Enhanced macrophagic attack on beta-thalassemia major erythroid precursors

In beta-thalassemia major (Cooley's anemia), ferrokinetic studies show that 60-80% of erythroid precursors die in the marrow or extramedullary sites. However, study of marrow aspirates does not reveal huge numbers of dead and dying erythroid precursors. We explored this apparent discrepancy with the hypothesis that enhanced phagocytosis of thalassemic erythroid precursors was a likely explanation. Prior studies had reported on an increase in thalassemic marrow macrophages and their enhanced state of activation. Therefore this study explored the characteristics of thalassemic erythroid precursors which might lead to enhanced susceptibility to phagocytosis. We have shown that enhanced erythroid apoptosis parallels the extent of ineffective erythropoeisis in thalassemic patients, and apoptotic cells are rapidly phagocytosed. Thus, increased apoptosis and perhaps other features of thalassemic erythroid precursors might be the cause of their enhanced phagocytic removal.

Erythroid precursors were isolated from normal and beta-thalassemia major marrow, and incubated with uniform cultures of murine macrophages. The extent of phagocytosis was measured and then specific inhibitors were added to identify some of the messages effete erythroid precursors use to signal their condition to macrophages.

Beta-thalassemia major erythroid precursors are phagocytosed twice as effectively as normal erythroid precursors.

Experiments using inhibitors of phagocytosis showed that enhanced apoptosis is certainly responsible for part of the increased phagocytosis of thalassemic erythroid precursors. Interestingly, normal erythroid precursors are also subject to phagocytosis by qualitatively similar mechanisms.