Also known as: SCD, HbSS, sickle cell anemia, sickle cell disease
Overview
Group of inherited hemoglobinopathies caused by a point mutation in the beta-globin gene (Glu→Val at position 6). Homozygous HbSS produces sickle cell anemia; HbSC and HbS/beta-thalassemia are clinically related compound heterozygous states. Sickle cell trait (HbAS) is generally asymptomatic.
Epidemiology
Most common hemoglobinopathy in the US; ~100,000 affected, predominantly Black/African ancestry (~1 in 365 Black births). HbS trait carriers ~8% of US Black population. Geographic distribution overlaps with historical malaria endemicity (heterozygote advantage).
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Question 1HematologyEasy
A 35-year-old man with sickle cell disease has been hospitalized four times in the past year for acute vaso-occlusive pain crises and has had one episode of acute chest syndrome. His steady-state hemoglobin is 8.0 g/dL with a reticulocyte count of 9%. He asks which treatment could reduce the frequency of his pain crises and hospitalizations. Which of the following is the most appropriate long-term disease-modifying therapy?
AHydroxyurea
BIron supplementation
CExchange transfusion
DFolate supplementation
EPenicillin prophylaxis
Reveal answer & full explanation
Correct answer: A — Hydroxyurea
AHydroxyurea✓
BIron supplementation
CExchange transfusion
DFolate supplementation
EPenicillin prophylaxis
Why Hydroxyurea is correct
Hydroxyurea raises fetal hemoglobin (HbF), which interferes with HbS polymerization and reduces the frequency of vaso-occlusive crises, acute chest syndrome, transfusions, and hospitalizations by roughly half.
It is the established long-term disease-modifying therapy for patients with frequent pain crises or prior acute chest syndrome, per current NHLBI sickle cell disease guidance.
This patient's recurrent crises and prior acute chest syndrome are exactly the indication to start it.
Why the others are wrong
Exchange transfusion — Used acutely for stroke or severe acute chest syndrome (or as chronic transfusion in selected patients), not as the routine first-line agent to lower baseline crisis frequency (right-therapy-wrong-setting).
Iron supplementation — Not indicated; sickle cell anemia is hemolytic rather than iron-deficient, and repeated transfusions risk iron overload, so iron would be harmful (buzzword-matching anemia to iron).
Folate supplementation — Supports red-cell production during chronic hemolysis but does not modify disease course or prevent vaso-occlusion (premature closure on supportive care).
Penicillin prophylaxis — twice-daily oral penicillin prevents invasive pneumococcal infection in young children with sickle cell anemia and is typically stopped at age 5 unless there was prior invasive pneumococcal disease or splenectomy; it does not reduce vaso-occlusive crises or acute chest syndrome (right-therapy-wrong-age).
Question 2HematologyMedium
A 22-year-old woman with homozygous HbSS sickle cell disease presents to the ED with 9/10 diffuse bone pain in the back, arms, and legs that started 6 hours ago. She reports no fever, cough, or chest pain. Temperature is 37.1 C, BP 128/76 mmHg, HR 104/min, RR 18/min, SpO2 98% on room air. Exam shows tenderness over the long bones without swelling or erythema. Labs show Hgb 8.1 g/dL (baseline 8 g/dL), WBC 9.8, reticulocytes 9%. Which of the following is the most appropriate next step in management?
AIV fluids and IV opioid analgesia
BSimple packed red blood cell transfusion
CInitiate oral hydroxyurea therapy
DExchange transfusion
ESupplemental oxygen via nasal cannula
Reveal answer & full explanation
Correct answer: A — IV fluids and IV opioid analgesia
AIV fluids and IV opioid analgesia✓
BSimple packed red blood cell transfusion
CInitiate oral hydroxyurea therapy
DExchange transfusion
ESupplemental oxygen via nasal cannula
Why IV fluids and IV opioid analgesia is correct
This patient is in an uncomplicated vaso-occlusive crisis (VOC), the hallmark acute presentation of sickle cell disease
VOC is driven by HbS polymerization, RBC sickling, and microvascular occlusion producing ischemic bone pain
First-line acute management is prompt parenteral opioid analgesia within 30–60 minutes of arrival, titrated to pain control
IV hydration should target euvolemia (oral preferred; IV fluids only if the patient is volume-depleted or cannot take oral intake) — over-aggressive fluids worsen acute chest syndrome and pulmonary edema risk
Supplemental oxygen is given only for hypoxia; this patient's SpO2 is 98% on room air
Hemoglobin is at baseline (8.1 g/dL vs. baseline 8 g/dL), so transfusion is not indicated
Why the others are wrong
Exchange transfusion — reserved for severe complications such as acute chest syndrome, stroke, or multiorgan failure; not indicated for uncomplicated VOC
Initiate oral hydroxyurea therapy — hydroxyurea raises fetal hemoglobin and lowers the frequency of future crises, but its effect takes weeks to months; it is chronic outpatient prophylaxis that does nothing for the pain of an acute VOC, so it is not an ED intervention
Simple packed red blood cell transfusion — not routinely indicated for VOC because Hgb is at baseline; transfusion is used for symptomatic anemia, aplastic crisis, or acute chest syndrome
Supplemental oxygen via nasal cannula — oxygen is often assumed to reverse sickling, but in a patient who is not hypoxemic it neither shortens a vaso-occlusive crisis nor relieves pain; it is reserved for hypoxia, and this patient's SpO2 is 98% on room air while her 9/10 pain still needs prompt parenteral opioids
Additional high-yield points
Hydroxyurea is used for chronic prophylaxis of VOC, not for acute crisis management
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Autosomal recessive: both parents must carry HbS, HbC, or beta-thalassemia variant
African, Mediterranean, Middle Eastern, Indian, and Caribbean ancestry
Triggers for vaso-occlusion: hypoxia, dehydration, infection, acidosis, cold exposure, stress, high altitude
Pathophysiology
HbS polymerizes when deoxygenated, deforming red cells into a sickle shape. Sickled cells are rigid, adhesive to endothelium, and short-lived (lifespan 10-20 days vs normal 120). Two consequences: chronic hemolytic anemia and microvascular occlusion → ischemia/infarction of multiple organs. Repeated splenic infarction → functional asplenia by early childhood, increasing risk of encapsulated organism infections.
Clinical presentation
Symptoms
Vaso-occlusive pain crises — deep bony pain in back, chest, extremities; lasts hours to days
Fatigue, dyspnea from chronic anemia (baseline Hb 6-9 g/dL)
Dactylitis (hand-foot syndrome) — first manifestation in infants 6-12 months
Recurrent infections (encapsulated organisms: pneumococcus, H. flu, meningococcus, Salmonella)
Splenomegaly in young children, autosplenectomy by ~5 years
Bone tenderness over affected areas during crisis
Retinopathy on fundoscopy (especially HbSC)
Cardiomegaly, systolic flow murmur
Classic findings
African-American child with dactylitis at 6-12 months age and family history of sickle cell disease.
Differential diagnosis
Acute chest syndrome — New pulmonary infiltrate + fever/respiratory symptoms in SCD patient — leading cause of death; caused by infection (S. pneumoniae, Mycoplasma/Chlamydia, viruses), fat embolism from infarcted bone marrow, and in situ pulmonary sickling; treat with antibiotics, transfusion, bronchodilators, analgesia
Vaso-occlusive crisis — Severe deep bony pain without infiltrate or other organ failure; treat with hydration, analgesia, oxygen if hypoxic
Splenic sequestration — Pediatric SCD, acute splenomegaly, drop in Hb >2 g/dL, hypovolemia; medical emergency, transfuse
Aplastic crisis — Sudden severe anemia with low reticulocytes, often parvovirus B19; transfusion supportive
MRI brain for stroke evaluation; MRI of bone if osteomyelitis vs infarction unclear
Echocardiogram if symptoms or signs suggest pulmonary hypertension (routine screening of asymptomatic patients is not recommended); an elevated TRV (≥2.5 m/s) with reduced 6-minute walk distance or elevated NT-proBNP warrants right heart catheterization and pulmonary hypertension specialist referral
Diagnostic algorithm
flowchart TD
A[HbSS homozygote] --> B[HbS polymerization<br/>when deoxygenated]
B --> C[RBC sickling<br/>rigid, adhesive]
C --> D[Chronic hemolysis<br/>Hb 6-9, retic ↑, LDH ↑]
C --> E[Microvascular<br/>occlusion]
E --> F[Vaso-occlusive<br/>pain crisis]
E --> G[Acute chest<br/>syndrome]
E --> H[Stroke]
E --> I[Splenic infarction<br/>→ autosplenectomy]
E --> J[Avascular necrosis]
I --> K[Encapsulated<br/>organism infection<br/>S. pneumoniae, H. flu,<br/>Salmonella]
D --> L[Pigment gallstones]
D --> M[Pulmonary HTN]
Sickle cell disease pathophysiology — single point mutation drives both hemolytic and vaso-occlusive complications.
Treatment
First-line
Hydroxyurea — disease-modifying therapy; increases HbF and reduces sickling; offered to all children ≥9 months with HbSS or HbSβ0 regardless of severity and to adults with ≥3 pain crises per year, recurrent ACS, or severe symptomatic anemia (HbSC/HbSβ+ per sickle cell expert); reduces vaso-occlusive crises, acute chest syndrome, transfusion need, and mortality
Penicillin prophylaxis (penicillin V 125 mg BID <3 years, 250 mg BID ages 3-5; continue to age 5 minimum) — reduces pneumococcal sepsis
Routine immunizations PLUS pneumococcal per current CDC/ACIP risk-based schedule (PCV15 or PCV20; PPSV23 only after PCV15; adults may use PCV20 or PCV21 alone), meningococcal (MenACWY + MenB), and annual influenza
Folic acid 1 mg daily (chronic hemolysis)
Vaso-occlusive crisis management: parenteral opioids within 60 minutes of arrival (morphine, hydromorphone — avoid meperidine), given scheduled or by PCA rather than PRN, plus an NSAID (e.g., ketorolac) as an adjunct if no contraindication; hydration to euvolemia (oral if able, IV at no more than maintenance rate if unable to drink — over-hydration can precipitate acute chest syndrome); incentive spirometry; oxygen only if hypoxic; treat underlying trigger
Acute chest syndrome: broad-spectrum antibiotics (ceftriaxone + azithromycin), incentive spirometry, simple or exchange transfusion based on severity
Exchange transfusion for acute stroke, severe ACS, multiorgan failure; not for priapism (episode ≥4 hours: hydration, analgesia, and urgent urology for aspiration/irrigation)
Second-line / adjunct
L-glutamine — reduces frequency of vaso-occlusive crises
Crizanlizumab (P-selectin inhibitor) — monthly IV; approved on phase 2 data showing fewer vaso-occlusive crises, but the phase 3 STAND trial showed no reduction vs placebo (EU authorization revoked 2023)
Voxelotor — increases hemoglobin oxygen affinity, raises Hb; withdrawn from market in 2024 due to mortality signal
Chronic transfusion for stroke prevention (TCD >200) or recurrent ACS — requires iron chelation (deferasirox, deferiprone, deferoxamine)
Avascular necrosis of femoral/humeral head — hip or groin pain with weight bearing; plain films normal early and MRI most sensitive; a subchondral crescent sign marks subchondral fracture before collapse
Retinopathy (especially HbSC), leg ulcers, priapism, cholelithiasis (pigment stones)
Functional asplenia — pneumococcal sepsis is the historic leading cause of pediatric mortality
Hydroxyurea works primarily by inducing HbF (fetal hemoglobin), which does not sickle; benefits accrue over weeks to months. Monitor CBC for myelosuppression. Teratogenic — discontinue in pregnancy and breastfeeding and counsel on contraception.
Salmonella osteomyelitis is the classic SCD-associated infection; Staphylococcus aureus is still the most common organism overall.
Parvovirus B19 infects erythroid progenitors (via the P antigen) and halts red cell production for about 7-10 days, causing transient aplastic crisis — severe anemia with reticulocyte count <1%.
Howell-Jolly bodies on smear indicate functional asplenia and the need for encapsulated-organism prophylaxis.
Avoid meperidine — accumulation of normeperidine causes seizures, especially with renal dysfunction.
Exchange transfusion (not simple) is preferred when HbS reduction is needed quickly without volume overload — acute stroke, severe ACS.
TCD screening starting at age 2 has dramatically reduced primary stroke incidence in SCD children (STOP trial).
References
ASH 2020 — American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain (Brandow AM et al., Blood Adv 2020;4(12):2656-2701)
STOP Trial — Prevention of a First Stroke by Transfusions in Children with Sickle Cell Anemia (Adams et al., NEJM 1998)
MSH Trial — Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia (Charache et al., NEJM 1995)
Frangoul et al. — Exagamglogene autotemcel for Severe Sickle Cell Disease (NEJM 2024)
ASH 2019 — American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease (Liem RI et al., Blood Adv 2019;3(23):3867-3897)
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