Platelets are activated by contact with the tubing surface and by thrombin and complement. Activated platelets foster the generation of pro-inflammatory cytokines, thromboxane A2 (TXA2), platelet-activating factor (PAF), P-selectin, and serotonin. TXA2 induces ECs activation and local vasoconstriction, while serotonin and P-selectin promote PMN-endothelial interactions [
20]. Platelet activation is maximal at the initiation of VA-ECMO and progressively decreases over hours to days but remains persistent [
21]. EC activation leads to their detachment from the basal membrane and disassembly of tight junctions, increasing vascular permeability with the development of sub-endothelial edema [
22]. Moreover, activated ECs display an upregulated expression of adhesion molecules favoring PMN adhesion and transendothelial migration [
23], and they also release cytokines, tissue factor, and ROS. Circulating PMNs, monocytes, and macrophages are spontaneously activated by tubing surfaces [
24]. Furthermore, PMNs are activated by complement, histamine, serotonin, and PAF, which facilitate their adhesion to ECs, diapedesis, tissue infiltration [
25], and the release of cytotoxic mediators, including proteases, cytokines, and ROS.