Red blood cells mediate the onset of thrombosis in the ferric chloride murine model.
Application of ferric chloride (FeCl(3)) to exposed blood vessels is widely used to initiate thrombosis in laboratory mice. Because the mechanisms by which FeCl(3) induces endothelial injury and subsequent thrombus formation are little understood, we used scanning electron and brightfield intravital microscopy to visualize endothelial damage and thrombus formation occurring in situ. Contrary to generally accepted belief, FeCl(3) does not result in appreciable subendothelial exposure within the time frame of thrombosis. Furthermore, the first cells to adhere to FeCl(3)-treated endothelial surfaces are red blood cells (RBCs) rather than platelets. Energy dispersive x-ray spectroscopy demonstrated that ferric ions predominantly localize to endothelial-associated RBCs and RBC-derived structures rather than to the endothelium. With continuing time points, RBC-derived structures rapidly recruit platelets, resulting in large complexes that subsequently enlarge and coalesce, quickly covering the endothelial surface. Further studies demonstrated that neither von Willebrand factor nor platelet glycoprotein Ib-α receptor (GPIb-α) is required for RBCs to adhere to the endothelium, and that deficiency of GPIb-α greatly abrogated the recruitment of platelets to the endothelial-associated RBC material. These findings illuminate the mechanisms of FeCl(3)-mediated thrombosis and reveal a previously unrecognized ability of RBCs to participate in thrombosis by mediating platelet adhesion to the intact endothelial surface.
Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Justin D
JD
Barr
Anil K
AK
Chauhan
Gilbert V
GV
Schaeffer
Jessica K
JK
Hansen
David G
DG
Motto
D000818:Animals; D002478:Cells, Cultured; D002712:Chlorides / Q000494:pharmacology; D004195:Disease Models, Animal; D004903:Erythrocyte Aggregation / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects* / Q000502:physiology*; D005290:Ferric Compounds / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010973:Platelet Adhesiveness / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000235:genetics; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced* / Q000235:genetics; D014841:von Willebrand Factor / Q000235:genetics; D053662:Interleukin-4 Receptor alpha Subunit
D002712:Chlorides; D005290:Ferric Compounds; D011956:Receptors, Cell Surface; D014841:von Willebrand Factor; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C024555:ferric chloride