing.
Adults can be diagnosed with HPLC (the preferred method), thin-layer isoelectric focusing, electrophoresis or solubility tests The results of these tests will show the types of hemoglobin present and its levels.
Normal individuals will have hemoglobin A (95-98%) and hemoglobin A2 (2-3%). Newborns and even adults may have also some hemoglobin F.
Individuals with sickle cell trait will have around 40% of HbS and 60% of HbA. These individuals are just carriers and do not have increased mortality, but are at higher risk for hematuria, splenic infarction at high altitude, and sudden death with prolonged exercise. Genetic counseling is also relevant for carriers of the trait if they plan to have a baby.
Individuals with hemoglobin SC disease will have similar numbers of HbS and HbC.
Individuals with sickle cell anemia (HbSS) will have around 75-90% of HbS, absent HbA, some HbF and normal HbA2.
Other forms may also be identified: sickle cell-beta+ thalassemia (high HbS, HbA 5-30%, increased HbA2) and sickle cell-beta0 thalassemia (high HbS, absent HbA, increased amounts of HbA2 and variable amounts of HbF).
Prenatal testing may be conducted on couples at risk, in order to identify sickle cell traits. Chorionic villus sampling at 8-10 weeks of gestation can obtain DNA samples and diagnose SCD, although this method is not commonly used.
The disease may have acute complications or chronic complications.
Signs and symptoms of sickle cell disease may appear acutely if the demand for oxygen is increased (exercise, trauma, infections, extreme temperatures) or the concentration of oxygen is reduced (change in altitude-pressure). The acute manifestations of sickle cell disease are discussed in detail below.
Acute complications include:
- Anemia (hemolysis, splenic sequestration, aplastic crisis)
- Vasooclusive phenomena (acute chest syndrome, acute vasooclusive pain, stroke, dactylitis, MI, priapism, pregnancy complications, VTE, acute multi-organ failure)
Chronically, patients with sickle cell anemia usually have chronic hemolytic anemia, with a hemoglobin level around 8-10g/dL and reticulocytosis. They may also have increased LDH, decreased haptoglobin, and Howell Jolly bodies and sickled cells when blood is visualized under the microscope.
Chronic complications may include:
- Chronic pain
- Cardiac issues (diastolic dysfunction)
- Hepatic issues (iron overload, elevation in bilirubin, viral hepatitis)
- Pulmonary issues (pulmonary hypertension, asthma)
- Neurological disorders (deficits or seizures)
- Leg ulcers
- Bone issues (slow growth, avascular necrosis, osteomyelitis)
CHRONIC MANAGEMENT OF SCD:
Antibiotic prophylaxis: Within the three first months of life, patients with SCD should receive antibiotics. Penicillin PO 125mg BID can be used (250mg BID after three years) and may be continued until 5 years of age. After that, the decision to continue antibiotics or not should be done in a case by case basis.
All vaccinations should be up to date in patients with SCD due to their increased risk of infection. Particularly the vaccines against pneumococcus (both PPSV21 and PCV13) and meningococcus (MCV4).
Folic acid supplementation (1mg daily) should be provided to all patients. A multivitamin (without iron) may also be provided.
Painful leg ulcers may also happen in patients with SCD, so it is important to adopt preventive measures such as appropriate fitting shoes and regular foot exams. All patients with ulcers should receive doppler ultrasound to rule out DVT since many ulcers in these patients are associated with DVT. Proper wound care, rest and debridement should be used. In some cases, a skin graft may be necessary. Transfusion therapy is beneficial and may increase the ulcer healing speed.
Relevant Screening and Particular areas of care to pay attention:
For patients with SCD, frequent office visits with complete history and physical examination are important since these patients have a high risk to develop certain complications.
Central Nervous System particularities: Patients with HbSS or sickle cell beta 0 thalassemia should be screened from ages 2-16 with transcranial doppler (TCD). If normal, it may be repeated yearly. If abnormal, it should be repeated earlier, according to the degree of flow velocity. MRI can be ordered for patients with neurological or cognitive deficits and those with altered TCD.
Eye particularities: The retina should be evaluated yearly, starting at 10 years of age.
Pulmonary particularities: Spirometry every two years (asthma is common in children with SCD). Echocardiogram may be used in individuals older than 8 that complain of respiratory symptoms to evaluate for pulmonary hypertension.
Kidneys particularities: Kidney function should be measured at the office visits (starting ideally before the age of 10 years) since patients are at higher risk for CKD. Hypertension is also common and should be managed.
Hepatic particularities: Patients with SCD are at increased risk for hepatitis B and C if they receive multiple transfusions. Patients also have high basal levels of unconjugated bilirubin that may increase during a crisis.
Genital/Reproductive particularities: Men should be asked about the incidence of priapism since the risk is very high among SCD patients. Hydroxyurea, transfusions or pseudoephedrine (30-60mg/day at bedtime) may reduce the incidence of priapism. Men and woman should be asked about their fertility plans and oriented accordingly.
Osteoarticular and Musculoskeletal particularities: Bone density should be evaluated starting at age 12 and should be repeated every 1-3 years. Vitamin D levels should be ordered annually. Children with SCD may have decreased growth speed (which may respond to transfusions or hydroxyurea).
Pain particularities: Patients may have acute episodes of pain but also chronic pain. To reduce chronic pain, the patient should be oriented to keep himself hydrated and avoid physical or psychological stress. If medications are needed, long-acting opiates (methadone, oxycodone, morphine) may be used. Short-acting opiates may also be used during episodes of acute pain worsening. Hydroxyurea therapy may help reducing painful episodes. Ketorolac and other NSAIDs should be avoided because of their additional risk to the kidneys. If the patient refers a neuropathic component, medications for neuropathic pain may be used as well.
Treatments to control the number of crisis:
Hydroxyurea (10-15mg/kg/day if creatinine clearance > 60mL/min) can be used to minimize the number of severe clinical events in children over 18 months and adults. It is indicated in patients with history of severe vasooclusive events (e.g. acute chest syndrome), frequent painful episodes or severe symptomatic anemia. The effectiveness should be assessed after 6 months. If it works, it may be continued indefinitely. Hydroxyurea should not be used during pregnancy.
Chronic periodic transfusions may be used to prevent future events. Exchange transfusions are better than simple transfusions. The frequency of transfusions is guided by the frequency of symptoms and the goal for most patients is to keep HbS < 30% with Hb >9 g/dL (avoid higher Hb numbers to avoid hyperviscosity). In patients receiving multiple transfusions, it is important to start iron chelation once ferritin reaches 1000-1500 ng/mL.
Patients should also receive transfusions before surgery.
Patients that do not respond to hydroxyurea or transfusions may benefit from hematopoietic cell transplantation, which is a curative therapy. A big limitation for the transplantation is the necessity of a sibling donor with a matching HLA.
ACUTE MANAGEMENT OF SCD PRESENTATIONS:
ACUTE CHEST SYNDROME:
Around 50% of patients with SCD will have at least one episode of acute chest syndrome (ACS). ACS is defined as a new opacity on the chest x-ray in a SCD patient with at least one of the following signs or symptoms:
More than 2 percent decrease in SpO2 (O2 saturation) from a documented steady-state value on room air (FiO2 = 0.21)
Tachypnea (per age-adjusted normal)
Signs of significant respiratory distress (intercostal retractions, nasal flaring, or use of accessory muscles of respiration
Rales on auscultation
Patients with SaO2 < 95% or PaO2 <70mmHg should receive oxygen. Incentive spirometry and chest physiotherapy may also be helpful.
Fluids should be provided to prevent hypovolemia and maintain a proper hydration. However fluid overload should be avoided due to the risk of pulmonary edema.
Antibiotics should be given to any patient since it is hard to differentiate ACS from pneumonia initially (e.g. ceftriaxone 2g IV + azithromycin 500mg IV for 7 days).
Adequate pain control is vital, since most patients with ACS also have some degree of vasooclusive pain in the chest or elsewhere (that may precede the ACS). Over sedation due to opiates is particularly dangerous in these patients, so they should be monitored properly.
Transfusion therapy is an important treatment option for ACS and can produce rapid and dramatic improvements. Simple transfusion should be enough for the milder cases, while exchange transfusion may benefit the more severe cases.
Bronchodilators can be used in patients with asthma or wheezing, but most patients probably do not benefit from them.
Glucocorticoids should NOT be used.
ACUTE VASOOCLUSIVE PAIN:
Acute pain episodes in patients with SCD should be promptly evaluated and managed. The pain may be located on the back (upper or lower), arms, legs, chest, or abdomen, and it can vary from mild to excruciating and can last for hours.
It is important to notice that sometimes a patient with SCD can present with multiple syndromes, so the physician should try to differentiate the pain from a vasooclusive episode from other painful conditions (organ ischemia for instance) that may require a different treatment.
Severe vasooclusive pain should be treated with potent analgesics – opiates (morphine 0.1-0.15mg/kg IV, or hydromorphone 0.02-0.05mg/kg IV) and reassessed after 15-30 minutes. The doses may be repeated if there is no improvement. If there is substantial improvement after the first dose and the patient does not have signs or symptoms of any other syndrome, the patient may be discharged with a prescription of long-acting opiates. Otherwise the patient should be admitted and kept on IV opiates. To provide comfort for the patient and reduce the risk of complications it is important to foresee and manage the side effects of opiates, such as pruritus (use anti-histamines, ondansetron or low-dose naloxone – 0.25mcg/kg/h), nausea (ondansetron), constipation (laxatives) and respiratory depression (provide incentive spirometry every two hours while the patient is awake).
Fluid replacement is important since many individuals are hypovolemic during presentation and, for that reason, a bolus of normal saline may be used.
Transfusions are NOT indicated for episodes of vasooclusive pain alone. Hydroxyurea may be used chronically to reduce the number of episodes (individuals already taking hydroxyurea before admission should continue during the admission).
Consists in a sudden drop of Hb levels and reticulocytes due to transient bone marrow malfunction. It is often caused by infections, particularly parvovirus B19.
Transfusion may be necessary to treat the anemia. The condition usually improves in less than 2 weeks.
SPLENIC SEQUESTRATION CRISIS:
Splenic sequestration is a condition characterized by splenic enlargement, a reduction of the patient’s base Hb levels of at least 2g/dL, thrombocytopenia and reticulocytosis.
During splenic sequestration, the circulating blood gets retained in the spleen and this can lead to hypovolemic shock. Therefore the treatment is aimed at maintaining proper hemodynamics using fluids to keep an euvolemic state. Normal saline (0.9%) is used in hypovolemic patients, while half-saline (0.45%) may be used for hydration in patients that are euvolemic.
HEPATIC SEQUESTRATION CRISIS:
Presents as right upper quadrant pain, hepatomegaly and hypovolemia or shock. Jaundice can also be present. Treatment is with simple transfusion can help, however the level of Hb should be monitored carefully.
ACUTE SICKLE HEPATIC CRISIS AND ACUTE INTRAHEPATIC CHOLESTASIS:
Patients acute sickle hepatic present with acute pain, jaundice and elevation of AST and ALT. The treatment is supportive (analgesia and fluids) and the condition resolves in usually less than two weeks.
Patients with intrahepatic cholestasis, however, present with more serious symptoms including pain, jaundice, nausea and vomit, leukocytosis and marked elevations of bilirrubin, LDH and prolongation of PT and PTT. This syndrome has high mortality and the management may include exchange transfusions and fresh frozen plasma;
Priapism may occur in up to 45% of males with SCD and presents as a painful erection that lasts for hours (more than 4 hours). It often occurs during sleep.
It can be divided in high flow priapism (arterial, nonischemic) or low flow priapism (venous, ischemic).They can be differentiated through doppler ultrassound or blood gas analysis of a corpus cavernosum aspirate. High-flow priapism is usally related to trauma that leads to an injury of the cavernosal artery. It is not an emergency and it may be treated with observation or endovascular embolization or surgical ligation if it does not resolve.
Low flow priapism, however, is the most common kind of presentation in patients with SCD and it is an emergency. The treatment for low flow priapism includes aspiration of blood from the corpus cavernosum and subsequent irrigation with saline or adrenergic agonists (phenylephrine, 1mL of a 100-500mcg/mL solution every 3-5 minutes for three times). Patients that do not respond to aspiration & irrigation may be treated with exchange transfusion – erythrocytapheresis is best modality (be careful to not increase Hb over 10g/dL to reduce the risk of hyperviscosity). Patients that do not respond to any of other therapies after 12 hours should be considered for surgical intervention (usually a shunt between the corpus cavernosum and other structure).
DACTYLITIS (HAND-FOOT SYNDROME):
More common in children with SCD, it consists in symmetrical swelling of hands and/or feet with pain. Treatment consists on hydration, analgesic and anti-inflammatory medications. Hydroxyurea may be used after that.
May affect the humeral head or the femoral head and can be asymptomatic or present as pain during weight bearing. Radiographic studies of the affected area should be conducted to confirm the disease (X-ray and MRI). Treatment can be done using a conservative approach (pain management, rest, mobilization, physical therapy) or an invasive approach if needed (core decompression or arthroplasty).
Patients with SCD acute neurological deficits should be evaluated because they may have an acute stroke (ischemic or hemorrhagic), a TIA, cerebral venous sinus thrombosis, or meningitis.
After history, physical examination, stabilization (A-B-C) and monitoring, the a patient with SCD and high suspicion of stroke should receive a simple transfusion in order to raise the Hb to ~10g/dL and reduce HbS to <30%.
Laboratory tests and imaging (CT/MRI) should be obtained.
Patients with a stroke that is related to SCD should not receive thrombolytics, except in patients in which a thromboembolic stroke is very likely (e.g. atrial fibrillation, atherosclerosis).
BP should be treated only if SBP > 220mmHg, DBP > 120mmHg or if the patient has another indication of hypertensive emergency (e.g. CAD, hypertensive encephalopathy). In such cases, BP should be reduced by only ~15% in the first 24h. If the patient receives thrombolytics, however, his BP should be reduced below 185/110mmHg before the treatment and should remain under that range for the next 24 hours. Intravenous drugs may be used (labetalol 10-20mg IV, may be repeated once OR nicardipine IV 5-15mg/h).
Antiplatelet therapy should be provided for ischemic stroke (aspirin 160 to 325mg/day).
Prophylactic anticoagulation may be used for ischemic stroke. Therapeutic anticoagulation should not be used.
Patients with hemorrhagic stroke should not receive any antiplatelet therapy or anticoagulation.
In such cases, platelets should be transfused if it falls under 100.000/microL.
Very high BP (SBP >200 or MAP >150mmHg) should be reduced with intravenous agents, but if there is evidence of elevated intracranial pressure the reduction should not be below 160/90mmHg or MAP 110mmHg. In such cases of suspected intracranial hypertension (ICP), the BP management should aim to keep a MAP that would correspond to a cerebral perfusion pressure (CPP) in the range of 61-80mmHg (CPP = MAP – ICP).
Angiography should be obtained, as well as neurosurgical consultation if appropriate.
FEVER IN PATIENTS WITH SCD:
Patients with SCD and fever > 101.5F (38.5C) should be promptly evaluated After history, physical examination and auxiliary tests (CBC, chest X-Ray, cultures) empiric antibiotics should be started and the patient should be admitted to the hospital if necessary.
REFERENCES & FURTHER READING:
- NIH. Evidence-Based Management of Sickle Cell Disease. Expert Panel Report. 2014.
- Howard J, et al. Guideline on the management of acute chest syndrome in sickle cell disease. BJH. Volume 169, Issue 4 May 2015 Pages 492–505.
- Steinberg MH, et al. Effect of Hydroxyurea on Mortality and Morbidity in Adult Sickle Cell AnemiaRisks and Benefits Up to 9 Years of Treatment. JAMA. 2003;289(13):1645-1651.
- National Institute for Health and Care Excellence.Sickle cell disease: managing acute painful episodes in hospital painful episodes in hospital. Published: 27 June 2012.
- Davis BA, et al. Guidelines on red cell transfusion in sickle cell disease. Part I: principles and laboratory aspects. British Society for Haematology.
- NIH. The management of Sickle Cell Disease. 4th edition.
- Yawn BP, et al. Management of Sickle Cell Disease: Recommendations from the 2014 Expert Panel Report. Am Fam Physician. 2015 Dec 15;92(12):1069-1076A.
- The Royal Children`s Hospital Melbourne. Sickle cell disease. Clinical Practice Guidelines.
- McCavit T, Desai P. Management of Acute Complications of Sickle Cell Disease. A pocket guide for the clinician.