The survival of red cells in the circulation can be measured in a variety of ways: (1) by labeling with radioactive isotopes, particularly chromium-51 (51Cr), and assessing the disappearance of the radioactive tag from the circulation over time; (2) by labeling the erythrocytes with biotin or a fluorescent dye and measuring this marker over time; (3) by determining the disappearance of transfused antigen-matched allogeneic erythrocytes using immunologic markers; and (4) by measuring the excretion of carbon monoxide, a product of heme catabolism.
Such studies show that normal human red cells have a finite life span averaging 120 days, with very little random destruction. The mitochondrial and ribosomal removal highlighting maturation of the reticulocyte is accompanied by increasing cell density, but after a few days of intravascular life span there is little further increase in density or other changes in the physical property of the red cells. Thus, cell density is not a good marker for aged red cells. This has made the senescent changes in the red cell that mark it for destruction difficult to study. Candidates for such changes include changes in membrane band 3 and exposure of phosphatidylserine on the membrane, which may be of major importance.
Acronyms and Abbreviations:
ADP, adenosine diphosphate; AMP, adenosine monophosphate; BNIP3L, an hypoxic regulated gene that facilitates mitochondrial autophagy; C3, third component of complement; 14C, radioactive carbon; CD44, cell differentiation antigen; CO, carbon monoxide; 50Cr, chromium-50; 51Cr, chromium-51; DFP, diisopropylfluorophosphate; 55Fe or 59Fe, radioactive iron; G6PD, glucose-6-phosphate dehydrogenase; HO, heme oxygenase; Ig, immunoglobulin; 111In, indium-111; 15N, nitrogen; PK, pyruvate kinase; 99mTc, technetium-99m.
Normal human red blood cells have a life span of approximately 120 days, after which they are engulfed by macrophages. This is an extremely efficient process as macrophages phagocytose approximately 5 million erythrocytes every second without a significant release of hemoglobin into the circulation. The precise molecular mechanism by which macrophages recognize senescent red blood cells for phagocytosis remains largely unknown. As red blood cells age, several physiologic changes occur that may serve as signals for recognition by macrophages.1,2 These include a decrease in the activity of enzymes,3 a progressive decrease of ATP content,4 a loss of lipid asymmetry with exposure of phosphatidylserine,5 an accumulation of lipid peroxidation products,6 a desialylation of membrane glycoprotein,7 an exposure of cryptic senescent antigens,8 aggregation of band 3 protein (Chap. 46),9 a decrease in deformability as the result of increased oxidative stress,10 and an increase in cell surface-bound immunoglobulins and complement components (Chap. 54).11,12 All of these changes have been investigated as signals for recognition by the macrophages.
MEASUREMENT OF RED CELL DESTRUCTION
The original method for the measurement of the ...