Anemia

Hemoglobinopathies

Interpret hemoglobin testing, distinguish sickle cell disease from trait, evaluate alpha and beta thalassemia, recognize acute complications, and understand the roles of hydroxyurea, transfusion, iron chelation, transplantation, and gene-based therapy.

Audience: internal medicine residents Last reviewed: July 2026

Bedside approach

Answer these questions first

Is this disease or carrier status? Sickle cell trait and thalassemia trait generally differ greatly from sickle cell disease or transfusion-dependent thalassemia.
Was the patient recently transfused? Donor hemoglobin can alter hemoglobin fractions and obscure the patient’s underlying pattern.
Is HbA present? The presence or absence of HbA helps distinguish several sickling and beta-thalassemia patterns.
Is the MCV unexpectedly low? Consider iron deficiency, alpha-thalassemia, beta-thalassemia, or a sickle-beta-thalassemia genotype.
Is the patient taking hydroxyurea? Hydroxyurea can increase MCV and HbF and must be considered when interpreting results.
Does the phenotype fit? Confirm that laboratory findings align with anemia severity, hemolysis, pain history, splenic function, transfusion dependence, and family history.

Urgent escalation

  • Suspected acute chest syndrome
  • New focal neurologic deficit or suspected stroke
  • Severe hypoxemia or respiratory distress
  • Rapid hemoglobin decline or acute splenic sequestration
  • Severe pain with hemodynamic instability or organ dysfunction
  • Fever or sepsis in a functionally asplenic patient
  • Priapism lasting four hours or longer
  • Suspected delayed hemolytic transfusion reaction

1. Diagnostic evaluation

  1. Review the newborn-screening result, prior hemoglobin analysis, family history, ancestry, and established genotype.
  2. Obtain a CBC, reticulocyte count, peripheral smear, bilirubin, LDH, and haptoglobin when hemolysis is being assessed.
  3. Check ferritin and transferrin saturation when microcytosis or iron deficiency is possible.
  4. Confirm the date and type of any recent transfusion or red-cell exchange.
  5. Review hydroxyurea use because it can raise MCV and HbF.
  6. Use molecular testing when routine hemoglobin analysis does not resolve the suspected alpha- or beta-globin disorder.

Hemoglobin-analysis methods

  • High-performance liquid chromatography
  • Capillary electrophoresis
  • Isoelectric focusing
  • Gel electrophoresis
  • Molecular globin-gene testing

Important modifiers

  • Recent transfusion
  • Hydroxyurea therapy
  • Iron deficiency
  • Age and persistence of fetal hemoglobin
  • Pregnancy
  • Coexisting alpha-thalassemia

2. Common hemoglobin-analysis patterns

Pattern HbA Other fractions Interpretive clues
Normal adult pattern Predominant Small HbA2 fraction and low HbF Interpret using the laboratory’s method-specific reference ranges.
Sickle cell trait Present and usually greater than HbS HbS present Carrier state rather than sickle cell disease in the usual clinical setting.
HbSS Absent unless donor cells are present Predominant HbS with variable HbF and HbA2 Chronic hemolytic anemia and sickle cell disease phenotype.
HbSC disease Absent unless transfused HbS and HbC are both present Hemoglobin may be higher than in HbSS, but vaso-occlusive and end-organ complications still occur.
HbS/β0-thalassemia Absent unless transfused HbS predominant with increased HbA2 and variable HbF Microcytosis and a clinical phenotype often resembling HbSS.
HbS/β+-thalassemia Present HbS, increased HbA2, and variable HbF Presence of HbA indicates residual beta-globin production.
β-thalassemia trait Predominant HbA2 is typically increased; HbF may be mildly increased Microcytosis, relatively preserved RBC count, and usually mild anemia.
α-thalassemia trait Usually appears normal on routine adult analysis No defining abnormal adult fraction in many patients Suspect from persistent microcytosis with adequate iron stores; molecular testing may be required.
These are broad patterns, not rigid percentage rules. Confirm the result with the reporting laboratory or hematology when transfusion, hydroxyurea, iron deficiency, unusual variants, or mixed genotypes may alter interpretation.

Interactive tool

Hemoglobin-pattern interpreter

This tool identifies broad possibilities from the dominant fractions. It does not replace laboratory review or molecular confirmation.

Enter the pattern

Interpretation

Enter the available hemoglobin fractions.

Results may be unreliable after transfusion. Review MCV, iron studies, reticulocyte count, hydroxyurea use, age, and clinical phenotype.

3. Sickle cell disease

Sickle cell disease includes HbSS, HbSC, HbS/β0-thalassemia, HbS/β+-thalassemia, and other less common sickling genotypes.

Chronic manifestations

  • Chronic hemolytic anemia
  • Recurrent vaso-occlusive pain
  • Functional asplenia and infection risk
  • Stroke and silent cerebral infarction
  • Acute chest syndrome
  • Chronic kidney disease and albuminuria
  • Pulmonary and cardiac complications
  • Retinopathy
  • Avascular necrosis
  • Leg ulcers
  • Priapism

Long-term disease-modifying management

  • Hydroxyurea remains a major disease-modifying therapy and can reduce vaso-occlusive complications.
  • Chronic transfusion may be used for selected stroke-prevention and other high-risk indications.
  • L-glutamine and crizanlizumab may be considered in selected patients under current specialist guidance and prescribing information.
  • Voxelotor was voluntarily withdrawn from the market in 2024 and should not be newly prescribed.
  • Hematopoietic stem-cell transplantation and gene-based therapies may provide potentially curative options for selected patients.
Continue established hydroxyurea during most hospitalizations unless a specific contraindication or toxicity requires interruption. Review cytopenias, renal function, pregnancy status, adherence, and the patient’s established treatment plan.

4. Acute sickle cell complications

Complication Clinical clues Immediate priorities
Vaso-occlusive pain Acute severe pain consistent with the patient’s established pattern Rapid analgesia, reassessment, hydration based on volume status, incentive spirometry when appropriate, and evaluation for another acute process.
Acute chest syndrome New pulmonary infiltrate with respiratory symptoms, fever, chest pain, or hypoxemia Oxygen, antibiotics, incentive spirometry, pain control, hematology involvement, and consideration of simple or exchange transfusion.
Acute stroke New focal neurologic deficit, seizure, altered mental status, or severe acute neurologic symptoms Activate stroke evaluation immediately and urgently coordinate exchange transfusion with hematology and transfusion medicine.
Splenic sequestration Rapid splenic enlargement, acute anemia, thrombocytopenia, hypovolemia, or shock Hemodynamic stabilization and cautious urgent transfusion.
Aplastic crisis Acute anemia with severe reticulocytopenia, often related to parvovirus B19 Confirm reticulocytopenia, provide supportive care, and use transfusion when clinically required.
Delayed hemolytic reaction Falling hemoglobin after transfusion, pain, jaundice, hemoglobinuria, or hemoglobin below the pretransfusion level Contact hematology and transfusion medicine before additional transfusion unless life-threatening anemia requires it.
A pain crisis is a diagnosis made within the patient’s clinical context. Do not attribute fever, hypoxemia, focal neurologic findings, abdominal catastrophe, osteomyelitis, or another emergency to pain alone.

5. Sickle cell trait

Sickle cell trait is a carrier state and is not equivalent to sickle cell disease. Most people do not have chronic hemolytic anemia or recurrent vaso-occlusive crises.

Recognized associations

  • Hematuria and renal papillary injury
  • Impaired urinary concentrating ability
  • Splenic infarction during severe hypoxia or high-altitude exposure
  • Rare exertional complications under extreme conditions
  • Increased risk of renal medullary carcinoma
  • Reproductive implications when a partner carries a hemoglobin variant
Do not label recurrent pain, anemia, or hemolysis as being caused by sickle cell trait without evaluating another diagnosis.

6. Thalassemia

Alpha-thalassemia

Genotype pattern Typical phenotype Clinical notes
One affected alpha gene Silent carrier CBC may be normal or show minimal microcytosis.
Two affected alpha genes Alpha-thalassemia trait Microcytosis with mild or no anemia; routine adult hemoglobin analysis may be normal.
Three affected alpha genes HbH disease Chronic hemolytic anemia of variable severity with risk of worsening during oxidative stress, infection, or pregnancy.
Four affected alpha genes Alpha-thalassemia major Severe fetal disease requiring specialized prenatal and postnatal management.

Beta-thalassemia

  • Beta-thalassemia trait usually causes microcytosis, a relatively preserved RBC count, mild anemia, and increased HbA2.
  • Non-transfusion-dependent beta-thalassemia has variable anemia and complications from ineffective erythropoiesis and iron loading.
  • Transfusion-dependent beta-thalassemia requires regular transfusion support and structured iron-overload management.
  • Iron deficiency may lower HbA2 and complicate interpretation.
Do not prescribe iron for thalassemia trait solely because the MCV is low. Confirm iron deficiency first.

7. Transfusion principles

Before transfusing a patient with sickle cell disease

  • Review the patient’s transfusion and antibody history.
  • Notify the blood bank that the patient has sickle cell disease.
  • Use appropriately antigen-matched red cells according to local policy.
  • Avoid unnecessary transfusion for uncomplicated pain alone.
  • Consider the risk of hyperviscosity when hemoglobin is increased excessively.
  • Choose simple versus exchange transfusion based on the indication.

Common reasons to consider exchange transfusion

  • Acute ischemic stroke
  • Severe or rapidly progressive acute chest syndrome
  • Severe multiorgan sickling complications
  • Selected perioperative or chronic transfusion indications
A patient with suspected delayed hemolytic transfusion reaction or hyperhemolysis may worsen after additional transfusion. Coordinate urgently with hematology and transfusion medicine.

8. Transfusional iron overload

Repeated transfusion can produce progressive hepatic, endocrine, and cardiac iron accumulation. Ferritin is useful for trends but is influenced by inflammation and does not precisely quantify organ iron.

Monitoring may include

  • Serial ferritin trends
  • Liver iron concentration by validated MRI methods
  • Cardiac iron assessment when clinically indicated
  • Liver function and endocrine assessment
  • Review of cumulative transfusion exposure
  • Assessment of chelation adherence and toxicity
Iron chelation selection and monitoring depend on the underlying hemoglobinopathy, degree of iron loading, organ function, age, pregnancy considerations, toxicity, and patient preference.

9. Transplantation and gene-based therapy

Allogeneic hematopoietic stem-cell transplantation may provide a cure for selected patients with sickle cell disease or severe thalassemia. Eligibility depends on disease severity, donor availability, comorbidities, age, fertility considerations, and transplant risk.

Gene-based therapies are also available for selected patients. In the United States, current indications, age requirements, risk profiles, and product availability must be verified through the treating specialty center and current FDA labeling.

Topics for shared decision-making

  • Expected disease burden without curative treatment
  • Conditioning-related toxicity
  • Infertility risk and fertility preservation
  • Transplant-related mortality and graft complications
  • Long-term malignancy surveillance
  • Hospitalization and caregiver requirements
  • Access, insurance, and treatment-center availability
These treatments require evaluation at an experienced sickle cell, thalassemia, transplant, or gene-therapy center. They are not routine inpatient decisions.

10. Pregnancy and genetic counseling

  • Confirm the specific maternal genotype.
  • Test the reproductive partner when carrier status is unknown.
  • Offer genetic counseling when both partners carry relevant variants.
  • Coordinate sickle cell disease pregnancies with maternal-fetal medicine and hematology.
  • Review hydroxyurea and other disease-modifying drugs before conception.
  • Discuss prenatal and preimplantation testing options when appropriate.
The reproductive risk depends on both parents’ globin genotypes, not simply whether one parent has “trait.”

11. Resident summary

  1. Interpret hemoglobin fractions with the CBC, iron studies, transfusion history, hydroxyurea use, and clinical phenotype.
  2. HbA is usually absent in HbSS and HbS/β0-thalassemia unless donor cells are present.
  3. HbA is present in sickle cell trait and HbS/β+-thalassemia.
  4. Increased HbA2 with microcytosis supports beta-thalassemia trait, but iron deficiency can complicate interpretation.
  5. Routine adult hemoglobin analysis may be normal in alpha-thalassemia trait.
  6. Treat acute chest syndrome and stroke as hematologic emergencies.
  7. Review antibody history and coordinate with the blood bank before transfusing a patient with sickle cell disease.
  8. Repeated transfusion requires structured monitoring for iron overload.

12. Knowledge check

Question 1

Hemoglobin analysis shows HbS with no HbA in a patient who has not recently been transfused. Which diagnosis remains possible?

Question 2

A patient has lifelong microcytosis, normal iron stores, and normal routine hemoglobin analysis. Which diagnosis remains possible?

Question 3

A patient with sickle cell disease develops a new pulmonary infiltrate, fever, chest pain, and hypoxemia. What diagnosis should be presumed?

Question 4

Which statement about iron treatment in thalassemia trait is most accurate?

References

  1. American Society of Hematology. Clinical Practice Guidelines on Sickle Cell Disease. ASH guidelines
  2. American Society of Hematology. Sickle Cell Disease Guidelines: Transfusion Support. Transfusion guideline
  3. American Society of Hematology. Sickle Cell Disease Guidelines: Management of Acute and Chronic Pain. Pain guideline
  4. American Society of Hematology. Sickle Cell Disease Guidelines: Cerebrovascular Disease. Cerebrovascular guideline
  5. National Heart, Lung, and Blood Institute. Sickle Cell Disease: Treatment. NHLBI resource
  6. Centers for Disease Control and Prevention. About Sickle Cell Disease. CDC resource
  7. Centers for Disease Control and Prevention. About Thalassemia. CDC resource
  8. United States Food and Drug Administration. Voluntary withdrawal of Oxbryta due to safety concerns. 2024. FDA safety notice
  9. United States Food and Drug Administration. Approved Cellular and Gene Therapy Products. FDA products
  10. United States Food and Drug Administration. Casgevy. FDA information
  11. Cappellini MD, et al. Inherited microcytic anemias. ASH Education Program. 2020. Open article
  12. Taher AT, Musallam KM, Cappellini MD. How I treat non-transfusion-dependent beta-thalassemia. Blood. 2023. Open article

Educational disclaimer

This guide is intended for clinician education and does not replace hematology consultation, transfusion-service guidance, genetic counseling, current prescribing information, institutional protocols, or individualized clinical judgment. Suspected acute chest syndrome, stroke, severe anemia, sepsis, splenic sequestration, and delayed hemolytic transfusion reactions require urgent local escalation.