Blood & Lymphoreticular

Sickle cell disease: outpatient management and crisis care

Clinical Overview and When to Suspect Sickle Cell Disease

— HbSS (sickle cell anemia): most severe; baseline Hb 6–9 g/dL, reticulocytosis, frequent crises

— HbSβ⁰-thalassemia: clinically similar to SS

— HbSC and HbSβ⁺-thalassemia: milder anemia (Hb 10–12), but higher rates of proliferative retinopathy, avascular necrosis, and splenic infarction in adulthood

— Sickle trait (HbAS): generally asymptomatic; risks include renal medullary carcinoma, hematuria, exertional rhabdomyolysis, splenic infarct at altitude

— Recurrent unexplained bone/joint pain in young adult of African descent

— Microscopic hematuria + isosthenuria (hyposthenuria from medullary infarction)

— Unexplained avascular necrosis of femoral head before age 40

— Priapism, leg ulcers, retinal hemorrhage in a young patient

— Family history of "anemia" or early stroke

Board pearl: A "normal" CBC does NOT rule out sickle trait — trait carriers have normal Hb and smear. Only electrophoresis/HPLC distinguishes AS from AA. Conversely, HbSS patients have chronic anemia and reticulocytosis at baseline; a sudden Hb drop of >2 g/dL below their personal baseline defines an acute drop and demands workup for aplastic crisis, splenic sequestration, or hyperhemolysis.

Definition: Autosomal recessive hemoglobinopathy from a point mutation (Glu→Val at position 6 of β-globin) producing HbS, which polymerizes when deoxygenated → rigid, sickled RBCs causing chronic hemolysis and vaso-occlusion.

Genotypes (severity matters for exam):

Epidemiology in US practice: ~100,000 affected; predominantly African ancestry but also Mediterranean, Middle Eastern, South Asian, Hispanic Caribbean. Universal newborn screening in all 50 states.

When to suspect in an adult with no known diagnosis (Step 3 ambulatory clue):

Confirmatory test: Hemoglobin electrophoresis or HPLC (not sickle prep, which only detects HbS presence, not genotype).

Presentation Patterns and Key History

— Deep, throbbing pain in back, chest, extremities, or abdomen

— Triggers: dehydration, cold exposure, infection, hypoxia, stress, alcohol, high altitude, menses, pregnancy — but ~50% have no identifiable trigger

— Patient often reports pain similar to prior crises; trust the patient's self-report of pain severity (a Step 3 safety/equity theme)

Step 3 management: In any SCD patient presenting with pain, ask explicitly about (1) fever, (2) chest/respiratory symptoms, (3) neurologic symptoms, (4) priapism duration, and (5) recent transfusion. These five screens drive whether you're treating a routine VOC or escalating for ACS, sepsis, stroke, urologic emergency, or hyperhemolysis.

Vaso-occlusive crisis (VOC) / acute pain episode:

Acute chest syndrome (ACS): new pulmonary infiltrate + one of: fever, chest pain, hypoxia, tachypnea, wheezing, cough. Often evolves 24–72 h into a VOC admission — ask about new respiratory symptoms daily.

Dactylitis: painful swelling of hands/feet in infants 6–24 months; often the first presentation of HbSS.

Splenic sequestration: sudden left-sided abdominal pain, splenomegaly, hypovolemic shock, Hb drop ≥2 g/dL with reticulocytosis. Common in children with HbSS (before autoinfarction) and adults with HbSC.

Aplastic crisis: sudden severe anemia with low reticulocyte count — classic parvovirus B19 trigger.

Hyperhemolytic crisis: post-transfusion drop in Hb below pre-transfusion level, with hemoglobinuria, often delayed hemolytic transfusion reaction.

Stroke: overt CVA peaks ages 2–10; silent infarcts cumulative.

Priapism: stuttering (≥4 episodes <4 h) vs ischemic (>4 h, urologic emergency).

Chronic findings to elicit on history: leg ulcers, vision changes (proliferative retinopathy in SC), gallstones (pigmented), AVN hip/shoulder, prior pulmonary HTN screen, renal disease, transfusion history, alloantibodies.

Physical Exam Findings and Hemodynamic Assessment

— Systolic flow murmur from chronic anemia

— Loud P2, RV heave → pulmonary hypertension (TRV ≥2.5 m/s on echo screen)

— Crackles, focal decreased breath sounds, wheeze → ACS

— Orthostatics if any volume concern

— Compare current Hb to personal baseline (review the chart — never use 13 g/dL as the reference)

— Reticulocyte count: high = ongoing hemolysis/VOC; low (<1%) = aplastic crisis

— LDH, indirect bili, haptoglobin trend hemolysis intensity

Key distinction: Bone infarct vs osteomyelitis — both present with focal pain, swelling, warmth, elevated CRP. MRI is the test of choice; blood and bone cultures, and ultimately bone biopsy/aspirate if unclear. Don't reflexively call every focal bone pain a VOC — fever + focal point tenderness + leukocytosis warrants imaging and empiric coverage for Salmonella and S. aureus (e.g., ceftriaxone).

General/vitals: assess for fever (≥38.5°C is sepsis until proven otherwise — functional/anatomic asplenia), tachycardia, hypoxia (SpO₂ <95% or ≥3% below baseline triggers ACS workup), hypotension (sequestration, sepsis), tachypnea.

HEENT: scleral icterus (chronic hemolysis), conjunctival pallor, retinal exam findings of proliferative sickle retinopathy ("sea-fan" neovascularization, more in SC disease).

Cardiopulmonary:

Abdomen: RUQ tenderness (cholelithiasis/cholecystitis from pigmented stones), splenomegaly (children, HbSC adults — adults with HbSS typically have autosplenectomy by age 5–8), hepatomegaly.

GU: rigid painful erection (priapism — examine and document duration).

Musculoskeletal: hip/shoulder range-of-motion limitation (AVN), focal bone tenderness (osteomyelitis vs infarct — Salmonella > S. aureus in SCD osteo).

Skin: malleolar leg ulcers (chronic, painful, slow-healing).

Neuro: focal deficit → stroke until imaging clears; altered mental status → ACS, fat embolism, narcotic toxicity.

Hemodynamic assessment in acute presentation:

Diagnostic Workup — Initial Labs, Imaging, and Biomarkers

— Baseline HbSS: Hb 6–9, MCV often elevated (hydroxyurea effect or folate deficiency mimics), reticulocytes 5–15%

— Acute drop with high retics → sequestration, hyperhemolysis, ongoing VOC

— Acute drop with low retics → aplastic crisis (parvovirus B19 PCR)

— WBC may be chronically 12–15 from marrow stress; >20K or left shift suggests infection

CCS pearl: On a CCS case of a febrile SCD patient, your initial order set should be: CBC w/ retic, BMP, LDH, bilirubin, blood cultures ×2, UA + urine culture, CXR, type & screen, IV access, NS bolus (cautious in ACS), acetaminophen, parenteral opioid, and empiric ceftriaxone — all within the first simulated 30 minutes. Then advance the clock to reassess.

CBC with differential and reticulocyte count (compare to baseline):

Peripheral smear: sickle cells, target cells, Howell-Jolly bodies (functional asplenia), nucleated RBCs, polychromasia.

Chemistry: LDH (hemolysis), indirect bilirubin, haptoglobin (low), Cr (sickle nephropathy), LFTs (intrahepatic cholestasis, gallstone disease).

Type & screen with extended phenotype if transfusion possible — SCD patients are frequently alloimmunized; match for C, E, K minimum (many centers extend to Fy, Jk, S).

Blood cultures + UA + CXR if febrile.

Pulse oximetry continuous; ABG if oxygenation concern (correlates with PaO₂ better than SpO₂ in some SCD patients).

CXR: mandatory if any chest/respiratory symptom, fever, or significant chest/back pain — ACS infiltrate may take 24–72 h to appear, so repeat CXR if clinical suspicion persists.

CT angiography chest: consider if PE is on the differential (pregnancy, immobilization, central line).

MRI for suspected stroke (diffusion-weighted) or AVN/osteomyelitis.

Transcranial Doppler (TCD): screening test in children ages 2–16 for stroke risk (MCA/ICA velocity ≥200 cm/s = high risk → chronic transfusion).

Diagnostic Workup — Advanced or Confirmatory Studies

— HbSS: HbS ~90%, HbF 2–20%, no HbA

— Sβ⁰-thal: indistinguishable from SS on electrophoresis without family studies/genetics

— Sβ⁺-thal: HbS ~60–80%, HbA present (residual β-chain production)

— HbSC: roughly equal HbS and HbC

— HbAS (trait): HbA >50%, HbS ~35–40%, normal CBC

Board pearl: Sickle solubility test ("sickle prep") detects HbS but cannot distinguish AS trait from SS disease or SC. Always confirm with electrophoresis/HPLC. On newborn screen, the convention is to list hemoglobins in order of abundance — FS = HbF predominant + HbS (consistent with SS or Sβ⁰); FSC = HbSC; FAS = trait. The "F" reflects normal newborn HbF predominance, not disease.

Hemoglobin electrophoresis or HPLC — confirms genotype (HbSS, SC, Sβ⁰, Sβ⁺, AS).

Quantitative HbF level: used to assess hydroxyurea response (target HbF >20%).

G6PD screening before starting medications that cause oxidative stress; many coexist.

Iron studies and ferritin annually in chronically transfused patients (target ferritin <1000, escalate chelation if higher; LIC by MRI T2* / FerriScan is gold standard for iron overload).

Echocardiogram with TRV every 1–3 years to screen pulmonary HTN; right heart cath confirms if TRV ≥2.9 m/s or symptomatic.

Pulmonary function tests if chronic lung disease suspected (restrictive pattern post-recurrent ACS).

Renal: annual UA for proteinuria; spot urine albumin:creatinine — sickle nephropathy starts as hyperfiltration then microalbuminuria.

Ophthalmology dilated exam annually starting age 10 (proliferative retinopathy more common in HbSC).

DEXA for AVN risk and chronic steroid/opioid users.

Hip MRI for early AVN — plain films lag.

Brain MRI/MRA at least once in childhood; repeat for any neurologic event; silent infarcts present in ~25% by age 6.

Risk Stratification and First-Line Management Logic

— High-severity HbSS/Sβ⁰: ≥3 VOCs/year requiring healthcare, any ACS, stroke or abnormal TCD, dactylitis in infancy, Hb <7, persistent retic >10% — all push toward disease-modifying therapy.

— Moderate HbSC/Sβ⁺: fewer crises but cumulative end-organ damage; still merits hydroxyurea consideration if symptomatic.

1. Disease modification: hydroxyurea (offer to ALL HbSS/Sβ⁰ ≥9 months old regardless of symptoms), L-glutamine, crizanlizumab, voxelotor (newer agents)

2. Infection prevention: penicillin prophylaxis to age 5 (longer if splenectomy or prior pneumococcal sepsis), full immunizations including PCV15/20 + PPSV23, meningococcal ACWY + B, annual influenza, COVID

3. Surveillance: TCD (children), echo, retinal, renal, hepatic iron

4. Acute crisis prevention: hydration, avoid cold/altitude/hypoxia triggers, pain action plan

— Allogeneic HSCT from HLA-matched sibling: ~90% event-free survival in children; expanding to haploidentical

— Gene therapy (lovo-cel, exa-cel/CRISPR-edited) FDA-approved 2023 for severe SCD ≥12 years

Step 3 management: A 6-month-old with newly confirmed HbSS in clinic — your action items: (1) start penicillin V 125 mg BID, (2) ensure all routine vaccines + PCV on schedule, (3) educate family on palpating spleen daily and fever-as-emergency rules, (4) prescribe folate 1 mg daily (optional but common), (5) plan hydroxyurea initiation at 9 months, (6) baseline labs, (7) refer to comprehensive SCD center, (8) screen siblings via electrophoresis. Document this anticipatory guidance — it's the highest-yield well-child visit on the exam.

Severity stratification (drives outpatient intensity):

Four pillars of outpatient SCD care (memorize for Step 3):

Curative options:

Pharmacotherapy — First-Line Disease-Modifying Regimen

— Mechanism: ribonucleotide reductase inhibitor → increases HbF (which doesn't sickle), reduces neutrophil/platelet activation, increases NO, reduces RBC adhesion

— Indications (offer to ALL): HbSS or Sβ⁰ ≥9 months regardless of clinical severity (NHLBI 2014, ASH 2020)

— Dose: start 15–20 mg/kg/day, titrate by 5 mg/kg every 8 weeks to maximum tolerated dose (typically 30–35 mg/kg/day) targeting mild myelosuppression (ANC 2,000–4,000)

— Monitoring: CBC q2–4 weeks during titration, then q2–3 months. Hold if ANC <1,250, platelets <80K, Hb <5 or >2 below baseline, reticulocytes <80K with Hb <8

— Adverse effects: myelosuppression, hyperpigmentation, nail changes, GI upset, mild teratogenicity concern (counsel contraception, but ASH says hold 3 months pre-conception)

— Benefits proven: ↓ VOCs, ↓ ACS, ↓ transfusion need, ↓ mortality

Board pearl: Hydroxyurea is the most commonly tested wrong-answer-becomes-right-answer drug in SCD. Even an asymptomatic HbSS infant ≥9 months should be started. The rise in HbF is the surrogate marker; macrocytosis (MCV ↑) on follow-up CBC is a sign of adherence.

Hydroxyurea (HU) — cornerstone disease-modifying therapy:

L-glutamine (Endari): ≥5 years; reduces VOC frequency; oral powder BID; works via reducing oxidative stress.

Crizanlizumab: monoclonal anti-P-selectin IV monthly; ≥16 years; ↓ VOC rate (note: STAND trial raised efficacy questions — board still treats as approved).

Voxelotor: HbS polymerization inhibitor; raises Hb ~1 g/dL; withdrawn from US market in Sept 2024 due to mortality signal — know this for currency but don't pick it as best answer.

Folic acid 1 mg daily: standard adjunct for chronic hemolysis.

Chronic transfusion program: indicated for stroke prevention (abnormal TCD), secondary stroke prevention, recurrent ACS despite HU, pulmonary HTN. Goal: HbS <30%, requires iron chelation (deferasirox PO, deferoxamine SC).

Acute Crisis Care and Procedural Management

— Triage to analgesia within 30 min of arrival (quality measure)

— IV opioid: morphine 0.1 mg/kg or hydromorphone 0.015 mg/kg; reassess q15–30 min; transition to PCA if admitted

— NSAID adjunct (ketorolac) if no renal contraindication

— Avoid meperidine (seizure risk from normeperidine; renal accumulation)

— IV fluids: maintenance, NOT aggressive bolus unless hypovolemic — over-hydration worsens ACS. Use D5 ½NS at 1–1.5× maintenance (hypotonic preferred — sickle cells dehydrate intracellularly)

— Incentive spirometry q2h while awake — proven to reduce ACS in admitted VOC patients

— Supplemental O₂ only if SpO₂ <95% (routine O₂ in normoxic patients may suppress erythropoiesis)

— VTE prophylaxis: enoxaparin (high VTE risk in SCD admissions)

— Empiric ceftriaxone + azithromycin (atypicals common)

— Oxygen, bronchodilators, incentive spirometry

— Simple transfusion if Hb >1 below baseline and symptomatic

— Exchange transfusion if severe (PaO₂ <60 on supplemental O₂, multilobar, rapid progression, neurologic involvement) — target HbS <30%

CCS pearl: In a CCS ACS case, advancing the clock without ordering incentive spirometry, transfusion, and antibiotics is a classic miss. If hypoxia worsens or infiltrates progress on repeat CXR, escalate to exchange transfusion and ICU — don't wait for intubation.

Uncomplicated VOC management (CCS-style sequence):

Acute chest syndrome:

Acute stroke: emergent exchange transfusion to HbS <30% (not tPA first-line in SCD); neurology + hematology consult; MRI/MRA.

Priapism >4 h: urology emergency — aspiration of corpora + intracavernosal phenylephrine; exchange transfusion adjunct.

Splenic sequestration: volume resuscitation + simple transfusion; splenectomy after 2nd episode.

Cholecystectomy: elective for symptomatic pigmented stones; transfuse to Hb ~10 preoperatively for any general anesthesia case.

Special Populations — Elderly, Renal, and Hepatic Impairment

— Cumulative organ damage dominates: sickle nephropathy, pulmonary HTN, AVN, retinopathy, iron overload, chronic pain

— Screen annually: BP, UA + ACR, eGFR, echo with TRV, retinal exam, DEXA, hepatic iron (if transfused)

— Pathophysiology: medullary hypoxia → papillary necrosis, hyposthenuria, hyperfiltration → FSGS-like glomerulopathy → CKD

— Start ACEi/ARB at first sign of microalbuminuria even with normal BP (renoprotection)

— Avoid NSAIDs chronically; cautious dosing during VOC

— Hydroxyurea dose-reduce when eGFR <60; hold or reduce when eGFR <30

— Anemia of CKD worsens baseline — erythropoietin can be added (some risk of hyperviscosity if HbS rises rapidly; combine with HU)

— Renal medullary carcinoma: rare but lethal; investigate painless gross hematuria in any SCD/trait patient with imaging

— Intrahepatic cholestasis of sickle cell — severe form mimics fulminant liver failure; treated with exchange transfusion

— Iron overload hepatopathy in chronically transfused — monitor LIC by MRI T2*

— Hepatitis C from older transfusion exposure — screen all adults at least once

— Opioids: reduce in CKD; avoid morphine and codeine in eGFR <30 (active metabolite accumulation) → use hydromorphone or fentanyl

— Ketorolac: max 5 days, contraindicated in CKD

— Deferasirox: monitor Cr and LFTs; hold if Cr rises >33% above baseline

Step 3 management: In the SCD adult with new microalbuminuria (ACR 30–300), urine ACR even with normal BP — initiate lisinopril 5–10 mg daily, recheck Cr and K in 1–2 weeks, titrate to maximum tolerated, and re-screen ACR in 3 months. This is the equivalent of diabetic kidney disease management for SCD.

Adults aging with SCD (life expectancy now mid-50s in US, climbing):

Sickle nephropathy:

Hepatic impairment:

Drug dosing pearls:

Special Populations — Pregnancy and Pediatrics

— High-risk: ↑VOC, ACS, preeclampsia, VTE, IUGR, preterm birth, fetal demise

— Co-manage with MFM + hematology from early first trimester

— Hold hydroxyurea ideally 3 months before conception (animal teratogen; human data reassuring but standard practice is to discontinue)

— Folate 4 mg/day (higher than usual prenatal due to hemolysis)

— Penicillin prophylaxis if asplenic

— Low-dose aspirin 81 mg from 12 weeks (preeclampsia prevention — SCD is a high-risk indicator per USPSTF)

— VTE prophylaxis during admissions; consider antepartum LMWH if prior VTE

— Prophylactic transfusion: controversial; reserve for severe disease, prior bad pregnancy outcomes, or recurrent crises — target HbS <30%

— Avoid NSAIDs after 20 weeks; opioids OK with neonatology aware near delivery

— Mode of delivery: obstetric indications; epidural OK

— Newborn screen → confirmatory electrophoresis by 2 months

— Penicillin V 125 mg BID from age 2 months → 250 mg BID at age 3 → continue to at least age 5 (longer if prior pneumococcal sepsis or surgical splenectomy)

— Immunizations critical: PCV series + PPSV23 at age 2 and booster at age 7, MenACWY + MenB, annual flu, COVID, RSV per current schedule

— Hydroxyurea by 9 months for HbSS/Sβ⁰ regardless of symptoms

— TCD screening annually ages 2–16; abnormal velocity (≥200 cm/s) → chronic transfusion to prevent first stroke (STOP trial); conditional velocity (170–199) → repeat

— Parental education: palpate spleen, fever ≥38.5°C is emergency, hydration, avoid extreme temperatures

— Transition to adult care planning starting age 12–14, completed by 18–21

Board pearl: A pregnant SCD patient on hydroxyurea who presents at 8 weeks — stop hydroxyurea, start folate 4 mg, start ASA 81 mg at 12 weeks, ensure penicillin, refer MFM. Resume HU postpartum (compatible with breastfeeding per most expert opinion but data limited — decision is individualized).

Pregnancy in SCD:

Pediatrics:

Complications and Adverse Outcomes

— Acute chest syndrome (#1 cause of SCD mortality in adults) — recurrent ACS → restrictive lung disease

— Pulmonary hypertension — TRV ≥2.5 m/s, ↑mortality; confirm with right heart cath

— Asthma comorbidity worsens ACS risk

— Overt stroke (ischemic in children, hemorrhagic more in adults)

— Silent cerebral infarcts (~25% of children) → cognitive deficits

— Moyamoya syndrome from chronic cerebral vasculopathy

— Hyposthenuria, papillary necrosis, hematuria, FSGS, CKD, ESRD

— Renal medullary carcinoma (especially HbAS trait)

Key distinction: Delayed hemolytic transfusion reaction (DHTR) vs hyperhemolysis — both occur ~7–14 days post-transfusion. DHTR: positive new alloantibody, hemolysis of transfused cells only. Hyperhemolysis: destruction of BOTH transfused and native RBCs, Hb falls BELOW pre-transfusion level, reticulocytopenia possible. Treatment: IVIG + steroids; AVOID further transfusion unless life-threatening.

Pulmonary:

Neurologic:

Renal:

Cardiovascular: LV diastolic dysfunction, cardiomyopathy from chronic anemia and iron overload, sudden cardiac death.

Hepatobiliary: pigmented gallstones (very common — screen with RUQ US), intrahepatic cholestasis, iron overload.

Splenic: functional asplenia by age 5 (HbSS), splenic sequestration (peds, SC adults), splenic infarction at high altitude.

Musculoskeletal: AVN (femoral and humeral heads), osteomyelitis (Salmonella, S. aureus), vertebral H-shaped bodies, chronic pain syndrome.

Endocrine: delayed puberty, growth failure, hypogonadism (transfusional iron deposition into pituitary).

Hematologic: alloimmunization, delayed hemolytic transfusion reactions, hyperhemolysis syndrome, VTE (4× risk).

Ocular: proliferative sickle retinopathy (especially HbSC), vitreous hemorrhage, retinal detachment.

Dermatologic: chronic leg ulcers (often medial malleolus).

Psychosocial: chronic pain, opioid dependence concerns, depression, missed school/work, stigma in ED settings (the "patient credibility" trap).

When to Escalate — ICU, Consults, and Inpatient Triage

— Pain not controlled with home regimen after 2–3 doses

— Fever ≥38.5°C (101.3°F) — always

— New respiratory symptoms, chest pain, SOB, hypoxia

— Neurologic symptoms — any focal deficit, headache with change in character, seizure, altered mental status

— Priapism >4 hours

— Abdominal distension or LUQ pain (sequestration)

— Pallor with fatigue/dyspnea (anemia worse than baseline)

— Sustained vomiting → can't maintain hydration or oral meds

— VOC requiring parenteral opioids beyond 4–6 h of ED management

— Any ACS (admit all)

— Febrile with concerning vitals or unable to tolerate PO antibiotics

— Hb drop ≥2 below baseline

— Hypoxia requiring >4 L NC or noninvasive ventilation

— Multilobar infiltrates or rapidly progressive ACS

— Acute stroke or seizures

— Hemodynamic instability (sequestration, sepsis, hyperhemolysis)

— Need for exchange transfusion or apheresis

— Multi-organ failure

— Hematology: all admissions; longitudinal

— Transfusion medicine/apheresis: exchange transfusion needs

— Pulmonary/ICU: severe ACS

— Neurology + neuroIR: stroke

— Urology: priapism not resolving with conservative measures within 1 h

— Orthopedics: suspected osteomyelitis, AVN with collapse

— Pain management/palliative care: complex chronic pain

CCS pearl: In a CCS case, the order "Admit to medicine, telemetry, NPO except meds, IVF D5½NS at 125 mL/h, PCA hydromorphone, ketorolac IV q6h, incentive spirometry, DVT prophylaxis, repeat CBC q12h, repeat CXR if new symptoms" is a high-yield bundle for VOC admission. Add ceftriaxone + azithromycin if febrile or any CXR finding, and call transfusion service early if Hb is trending down or hypoxia worsens.

Outpatient → ED criteria:

ED → Floor admission criteria:

Floor → ICU escalation:

Consultations:

Key Differentials — Same-Category (Hemolytic and Hemoglobinopathies)

Key distinction: Hemolytic crisis in SCD vs new-onset AIHA in SCD — both have anemia, jaundice, reticulocytosis. Check DAT. A positive DAT in an SCD patient with falling Hb after recent transfusion points to delayed hemolytic transfusion reaction or hyperhemolysis, not just a VOC. This changes management entirely (IVIG, steroids, avoid transfusion).

β-thalassemia major: microcytic anemia, transfusion-dependent from infancy, HbF and HbA₂ elevated, no HbS. Iron overload from transfusions. Skull "hair-on-end" radiograph.

HbC disease (HbCC): mild hemolytic anemia, splenomegaly, target cells, no vaso-occlusion — distinguishes from SC.

HbE/β-thalassemia: Southeast Asian; severe transfusion-dependent thalassemia phenotype.

Hereditary spherocytosis: Coombs-negative hemolytic anemia, spherocytes (no central pallor), ↑MCHC, splenomegaly, family history, osmotic fragility or EMA binding test positive. No sickle cells.

G6PD deficiency: episodic hemolysis after oxidative stress (fava beans, sulfa, dapsone, nitrofurantoin, infection); bite cells, Heinz bodies; X-linked; African and Mediterranean ancestry. Often coexists with SCD — screen before prescribing.

Pyruvate kinase deficiency: chronic non-spherocytic hemolytic anemia; echinocytes; autosomal recessive.

Paroxysmal nocturnal hemoglobinuria (PNH): intravascular hemolysis, thrombosis, pancytopenia, dark morning urine; flow cytometry for CD55/CD59 loss.

Autoimmune hemolytic anemia: positive direct Coombs (DAT), spherocytes, often secondary to lupus, CLL, drugs. SCD patients can develop AIHA, complicating chronic transfusion.

Microangiopathic hemolytic anemia (TTP, HUS, DIC, HELLP): schistocytes on smear, thrombocytopenia. ADAMTS13 in TTP. Important consideration in pregnant SCD patient with new hemolysis + low platelets.

Key Differentials — Other-Category Causes

— Cholecystitis (pigmented stones) — RUQ tenderness, Murphy sign, US shows wall thickening, pericholecystic fluid

— Splenic sequestration — LUQ pain, splenomegaly, Hb drop

— Mesenteric ischemia / bowel infarct from vaso-occlusion

— Acute pancreatitis (gallstone) — lipase >3× ULN

— Pyelonephritis / nephrolithiasis — flank pain, UA, imaging

— Hepatic sequestration / intrahepatic cholestasis

— Always reconsider: appendicitis, PID, ectopic pregnancy — don't anchor on "abdominal VOC"

— ACS is the leading concern but also consider PE (high baseline VTE risk), MI (CAD increasing as SCD adults live longer), pneumonia, pneumothorax, costochondritis, rib infarct (very common — focal rib tenderness, can trigger atelectasis → ACS)

— VOC vs osteomyelitis (Salmonella, S. aureus) vs AVN (especially hips/shoulders) vs acute leukemia (rare but bone pain + cytopenias) vs rheumatologic (parvovirus arthropathy)

— Stroke vs opioid toxicity / withdrawal, PRES (especially with hypertension or recent transfusion), fat embolism syndrome (after bone marrow infarct — petechiae, neuro signs, hypoxia), meningitis (asplenia → encapsulated organisms)

— Bacteremia/sepsis (encapsulated: pneumococcus, H. influenzae, meningococcus, Salmonella), parvovirus B19 (aplastic crisis), pyelo, osteo, ACS, line infection if port

Board pearl: Bone marrow fat embolism syndrome is a rare but lethal differential — after a severe VOC with extensive marrow necrosis, fat globules embolize, producing hypoxia, neurologic deterioration, petechial rash, thrombocytopenia, and renal failure. Treatment is emergent exchange transfusion and supportive ICU care. Mortality >60% without prompt recognition.

Acute abdominal pain in SCD — beyond VOC:

Acute chest pain in SCD:

Bone pain:

Neurologic:

Fever:

Secondary Prevention, Discharge Meds, and Long-Term Plan

— Confirm or initiate hydroxyurea before discharge if eligible and not yet on it

— Document target dose and titration plan

— Ensure follow-up CBC scheduled in 2–4 weeks

— Provide a written individualized pain plan (home regimen + breakthrough plan + when to seek care)

— Bridge opioids for 5–7 days post-discharge; co-prescribe stool softener/laxative + antiemetic PRN

— Naloxone co-prescribed if MME high

— Avoid abrupt discontinuation; taper if chronic exposure

— Verify pneumococcal (PCV20 or PCV15→PPSV23), meningococcal ACWY + B, annual flu, COVID, Hib, hep B status

— Penicillin V 250 mg BID for asplenic adults (some centers continue lifelong post-pneumococcal sepsis)

— ACEi or ARB if microalbuminuria

— Statin if ASCVD risk indicates

— Smoking cessation (smoking is a major ACS trigger)

— Iron chelation (deferasirox) if ferritin >1000 or LIC elevated

— Extended RBC phenotype on file

— Contraception counseling: progestin-only methods preferred (DMPA, IUD, implant) — estrogen increases VTE risk

— Preconception counseling: partner electrophoresis screening (carrier risk)

Step 3 management: Every SCD discharge summary should answer: (1) Why was the patient admitted? (2) What was their baseline Hb and current Hb? (3) Were any new alloantibodies identified? (4) Was hydroxyurea initiated or adjusted? (5) When is hematology follow-up? (6) What is the pain plan? Failure to communicate any of these is a high-yield transition-of-care safety event.

Disease-modifying therapy at discharge:

Pain plan:

Infection prevention bundle:

Cardiovascular/renal:

Transfusion management:

Reproductive health:

Mental health: screen PHQ-9 at routine visits; refer for chronic pain coping skills, CBT.

Transition of care (adolescent → adult): structured program starting age 12, completed by 21; warm handoff to adult hematology with shared records.

Follow-Up, Monitoring Parameters, and Counseling

— Stable adult HbSS on HU: every 3–6 months

— Pediatric SCD: every 3 months in early childhood, every 6 months when stable

— Post-VOC admission: follow-up in 1–2 weeks

— Pregnancy: monthly hematology + MFM through 28 weeks, then more frequent

— CBC, retic, CMP, LDH, ferritin, urine ACR

— Echo with TRV (q1–3 years)

— Pulmonary function tests if recurrent ACS

— Retinal exam annually starting age 10

— Brain MRI at least once in childhood; repeat for any neuro change

— TCD annually ages 2–16 (HbSS/Sβ⁰)

— DEXA for chronic opioid users or post-AVN

— Hep C screen once in any adult with transfusion exposure

— HIV screen per USPSTF

— Hydration (≥2–3 L/day adults)

— Avoid hypoxia triggers (smoking, high altitude without acclimatization, scuba diving contraindicated)

— Avoid extreme temperatures; layer clothing

— Vaccinations up to date

— Recognize fever, ACS, stroke, priapism, sequestration warning signs

— Adherence to HU and penicillin

— Family planning, partner testing

CCS pearl: On a CCS follow-up case, after a VOC discharge, the 2-week follow-up visit should include CBC + retic, review of pain control, assess adherence to hydroxyurea (MCV trend confirms compliance), check vaccination status, and renew pain plan. Missing the f/u visit is a common CCS scoring pitfall.

Routine outpatient hematology cadence:

Annual surveillance package:

Hydroxyurea monitoring: CBC q2–4 weeks during titration → q2–3 months stable; HbF level q6–12 months.

Iron-overloaded patients: ferritin q3 months, LIC by MRI annually, cardiac T2* MRI annually if heavily transfused.

Counseling priorities at every visit:

Patient advocacy: carry a wallet card / medical alert noting diagnosis, baseline Hb, allergies, alloantibodies, home pain regimen.

Ethical, Legal, and Patient Safety Considerations

— SCD patients (predominantly Black in the US) face documented bias in pain management — longer wait times, lower opioid doses, more often labeled "drug-seeking"

— Step 3 principle: trust the patient's self-reported pain; use the individualized pain plan; document objectively without pejorative language

— Use of an individualized care plan in the chart reduces inconsistent management

— Gene therapy (lovo-cel, exa-cel): discuss conditioning chemotherapy risks (infertility — offer fertility preservation), secondary malignancy risk, durability uncertainty, cost (~$2–3 million)

— HSCT: mortality 5–10%, GVHD risk; require detailed informed consent and ethics involvement when donor is a minor sibling

— Hydroxyurea in adolescents: discuss reproductive considerations frankly

— Adolescents should participate in transition planning and treatment decisions (assent at age 7+, formal at 14+ in many states)

— Offer partner screening and preconception genetic counseling

— Discuss preimplantation genetic diagnosis (PGD) options without coercion

— Pediatric → adult care gap is a notorious mortality window; warm handoff with overlap visits is the standard of care

— Suspected opioid diversion: clinical concern handled per institutional policy, not via discriminatory dismissal

— Newborn screening results are state-mandated; positive screen requires parental notification and follow-up

Step 3 management: A 26-year-old HbSS man arrives at the ED at his 4th visit this month for pain. He is afebrile, vitals stable, and his individualized pain plan in the EHR calls for hydromorphone 1.5 mg IV with reassessment q20 minutes. Correct action: follow the documented plan, treat the pain, perform routine VOC workup, and arrange hematology follow-up — do NOT withhold opioids based on visit frequency. Frequent ED use is a marker of disease severity, not deception.

Stigma and analgesia disparities:

Informed consent for emerging therapies:

Pediatric assent and parental decision-making:

Reproductive autonomy:

Transition-of-care safety:

Mandatory reporting and chain of custody:

Research participation: historic harms (Tuskegee era) create justifiable mistrust — disclose conflicts, ensure community engagement.

High-Yield Associations and Rapid-Fire Facts

— SS: severe anemia, more VOC, autosplenectomy early

— SC: milder anemia, retains spleen, more retinopathy and AVN, splenic infarct at altitude

Board pearl: When the stem mentions "young African American athlete who collapsed during high-intensity workout" — think sickle cell trait + exertional rhabdomyolysis + sudden death. NCAA mandates trait screening for Division I athletes; management focuses on graduated conditioning, hydration, heat acclimatization, not exclusion from sport.

Genetics: Glu→Val at codon 6 of β-globin; chromosome 11; autosomal recessive

Howell-Jolly bodies on smear = functional asplenia

Target cells prominent in HbSC and HbS/β-thal

Salmonella > S. aureus in SCD osteomyelitis

Parvovirus B19 → aplastic crisis (low retics)

Streptococcus pneumoniae → #1 fatal infection in young SCD children → penicillin prophylaxis and PCV

Encapsulated organisms dangerous due to asplenia: pneumo, H. flu, meningococcus, Salmonella, Klebsiella

HbF protective: HbF >20% reduces sickling; hydroxyurea's main mechanism

HbSS vs HbSC:

Sickle trait: isosthenuria, painless hematuria, renal medullary carcinoma (lethal), exertional rhabdomyolysis in athletes, sudden death at extreme exertion

Acute chest syndrome: #1 cause of mortality in adult SCD

Stroke: peaks in childhood; primary prevention with TCD + chronic transfusion (STOP trial)

Priapism: stuttering vs ischemic >4 h = emergency

Cholelithiasis: pigmented stones, often by adolescence

Avascular necrosis: femoral and humeral heads

Hydroxyurea benefits: ↓ VOC, ↓ ACS, ↓ mortality, ↓ transfusion need

L-glutamine, crizanlizumab: approved disease-modifiers

Voxelotor: withdrawn 2024 (mortality signal)

Curative options: allo-HSCT, gene therapy (exa-cel, lovo-cel) approved 2023

Pregnancy: stop HU, start ASA 81 mg at 12 weeks, folate 4 mg, MFM co-management

Contraception: progestin-only preferred

Penicillin V prophylaxis age 2 months to 5 years (HbSS)

Exchange transfusion indications: stroke, severe ACS, multiorgan failure, preoperative for major surgery, refractory priapism, fat embolism

Board Question Stem Patterns

— Stem: positive newborn screen "FS." Next step?

— Answer: confirmatory hemoglobin electrophoresis at 2 months + start penicillin prophylaxis at 2 months + pneumococcal vaccination schedule.

— Any T ≥38.5°C in HbSS = blood cultures, CBC, CXR, empiric ceftriaxone without waiting for source.

— Diagnosis: acute chest syndrome.

— Management: oxygen, ceftriaxone + azithromycin, incentive spirometry, transfusion (simple → exchange if severe).

— Splenic sequestration → volume + transfusion; splenectomy after second episode.

— Aplastic crisis from parvovirus B19; transfuse, supportive care.

— Hyperhemolysis or DHTR → IVIG + steroids, avoid further transfusion.

— Ischemic priapism → urology emergency, aspiration + phenylephrine, hydration, analgesia, consider exchange transfusion.

— Start chronic exchange transfusion to keep HbS <30% (STOP trial); not hydroxyurea alone for primary stroke prevention.

— Stop HU, start folate 4 mg, ASA 81 mg at 12 weeks, MFM referral.

— Sickle trait + exertional rhabdo; check CK, monitor renal.

— Rule out renal medullary carcinoma (CT urogram).

— Avascular necrosis → MRI (X-ray lags).

— Start hydroxyurea; titrate to MTD.

Key distinction: When the stem says "reticulocyte count 0.2%" in a patient with falling Hb, think APLASTIC crisis (parvovirus) — not VOC. Treatment is transfusion + supportive care, and the marrow typically recovers in 7–10 days. Contrast with hemolytic crisis (high retics, high LDH, low haptoglobin).

Pattern 1 — Newborn with FS pattern:

Pattern 2 — Febrile child with SCD:

Pattern 3 — VOC patient with new hypoxia and infiltrate at 48 hours:

Pattern 4 — Sudden Hb drop in young child with splenomegaly:

Pattern 5 — Hb 3 g/dL with reticulocytes 0.5%:

Pattern 6 — Post-transfusion 10 days, Hb now below pre-transfusion:

Pattern 7 — Painful rigid erection >4 hours:

Pattern 8 — Child age 4 with abnormal TCD (MCA 220 cm/s):

Pattern 9 — Pregnant HbSS at 8 weeks on hydroxyurea:

Pattern 10 — Young Black athlete collapses during sprints:

Pattern 11 — SCD adult with painless gross hematuria:

Pattern 12 — Right hip pain in 30-year-old HbSS, normal X-ray:

Pattern 13 — Recurrent VOC ≥3/yr in adult on no therapy:

One-Line Recap

Sickle cell disease is a lifelong multisystem hemoglobinopathy whose outpatient backbone is hydroxyurea, vaccination, penicillin prophylaxis, and structured surveillance, while acute crises demand rapid analgesia, infection workup, judicious hydration, and early transfusion or exchange when chest, brain, or hemodynamics are threatened.

— Hydroxyurea for all HbSS/Sβ⁰ ≥9 months at maximum tolerated dose

— Penicillin prophylaxis (peds), full vaccinations (pneumococcal, meningococcal, flu, COVID), folate

— Annual surveillance: TCD (peds), echo with TRV, urine ACR, retinal exam, brain MRI baseline

— Pain plan + chronic disease self-management education

— Analgesia within 30 minutes — opioid + NSAID; avoid meperidine

— Hypotonic maintenance IVF, NOT aggressive bolus

— Incentive spirometry q2h to prevent ACS

— Fever ≥38.5°C → blood cultures + empiric ceftriaxone immediately

— ACS → add azithromycin, transfuse, escalate to exchange if severe

— Stroke, severe ACS, multiorgan failure, refractory priapism → exchange transfusion to HbS <30%

— Trust the patient's pain; bias-driven undertreatment is a safety event

— Stop hydroxyurea in pregnancy; start ASA 81 mg at 12 weeks; folate 4 mg

— Sudden Hb drop with LOW retics = parvovirus aplastic crisis; with HIGH retics post-transfusion = hyperhemolysis (IVIG, steroids, avoid more transfusion)

Board pearl: If you can recite the fever rule, hydroxyurea rule, exchange transfusion indications, and pregnancy adjustments in your sleep, you will get nearly every SCD question right on Step 3 — these four touchpoints anchor the discipline.

Outpatient core (the four pillars):

Acute crisis bundle:

Three highest-yield Step 3 traps:

Curative horizon: allogeneic HSCT and FDA-approved gene therapies (exa-cel, lovo-cel) reshape long-term counseling — discuss fertility preservation and informed consent depth.