Medication Summary
The goals of pharmacotherapy are to reduce and prevent complications. The drugs used in treatment of sickle cell disease (SCD) include antimetabolites, analgesics, antibiotics, vaccines, and nutritional agents.
Antimetabolites
Class Summary
Hydroxyurea affects DNA, resulting in increased production of Hb F, which inhibits sickling. Considerable effort is being expended to identify agents whose ultimate effect interferes with the sickling process and prevents the many complications of sickle cell disease.
Hydroxyurea (Siklos)
Hydroxyurea inhibits deoxynucleotide synthesis. Its myelosuppressive effects last a few days to a week and are easier to control than those of alkylating agents.
Opioid Analgesics
Class Summary
Opioid analgesics are used to control acute crisis and chronic pain.
Oxycodone and aspirin (Percodan)
This drug combination is indicated for the relief of moderate to severe pain. Oxycodone binds to opiate receptors in the CNS inhibiting the ascending pain pathways, altering pain response and perception. Aspirin inhibits platelet aggregation; has analgesic and anti-inflammatory properties.
Methadone (Dolophine, Methadose)
Methadone is used in the management of severe pain. It inhibits ascending pain pathways, diminishing the perception of and response to pain.
Morphine sulfate (Duramorph, Infumorph, MorphaBond ER, MS Contin, Kadian)
An opioid analgesic, morphine interacts with endorphin receptors in the CNS, inhibiting the pain pathways, altering pain response and perception.
Oxycodone and acetaminophen (Percocet, Endocet, Primlev)
This drug combination is indicated for the relief of moderate to severe pain. It is the drug of choice for patients who are hypersensitive to aspirin.
Fentanyl (Sublimaze PF, Duragesic, Abstral, Actiq, Fentora)
A synthetic opioid analgesic that is primarily a mu receptor agonist, fentanyl is 50-100 times more potent than morphine. Unlike morphine, fentanyl is not commonly associated with histamine release.
Nalbuphine
An opioid agonist/antagonist, nalbuphine stimulates kappa opioid receptor in the CNS, which causes inhibition of ascending pain pathways. An antagonist at the opioid mu receptors, it is useful for moderate-to-severe pain in sickle cell disease.
Codeine
Codeine binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering perception and response to pain.
Codeine/acetaminophen (Tylenol with Codeine #3,Tylenol with Codeine #4 )
This combination is a mild narcotic analgesic. Acetaminophen believed to inhibit the synthesis of prostaglandins in the CNS, and peripherally block pain impulse generation. Codeine binds to in the CNS; causing inhibition of ascending pain pathways, altering pain perception and response.
Nonsteroidal Analgesics
Class Summary
Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) add to the effects of opioids during painful crisis. This allows use of lower doses of narcotics.
Ketorolac
Ketorolac is an intravenously administered NSAID and a very powerful analgesic. It inhibits prostaglandin synthesis by decreasing activity of the enzyme cyclooxygenase, which results in decreased formation of prostaglandin precursors. In turn, this results in reduced inflammation.
Aspirin (Ecotrin, Ascriptin, Bayer Aspirin, St. Joseph Adult Aspirin, Durlaza)
Aspirin treats mild to moderate pain. It inhibits prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2.
Acetaminophen (Tylenol, Aspirin-Free Anacin, Acephen, Cetafen Extra, Ofirmev)
Acetaminophen is the drug of choice for pain in patients with documented hypersensitivity to aspirin or NSAIDs, with upper GI disease, or who are taking oral anticoagulants. Acetaminophen is believed to work peripherally to block pain impulse generation.
Ibuprofen (Advil, Genpril, I-Prin, Motrin IB, Addaprin)
Ibuprofen is usually the drug of choice for treatment of mild to moderate pain, if no contraindications exist. It inhibits inflammatory reactions and pain by decreasing the activity of the enzyme cyclo-oxygenase, resulting in inhibition of prostaglandin synthesis.
Tricyclic Antidepressants
Class Summary
Tricyclic antidepressants (TCAs) increase the levels of certain brain chemicals which improve mood and regulate pain signals. Low doses of TCAs relieve pain, although its mechanism is still unknown.
Amitriptyline (Elavil)
Amitriptyline inhibits presynaptic reuptake of serotonin and norepinephrine and blocks cholinergic, adrenergic, histaminergic, and sodium channels.
Nortriptyline (Pamelor)
Nortriptyline may increase the synaptic concentration of serotonin and/or norepinephrine in the CNS by reuptake inhibition via the presynaptic neuronal membrane; inhibits the activity of histamine, 5-hydroxytryptamine, and acetylcholine. It increases the pressor effect of norepinephrine but blocks the pressor response of phenethylamine.
Vitamins
Class Summary
Supplemental folic acid replenishes the depleted folate stores necessary for erythropoiesis.
Folic acid (FA-8)
Folic acid is necessary for proper nucleotide metabolism. It is an important cofactor for enzymes used in production of RBCs.
Nutritionals
Class Summary
Severe anemia and vaso-occlusive processes results in incapacitating complications. Glutamine reduces acute complications (eg acute chest syndrome) associated with SCD.
Glutamine (Endari)
Glutamine is an amino acid oral powder for acute complications associated with SCD. The precise mechanism of action is unknown. Sickle RBCs are more susceptible to oxidative damage than normal RBCs, which may contribute to chronic hemolysis and vaso-occlusive events associated with SCD. Pyridine nucleotides, NAD+ and its reduced form NADH, regulates and prevents oxidative damage in RBCs. Glutamine is believed to improve the NAD redox potential in sickle RBCs by increasing reduced glutathione’s availability.
Hemoglobin Oxygen-Affinity Modulators
Class Summary
Voxelotor is a hemoglobin S (HbS) polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to RBCs. By increasing the affinity of Hb for oxygen, voxelotor demonstrates dose-dependent inhibition of HbS polymerization.
Voxelotor (Oxbryta)
Indicated for treatment of sickle cell disease in adults and adolescents aged 12 years or older.
P-Selectin Inhibitor
Class Summary
Binding P-selectin on the surface of the activated endothelium and platelet cells blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes; thereby, decreasing vaso-occlusive crises.
Crizanlizumab (Adakveo, crizanlizumab-tmca)
P-selectin inhibitor indicated to reduce frequency of vasoocclusive crises in adults with sickle cell disease.
Antibiotics
Class Summary
The absence of a spleen inhibits immunological functions of clearing bacteria from the blood and synthesizing antibodies leading to an increased frequency of infetion. These agents are used for treatment of suspected or confirmed infections.
Cefuroxime (Ceftin, Zinacef)
Cefuroxime is a second-generation cephalosporin that maintains the gram-positive activity of first-generation cephalosporins and adds activity against Proteus mirabilis, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, and Moraxella catarrhalis. The condition of the patient, severity of infection, and susceptibility of the microorganism should determine proper dose and route of administration.
Amoxicillin and clavulanate (Augmentin, Augmentin XR, Augmentin ES-600)
This drug combination extends the antibiotic spectrum of this penicillin to include bacteria normally resistant to beta-lactam antibiotics. It is indicated for skin and skin structure infections caused by beta-lactamase-producing strains of Staphylococcus aureus.
Penicillin VK
Penicillin inhibits the biosynthesis of cell wall mucopeptide.
Cefixime (Suprax)
Cefixime inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs); thus inhibiting cell wall biosynthesis. Bacteria lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.
Ceftriaxone
A third-generation cephalosporin, inhibits bacterial cell wall synthesis by binding to one or more PBPs; downstream inhibits cell wall biosynthesis via inhibition the final steps of peptidoglycan synthesis along the bacterial cell walls.
Azithromycin (Zithromax, Zmax)
Azithromycin is a macrolide antibiotic that is useful for treatment of community-acquired pneumonia in sickle cell disease, as an adjunct to a cephalosporin to cover Chlamydia or Mycoplasma infections.
Cefaclor
A second-generation cephalosporin, cefaclor is indicated for infections caused by susceptible gram-positive cocci and gram-negative rods.
Clarithromycin (Biaxin, Biaxin XL)
Clarithromycin exerts its antibacterial action by binding to 50S ribosomal subunit resulting in inhibition of protein synthesis. The 14-OH clarithromycin metabolite is twice as active as the parent compound against certain organisms.
Phosphodiesterase Type 5 Inhibitors
Class Summary
Phosphodiesterase type 5 (PDE5) inhibitors are used to treat pulmonary hypertension associated with sickle cell disease. These agents are also used to prevent priapism associated with sickle cell disease.
Sildenafil (Revatio)
Sildenafil promotes selective smooth muscle relaxation in lung vasculature, possibly by inhibiting PDE5. This results in a subsequent reduction of blood pressure in pulmonary arteries and an increase in cardiac output.
Tadalafil (Adcirca)
Inhibits PDE-5 in smooth muscle of pulmonary vasculature where PDE-5 is responsible for the degradation of cyclic guanosine monophosphate (cGMP). Increased cGMP concentration results in pulmonary vasculature relaxation; vasodilation in the pulmonary bed and the systemic circulation may occur.
Endothelin Receptor Antagonists
Class Summary
These agents are used for pulmonary hypertension associated with sickle cell disease.
Bosentan (Tracleer)
Bosentan improves pulmonary arterial hemodynamics by competitively binding to ET-1 receptors endothelin-A and endothelin-B in pulmonary vascular endothelium and pulmonary vascular smooth muscle. This leads to a significant increase in cardiac index associated with a significant reduction in pulmonary artery pressure, pulmonary vascular resistance, and mean right atrial pressure.
Iron Chelators
Class Summary
Iron overload is a consequence of the numerous transfusions required and may lead to complications such as heart or liver failure. Iron chelators help maintain hemoglobin levels within the desired range.
Deferoxamine mesylate (Desferal)
Deferoxamine helps prevent damage to the liver and bone marrow from iron deposition by promoting renal and hepatic excretion in urine and bile in feces. It readily chelates iron from ferritin and hemosiderin but not from transferrin. It does not affect iron in the cytochromes or hemoglobin. This agent is most effective when administered by continuous infusion. It gives urine a red discoloration.
Deferasirox (Exjade, Jadenu)
Deferasirox is an orally administered iron chelation agent that has been shown to reduce the liver iron concentration in adults and children who receive repeated RBC transfusions. It binds iron with high affinity in a 2:1 ratio.
Deferiprone (Ferriprox)
Deferiprone (1,2 dimethyl-3-hydroxypyridine-4-one) is a member of a family of hydroxypyridine-4-one (HPO) chelators that requires 3 molecules to fully bind iron (III), each molecule providing 2 coordination sites (bidentate chelation). It is indicated for adults and children aged 3 years and older with iron overload caused by transfusions for sickle cell disease, thalassemia syndromes, or other anemias. It is available as tablets and oral solution.
Antiemetics
Class Summary
These agents are useful in the treatment of symptomatic nausea.
Promethazine (Phenadoz, Phenergan)
Phenergan is used for symptomatic treatment of nausea in vestibular dysfunction. Antidopaminergic agent effective in the treatment of emesis. It blocks postsynaptic mesolimbic dopaminergic receptors in the brain and reduces stimuli to the brainstem reticular system.
Adrenergic Agonists
Class Summary
These agents have been used successfully for priapism, possibly due to their sympathomimetic vasopressor activity.
Pseudoephedrine (Nexafed, Sudafed, Zephrex-D, Genaphed, SudoGest)
Pseudoephedrine promotes vasoconstriction by directly stimulating alpha-adrenergic receptors.
Vaccines
Class Summary
It is recommended to maintain an up-to-date immunization schedule for pneumococcal, haemophilus influenzae and meningococcal vaccine
Pneumococcal vaccine 13-valent (Prevnar 13)
The pneumococcal 13-valent vaccine contains capsular antigens extracted from Streptococcus pneumoniae and are used to stimulate active immunity to pneumococcal infection.
Pneumococcal vaccine polyvalent (Pneumovax 23)
Pneumococcal polysaccharide polyvalent is an inactive bacterial vaccine that induces active immunization to the 23 pneumococcal serotypes contained in the vaccine.
Haemophilus influenzae type b vaccine (ActHIB, Hiberix, PedvaxHIB)
The vaccine consists of Haemophilus influenzae type b capsular polysaccharide (polyribosyl-ribitol-phosphate, PRP). IgG acts as an anti-capsular PRP antibody, demonstrating bactericidal activity against H influenzae type b.
Meningococcal A C Y and W-135 diphtheria conjugate vaccine (Menactra, Menveo)
The vaccine induces bactericidal antibody production specific to the capsular polysaccharides (eg, serogroups A, C, Y and W-135). The presence of anti-capsular meningococcal antibodies are associated with protecting against invasive meningococcal diseases.
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Molecular and cellular changes of hemoglobin S.
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Skeletal sickle cell anemia. H vertebrae. Lateral view of the spine shows angular depression of the central portion of each upper and lower endplate.
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Peripheral blood with sickled cells at 400X magnification. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
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Peripheral blood smear with sickled cells at 1000X magnification. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
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Peripheral blood smear with Howell-Jolly body, indicating functional asplenism. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
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Effects of therapy with hydroxyurea.
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Skeletal sickle cell anemia. Bone-within-bone appearance. Following multiple infarctions of the long bones, sclerosis may assume the appearance of a bone within a bone, reflecting the old cortex within the new cortex.
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A 12-year-old boy with HgbSS disease presents to the pediatric emergency department after his mother tried to wake him for school this morning and noted altered mental status, left-sided gaze paralysis with his head tilted to the left, and flaccid paralysis of the right arm and leg. A CT scan of the brain was obtained immediately.
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Embolic stroke of the left middle cerebral artery. SCD is the most common cause of stroke in children and one of the most devastating complications of SCD. Clinically overt strokes are typically due to embolism of the intracranial internal carotid artery and proximal middle cerebral artery (MCA), while "silent strokes" more typically occur in the smaller lacunar and penetrating arteries. As RBCs undergo sickling and hemolysis within the cerebral circulation, they adhere to the vascular endothelium and promote a hypercoaguable state and fuel thromboembolism formation. Treatment options include prophylactic therapy with hydroxyurea to promote HgbF concentrations and monitoring via transcranial Doppler to evaluate MCA blood flow velocity. Children found to have high velocities are at increased risk for stroke and commonly receive RBC transfusions to decrease the concentration of HgbS.
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The spleen enlarges during the first year of life in SCD, as it becomes congested with trapped slow-flowing sickled cells within the splenic sinuses and reticuloendothelial system. The histology image shown demonstrates splenic congestion from sequestered sickled RBCs (arrows). Microvascular occlusions produce chronic tissue hypoxia and microinfarctions. Over time, fibrosis induces autosplenectomy. With functional asplenia, patients are particularly susceptible to infection by the encapsulated organisms Streptococcus pneumoniae and Haemophilus influenzae. Vaccination and prophylactic daily penicillin throughout childhood are mainstays of treatment to prevent sepsis and meningitis
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Splenic sequestration is an important cause of morbidity that occurs when sudden splenic pooling of blood within the reticuloendothelial system causes an acute drop in circulatory volume and shock-like symptoms (hypotension, tachycardia) with a rigid distended abdomen. It is an acute emergency and can be fatal in 1-2 hours secondary to circulatory hypovolemia. Treatment is with volume resuscitation and blood transfusion. The CT image shown demonstrates splenomegaly with a mass-like process (arrows) from splenic sequestration.
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Patients with SCD are also at increased risk of developing pulmonary arterial hypertension (PAH). The etiology is most likely multifactorial but likely related to increased cardiac output secondary to underlying chronic anemia. Impedance to the elevated blood flow will cause further dilation and increase in pulmonary pressures. Postsickling changes including interstitial fibrosis secondary to vaso-occlusive crisis of ACS and hypoperfusion with resultant hypoxia of the pulmonary vascular beds are both proposed offenders inciting further dilation and elevation of pulmonary pressures. A pulmonary arteriogram depicting the markedly dilated vascular supply of the lungs seen in PAH is shown.
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Proliferative sickle cell retinopathy. Sickle cell retinopathy is believed to be vaso-occlusion of peripheral arterioles of the retina leading to retinal hypoxia, ischemia, and infarction. New vessels then form at the junction of the vascular and avascular areas of retina. This neovascularization of retinal tissue and resultant traction of fibrovascularization places patients at risk for vitreous hemorrhage (arrows) and retinal detachment. Another common ocular manifestation is hyphema. Anterior chamber bleeding occurs spontaneously, but sickled erythrocytes obstruct the trabecular meshwork leading to significant elevations of intraocular pressure. Patients are particularly susceptible to glaucomatous optic nerve damage from even mildly elevated intraocular pressures. Pressures greater than 36 mm Hg for 24 hours are an indication for surgical drainage in both SCD and sickle cell trait, regardless of the size of hyphema. Image courtesy of the National Eye Institute, National Institutes of Health (NEI/NIH).
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A 19-year-old man with known HgbSS disease presents because his girlfriend reports his eyes are yellow. He has no complaints. Physical exam is notable for mild abdominal pain, but is otherwise within normal limits. What imaging test is warranted for this work-up? The image shown is of a male child with similar symptoms. Image courtesy of Wikimedia Commons.
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Right upper quadrant ultrasoundChronic hemolysis of sickled cells in HgbSS disease and high heme turnover yields hyperbilirubinemia and is associated with increased formation of bile stones. Stone formation occurs as substances in bile reach concentrations that approach the limits of their solubility. As saturation levels are reached, crystals precipitate, become trapped in mucus, and produce sludge (shown). Over time, the crystals aggregate and form stones. Occlusion of the biliary tree by sludge and/or stones produces clinical disease, typically right upper quadrant pain. The scleral icterus seen in the image of the previous slide is most likely secondary to the elevated circulating levels of bilirubin as a result of an acute hemolytic event (such as an acute vaso-occlusive crisis).
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Renal papillary necrosisThe microvascular beds of the renal parenchyma are susceptible to sickling and vaso-occlusive crisis because of their inherent low-oxygen and high-osmolarity state. Depending on the location of occlusion, symptoms vary from a decreased ability to concentrate urine (yielding nocturia and polyuria), a disruption of exchange mechanisms (yielding hyperkalemia) or hematuria, which further damages renal tubules. In renal papillary necrosis, repeated vascular occlusion infarcts the renal medullary pyramids and papillae. This causes sloughing of papillae, which obstructs the urinary tract. Treatment options include hydration, high-dose antibiotics for resulting pyelonephritis, and possible percutaneous nephrostomy tube or invasive retrieval of sloughed papillae in acute urinary obstruction. The intravenous pyelogram demonstrates the "egg-in-a-cup" appearance of sloughed renal papillae (arrows) secondary to renal papillary necrosis.
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Skeletal sickle cell anemia. Hand-foot syndrome. Soft tissue swelling with periosteal new-bone formation and a moth-eaten lytic process at the proximal aspect of the fourth phalanx.
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Skeletal sickle cell anemia. Advanced dactylitis. Lytic processes are present at the first and fifth metacarpals, along with periostitis, which is most prominent in the third metacarpal.
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Skeletal sickle cell anemia. Expanded medullary cavity. The diploic space is markedly widened due to marrow hyperplasia. Trabeculae are oriented perpendicular to the inner table, giving a hair-on-end appearance.
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Skeletal sickle cell anemia. Detailed view of the expanded medullary cavity in the same patient as in the previous image.
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Skeletal sickle cell anemia. Osteonecrosis. Image shows flattening of the femoral heads with a mixture of sclerosis and lucency characteristic of osteonecrosis.
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Skeletal sickle cell anemia. Osteonecrosis. Detail of the right hip.
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Skeletal sickle cell anemia. Osteonecrosis. Detail of the left hip.
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Skeletal sickle cell anemia. Bone infarct. Image shows patchy sclerosis of the humeral head and shaft representing multiple prior bone infarcts.
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Skeletal sickle cell anemia. Chronic infarcts and secondary osteoarthritis. Image shows advanced changes of irregular sclerosis and lucency on both sides of the knee joint reflecting numerous prior infarcts. The joint surfaces are irregular and the cartilages are narrowed due to secondary osteoarthritis.
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Skeletal sickle cell anemia. Osteonecrosis. Coronal T1-weighted MRI shows a slightly flattened femoral head with a serpentine margin of low signal intensity around an area of ischemic marrow with signal intensity similar to that of fat.
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Skeletal sickle cell anemia. Osteonecrosis in the same patient as in the previous image. Coronal T2-weighted MRI shows a serpentine area of low signal intensity and additional focal areas of abnormal low signal intensity in the femoral head; these findings reflect collapse of bone and sclerosis.
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Skeletal sickle cell anemia. Osteomyelitis. CT scan in a soft tissue window demonstrates a large abscess in the left thigh encircling the femur, with hypoattenuating pus surrounded by a rim of vivid enhancement.
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Skeletal sickle cell anemia. Osteomyelitis and bone-within-bone. Bone-window CT scan in the same patient as in the previous image shows a bone-within-bone appearance (concentric rings of cortical bone) in the right femur. On the left, a sinus tract (cloaca) traverses the lateral aspect of the femoral cortex, and a small, shardlike sequestrum is present deep to the sinus tract.
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Skeletal sickle cell anemia. Bone scan of bone infarct shows an area of increased uptake in the distal femoral metaphysis corresponding to the infarct demonstrated on the previous plain radiograph.
Tables
Tests |
Age |
Frequency |
CBC count with WBC differential, reticulocyte count |
3-24 mo >24 mo |
every 3 mo every 6 mo |
Percent Hb F |
6-24 mo >24 mo |
every 6 mo annually |
Renal function (creatinine, BUN, urinalysis) |
≥ 12 mo |
annually |
Hepatobiliary function (ALT, fractionated bilirubin) |
≥ 12 mo |
annually |
Pulmonary function (transcutaneous O2 saturation) |
≥ 12 mo |
every 6 mo |
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- Overview
- Presentation
- DDx
- Workup
- Approach Considerations
- Baseline Blood Study Abnormalities
- Suggested Routine Clinical Laboratory Evaluations
- Laboratory Studies in the Ill Child
- Additional Tests
- Radiography
- Magnetic Resonance Imaging
- Nuclear Medicine Scans
- Transcranial Doppler Ultrasonography
- Abdominal Ultrasonography
- Echocardiography
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- Treatment
- Approach Considerations
- Hydroxyurea Therapy
- Transfusion
- Management of Ophthalmic Manifestations
- Vaso-Occlusive Crisis Management
- Control of Acute Pain
- Treatment of Acute Chest Syndrome
- Control of Chronic Pain
- Management of Chronic Anemia
- Prevention and Treatment of Infections
- Treatment of Gallstones
- Treatment of Priapism
- Treatment of Leg Ulcers
- Stroke Prevention
- Treatment of Pulmonary Hypertension
- Sickle Cell Nephropathy
- Treatment of Other Complications
- Stem Cell Transplantation
- Diet and Activity Restrictions
- Investigational Treatments
- Consultations
- Long-Term Monitoring
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- Guidelines
- Medication
- Medication Summary
- Antimetabolites
- Opioid Analgesics
- Nonsteroidal Analgesics
- Tricyclic Antidepressants
- Vitamins
- Nutritionals
- Hemoglobin Oxygen-Affinity Modulators
- P-Selectin Inhibitor
- Antibiotics
- Phosphodiesterase Type 5 Inhibitors
- Endothelin Receptor Antagonists
- Iron Chelators
- Antiemetics
- Adrenergic Agonists
- Vaccines
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