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).
Try two board-style Sickle Cell Disease questions
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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?
AExchange transfusion
BIron supplementation
CHydroxyurea
DFolate supplementation
Reveal answer & full explanation
Correct answer: C — Hydroxyurea
AExchange transfusion
BIron supplementation
CHydroxyurea✓
DFolate supplementation
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, severe acute chest syndrome, or priapism (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).
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?
AExchange transfusion
BIV fluids and IV opioid analgesia
CSimple packed red blood cell transfusion
DInitiate oral hydroxyurea therapy
Reveal answer & full explanation
Correct answer: B — IV fluids and IV opioid analgesia
AExchange transfusion
BIV fluids and IV opioid analgesia✓
CSimple packed red blood cell transfusion
DInitiate oral hydroxyurea therapy
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
A) Exchange transfusion — reserved for severe complications such as acute chest syndrome, stroke, multiorgan failure, or priapism unresponsive to therapy; not indicated for uncomplicated VOC
D) 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
C) 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
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; 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 for pulmonary hypertension screening in adults
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; indicated for all SCD patients ≥9 months; 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 (PCV13/PCV15 + PPSV23), meningococcal (MenACWY + MenB), and annual influenza
Hydroxyurea works primarily by inducing HbF (fetal hemoglobin), which does not sickle; benefits accrue over weeks to months. Monitor CBC for myelosuppression.
Salmonella osteomyelitis is the classic SCD-associated infection; Staphylococcus aureus is still the most common organism overall.
Parvovirus B19 causes 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 complications
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