Fiche publication
Date publication
août 2015
Journal
Blood
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GACHET Christian
Tous les auteurs :
Ciciliano JC, Sakurai Y, Myers DR, Fay ME, Hechler B, Meeks S, Li R, Dixon JB, Lyon LA, Gachet C, Lam WA
Lien Pubmed
Résumé
The mechanism of action of the widely used in vivo ferric chloride (FeCl3) thrombosis model remains poorly understood; although endothelial cell denudation is historically cited, a recent study refutes this and implicates a role for erythrocytes. Given the complexity of the in vivo environment, an in vitro reductionist approach is required to systematically isolate and analyze the biochemical, mass transfer, and biological phenomena that govern the system. To this end, we designed an "endothelial-ized" microfluidic device to introduce controlled FeCl3 concentrations to the molecular and cellular components of blood and vasculature. FeCl3 induces aggregation of all plasma proteins and blood cells, independent of endothelial cells, by colloidal chemistry principles: initial aggregation is due to binding of negatively charged blood components to positively charged iron, independent of biological receptor/ligand interactions. Full occlusion of the microchannel proceeds by conventional pathways, and can be attenuated by antithrombotic agents and loss-of-function proteins (as in IL4-R/Iba mice). As elevated FeCl3 concentrations overcome protective effects, the overlap between charge-based aggregation and clotting is a function of mass transfer. Our physiologically relevant in vitro system allows us to discern the multifaceted mechanism of FeCl3-induced thrombosis, thereby reconciling literature findings and cautioning researchers in using the FeCl3 model.
Mots clés
Aspirin, pharmacology, Biomechanical Phenomena, Blood Platelets, chemistry, Cell Aggregation, drug effects, Chlorides, antagonists & inhibitors, Erythrocytes, chemistry, Ferric Compounds, antagonists & inhibitors, Fibrinolytic Agents, pharmacology, Heparin, pharmacology, Humans, Microfluidic Analytical Techniques, Models, Biological, Platelet-Rich Plasma, chemistry, Primary Cell Culture, Protein Aggregates, drug effects, Protein Binding, Static Electricity, Thrombosis, metabolism
Référence
Blood. 2015 Aug 6;126(6):817-24
