<em>Plasmodium falciparum</em> (<em>Pf</em>), Coevolutionary Balance, and Therapeutically-Rational Exchange Transfusion (T-REX): Nearly All <em>Pf</em> Genomes Allow HbAS Hemoglobin to Promote Human Survival

Background: While Plasmodium falciparum (Pf) genomes are constantly evolving to counter new antimalarial drugs, Pf parasites currently allow ancient Pf-malaria-combating red blood cell (RBC) genetic variants to markedly protect humans against onset of severe Pf disease and death. The prevalences of sickle-trait hemoglobin (HbAS) RBCs and “dual-gene protection” type-O HbAS RBCs are substantial in Pf-endemic regions thousands of years after the “sickle” HbS hemoglobin allele (HBB gene variant) and the type-O ABO blood group first emerged. Do Pf-human coevolution data and growing interest in transfusion services in Africa suggest rescue exchanges of “evolution-engineered” RBCs warrant evaluation? Methods: We reviewed transfusion-related publications and data regarding Pf-combating RBC genetic variants and a worrisome Pf genotype (Pfsa+++) that completely eliminates HbAS survival-promotion. Results: Clinicians in Africa are eager to advance transfusion therapies and exploit automated continuous-flow apheresis machines for RBC exchange. There is no evidence the low prevalence of Pfsa+++ is increasing or the combination of the survival-promoting effects of HbAS hemoglobin and type-O blood group provides less than an additive increase in protection. Conclusions: Geneticists can support evaluating therapeutic use of HbAS RBCs by explaining how the prevalence of the worrisome Pfsa+++ genotype might be low and unchanging due to an equilibrium between competing selection pressures and “fitness costs.” Since HbAS hemoglobin alone provides 90% protection against death, conceivably, no human with type-O HbAS RBCs has ever died from Pf malaria. So, it seems prudent to evaluate converting children with life-threatening Pf infections into type-O HbAS patients via exchange transfusion – now.