Presence of Rigid Red Blood Cells in Blood Flow Interferes with the Vascular Wall Adhesion of Leukocytes

Abstract

The symptoms of many blood diseases can often be attributed to irregularities in cellular dynamics produced by abnormalities in blood cells, particularly red blood cells (RBCs). Contingent on the disease and its severity, RBCs can be afflicted with increased membrane rigidity as seen in malaria and sickle cell disease. Despite this understanding, little experimental work has been conducted toward understanding the effect of RBC rigidity on cellular dynamics in physiologic blood flow. Though many have computationally modeled complex blood flow to postulate how RBC rigidity may disrupt normal hemodynamics, to date, there lacks a clear understanding of how rigid RBCs affect the blood cell segregation behavior in blood flow, known as margination, and the resulting change in the adhesion of white blood cells (WBCs). In this work, we utilized an in vitro blood flow model to examine how different RBC rigidities and volume fractions of rigid RBCs impact cell margination and the downstream effect on white blood cell (WBC) adhesion in blood flow. Healthy RBC membranes were rigidified and reconstituted into whole blood and then perfused over activated endothelial cells under physiologically relevant shear conditions. Rigid RBCs were shown to reduce WBC adhesion by up to 80%, contingent on the RBC rigidity and the fraction of treated RBCs present in blood flow. Furthermore, the RBC core was found to be slightly expanded with the presence of rigid RBCs, by up to ∼30% in size fully composed of rigid RBCs. Overall, the obtained results demonstrate an impact of RBC rigidity on cellular dynamics and WBC adhesion, which possibly contributes to the pathological understanding of diseases characterized by significant RBC rigidity.

The influence of red blood cell deformability on hematocrit profiles and platelet margination

“…Microfluidic experiments found a decrease in self-organization in quasi-2D confined flows with decreasing RBC deformability [26]. In vitro work also found that with increasing populations of rigid RBCs in flow reduces the amount of leukocyte adhesion to P-selectin coated substrates [27] and recently to an inflamed endothelium [28]. Previous numerical studies found that the rigid body inside a malaria-infected RBC significantly affects the RBC adhesive dynamics and increases whole blood viscosity [29], as well as the reduction of contact area to the vessel wall in sickled RBCs [30].…”

Quantifying Platelet Margination in Diabetic Blood Flow

“…The RBC deformability is crucial to the platelet transport, and the impaired deformability of DRBCs compared to NRBCs may cause weaker platelet margination toward the wall. There is in vitro evidence showing that the presence of rigid RBCs interferes with the WBC recruitment and platelet margination (82,83). In addition, Kumar and Graham have presented a detailed analysis of the segregation mechanism incorporating binary mixtures of capsules with different rigidities by performing a computational study with the boundary integral method (84).…”

An experimental erythrocyte rigidity index (Ri) and its correlations with Transcranial Doppler velocities (TAMMV), Gosling Pulsatility Index PI, hematocrit, hemoglobin concentration and red cell distribution width (RDW)

“…However, even if hyper aggregation and stiffness simultaneously occur, the main effect on the arterial circulation is the presence of rigid RBCs altering the flow, which may affect the function of leukocytes. [90]. Recent studies discuss the effect of rigid cells on margination (movement towards endothelial walls) [91], and results, unfortunately, are not conclusive [92].…”

“…Hundreds of studies [10] and especially numerous new techniques have been proposed to quantify RBC aggregation and deformability, which helps to understand the origin of symptoms of various diseases, including SCA. The quantification of RBC deformability has received increasing attention from researchers [11,12,13,14] and various experimental techniques (filtration, micropipette, ektacytometry, Dientenfass equation based on viscosity and hematocrit values [15,16], etc.) that analyze the deformability-or its inverse, the stiffness of the RBChave been proposed and applied over the last 50 years [17,18,19,20,21,22,23].…”