Erythrocyte aggregation in sudden flow arrest is linked to hyperthermia, hypoxemia, and band 3 availability

Abstract

Background Erythrocyte aggregation is a phenomenon that is commonly found in several pathological disease states: stroke, myocardial infarction, thermal burn injury, and COVID‐19. Erythrocyte aggregation is characterized by rouleaux, closely packed stacks of cells, forming three‐dimensional structures. Healthy blood flow monodisperses the red blood cells (RBCs) throughout the vasculature; however, in select pathological conditions, involving hyperthermia and hypoxemia, rouleaux formation remains and results in occlusion of microvessels with decreased perfusion. Objectives Our objective is to address the kinetics of rouleaux formation with sudden cessation of flow in variable temperature and oxygen conditions. Methods RBCs used in this in vitro system were obtained from healthy human donors. Using a vertical stop‐flow system aligned with a microscope, images were acquired and analyzed for increased variation in grayscale to indicate increased aggregation. The onset of aggregation after sudden cessation of flow was determined at proscribed temperatures (37–49°C) and oxygen (0%, 10%), and in the presence and absence of 4, 4′‐Diisothiocyano‐2,2′‐stilbenedisulfonic acid (DIDS). Both autologous and homologous plasma were tested. Results RBCs in autologous plasma aggregate faster and with a higher magnitude with both hyperthermia and hypoxemia. Preventing deoxyhemoglobin from binding to band 3 with DIDS (dissociates the cytoskeleton from the membrane) fully blocks aggregation. Further, RBC aggregation magnitude is greater in autologous plasma. Conclusions We show that the C‐terminal domain of band 3 plays a pivotal role in RBC aggregation. Further, aggregation is enhanced by hyperthermia and hypoxemia.

Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis

“…Before apheresis treatment, it became apparent that some Long-Covid patients had high levels of erythrocyte aggregation, which is common in diseases associated with hyperthermia and hypoxemia, such as stroke or COVID-19 [ 36 ]. Elevated blood lipids, as observed in Long-Covid [ 27 , 29 ], may also increase the risk of cardiovascular diseases highlighting the necessity of lowering both lipids and thrombotic factors [ 37 ].…”

Assessment of Red Blood Cell Aggregation in Preeclampsia by Microfluidic Image Flow Analysis—Impact of Oxidative Stress on Disease Severity

“…The elevated RBC aggregation could influence tissue hypoxia in PE. In this regard, rouleaux was found to be present in pathological conditions involving hypoxia [54].…”

Metabolite and protein shifts in mature erythrocyte under hypoxia

“…Erythrocyte aggregation is faster and more severe under hypoxic conditions in vitro than under normoxic conditions, whereas the aggregation is drastically reduced by treatment with 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, an inhibitor of the anion exchange function of band 3. 75 This indicates that the erythrocyte aggregation under hypoxic conditions is related to band 3. In the high-altitude polycythemia (HAPC) rat model, 76 the erythrocyte aggregation index and whole blood viscosity were substantially greater than those in the control group.…”