Sickle Cell Disease

Name: Sickle Cell Disease: Hematology Oncology Board Review | HemeOncBuddy
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Benign Hematology·Hemoglobinopathies·2026

Sickle Cell Disease

Mutations

Hemoglobin S: the sixth amino acid in the β chain changes from glutamate (charged) to valine (hydrophobic). Different electrophoretic mobility allows diagnosis by electrophoresis. Deoxygenated HbS is ~50x less soluble than deoxy HbA, so it polymerizes into long fibers; the rate of polymerization rises with intracellular HbS concentration (↑ HbS → ↑ polymerization → ↑ sickling). Heterozygous (trait, HbAS) cells do not usually sickle in vivo.
Hemoglobin C: the sixth amino acid in the β chain changes from glutamate to lysine, leading to increased cellular dehydration and crystallization. Found in people of West African descent; homozygous CC shows target cells and HbC crystals.

Pathophysiology

HbS polymerization under deoxygenation → rigid sickled RBCs → vaso-occlusion plus chronic hemolysis. RBC lifespan ~10 to 20 days (vs 120 normal).
Vaso-occlusion mechanisms: sickled cells, endothelial activation, platelet activation, ↑ neutrophil-RBC adhesion, NO depletion (cell-free Hb scavenges NO; released arginase depletes L-arginine, the NOS substrate), and inflammation.
Modulators of sickling: HbF (anti-sickling, the basis for hydroxyurea therapy), HbS concentration, dehydration, acidosis, hypoxia, and fever.

SCD Hemoglobins and Genotypes

Main genotypes causing sickling disease: SS, SC, and S/β-thalassemia (rarer: S/D-Punjab, S/O-Arab, S/E). SS = sickle cell anemia.
HbSS (homozygous): most severe; Hb 7 to 9 g/dL; ↑ retics (>10%), hemolysis (↑ LDH, ↑ bili, ↓ hapto); frequent VOCs, ACS, stroke; life expectancy ~50 yrs.
HbSC (heterozygous S + C): HbC drives intracellular dehydration and sickling; mild to moderate; Hb 11 to 13 g/dL; less hemolysis; fewer VOCs; spleen often persists into adulthood (splenomegaly, adult splenic sequestration, infarction at altitude); less ACS/stroke; near-normal life expectancy.
HbS/β0-thalassemia: indistinguishable from SS; no β-globin from the thal chromosome; Hb 7 to 9 g/dL.
HbS/β+-thalassemia: milder; some β-globin produced; Hb 10 to 11 g/dL; fewer VOCs/ACS; better prognosis.
HbS/HPFH: mildest; high HbF (15 to 30%) protective; minimal VOCs; normal life expectancy; rare.

Genotype Severity Summary

Severity hierarchy: SS = Sβ0 > SC ~ Sβ+ > S/HPFH.
Baseline Hb: SS 7 to 9, Sβ0 7 to 9, SC 11 to 13, Sβ+ 10 to 11, S/HPFH 13 to 15 g/dL.
Hemolysis markers: SS ↑↑ (LDH >500, bili >3); SC ↑ (milder); S/HPFH normal.
Complications: SS shows VOC, ACS (mortality peak), and stroke; SC shows retinopathy, AVN, and persistent splenomegaly (adult splenic sequestration or infarction); S/HPFH rarely symptomatic.
Hydroxyurea response: SS best (↑ HbF); SC modest.

Sickle Cell Trait (HbAS)

Hematologic parameters normal (NOT microcytic): HbA ~60%, HbS ~40%, HbA2 and HbF normal.
Usually no crises or splenic infarction unless severely hypoxic. NOT a disease.
Renal: hyposthenuria (impaired urine concentration, dilution preserved), microscopic hematuria, papillary necrosis. Renal medullary carcinoma is a rare but classic association (younger Black patients).
Athletes and military: more prone to heat stroke and rhabdomyolysis under unfavorable training conditions (reported ~30x increase in sudden death during boot camp), mitigated by frequent breaks and good hydration; splenic infarct at altitude.
VTE risk modestly increased; counsel partners before pregnancy about offspring genetic risk.

Hemoglobin C Disease

Hemoglobin C trait: 30 to 40% HbC; not anemic; microcytic with ↑ MCHC.
Hemoglobin C disease (CC): mild hemolysis; microcytosis and target cells with ↑ MCHC; splenomegaly.

Acute Complications

SCD: acute complications

System	Complication	Key points	Management
Pain	Acute painful episodes (VOC)	Most common complication; microvascular red cell entrapment, capillary occlusion, and ischemia/reperfusion Most episodes are managed at home; ~1/3 of patients have daily pain Triggers: cold, dehydration, stress, infection	Rapid pain control; ED door to first analgesic in 60 min; reassess every 30 to 60 min Tailored IV opioids; NSAIDs 5 to 7 days; ketamine drip or regional anesthesia for refractory pain Hydration (IV or oral, avoid overload); search for infection; give empiric antibiotics (3rd-gen cephalosporin plus macrolide) only for fever or suspected infection/ACS, not routinely Incentive spirometry hourly (prevents ACS); oxygen if hypoxic Transfusion NOT indicated for uncomplicated pain.
Lung	Acute chest syndrome (ACS)	2nd most common cause of admission and the leading cause of premature death; recurrence ~80% New pulmonary infiltrate plus fever, chest pain, dyspnea, cough, hypoxia Onset usually 24 to 72 h after an acute pain episode; CXR changes may lag up to 12 h Causes: infection, fat embolism, PE, hypoventilation Outcomes: death ~3%, neurologic event ~11%	CBC, retic, type and screen, blood/viral cultures, CXR; ABG if O₂ sat <94% on room air IV fluids to euvolemia; pain relief; broad-spectrum IV antibiotics plus atypical coverage; oxygen to keep sat >95%; incentive spirometry Simple transfusion for symptomatic ACS when Hb is >1 g/dL below baseline (if baseline ≥9, may not be needed), for lobar involvement, or rising O₂ needs; severity and oxygenation guide simple vs exchange; avoid overcorrection/hyperviscosity Red cell exchange if worsening over 6 to 12 h or progressive hypoxia Secondary prevention: hydroxyurea and chronic transfusion
Brain	Stroke	Ischemic strokes peak in children <20 and adults >30; hemorrhagic in ages 20 to 29; highest in SS then SC Usually stenosis/occlusion of ICA or MCA Risk factors: abnormal TCD, silent infarct, prior TIA, low steady-state Hb, HbSS genotype, older age, hypertension TCD <200 cm/s gives ~93% 40-month stroke-free survival in children	Acute stroke: exchange transfusion Primary prevention in children: annual TCD ages 2 to 16 in HbSS/HbSβ0; if abnormal (≥200 cm/s) start regular transfusions to keep HbS <30% and Hb >9 g/dL for at least 1 year; if stopping after ≥1 year, consider replacing with maximum-tolerated-dose hydroxyurea only in selected children without severe vasculopathy (TWiTCH); assess by MRA and continue transfusion if severe vasculopathy or silent cerebral infarction is present Secondary prevention: chronic transfusion (HbS <30%, Hb >9); ~23% of children still have a second stroke despite transfusion; in adults also manage hypertension, diabetes, hyperlipidemia
Brain	Silent cerebral infarcts	Common and increase with age (children ~39%, adults ~50%) Associated with cognitive impairment, poor school performance, and future infarcts ASH: one-time MRI screening in early school-age children and adults	Children: regular transfusions prevent progression and overt stroke; cognitive evaluation Adults: no data
Spleen	Bacterial infections	Functional asplenia develops over infancy and early childhood (dysfunction can begin in infancy, usually functionally asplenic by age 2 to 4); timing varies by genotype. Risk of encapsulated organisms, especially Streptococcus pneumoniae (septicemia, meningitis, osteomyelitis); also Salmonella, H. influenzae b, meningococcus, mycoplasma	Reduced childhood mortality from newborn screening, penicillin prophylaxis (PROPS study), and conjugate pneumococcal vaccine
Spleen	Splenic sequestration	Vaso-occlusion causes RBC pooling in the spleen Common in infants with HbSS (usually <2 yrs); an emergency (hypovolemic shock) Milder forms in adults with HbSC or HbS/β+ (spleen not auto-infarcted) LUQ pain/fullness, Hb drop >2 g/dL from baseline, marked reticulocytosis, and splenomegaly	Simple transfusion in small aliquots (about 5 to 10 mL/kg PRBC; ~1 unit in adults) given slowly with reassessment; avoid volume overload and hyperviscosity (sequestered cells are later released)
Hepatobiliary	Hepatobiliary (sickling, gallstones)	Sickling causes sequestration and cholestasis; transfusions risk HBV/HCV Cholelithiasis, Budd-Chiari, hepatic abscess/bilioma Pigment gallstones may be asymptomatic or cause RUQ pain and cholangitis	Cholecystectomy and ERCP as indicated
	Acute sickle hepatic crisis	Vaso-occlusive; RUQ pain, jaundice, leukocytosis; bilirubin <15 mg/dL, ALT rarely >300 IU/L	Supportive; consider red cell exchange
	Hepatic sequestration	Enlarging liver and RUQ pain, anemia (Hb drop >2 g/dL), reticulocytosis	Slow transfusion; supportive
	Sickle cell intrahepatic cholestasis	Sickle occlusion of hepatic sinusoids; RUQ pain, leukocytosis, fever, jaundice Very high bilirubin (>50 mg/dL), ALT can reach the thousands; coagulopathy and renal failure	Red cell exchange; full supportive care
Kidney	Renal papillary necrosis	Medullary infarction, ~15 to 30% of SCD Painless hematuria or flank pain plus hematuria; may be complicated by UTI or obstruction	Hydration, urinary alkalinization, stop offending drugs, treat infection, relieve obstruction
Kidney	Acute renal failure	May occur during acute pain, ACS, or multiorgan failure	Monitor creatinine and fluid balance, avoid nephrotoxins, consider other etiologies, involve nephrology
Eye	Central retinal artery occlusion (CRAO)	Ocular emergency; more common in children/young adults with HbSS; presents with sudden vision loss	Simple or exchange transfusion
Eye	Orbital infarction	Can occur during a VOC; eye protrusion, eye pain, lid/orbital edema	IV fluids, pain control, steroids
Other	Priapism	Sustained painful erection >4 h from veno-occlusion (reduced venous outflow) Lifetime prevalence 29 to 89% in boys/men Severe or recurrent episodes can cause permanent erectile dysfunction	IV hydration and pain control, then urgent urology for corporal aspiration and intracavernosal phenylephrine; oral sympathomimetics (e.g., pseudoephedrine) are for prevention of recurrent stuttering priapism, not acute treatment, and must not delay it. If prolonged (>2 to 3 h): urology consult to relieve compartment syndrome and improve flow ≥4 h requires urgent corporal aspiration and intracavernosal phenylephrine irrigation Exchange transfusion is NOT primary treatment per AUA/SMSNA 2022 and NHLBI.
Other	Acute aplastic crisis	Parvovirus B19 infection; more common in children with HbSS Gradual fatigue, dyspnea, fever, syncope; Hb 3 to 6 g/dL with markedly ↓ reticulocytes	Supportive RBC transfusion; lifelong immunity, so it does not recur

Chronic Complications

SCD: chronic complications

System	Complication	Key points	Management
Lung	Pulmonary hypertension	Mean PA pressure >20 mmHg at rest (2022 ESC/ERS; older SCD guidelines used ≥25) by right heart catheterization ~6 to 11% of adults; 6-year mortality ~37% Do not routinely screen asymptomatic patients with TTE (ASH 2019 suggests against); obtain echo when symptoms/findings raise concern for PH; TRV (tricuspid regurgitant jet velocity) >2.5 m/s predicts increased death and pulmonary hypertension Higher-grade hemolysis (high LDH, ↓ NO) drives it	Hydroxyurea (↓ hemolysis, ↑ Hb); chronic transfusions if significant If TRV >3 m/s or high risk: specialist-directed right heart catheterization to characterize the PH; reserve PAH-specific therapy for confirmed precapillary PAH under a PH specialist (not for any elevated TRV or PH mechanism); oxygen if hypoxemic
Kidney	Chronic renal complications	All SCD patients have some renal dysfunction: glomerular hyperfiltration, hyposthenuria, microalbuminuria (albumin/Cr ≥30 mg/g), proteinuria (worse outcome and mortality), and declining GFR ~4 to 12% of adults reach ESRD needing renal replacement	Monitor proteinuria (annual albumin:creatinine) and hematuria Refer to nephrology/urology if GFR drops >10% or eGFR <60 Treat with ACE inhibitors/ARBs; co-manage advanced CKD with nephrology (ESAs, treat albuminuria/anemia); evaluate for kidney transplant; individualize transfusion for specific SCD indications, not solely for approaching CKD stage 5
Kidney	Renal medullary carcinoma	Rare; mainly in adolescents and young adults (median in the 20s); more common in sickle cell trait; gross hematuria, UTI, abdominal mass, flank pain, weight loss	Often metastatic at diagnosis; poor prognosis
Hepatobiliary	Gallstone disease	Pigment stones from chronic hemolysis; diagnose by standard imaging	Cholecystectomy (prophylactic when appropriate, and when symptomatic)
Hepatobiliary	Chronic cholestatic / end-stage liver disease	Chronic bilirubin elevation; may progress to biliary-type cirrhosis or a sclerosing-cholangitis pattern; exclude coincidental liver disease	Consider ursodeoxycholic acid; manage cirrhosis complications; role for liver transplant
Eye	Sickle cell retinopathy	Vaso-occlusion of retinal arterioles → ischemia, neovascularization, hemorrhage, autoinfarction Risk of vitreous hemorrhage and retinal detachment; more severe in HbSC than HbSS	Annual retinal exam; laser photocoagulation, vitrectomy
Bone	Avascular necrosis	Most common in the hip, also shoulder, knee, feet, back; intermittent progressive pain X-ray shows sclerosis, cysts, arthritic change, femoral head collapse; MRI most sensitive and specific	Early: conservative, physical therapy, pain control, core decompression Late (collapsed head): total hip arthroplasty
Iron	Transfusional iron overload	Check ferritin if multiple transfusions; monitor serum ferritin every 3 months Liver MRI for LIC (R2 or T2) every 1 to 2 years in chronically transfused patients, rather than gating by ferritin >1000 ng/mL alone Consider cardiac T2 MRI if LIC >15 mg Fe/g dry weight or cardiac dysfunction	Iron chelation for LIC >7 mg Fe/g dry weight (deferasirox or deferoxamine)

Other Chronic Sequelae

Cognitive impairment: silent cerebral infarcts (~39% by age 18, ~50% of adults); MRI screening.
Leg ulcers: chronic, painful, often at the medial malleolus; difficult to heal.
Cardiac: cardiomyopathy from chronic anemia and iron overload.
Psychosocial / pain: chronic pain, depression, and risk of opioid use disorder.
Sildenafil should be AVOIDED as routine/first-line therapy in SCD-PH (↑ VOCs per WALK-PHaSST); bosentan considered if confirmed.

Disease-Modifying Therapy

Hydroxyurea (Droxia): ribonucleotide reductase inhibitor; ↑ HbF (anti-sickling); rising HbF and MCV are response/adherence markers (not required thresholds); titrate to maximal tolerated dose (~35 mg/kg/d); ↓ VOC ~50%, ↓ ACS, ↓ death; start age 9 mo (BABY HUG); monitor CBC q2 wks then q3 mo; teratogenic (stop preconception).
L-glutamine (Endari, FDA Jul 2017): antioxidant; phase 3 L-glutamine trial (Niihara, NEJM 2018) showed ↓ VOC (median 3 vs 4 crises over 48 wks); adjunct or alternative to hydroxyurea; cost ~$40K/yr; less effective than hydroxyurea.
Crizanlizumab (Adakveo, P-selectin inhibitor, FDA Nov 2019; WITHDRAWN EU 2023 after STAND showed no VOC reduction vs placebo; still FDA approved in US): mAb to P-selectin (adhesion); ↓ VOC; IV q4 wk; no myelotoxicity; now rarely used.
Voxelotor (Oxbryta, HbS polymerization inhibitor, FDA Nov 2019; WITHDRAWN 2024 after HOPE-KIDS mortality): oral small molecule; ↓ HbS polymerization and ↑ RBC deformability; withdrawn after pediatric safety signals.
Exagamglogene autotemcel (exa-cel, Casgevy, CRISPR-Cas9 BCL11A edit, FDA Dec 2023): gene therapy; edits the BCL11A locus to ↑ HbF; curative potential; cost ~$2M; long-term data limited.
Lentiviral gene therapy (lovo-cel, Lyfgenia, FDA Dec 2023): autologous HSCT with a lentiviral βA-T87Q anti-sickling globin; curative with HSCT toxicity but durable remission; cost ~$3M.
Allogeneic HSCT (matched sibling): gold-standard curative; EFS ~90% with a matched sibling; risks of GVHD and graft failure; used in severe SCD (frequent VOC, stroke, ACS, AVN); haploidentical plus post-transplant cyclophosphamide is improving outcomes.

Hydroxyurea Practical Pearls

Start at 9 months of age (BABY HUG).
Titrate to maximal tolerated dose (up to 35 mg/kg/d in adults) guided by ANC and platelets; no fixed HbF target (rising HbF is a response marker).
Side effects: cytopenias (especially neutropenia), nausea, skin/nail hyperpigmentation, azoospermia/oligospermia (sometimes but not reliably reversible; counsel young men about fertility preservation).
Pregnancy: teratogenic; discontinue ~3 months preconception (transition to chronic transfusion).
Gene therapy considerations: lengthy process (months from collection to infusion); busulfan conditioning has fertility and secondary-malignancy risks; Lyfgenia carries a black-box warning for hematologic malignancy (AML cases in lovo-cel trials; beti-cel and exa-cel have no boxed warning).

Preventive Care

Penicillin V prophylaxis: 125 mg BID (<3 yo), 250 mg BID (≥3 yo) until age 5; ↓ pneumococcal sepsis ~90% (PROPS study); stop at age 5 if immunized and no prior pneumococcal disease.
Vaccinations: PCV15 or PCV20 (2, 4, 6, 12 to 15 mo), plus PCV20 or PPSV23 at age ≥2 (≥8 wks after last PCV) if PCV20 not used; adults PCV20 or PCV21 alone, or PCV15 then PPSV23; Hib series; MenACWY and MenB; annual flu; COVID-19.
Transcranial Doppler (TCD): age 2 to 16; velocity ≥200 cm/s (abnormal) triggers transfusion prophylaxis (monthly transfusions, HbS <30%), reducing stroke ~90% (STOP); 170 to 199 (conditional) warrants repeat TCD in 3 to 6 mo.
Dilated retinal exam: start at age 10, then every 1 to 2 years if normal (NHLBI 2014); monitor proliferative retinopathy; laser photocoagulation if neovascularization.
Folic acid: 1 mg daily (increased demand from chronic hemolysis).
Education: hydration (3 to 4 L/d), avoid hypoxia and temperature extremes, infection precautions, pain-crisis recognition, avoid smoking/alcohol, genetic counseling.

Pregnancy in SCD

High-risk pregnancy: increased VOCs, ACS, pre-eclampsia, IUGR, preterm delivery.
Stop hydroxyurea before conception (teratogenic).
Consider chronic prophylactic transfusion (HbS <30%) for high-risk patients (severe disease, prior stroke).
VTE prophylaxis postpartum (LMWH).
Contraception: avoid all estrogen-containing combined contraception (pills, patch, ring): category 4 in SCD under US MEC 2024; progestin-only pills, implants, and LNG-IUDs are acceptable, DMPA is category 2 to 3.

High Yield (SCD)

Start hydroxyurea at 9 months (BABY HUG) regardless of severity in HbSS/HbSβ0-thalassemia; do not auto-apply to HbSC or HbSβ+.
TCD screening age 2 to 16; transfuse if velocity ≥200 cm/s (primary stroke prevention), keeping HbS <30% and Hb >9 for at least 1 year.
VOC management: IV opioids plus gentle fluids (avoid pulmonary edema/ACS); transfusion NOT needed for uncomplicated pain.
ACS: simple transfusion for mild disease, exchange for severe; incentive spirometry prevents ACS.
Stroke: exchange transfusion to HbS <30%.
Splenic sequestration: cautious weight-based transfusion (about 5 to 10 mL/kg PRBC) with reassessment, avoid overcorrection (sequestered cells are later released); urgently resuscitate hypovolemic shock.
Voxelotor WITHDRAWN 2024 (mortality concern).
Gene therapy (FDA Dec 8, 2023), Casgevy for age ≥12 with recurrent VOCs, Lyfgenia for age ≥12 with a history of vaso-occlusive events (exa-cel expanded to age ≥2 in July 2026): exa-cel (Casgevy), CRISPR/Cas9 ex vivo edit of the BCL11A erythroid enhancer → ↑ HbF (CLIMB-121, Frangoul NEJM 2024); lovo-cel (Lyfgenia), lentiviral βT87Q vector (HGB-206), black-box for hematologic malignancy (specific to lovo-cel). Both require myeloablative busulfan conditioning.
Sildenafil: avoid as first-line in SCD-PH (walk-PHaSST: ↑ hospitalization for pain).
Functional asplenia by age 2 to 4 raises encapsulated-organism risk; vaccinate aggressively.
Pigment gallstones: cholecystectomy when symptomatic.
Hydroxyurea teratogenic: stop preconception, transition to transfusion.
Renal medullary carcinoma: classic association with sickle cell trait.
Adenotonsillar hypertrophy plus sleep apnea in pediatrics: work up if suspected.

Veli Bakalov MD, Board Review Notes 2026