Red Blood Cell Dysfunction in Critical Illness

Abstract

Oxygen (O2) delivery, which is fundamental to supporting patients with critical illness, is a function of blood O2 content and flow. This article reviews red blood cell (RBC) physiology and dysfunction relevant to disordered O2 delivery in the critically ill. Flow is the focus of O2 delivery regulation: O2 content is relatively fixed, whereas flow fluctuates greatly. Thus, blood flow volume and distribution vary to maintain coupling between O2 delivery and demand. This article reviews conventional RBC physiology influencing O2 delivery and introduces a paradigm for O2 delivery homeostasis based on coordinated gas transport and vascular signaling by RBCs.

Keywords: Blood flow; Erythrocyte; O(2) delivery; Red blood cell; Vasoregulation.

Figure 1.

The normal whole blood oxygen equilibrium curve (OEC). P₅₀ is the pO₂ at which hemoglobin is half-saturated with O₂. The principal effectors that alter the position and shape of the curve under physiological conditions are indicated. From Winslow RM. The role of hemoglobin oxygen affinity in oxygen transport at high altitude. Respir Physiol Neurobiol 2007; 158:121–127; with permission.

Figure 2.

The quantitative behavior of the Carbaminohemoglobin (HbCO₂) dissociation curves at various oxygen tension levels. From Dash RK, Bassingthwaighte JB. Erratum to: Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3-DPG and temperature levels. Annals of biomedical engineering 2010; 38:1683–1701; with permission.

Figure 3

The RBC membrane is composed of a phospholipid membrane bilayer and transmembrane proteins including glycophorin A and Band 3 proteins. Glycophorin A is the major sialoglycoprotein of the RBC. Sialic acid (SA) bound to glycophorin A is responsible for the negative charge of the RBC membrane. The intracellular compartment (IC) is constituted by spectrin (α and β subunits), actin, protein 4.1, and ankyrin. From: Piagnerelli M, et al. Red blood cell rheology in sepsis. Intensive Care Med. 2003; 29(7):1052–1061; with permission.

Figure 4.

Local vascular reflexes support maintenance of O₂ delivery to tissue in the setting of progressive hypoxia. In a classic paper, Guyton demonstrated regional autoregulation of systemic blood flow in normal dogs (following spinal anesthesia) by observing variation in blood flow during constant pressure blood perfusion of the femoral artery, while reducing the hemoglobin oxygen saturation (Hb SO₂%) from 100% to 0% in the perfusing blood. (A) Stepwise reduction in Hb SO₂% caused a progressive increase in blood flow through the leg. (B) These data demonstrate that autoregulation of blood flow occurs at a local level and this regulation serves to improve oxygen supply when blood oxygen content falls. In addition, effects on blood flow were replicated by injecting partially deoxygenated versus oxygenated red blood cells into the artery, demonstrating that effects could be elicited during arteriovenous transit (<1 s). From Ross JM, Fairchild HM, Weldy J, Guyton AC. Autoregulation of blood flow by oxygen lack. Am J Physiol. 1962;202:21–24; with permission.

Figure 5.

RBCs transduce regional O₂ gradients in tissue to control nitric oxide (NO) bioactivity in plasma by trapping or delivering NO groups as a function of hemoglobin (Hb) O₂ saturation. (A) In this fashion, circulating NO groups are processed by Hb into the highly vasoactive (thiol-based) NO congener, S-nitrosothiol (SNO). By exporting SNOs as a function of Hb deoxygenation, RBCs precisely dispense vasodilator bioactivity in direct proportion to regional blood flow lack. (B) O₂ delivery homeostasis requires biochemical coupling of vessel tone to environmental cues that matches perfusion sufficiency to metabolic demand. Because oxy- and deoxy-Hb process NO differently (see text), allosteric transitions in Hb conformation afford context-responsive (O₂-coupled) control of NO bioavailability, thereby linking the sensor and effector arms of this system. Specifically, Hb conformation governs the equilibria among deoxy-HbFeNO (A; NO sink), SNO-oxy-Hb (B; NO store), and acceptor thiols including the membrane protein SNO-AE-1 (C; bioactive NO source). Direct SNO export from RBCs or S-transnitrosylation from RBCs to plasma thiols (D) or to endothelial cells directly (not shown) yields vasoactive SNOs, which influence resistance vessel caliber and close this signaling loop. Thus, RBCs either trap (A) or export (D) NO groups to optimize blood flow. (C) NO processing in RBCs (A and B) couples vessel tone to tissue PO₂; this system subserves hypoxic vasodilation in the arterial periphery and thereby calibrates blood flow to regional tissue hypoxia. From Doctor A, Stamler JS. NO Transport in Blood: A third gas in the respiratory cycle. In: Comprehensive Physiology: Respiratory Physiology. Wagner P and Hlastala M, Ed’s. American Physiological Society. Compr Physiol 1:541–568, 2011; with permission.

Figure 6

Simplified scheme of cdB3-based control of RBC metabolism and proposed causal path for sepsis induced red cell dysfunction: (A) Energy metabolism in RBCs proceeds through either the Embden-Meyerhof pathway (EMP, orange arrows), or the hexose monophosphate pathway (HMP, blue arrows, AKA ‘pentose shunt’). Both share glucose-6 phosphate (G6P) as initial substrate. The HMP is the sole source of NADPH in RBCs and generates fructose-6-phosphate (F6P) or glyceraldehyde-3-phosphate (G3P), which rejoin the EMP prior to glyceraldehyde-3-phosphate dehydrogenase (G3PD/GAPDH), a key regulatory point. The EMP generates NADH (utilized by metHb reductase), as well as ATP (to drive ion pumps) and 2,3-DPG (to modulate hemoglobin P₅₀). Hydrogen peroxide (H₂O₂) and superoxide anion (O₂⁻) are the principal endogenous reactive O₂ species (ROS) that are generated / encountered by RBCs. Both ROS are generated internally in the course of HbO₂ cycling.^– Notably, only H₂O₂ can cross the membrane directly. O₂⁻ enters/departs RBCs via the Band 3 channel (anion exchange protein 1, or AE-1). O₂⁻ and H₂O₂ are ultimately reduced to water by catalase (CAT) or glutathione peroxidase (GPx). (B) O₂ content modulates EMP/HMP balance via reciprocal binding for cdB3 between deoxyHb and key EMP enzymes (PFK, Aldo, G3PD, PK, and LDH). In oxygenated RBCs (right half of stylized O₂ dissociation plot), EMP enzyme sequestration to cdB3 inactivates this pathway, resulting in HMP dominance and maximal NADPH (and thus GSH) recycling capacity. In deoxygenated RBCs (left half of O₂ dissociation plot), deoxyHb binding to cdB3 disperses bound EMP enzymes, activating the EMP, creating G6P substrate competition, constraining HMP flux, limiting NADPH and GSH recycling capacity and weakening resilience to ROS, such as O₂⁻. (C) In sepsis, data suggest cdB3-complex assembly may be prevented (particularly, with coincident hypoxia, see text). As in settings similarly impacting the cdB3 complex, it appears that this disturbs normal EMP/HMP balance (disfavoring HMP), depowering antioxidant systems and rendering RBCs vulnerable to oxidant attack. GSH, glutathione; GR, glutathione reductase; NADPH, nicotinamide adenine dinucleotide phosphate; PFK, phosphofructokinase; Aldo, aldolase; PK, pyruvate kinase; LDH, lactate dehydrogenase