**Abstract**

β thalassemias arise from genetic defects that interfere with the synthesis of the β hemoglobin chain and the subsequent production of the normal α2β2 hemoglobin tetramer. As a consequence of this decreased β-chain synthesis, unpaired α-hemoglobin chains are found within the red blood cell (RBC). The unstable α-chains are associated with a number of cellular defects, including: membranebound globin; membrane thiol oxidation; altered cytoskeletal proteins; decreased cellular and membrane deformability; and increased susceptibility to both endogenous and exogenous oxidants. Surprisingly, while significant injury to human thalassemic RBC arise from the unpaired α-chains, the underlying intra-RBC mechanisms are not easily studied in patient samples or in mouse models. To better study the *fate of excess α-chains* in human RBC, the model β Thalassemic cell was developed. Model human β thalassemic RBC is made by entrapping purified human α-chains within normal RBC via osmotic lysis and resealing. This human model allows for the systematic examination of the mechanisms underlying the α-chain mediated damage in the β thalassemic RBC. Studies utilizing the model β thalassemic RBC have demonstrated that the α-chains give rise to an iron and glutathionedependent, self-amplifying and self-propagating oxidative reaction.

**Keywords:** β thalassemia, α-hemoglobin chains, iron, red blood cell, erythrocyte, oxidation, free radicals, glutathione, deformability
