What can we learn from variation of red cell size distribution?
Authors: H. Franklin Bunn
Journal: American Journal of Hematology (2015)

Hematologists are justifiably proud of their specialty; many share the hubris that they have a lot to teach their colleagues in internal medicine, pediatrics and laboratory medicine. However, sometimes the shoe is on the other foot. Occasionally observations made within the broad scope of medical practice can provide new and important information on the nature of blood cells in health and disease. In this issue of The American Journal of Hematology, Patel, Patel and Higgins 1 provide experimental and interpretive insights on the distribution profile of the volumes of individual red cells, the mean of that distribution being the mean corpuscular volume (MCV). Hundreds of papers in peer-reviewed journals have documented small but significant elevations of the distribution width (RDW) in patients with an astonishingly broad range of common medical disorders including cancer, infections, renal disease as well as cardiovascular and pulmonary disease. In many of these individuals elevated RDW is the only abnormality in the CBC and thus is likely to be an important biomarker, in many cases being an early harbinger of an underlying disease. Patel et al 1 analyzed CBCs and reticulocyte counts from over 60,000 blood samples randomly selected from those sent to the clinical laboratory at Massachusetts General Hospital. They found that the most important contributor to increased RDW was a delay in the clearance of senescent red cells, both in general and in a wide range of pathologic conditions. The authors’ postulation that increased RDW signifies prolonged RBC life span was buttressed by measurements of glycated hemoglobin. Hb AIc is a post-translational non-enzymatic modification of normal hemoglobin owing to the attachment of glucose to the N-terminus of the β-globin by means of a stable ketoamine linkage. Hemoglobin AIc accumulates linearly during the 100-120 day life span of normal red cells 2. Serial measurements of Hb AIc have proven to be of considerable utility in the monitoring of glycemic control in patients with diabetes. In non-diabetic individuals levels of Hb AIc are low in patients with shortened red cell life span owing to hemolysis 2, 3. More recently Hb AIc has been shown to correlate closely and directly with red cell life span measured to a high degree of accuracy by labeling with biotin 4 or with a stable isotope 5. There is no reason to propose that the kinetics of non-enzymatic glycation in non-diabetic individuals is affected by the wide range of disorders associated with increased RDW. Therefore accurate measurement of Hb AIc should be a reliable and reproducible surrogate marker of red cell survival in these patients. The disorders that have been shown to be associated with increased RDW are impressively diverse. Therefore it is a challenge to discern a uniform pathogenic mechanism that underlies this phenomenon. Among the culprits are cancer, infections, renal failure, pulmonary diseases and autoimmune disorders. In most of these patients inflammation plays a central role in pathogenesis. Chronic inflammatory stress often results in a mild to moderate normocytic anemia owing primarily to enhanced hepatic expression of hepcidin resulting in a reduction of iron absorption from the gut and iron release from tissue macrophages. In addition inflammatory cytokines can suppress erythropoiesis in an iron-independent manner. However, postulating inflammation as a mechanistic link responsible for increased RDW and delayed clearance of senescent red cells is difficult to reconcile with measurements of red cell survival in patients with anemia of chronic inflammation. Studies done over the last 50 years by a variety of methods (Ashby, radiochromium labeling, radioiron labeling, and endogenous carbon monoxide exhalation) have usually shown a slight diminution in red cell life span 6-9. It is difficult to obtain more up-to-date date data on RBC lifespan. Radio-isotopes are no longer in clinical use. Labeling of RBC with either biotin 4 or a stable isotope such as 15N-glycine 5 is safe, more accurate, and therefore superior methods for measuring red cell life span, but they are primarily research tools and not in widespread use. Even if the most refined and accurate methods of measuring red cell survival were done on individuals with increased RDW, it is unlikely conclusive results would emerge since the extent of prolongation estimated by Patel et al 1 is only a few days, considerably less than the variance in red cell survival observed both in normal individuals and in patients. Perhaps early in the development of the disease the modest prolongation of red cell survival is balanced by equally modest suppression of erythropoiesis resulting in increased RDW but no change in other values within the CBC. With further progression of the disease, anemia may develop owing to more disordered erythropoiesis characterized by now a modest shortening of red cell survival and a more marked defect in red cell production. Does the prolongation of RBC life span constitute a homeostatic mechanism that compensates for impairment in red cell production? This heuristic proposal is a tantalizing extension of the analysis of RDW by Patel et al1. There is virtually unanimous agreement that the primary determinant of red cell production and red cell mass is erythropoietin, a circulating hormone that is expressed in a tightly regulated manner in response to the sensing of intracellular oxygen tension. It is far from clear what evolutionary pressure would force the development of an independent, finely tuned, regulatory mechanism for erythropoietic homeostasis.