title: Pro-coagulant state resulting from high levels of soluble P-selectin in blood.
abstract: The plasma concentration of soluble adhesion receptors is increased under pathological circumstances, but their function remains enigmatic. Soluble P-selectin (sP-sel) is shed from activated platelets and endothelial cells. Mice genetically engineered to express P-selectin without the cytoplasmic tail (DeltaCT) constitutively show a 3- to 4-fold increase of sP-sel in plasma. We observed that the DeltaCT mice formed fibrin very readily. In an ex vivo perfusion chamber, there was more fibrin deposited at the site of platelet thrombus formation than in wild type (WT), whereas no fibrin deposits were detected using P-selectin-deficient blood during the same interval. Similarly, in vivo, the hemorrhage produced by local Shwartzman reaction was smaller in the DeltaCT mice than in WT. In contrast, we previously showed hemorrhage to be more prominent in P-selectin knock-out mice. Infusion of mouse P-sel-Ig chimera produced the same protective effect in WT mice as seen in the DeltaCT mice, indicating that the effect was due to increased levels of sP-sel. Mice infused with P-sel-Ig showed significantly more fibrin deposited on the luminal face of the injured vessels than control mice. Plasma from DeltaCT mice or mice infused with P-sel-Ig contained higher concentration of pro-coagulant microparticles and clotted one minute faster than WT. This pro-coagulant phenotype of DeltaCT mice could be reversed by a 4-day treatment with PSGL-Ig, a P-selectin inhibitor. We propose that sP-sel should no longer be considered only as a marker of inflammation or platelet activation, but also as a direct inducer of pro-coagulant activity associated with vascular and thrombotic diseases.
authors.affiliation: The Center for Blood Research, and Department of Pathology, Harvard Medical School, 800 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: P
authors.initials: P
authors.lastname: André
authors.forename: D
authors.initials: D
authors.lastname: Hartwell
authors.forename: I
authors.initials: I
authors.lastname: Hrachovinová
authors.forename: S
authors.initials: S
authors.lastname: Saffaripour
authors.forename: D D
authors.initials: DD
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D005337:Fibrin / Q000378:metabolism; D006470:Hemorrhage / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000097:blood* / Q000235:genetics; D013927:Thrombosis / Q000378:metabolism
chemical_list: D019007:P-Selectin; D005337:Fibrin