The terminal density reversal phenomenon of aging human red blood cells

Abstract

That red blood cells (RBCs) become progressively denser with age has become a universally acknowledged truth. However, as with all universally acknowledged truths, troublesome singularities often arise. We focus here on one particular departure from the rule, the terminal density reversal (TDR) phenomenon, discovered by Bookchin (Bookchin et al., 2000), and documented so far in RBCs from healthy subjects (Bookchin et al., 2000; Lew et al., 2007), from sickle cell anemia patients (SS RBCs) (Bookchin et al., 2000; Franco et al., 2000; Lew et al., 2002; Holtzclaw et al., 2002), from patients with β-thalassemia intermedia (Bookchin et al., 2000), and from diabetic subjects with sustained high levels of glycated hemoglobin, Hb A1c (Bookchin et al., 2009). There are a number of reasons that justify focusing on TDR: it is of substantial physiological and pathophysiological relevance as it defines the late and terminal homeostatic condition of RBCs in the circulation both in health and disease; it remains controversial and in need of further independent confirmation; its mechanism is still poorly understood, and on the evidence so far it is not yet clear whether it is the common final path of all RBCs or of only a selected RBC subpopulation. Let us start with a brief review of the facts. TDR was first reported by Bookchin et al. (2000). The original observations were made while studying the time-dependent changes in the volume distribution patterns of K+-permeabilized RBCs suspended in plasma-like media, as they became progressively dehydrated by the net loss of KCl and water. Bookchin's surprising discovery was that small fractions of cells (0.03 to 4%) failed to dehydrate, both in RBC samples from normal subjects (about 0.05%) and from patients with sickle cell anaemia (about 4%). Because of certain additional clues he speculated that these dehydration-resistant cells could represent a pre-terminal condition of RBCs in the circulation. Scepticism by his co-worker (Virgilio L. Lew), who suspected an artifactual origin of the results, led to the extended investigation that finally confirmed Bookchin's original findings and supported his interpretations. A brief explanation as to why these findings were so surprising follows below. © 2013 Lew and Tiffert.