What it is:Sickle cell syndromes are inherited hemoglobinopathies caused by a mutated β-globin gene that makes sickle hemoglobin (HbS). Whether someone has silent trait or full-blown disease depends entirely on which second gene they paired it with.
The core problem:Deoxygenated HbS polymerizes and drags the red cell into a rigid sickle shape. Those cells jam up in small vessels (vasoocclusion) and die early (hemolysis). Almost every symptom, acute complication, and chronic organ injury in this chapter traces back to one of those two mechanisms.
What you do about it:Prevent infection (these patients are functionally asplenic), manage pain crises aggressively and individually, and layer on disease-modifying therapy, hydroxyurea first, to cut how often the sickling cascade fires in the first place.
Think of it as one chain: polymerize → distort → sludge → occlude → hypoxia → more polymerization.It's a feed-forward loop, not a single event. Every disease-modifying drug in this chapter interrupts that chain at a different link: hydroxyurearaises HbF so fewer cells polymerize at all, voxelotorblocks polymerization directly, and crizanlizumabblocks the adhesion step that turns a sickled cell into a plug. None of them fix the underlying gene, they just interrupt the cascade downstream.
Sickle cell trait (SCT, HbAS)is heterozygous: one normal β-globin gene (HbA) plus one HbS gene. These patients are asymptomatic with a normal hemoglobin, and the only thing to know clinically is rare painless hematuria, with gross hematuria and complications possible under heavy exercise in extreme conditions.
Sickle cell disease (SCD)means either homozygous HbS (HbSS) or a compound heterozygous pairing of HbS with another abnormal β-globin gene. HbSS has historically been called sickle cell anemia (SCA), and that term now also covers HbSβ0-thalassemia because the two behave the same clinically.
| Genotype | Hemoglobin | Clinical picture |
|---|---|---|
| Sickle cell trait (HbAS) | Normal | Asymptomatic; rare painless hematuria; heavy exercise in extreme conditions can provoke gross hematuria and complications |
| Sickle cell anemia (HbSS) | 6–9 g/dL | Pain episodes; microvascular disruption of spleen, liver, bone marrow, kidney, brain, and lung; gallstones; priapism; leg ulcers |
| HbSC disease | 9–14 g/dL | Painless hematuria; rare aseptic bone necrosis; pain episodes less frequent and start later in life; ocular disease; pregnancy-related complications |
| HbSβ+-thalassemia | 9–12 g/dL, microcytic | Rare pain; milder than HbSS because some normal HbA is still produced |
| HbSβ0-thalassemia | 7–9 g/dL, microcytic | No HbA production at all; severity comparable to HbSS |
SCT is a carrier state, not a disease.Normal Hb, asymptomatic, no organ damage. Don't confuse it with HbSC or HbSβ+-thal, both of which are real SCD with real (if milder) complications. And remember: "sickle cell anemia" is a genotype label (HbSS, now including HbSβ0-thal), not a synonym for the whole disease category.
Everything downstream starts with one molecular event: when HbS gives up its oxygen, it doesn't stay dissolved like normal hemoglobin. It polymerizesinto a semisolid gel that protrudes into the red cell membrane, physically distorting the cell into the sickle shape.
Three other mechanisms compound the clinical picture: functional asplenia(repeated splenic infarction knocks out the spleen's filtering job, leaving these patients vulnerable to encapsulated organisms), deficient opsonization, and underlying coagulation abnormalitiesthat create a hypercoagulable state. That combination is why infection and thrombosis both show up so heavily in this chapter alongside pain.
Map the drugs onto the cascade. Hydroxyurearaises fetal hemoglobin (HbF), and HbF-containing cells resist polymerization, so more HbF means fewer cells ever reach the sickled state. Voxelotorworks one step later, it inhibits HbS polymerization directly. Crizanlizumabworks on the sludging step, it blocks P-selectin, the adhesion molecule that lets sickled cells stick to the endothelium and to each other and pile up into an occlusion. Three different drugs, three different links in the same chain.
Most patients in the US are identified through routine neonatal screeningusing isoelectric focusing, high-performance liquid chromatography, or electrophoresis, not by waiting for symptoms to show up.
Symptoms are notably absent at birth. They're delayed until 4-6 months of age, which is exactly when HbF (protective, doesn't polymerize) gets replaced by HbS. Once that switch happens, common early findings are pain with fever, pneumonia, splenomegaly, and in infants specifically, painful swelling of the hands and feet, called dactylitisor hand-and-foot syndrome.
| Category | Findings |
|---|---|
| Labs | Low hemoglobin, increased reticulocyte count, increased platelet count, increased WBC count, sickled forms on peripheral smear |
| Constitutional | Chronic anemia and pallor, fever, weakness, anorexia, fatigue |
| Exam | Arthralgia, scleral icterus, abdominal pain, enlarged liver, spleen, and heart, hematuria |
This timing is a favorite exam detail. A newborn with SCD looks completely normal at birth because fetal hemoglobin is still dominantand doesn't sickle. Symptoms appear only once HbS has taken over. It's the same logic that makes hydroxyurea work: push HbF back up, and you're pharmacologically recreating the newborn's protection.
Multiple organ systems are involved, and exactly which complications a patient gets depends on genotype (see the table above). The acute complications are the ones that bring patients to the ED and are the highest-yield to recognize fast.
| Complication | What's happening |
|---|---|
| Fever and infection | Functional asplenia leaves these patients exposed to encapsulated organisms, classically sepsis from Streptococcus pneumoniae. This is the reason for penicillin prophylaxis and vaccination, and why any fever gets treated as an emergency. |
| Vasoocclusive (painful) crisis | Microvascular occlusion in the bone marrow is the usual cause of sickle cell pain. Triggered by fever, infection, dehydration, hypoxia, acidosis, and sudden temperature changes. |
| Acute chest syndrome (ACS) | Pulmonary infiltration with fever and/or respiratory symptoms. Hypoxia predicts severity and outcome. |
| Stroke | Listed among the major acute complications of SCD. |
| Priapism | Painful, sustained erection from vasoocclusion of the corpus cavernosum. |
| Acute splenic sequestration | Sudden, massive splenic enlargement from trapped sickled RBCs, causing hypotension and shock. Can cause sudden death in young children. Repeated infarctions eventually cause autosplenectomy, so incidence declines as adolescence approaches. |
| Venous thromboembolism | Increased risk from the hypercoagulable state, endothelial dysfunction, and impaired blood flow. |
Acute splenic sequestration can kill a young child quickly. It's the sudden massive trapping of sickled cells in the spleen leading to hypotension and shock. This is why splenomegaly plus a sudden hemoglobin drop in a young child with SCD is an emergency, not a "watch and wait."
Years of repeated microvascular injury and hemolysis eventually touch nearly every organ system: pulmonary hypertension, airway inflammation and hyperresponsiveness, bone and joint destruction, ocular problems, cholelithiasis (from chronic hemolysis and bilirubin overload), cardiovascular abnormalities, and renal manifestations.
Chronic complications are why SCD care is lifelong and interprofessional, not just "manage the next pain crisis." Annual surveillance of renal, hepatobiliary, and pulmonary function, plus retinopathy screening, exists specifically to catch these before they become irreversible.
Goals of treatment:reduce hospitalizations, reduce complications, reduce mortality, and improve quality of life.
Protects against encapsulated-organism sepsis until at least age 5.
Raises HbF; cuts pain crisis frequency and transfusion need.
Reduces acute SCD complications; weight-based dosing.
Anti-adhesion mAb and anti-polymerization agent, for older patients.
HbF interferes with HbS polymerization.Patients with naturally low HbF have more frequent pain and higher mortality, while an HbF level of 20% or greater reduces the risk of acute sickle cell complications. That single number is the whole rationale for hydroxyurea therapy.
| Drug | Indication / age | Dose |
|---|---|---|
| Infection prophylaxis | ||
| Penicillin V potassium | Until at least age 5 | 125 mg PO BID until age 3, then 250 mg PO BIDuntil age 5 functional asplenia |
| Disease-modifying therapy | ||
| Hydroxyurea | Age ≥2 with recurrent moderate-severe pain crises | 15 mg/kg/day (adults), 20 mg/kg/day(children); may titrate up to 35 mg/kg/day ↓ pain crises |
| L-Glutamine | Age ≥5 | <30 kg: 5 g BID · 30-65 kg: 10 g BID · >65 kg: 15 g BID |
| Crizanlizumab | Age ≥16, IV | 5 mg/kg every 2 weeks × 2 doses, then 5 mg/kg every 4 weeks |
| Voxelotor | Age ≥21 | 1500 mg once daily; ↓ dose in severe hepatic impairment (Child-Pugh C) |
Hydroxyurea is a chemotherapeutic agent that stimulates HbF production, increasing both the number of HbF-containing reticulocytes and the intracellular HbF concentration. It's indicated in patients 2 years and olderwith recurrent moderate to severe painful crises, to reduce both pain crisis frequency and the need for blood transfusions.
Start at 15 mg/kg/day for adults, 20 mg/kg/day for children. May increase by 5 mg/kg/day every 8 weeks, up to a max of 35 mg/kg/day, cautiously. A trial period of 6-12 monthsis generally considered adequate to judge response. If there's no response after 3-6 months, or no rise in MCV or HbF, first check compliance before assuming the patient is a true non-responder.
| Parameter | Frequency |
|---|---|
| CBC | Every 4 weeks until maximum tolerated dose is reached (for 8-12 weeks), then every 8 weeks |
| HbF | Every 3 months × 2, then every 6 months |
| Bilirubin, ALT, creatinine | Every 12-24 weeks |
| Pregnancy test | PRN; if positive, stop therapy and provide teratogen risk counseling |
| History and physical exam | Every 4 weeks until max dose reached (for 8-12 weeks), then every 8 weeks |
ANC <2000 cells/mm³ · platelets <80,000 cells/mm³ · absolute reticulocyte count <80,000 cells/mm³ if Hgb <9 g/dL · Hgb <5 g/dL or more than 20% below baseline · serum creatinine increased 50% above baseline · ALT increased 100% above baseline. Hold hydroxyurea for at least 1 week and until toxicity resolves.Resume at 2.5-5 mg/kg/day less than the previous dose. May return to the previous dose if no toxicity recurs after 12 weeks at the lower dose; if toxicity recurs at the higher dose, stop again and resume at the lowest tolerated dose.
L-Glutamineis approved for patients with SCD age 5 and older to reduce acute complications of the disease. Dosing is strictly weight-based: 5 g twice daily under 30 kg, 10 g twice daily for 30-65 kg, and 15 g twice daily over 65 kg.
Crizanlizumabis a monoclonal antibody directed against P-selectin, the adhesion molecule that lets sickled cells stick to the vessel wall and to each other, one of the key steps that turns sickling into a vasoocclusive plug. It's given IV, approved for patients age 16 and older, at 5 mg/kg every 2 weeks for 2 doses, then 5 mg/kg every 4 weeksthereafter.
Voxelotorinhibits HbS polymerization directly, targeting the same event that hydroxyurea addresses indirectly through HbF. Approved for patients age 21 and older at 1500 mg once daily. Reduce the dose with severe hepatic impairment (Child-Pugh class C). Because voxelotor is a CYP3A4 substrate, avoid coadministration with strong CYP3A4 inducers or inhibitors.
General principles first: educate patients to recognize signs and symptoms that need urgent evaluation, keep fluid status balanced, and maintain an oxygen saturation of at least 92%to avoid exacerbating acute illness.
RBC transfusions are indicated for three scenarios: (1)acute exacerbation of baseline anemia, such as aplastic crisis, hepatic or splenic sequestration, or severe hemolysis; (2)acute chest syndrome, stroke, intrahepatic cholestasis, or acute multisystem organ failure; and (3)preparation for a procedure requiring general anesthesia.
Meperidine accumulates its metabolite normeperidine, which is neurotoxic, especially with impaired renal function. It's a common wrong-answer choice on exams because it's an opioid that "should" work for severe pain but is specifically avoided here. Ketamineis a reasonable option for opioid-dependent or opioid-tolerant patients with acute or chronic sickle pain.
Promptly evaluate any fever of 38.5°C (101.3°F) or higher. Empiric antibiotics should cover encapsulated organisms: ceftriaxonefor outpatients, unless it was used in the previous 8 weeks, in which case give ampicillininstead. Use clindamycinfor cephalosporin-allergic patients. Add a macrolide if Mycoplasma pneumoniaeis suspected.
Initiate incentive spirometry, appropriate fluid therapy, and broad-spectrum antibiotics including a macrolide or quinolone. Give oxygen for hypoxia or acute distress. Other potential adjuncts include steroids and nitric oxide.
Managed with analgesics, antianxiety agents, and vasoconstrictors(phenylephrine, epinephrine) to force blood out of the corpus cavernosum, or vasodilators(terbutaline, hydralazine) to relax smooth muscle.
| Chronic RBC transfusion | Allogeneic HSCT | |
|---|---|---|
| Purpose | Primary and secondary stroke prevention; ameliorate organ damage | Curativetherapy for SCD |
| Schedule | Every 3-4 weeks, or as needed to maintain a target HbS level | One-time procedure |
| Best candidates | Optimal duration in children is unknown | Age <16 years, severe complications, HLA-matched donor available |
| Risks | Alloimmunization, hyperviscosity, transfusion-transmitted viral infection (requires hepatitis A and B vaccination), volume and iron overload, nonhemolytic transfusion reactions | Mortality, graft rejection, secondary malignancies |
| Parameter | When | Watching for |
|---|---|---|
| CBC and reticulocyte count | Every 3-6 months up to age 2, then every 6-12 months | Anemia severity, hemolysis trend |
| HbF level | Annually until age 2; every 3 months × 2 then every 6 months if on hydroxyurea | Response to hydroxyurea; target ≥20% to cut acute complication risk |
| Renal, hepatobiliary, pulmonary function | Annually | Chronic organ damage from vasoocclusion and hemolysis |
| Retinopathy screen | Routine screening | Ocular chronic complications |
| Hydroxyurea CBC | Every 4 weeks until max tolerated dose × 8-12 weeks, then every 8 weeks | Myelosuppression (ANC, platelets, Hgb, reticulocytes) |
| Hydroxyurea chemistries | Bilirubin, ALT, creatinine every 12-24 weeks | Hepatic and renal toxicity |
| Pregnancy test | Baseline, then PRN on hydroxyurea | Teratogenicity; stop drug immediately if positive |
| Pain crisis pattern | Ongoing, every visit | Number, severity, and duration - the core measure of hydroxyurea efficacy |