Heterogeneity of Red Blood Cells: Causes and Consequences

Abstract

Mean values of hematological parameters are currently used in the clinical laboratory settings to characterize red blood cell properties. Those include red blood cell indices, osmotic fragility test, eosin 5-maleimide (EMA) test, and deformability assessment using ektacytometry to name a few. Diagnosis of hereditary red blood cell disorders is complemented by identification of mutations in distinct genes that are recognized "molecular causes of disease." The power of these measurements is clinically wellestablished. However, the evidence is growing that the available information is not enough to understand the determinants of severity of diseases and heterogeneity in manifestation of pathologies such as hereditary hemolytic anemias. This review focuses on an alternative approach to assess red blood cell properties based on heterogeneity of red blood cells and characterization of fractions of cells with similar properties such as density, hydration, membrane loss, redox state, Ca 2+ levels, and morphology. Methodological approaches to detect variance of red blood cell properties will be presented. Causes of red blood cell heterogeneity include cell age, environmental stress as well as shear and metabolic stress, and multiple other factors. Heterogeneity of red blood cell properties is also promoted by pathological conditions that are not limited to the red blood cells disorders, but inflammatory state, metabolic diseases and cancer. Therapeutic interventions such as splenectomy and transfusion as well as drug administration also impact the variance in red blood cell properties. Based on the overview of the studies in this area, the possible applications of heterogeneity in red blood cell properties as prognostic and diagnostic marker commenting on the power and selectivity of such markers are discussed.

Microvesicle Formation Induced by Oxidative Stress in Human Erythrocytes

“…The increase in intracellular calcium concentration leads to programmed cell death, so-called eryptosis for RBCs [ 59 ], which could be triggered by numerous xenobiotics and exogenous substances [ 60 ] as well as several pathological states including diabetes, hepatic failure, sepsis, and chronic kidney disease [ 61 , 62 , 63 , 64 , 65 ]. As expected [ 38 , 39 , 41 ], intracellular calcium increase mediated by A23187 led to RBC shrinkage ( Figure 3 and Figure 5 ) and subsequent rapid loss of flexibility ( Figure 5 and Figure 6 ), which could be explained by the opening of the Ca 2+ -sensitive Gardos channels resulting in hyperpolarisation and a loss of K - , Cl - , and water [ 66 ]. MPs formed during eryptosis by membrane shedding are around 200 nm in diameter and are characterized by surface phosphatidylserine (PS) exposure [ 9 ].…”

Micronutrient levels and their effect on the prognosis of visceral leishmaniasis treatment; a prospective cohort study.

“…This nding supports the results of previously published work [77]. This is due to the crucial role of iron in red blood cell production that is used to transport essential substances, including the antileishmaniasis drugs [78].…”

Lysophosphatidic Acid-Activated Calcium Signaling Is Elevated in Red Cells from Sickle Cell Disease Patients

“…However, tremendous heterogeneity in the LPA response of the RBCs of each donor [ 16 , 17 , 30 ] (cp. also Figure 1 Ac,Bc) could not be comprehensively explained by RBC age [ 30 , 71 ]. In light of the current results revealing a substantial signaling cascade with numerous directly involved molecular players, this provides a potential chain where each individual link may cause a modulation of the final Ca 2+ signal.…”