Hemoglobin Electrophoresis in Sickle Cell Trait with Thalassemia Compound Heterozygotes
In individuals with sickle cell trait (HbAS) who are also compound heterozygotes for thalassemia, the hemoglobin electrophoresis shows HbS levels below 35% (typically 23-34%), HbA levels around 65%, and microcytosis with reduced MCV, distinguishing them from typical sickle cell trait where HbS is 30-40% and HbA is 55-65%. 1, 2
Typical Sickle Cell Trait Pattern (Without Thalassemia)
For comparison, standard sickle cell trait (HbAS) without thalassemia shows:
- HbA: 55-65%
- HbS: 30-40%
- HbF: <1%
- HbA2: <3-5%
- Normal MCV and MCH 1
This represents the benign carrier state that is mostly asymptomatic except at extremes of physiology. 1
Sickle Cell Trait with Alpha-Thalassemia
When alpha-thalassemia coexists with sickle cell trait, the electrophoresis pattern changes significantly:
- HbS levels drop below 35% (mean 30.4%, range 23.4-34.2%) 3
- HbA levels increase to approximately 65.8% 2
- Microcytosis is present with MCV around 81.6 fl 2
- Reduced MCH and MCHC 2
The key mechanism is that alpha-thalassemia reduces overall hemoglobin production, which disproportionately affects the abnormal beta-S chain synthesis, resulting in relatively less HbS compared to HbA. 2 Studies demonstrate an alpha:beta chain synthesis ratio of 0.76 in these individuals, compared to unity in normal sickle cell trait. 2
Sickle Cell Trait with Beta-Thalassemia (Sickle β+ Thalassemia)
When beta-thalassemia (β+ variant) combines with sickle cell trait, creating compound heterozygosity:
- HbA levels vary from 10-25% (depending on severity of β+ mutation) 1
- HbS levels are 70-80% 1
- HbA2 levels are elevated >3-5% (characteristic of beta-thalassemia) 1
- HbF may be elevated <3% 1
- Microcytosis with low MCV, MCH, and MCHC 4
- Higher total hemoglobin and PCV than HbSS disease 4
This represents a mild clinical phenotype of sickle cell disease, not just trait. 1
Sickle Cell Trait with Beta-Zero Thalassemia (Sickle β⁰ Thalassemia)
When beta-zero thalassemia combines with sickle cell trait:
This creates a severe clinical phenotype resembling HbSS disease with early painful crises and severe anemia (hemoglobin 60-90 g/L). 1, 5
Critical Clinical Pitfalls
The most important caveat is that HbS levels below 35% in apparent "sickle cell trait" should prompt investigation for coexistent alpha-thalassemia, as this combination may be hematologically subtle but has implications for genetic counseling. 3, 2 The presence of microcytosis (MCV <80 fl) in someone with sickle cell trait is the key red flag. 2
In contrast, sickle β-thalassemia compound heterozygotes are not benign carriers but have actual sickle cell disease requiring disease-specific management, despite the presence of some HbA in the β+ variant. 1, 5 The elevated HbA2 (>3.5%) distinguishes beta-thalassemia combinations from alpha-thalassemia combinations. 1
The severity paradox in sickle β+ thalassemia is noteworthy: while higher HbA levels theoretically provide antisickling protection, the concurrent microcytosis and increased red cell count can increase blood viscosity, potentially worsening clinical outcomes despite adequate HbA levels. 6