Dynamic adhesion of eryptotic erythrocytes to immobilized platelets via platelet phosphatidylserine receptors

Abstract

Glucose depletion of erythrocytes triggers suicidal erythrocyte death or eryptosis, which leads to cell membrane scrambling with phosphatidylserine exposure at the cell surface. Eryptotic erythrocytes adhere to endothelial cells by a mechanism involving phosphatidylserine at the erythrocyte surface and CXCL16 as well as CD36 at the endothelial cell membrane. Nothing has hitherto been known about an interaction between eryptotic erythrocytes and platelets, the decisive cells in primary hemostasis and major players in thrombotic vascular occlusion. The present study thus explored whether and how glucose-depleted erythrocytes adhere to platelets. To this end, adhesion of phosphatidylserine-exposing erythrocytes to platelets under flow conditions was examined in a flow chamber model at arterial shear rates. Platelets were immobilized on collagen and further stimulated with adenosine diphosphate (ADP, 10 μM) or thrombin (0.1 U/ml). As a result, a 48-h glucose depletion triggered phosphatidylserine translocation to the erythrocyte surface and augmented the adhesion of erythrocytes to immobilized platelets, an effect significantly increased upon platelet stimulation. Adherence of erythrocytes to platelets was blunted by coating of erythrocytic phosphatidylserine with annexin V or by neutralization of platelet phosphatidylserine receptors CXCL16 and CD36 with respective antibodies. In conclusion, glucose-depleted erythrocytes adhere to platelets. The adhesive properties of platelets are augmented by platelet activation. Erythrocyte adhesion to immobilized platelets requires phosphatidylserine at the erythrocyte surface and CXCL16 as well as CD36 expression on platelets. Thus platelet-mediated erythrocyte adhesion may foster thromboocclusive complications in diseases with stimulated phosphatidylserine exposure of erythrocytes.

Platelet and red blood cell interactions and their role in rheumatoid arthritis

“…An example of this is thromboxane, which was found to stimulate RBCs by inducing PS exposure on their surfaces, followed by an increase in cytosolic calcium content [76]. These responses have been found to be associated with reduced membrane deformability, increased adhesion, formation of pathomorphologies and a precursor to eryptosis [91][92][93]. The PS exposure further increases the adherence of RBCs to platelets and induces thrombosis [93].…”

“…These responses have been found to be associated with reduced membrane deformability, increased adhesion, formation of pathomorphologies and a precursor to eryptosis [91][92][93]. The PS exposure further increases the adherence of RBCs to platelets and induces thrombosis [93]. It is hence likely that structural variants and adhesive associations observable within the RA RBC pool could also be a result of this interaction-based effect.…”

“…This is likely a preceding step to platelet-enabled coagulation during thrombotic events while the residues are opsonised for phagocytosis during clot resolution. However, RBCs that have undergone eryptosis, especially due to glucose deprivation, have been found to bind platelet PS receptors and potentially reduce the solubility of the thrombus [93]. It is therefore possible that biophysical changes, adhesive associations and thrombotic events observable within RA vasculature could also be a result of this interaction-based effect.…”

Pathology of human plaque vulnerability: Mechanisms and consequences of intraplaque haemorrhages

“…The agglutination of RBCs at the site of plaque injury probably depends on platelet aggregation. Indeed, Walker and colleagues recently showed that senescent erythrocytes could stick to immobilized platelets, via the platelet phosphatidyl receptors, CXCL16 and CD36 [18]. Thereafter, ulcerated plaques are healed by migration and proliferation of local VSMCs that accumulate at the rupture site.…”

Purified Lesser weever fish venom (Trachinus vipera) induces eryptosis, apoptosis and cell cycle arrest

“…However, the main signaling pathway documented as inducer of eryptosis is increase of cytosolic Ca 2+ activity ([Ca 2+ ] i )16. Calcium can directly cause the phosphatidylserine membrane translocation (cell scrambling)34. Moreover, calcium can activate K + channels with an efflux of KCl from the cell causing cell shrinkage35.…”