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Sickle Cell Anemia (SCA)

Sickle Cell Anemia (SCA) is an inherited hemoglobin disorder caused by a mutation in the β-globin gene, resulting in production of abnormal hemoglobin S (HbS). Under low-oxygen conditions, HbS polymerizes, causing red blood cells to become rigid and sickle-shaped, leading to chronic hemolytic anemia and recurrent vaso-occlusive episodes.

Also called

Sickle Cell Disease (SCD)

ICD-10

D57.1

Specialty

Hematology

Onset

Acute & Chronic

Reviewed

August 2026

On This Page

Overview

Sickle Cell Anemia (SCA) is an autosomal recessive inherited disorder caused by homozygous HbS (HbSS). Sickled red blood cells have reduced deformability and increased adherence to vascular endothelium, causing microvascular obstruction and tissue ischemia.

The disease produces two major problems: chronic hemolysis, causing anemia and jaundice, and vaso-occlusion, causing recurrent painful crises and progressive organ damage.

Etiology & Risk Factors

Sickle Cell Anemia (SCA) results from a point mutation in the β-globin gene (HBB), causing substitution of valine for glutamic acid at position 6 of the β-globin chain → formation of abnormal hemoglobin S (HbS).

The most severe form occurs in individuals who inherit HbS from both parents (HbSS).

Genetic Inheritance

  • Autosomal recessive
  • Both parents are usually carriers or affected

-Factors that promote HbS sickling include:

  • Dehydration
  • Hypoxia
  • Infection
  • Fever
  • Acidosis
  • Cold exposure
  • High altitude
  • Physical stress

Pathophysiology

β-globin gene mutation → production of abnormal HbS → deoxygenation causes HbS polymerization → red blood cells become rigid and sickle-shaped → repeated sickling causes membrane damage and hemolysis → chronic hemolytic anemia → sickled cells adhere to vascular endothelium → microvascular obstruction → tissue ischemia and inflammation → recurrent vaso-occlusive crises → progressive ischemic organ damage.

Repeated splenic infarction → functional asplenia → increased risk of severe infections with encapsulated bacteria.

Clinical Presentation

-Symptoms

  • Chronic fatigue

  • Weakness

  • Pallor

  • Jaundice

  • Recurrent severe pain episodes

  • Bone pain

  • Chest pain

  • Abdominal pain

  • Shortness of breath

  • Exercise intolerance

-Acute Complications

  • Vaso-occlusive crisis

  • Acute chest syndrome

  • Splenic sequestration

  • Aplastic crisis

  • Stroke

  • Priapism

  • Severe infection

-Chronic Complications

  • Chronic kidney disease

  • Pulmonary hypertension

  • Retinopathy

  • Avascular necrosis

  • Leg ulcers

  • Gallstones

  • Functional asplenia

  • Delayed growth and puberty

History Taking

-Ask about:

  • Fatigue and weakness
  • Shortness of breath
  • Dizziness
  • Palpitations
  • Dietary intake
  • Menstrual history
  • Pregnancy
  • Gastrointestinal symptoms
  • Melena
  • Hematochezia
  • Abdominal pain
  • Change in bowel habits
  • Weight loss
  • Dysphagia
  • NSAID use

Physical Examination

-General Examination

Look for:

  • Pallor

  • Jaundice

  • Fever

  • Tachycardia

  • Growth retardation

  • Signs of dehydration

-Systemic Examination

Assess for:

    • Splenomegaly in children

    • Signs of functional asplenia in adults

    • Hepatomegaly

    • Cardiac murmurs

    • Respiratory abnormalities

    • Neurological deficits

    • Bone or joint tenderness

    • Leg ulcers

    • Signs of avascular necrosis

Investigations

-Complete Blood Count (CBC)

Typical findings:

  • Low hemoglobin

  • Usually normocytic anemia

  • Increased reticulocyte count

  • Increased WBC count may occur

-Peripheral Blood Film

May show:

  • Sickle-shaped red blood cells

  • Target cells

  • Polychromasia

  • Howell-Jolly bodies

  • Nucleated RBCs

-Hemoglobin Analysis

Hemoglobin Electrophoresis / HPLC

Typical HbSS pattern:

  • HbS: predominant

  • HbA: absent

  • HbF: variable

  • HbA2: normal or mildly increased

-Hemolysis Markers

  • Increased indirect bilirubin

  • Increased LDH

  • Low haptoglobin

  • Increased reticulocyte count

-Genetic Testing

  • HBB gene mutation analysis

  • Useful when hemoglobin electrophoresis is unclear

-Additional Investigations

Depending on complications:

    • Renal function tests

    • Urinalysis

    • Urine albumin-to-creatinine ratio

    • Liver function tests

    • Transcranial Doppler in children

    • Echocardiography if pulmonary hypertension is suspected

    • Chest X-ray for acute chest syndrome

    • MRI for suspected avascular necrosis or stroke

Diagnosis

Sickle Cell Disease · Major Crises

The 4 Major Crises
Vaso-occlusive Crisis (VOC)
Most common
Sickled RBCs occlude microvasculature → severe ischaemic pain. Bones (long bones, spine), chest, abdomen. Triggered by most aggravating factors.
Acute Chest Syndrome (ACS)
Most common cause of death
New pulmonary infiltrate + fever + chest pain + hypoxia. Fat embolism from infarcted bone marrow + in-situ sickling in pulmonary vessels.
Sequestration Crisis
Children — life-threatening
Massive pooling of blood in spleen (or liver) → sudden ↓ Hb >2 g/dL + splenomegaly. Rapid cardiovascular collapse. Requires urgent transfusion.
Aplastic Crisis
Parvovirus B19
Parvovirus B19 infects erythroid precursors → temporary arrest of RBC production → severe anaemia with absent reticulocytes. Self-limiting (7–10 days).
Stroke / CNS
Children 6 months–20 years
Large vessel occlusion (ICA, MCA) → ischaemic stroke. Haemorrhagic stroke in adults (aneurysm rupture). Transcranial Doppler screening — if velocity >200 cm/s → chronic transfusion programme.
Infection / Sepsis
Functional asplenia
Repeated splenic infarction → functional asplenia by age 5. Encapsulated organisms: S. pneumoniae, H. influenzae, N. meningitidis. Salmonella osteomyelitis — classic association.

Sickle Cell Disease · Organ Complications

Organ-by-Organ Complications
Musculoskeletal
Vaso-occlusive bone pain — dactylitis (hand-foot syndrome) in infants
Avascular necrosis (AVN) — femoral & humeral heads
Osteomyelitis — Salmonella spp. most specific; also S. aureus
Bone marrow expansion → bossing, "hair-on-end" skull XR
Pulmonary
Acute Chest Syndrome — fever, chest pain, infiltrate, hypoxia
Pulmonary hypertension — TRV >2.5 m/s → ↑ mortality
Obstructive + restrictive pattern on PFTs
Recurrent ACS → chronic sickle lung disease
Neurological
Ischaemic stroke — children (large vessel occlusion)
Haemorrhagic stroke — adults
Silent cerebral infarcts — impair cognition/school performance
Moyamoya pattern — collateral vessel formation
Cardiovascular
High-output cardiac failure — chronic anaemia compensation
Cardiomegaly, flow murmurs
Pulmonary hypertension (see pulmonary)
Sudden cardiac death risk in adults
Renal
Sickle cell nephropathy — medullary ischaemia (hypertonic, low O₂ → sickling)
Haematuria — papillary necrosis
Nephrotic syndrome — FSGS
Inability to concentrate urine (isosthenuria) — earliest sign
CKD in adults — ↑ mortality marker
Ophthalmic
Proliferative sickle retinopathy — "sea fan" neovascularisation
Vitreous haemorrhage → retinal detachment → blindness
More common in HbSC than HbSS
Annual ophthalmology screening required
Hepatobiliary
Pigment gallstones — chronic haemolysis → unconjugated bilirubin → cholelithiasis
Sickle hepatopathy — intrahepatic sickling → hepatic crisis
Hepatic sequestration
Iron overload (transfusion-related) → cirrhosis
Genitourinary & Other
Priapism — prolonged painful erection; sickling in corpus cavernosum → erectile dysfunction if untreated >4h
Leg ulcers — medial malleolus; chronic, painful, slow-healing
Delayed growth & puberty
Splenomegaly (early) → autosplenectomy (late)

Sickle Cell Disease · Aggravating Factors

Aggravating / Precipitating Factors — "HHHH DIP"
Hypoxia
Low O₂ tension directly promotes HbS polymerisation and sickling. Triggers: high altitude, anaesthesia, poor ventilation, pulmonary disease. Avoid O₂ sat <95% in SCD patients.
Dehydration
↑ Blood viscosity + ↑ HbS concentration → promotes sickling. Very common trigger. Ensure adequate oral/IV hydration at all times, especially during illness, exercise, heat exposure.
Cold / Temperature Change
Cold causes vasoconstriction → stasis → sickling. Even mild cold (cold water swimming, air conditioning, cold weather) can precipitate VOC. Warm environments and clothing essential.
Infection
Most common precipitant of VOC and ACS. Fever + inflammation → sickling. Functional asplenia → high risk of encapsulated organisms (pneumococcus, H. influenzae). Parvovirus B19 → aplastic crisis specifically.
Strenuous Exercise / Fatigue
↑ O₂ consumption + lactic acidosis + dehydration → combined trigger. Moderate exercise is safe; strenuous unaccustomed exercise in high heat is dangerous. Acidosis independently promotes sickling.
Drugs & Alcohol
Alcohol → dehydration + acidosis. Opioid-induced respiratory depression → hypoxia. NSAIDs long-term → renal impairment (avoid in renal disease). Avoid nitrous oxide (oxidises HbS). Avoid vasoconstrictors.
Stress (Physical & Psychological)
Psychological stress → catecholamine surge → vasoconstriction → sickling. Surgery and trauma → combined hypoxia, acidosis, hypothermia. Menstruation → pain crises more frequent in women with SCD.
Acidosis
Low pH shifts O₂-dissociation curve (Bohr effect) → HbS releases O₂ → deoxygenated HbS polymerises readily. Causes: DKA, lactic acidosis, renal tubular acidosis (common in SCD), severe infection.
Pregnancy
High-risk state — increased VOC frequency, ACS risk, maternal mortality. Hypercoagulable state + physiological anaemia + increased O₂ demand. Requires specialist joint obstetric + haematology care throughout.

Sickle Cell Disease · Baseline Haematological Features

Baseline Haematological Features
Chronic haemolytic anaemia
Hb typically 6–9 g/dL (well-tolerated due to chronic adaptation)
↑ Reticulocytes (5–15%) — bone marrow compensating
↑ Unconjugated bilirubin + ↑ LDH + ↓ haptoglobin
Blood film: sickle cells, target cells, Howell-Jolly bodies (asplenia)
HbSS confirmed on HPLC / haemoglobin electrophoresis
Protective factors
HbF (fetal haemoglobin) — does not polymerise with HbS; high HbF → milder disease. Basis for hydroxyurea therapy.
HbSC disease — milder than HbSS but more retinopathy & AVN
HbS/β-thalassaemia — severity depends on β-thal type (β⁰ worse than β⁺)
Hydroxyurea — ↑ HbF → ↓ sickling, ↓ VOC frequency, ↓ ACS
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Management

-General Management

  • Adequate hydration

  • Avoid known triggers

  • Folic acid supplementation when appropriate

  • Vaccination

  • Penicillin prophylaxis in young children

  • Prompt treatment of infections

  • Regular follow-up

-Vaso-Occlusive Crisis

  • Rapid pain assessment

  • Opioid and/or non-opioid analgesia according to severity

  • Hydration when clinically indicated

  • Oxygen only if hypoxemia is present

  • Treat precipitating factors

  • Monitor for acute chest syndrome and other complications

-Disease-Modifying Therapy

Hydroxyurea

  • Reduces vaso-occlusive crises

  • Increases HbF

  • Reduces acute chest syndrome

  • May reduce the need for blood transfusions

Other options in selected patients:

  • L-glutamine

  • Crizanlizumab

  • Voxelotor, where available and appropriate

-Blood Transfusion

Used for selected indications:

  • Severe symptomatic anemia

  • Acute chest syndrome

  • Stroke

  • Splenic sequestration

  • Preoperative preparation in selected patients

-Curative Treatment

Hematopoietic Stem Cell Transplantation

  • Potentially curative

  • Considered in selected patients with severe disease

  • Best outcomes generally occur in younger patients with a suitable donor

-Newer Curative Approaches

  • Gene therapy and gene-editing approaches may be available for selected patients in specialized centers 

Complications

  • Vaso-occlusive crises
  • Acute chest syndrome
  • Stroke
  • Severe infections
  • Splenic sequestration
  • Aplastic crisis
  • Chronic hemolytic anemia
  • Gallstones
  • Chronic kidney disease
  • Pulmonary hypertension
  • Avascular necrosis
  • Retinopathy
  • Priapism
  • Leg ulcers
  • Delayed growth and puberty
  • Iron overload from repeated transfusions

Prognosis

Sickle Cell Anemia (SCA) is a lifelong condition with variable severity. Advances in vaccination, infection prevention, hydroxyurea, transfusion therapy, and disease-modifying treatments have significantly improved survival. Prognosis depends on the frequency of complications, organ involvement, access to treatment, and adherence to long-term care.

Key Points / Clinical Pearls

  • Sickle Cell Anemia (SCA) is an inherited autosomal recessive hemoglobin disorder.
  • The most severe form is HbSS disease.
    HbS polymerization causes red blood cell sickling.
  • Two major mechanisms are hemolysis and vaso-occlusion.
  • Common complications include pain crises and acute chest syndrome.
  • Functional asplenia increases the risk of severe infections.
  • Diagnosis is confirmed by hemoglobin electrophoresis or HPLC.
  • Hydroxyurea is an important disease-modifying treatment.
    Transfusions are used for specific severe complications.
  • Hematopoietic stem cell transplantation can be curative in selected patients.