Disorders of Hemoglobin¶
Chapter 103 | Part 4: Oncology and Hematology
KEY CLINICAL POINTS¶
- Hemoglobinopathies include structural variants of hemoglobin (e.g., HbS, HbC, HbE) and thalassemias ( α / β -globin deficiency).
- Anemia of aging is multifactorial, with ~10% prevalence in those >65 years and 50% in multimorbid elderly.
- Sickle cell disease (HbSS) is the most common hemoglobinopathy, characterized by HbS polymerization and vasoocclusion.
- Thalassemias are classified as β 0 (no globin production) or β + (reduced production) based on severity.
- Hydroxyurea is the standard therapy for sickle cell anemia, increasing HbF and reducing vasoocclusive events.
1. DEFINITION & OVERVIEW¶
Hemoglobinopathies are genetic disorders of hemoglobin structure or synthesis. Thalassemias involve defective globin chain production, while hemoglobinopathies include variants like HbS, HbC, and HbE. Anemia of aging is multifactorial with age-related iron deficiency and chronic inflammation.
Table 103-1 Disorders of Hemoglobin¶
| I. Hemoglobinopathies | II. Thalassemias | III. Hereditary Persistence of Fetal Hemoglobin | IV. Acquired Hemoglobinopathies |
|---|---|---|---|
| Common variants (HbS, HbE, HbC) | a/b thalassemias | Persistent HbF | Methemoglobin, sulfhemoglobin, carboxyhemoglobin |
| Altered oxygen affinity | Complex thalassemias | Deletions in HBB cluster | HbH in erythroleukemia |
| Unstable hemoglobins | HbE-b thalassemia | Point mutations in HBG2/1 promoters | Elevated HbF in myelodysplasia |
1.1 Hemoglobin Structure¶
Hemoglobin is a tetramer of α - and β -globin chains with heme. α -globin (141 AA) and β -globin (146 AA) form embryonic, fetal, and adult hemoglobins. HbF ( αγ 2) is predominant in fetal life, decreasing postnatally.
1.2 Hemoglobin Function¶
Hemoglobin transports O2 and CO2, with affinity regulated by pH, 2,3-BPG, and temperature. The hemoglobin-oxygen dissociation curve (P50) reflects this affinity, with normal P50 ~26 mmHg.
2. EPIDEMIOLOGY¶
Anemia of aging affects ~10% of those >65 years, 25% >85 years, and 50% in multimorbid elderly. Sickle cell disease (HbSS) is most common in Africa, India, and the Middle East. β -thalassemia major affects ~10,000/year in the U.S. with 1000 severe cases.
Table 103-2 Common Sickle Hemoglobinopathies¶
| GENOTYPE | CLINICAL ABNORMALITIES | HEMOGLOBIN LEVEL | HEMOGLOBIN FRACTIONS |
|---|---|---|---|
| HbAS (trait) | 8% African Americans; hematuria, chronic kidney disease | Normal HbA: 60–70 | HbS: 30–40 |
| HbSS (anemia) | Vasoocclusion, hemolysis | 70–100 (7–10)/80–100 | HbS: >75 |
| HbSC disease | Mild to severe; retinopathy risk | 100–140 (10–14)/70–100 | HbS: 50, HbC: 50 |
| HbSE | Similar to HbS-b+ thalassemia | 90–130 (9–13)/65–75 | HbS: 65, HbE: 35 |
2.1 Anemia of Aging¶
Prevalence ~10% at 65 years, 25% >85 years. Mild anemia (Hb 11–12 g/dL) with increased fracture risk, falls, and mortality. Iron deficiency is common due to poor intake, chronic gastritis, or PPI use.
2.2 Sickle Cell Disease¶
HbSS is most common, with ~150,000 newborns/year in Nigeria. Mortality before age 5 is ~30%. HbSC disease has milder complications. HbS trait prevalence is 2–15% in emigrant populations.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
HbS polymerization occurs when deoxygenated, leading to sickling. HbF (fetal hemoglobin) inhibits polymerization. Thalassemias result from α / β -globin chain deficiency, causing unpaired chains and ineffective erythropoiesis. Iron overload and oxidative stress exacerbate hemolysis.
Table 103-6 α -Thalassemias¶
| CLASSIFICATION | a-GLOBIN GENE ARRANGEMENT | HEMOGLOBIN LEVEL | CLINICAL FEATURES |
|---|---|---|---|
| a-Thalassemia trait | -a/aa, -a/-a | 120–150 (12–15)/65–80 | Mild anemia; a+ thalassemia (-a3.7/-a4.2) |
| HbH disease | --/-a | 50–120 (5–12)/60–70 | HbH inclusions; splenomegaly; hemolysis |
| Hb Bart’s hydrops fetalis | --/-- | 50–120 (5–12)/60–70 | Fetal death; Hb Bart’s inclusions |
3.1 Sickle Cell Pathophysiology¶
HbS polymerization (30th power of Hb concentration) causes sickling. Deoxygenation triggers polymerization, leading to vasoocclusion, hemolysis, and organ damage. Oxidative stress and nitric oxide depletion contribute to vasoocclusion.
3.2 Thalassemia Pathophysiology¶
Unpaired α / β -globin chains cause ineffective erythropoiesis and hemolysis. Iron overload from chronic transfusions leads to organ damage. β -thalassemia major has severe anemia, hepatosplenomegaly, and marrow expansion.
4. CLINICAL FEATURES¶
Sickle cell disease presents with vasoocclusive crises (pain, acute chest syndrome), hemolysis (jaundice, splenomegaly), and complications like stroke, leg ulcers, and priapism. Thalassemia major has microcytic anemia, hepatosplenomegaly, and iron overload. Anemia of aging is mild with increased fall risk.
Table 103-3 Complications of Sickle Cell Disease¶
| COMPLICATION | INCIDENCE | TREATMENT |
|---|---|---|
| Priapism | 30% males | a-adrenergic agonists, hydroxyurea |
| Stroke | 10–15% cases | Transcranial Doppler, transfusion, hydroxyurea |
| Gallstones | 40% patients | Cholecystectomy if symptomatic |
| Nephropathy | 30% adults >30 | ACE inhibitors, dialysis if renal failure |
4.1 Sickle Cell Complications¶
Acute chest syndrome (pneumonia-like), stroke, leg ulcers, priapism, and multiorgan failure. Chronic complications include pulmonary hypertension, osteonecrosis, and renal failure.
4.2 Thalassemia Features¶
Microcytic anemia, splenomegaly, hepatomegaly, and iron overload. β -thalassemia major has severe anemia, marrow expansion, and organ damage. α -thalassemia presents with mild anemia or HbH disease.
5. DIFFERENTIAL DIAGNOSIS¶
Anemia of aging vs. iron deficiency anemia: microcytic but normal Hb. Sickle cell trait vs. HbE trait: HPLC confirms HbS or HbE. Thalassemia vs. β -thalassemia: HbA2 and HbF levels differentiate. Acute chest syndrome vs. pneumonia: HbS polymerization and vasoocclusion are key.
6. INVESTIGATIONS & DIAGNOSIS¶
HPLC for hemoglobin fractions, peripheral blood smear for sickle cells, reticulocyte count, and DNA analysis for mutations. Iron studies (ferritin, TIBC) differentiate anemia of chronic disease from iron deficiency. MRI for iron overload in thalassemia.
Table 103-4 β -Thalassemias¶
| CLASSIFICATION | HEMOGLOBIN LEVEL | CLINICAL FEATURES |
|---|---|---|
| b-Thalassemia trait | 100–140 (10–14)/60–80 | Mild anemia; normal red cell indices |
| b-Thalassemia intermedia | 70–120 (7–12)/65–80 | Moderate anemia; splenomegaly |
| b-Thalassemia major | 20–40 (2–4)/50–80 | Severe anemia; transfusion-dependent |
6.1 Diagnostic Tests¶
HPLC (capillary electrophoresis) identifies hemoglobin variants. DNA sequencing confirms mutations. Transcranial Doppler for stroke risk in sickle cell. MRI for iron overload in thalassemia.
6.2 Hemoglobin Fractionation¶
HPLC profiles show HbS, HbC, HbE, and HbF. HbH and Hb Bart’s inclusions are detected by brilliant cresyl blue staining.
7. MANAGEMENT & TREATMENT¶
Hydroxyurea (standard for sickle cell), transfusion therapy for severe anemia, iron chelation (deferoxamine, deferasirox), and gene therapy (CRISPR/Cas9, lentiviral vectors). Stem cell transplantation for severe cases. Crizanlizumab and voxelotor reduce vasoocclusion.
Table 103-5 Complications of Thalassemia¶
| COMPLICATION | INCIDENCE | TREATMENT |
|---|---|---|
| Iron overload | Common in transfusion-dependent | Deferoxamine, deferasirox |
| Cardiac failure | 50% of patients | Iron chelation, cardiac monitoring |
| Endocrinopathy | Common in adults | Hormone replacement therapy |
| Hepatic disease | Fibrosis/cirrhosis | Liver transplantation if severe |
7.1 Sickle Cell Treatment¶
Hydroxyurea (20–25 mg/kg) increases HbF, reduces pain crises. Exchange transfusion for acute chest syndrome. Crizanlizumab (600 mg IV monthly) reduces vasoocclusion. Voxelotor (1500 mg/day) increases O2 affinity.
7.2 Thalassemia Management¶
Regular transfusions with iron chelation (deferoxamine, deferasirox). Luspatercept for ineffective erythropoiesis. Stem cell transplantation for curative therapy. Gene therapy (CRISPR/Cas9) for β -thalassemia.
8. PROGNOSIS & COMPLICATIONS¶
Sickle cell disease: median age of death ~50 years without treatment. Thalassemia major: life expectancy ~50 years with chelation. Complications include stroke, organ failure, infections, and iron toxicity. Anemia of aging is associated with increased fall risk and mortality.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: increased risk of miscarriage, preeclampsia, and fetal hydrops. Pediatric: growth retardation, splenomegaly, and iron overload. Elderly: increased fall risk, frailty, and comorbidities. Genetic counseling for carriers and families.
10. KEY POINTS & CLINICAL PEARLS¶
- Hydroxyurea is first-line for sickle cell anemia, increasing HbF and reducing vasoocclusion.
- Transfusion therapy must be balanced with iron chelation to prevent overload.
- HPLC and DNA analysis are essential for diagnosing hemoglobinopathies.
- Crizanlizumab and voxelotor target vasoocclusion, while gene therapy offers curative potential.
- Anemia of aging is multifactorial, with iron deficiency and inflammation as key drivers.