High plasma levels of soluble P-selectin are associated with thrombotic disorders and may predict future cardiovascular events. Mice with high levels of soluble P-selectin have more microparticles in their plasma than do normal mice. Here we show that chimeras of P-selectin and immunoglobulin (P-sel-Ig) induced formation of procoagulant microparticles in human blood through P-selectin glycoprotein ligand-1 (PSGL-1; encoded by the Psgl1 gene, officially known as Selpl). In addition, Psgl1-/- mice produced fewer microparticles after P-sel-Ig infusion and did not spontaneously increase their microparticle count in old age as do wild-type mice. Injected microparticles specifically bound to thrombi and thus could be involved in thrombin generation at sites of injury. Infusion of P-sel-Ig into hemophilia A mice produced a 20-fold increase over control immunoglobulin in microparticles containing tissue factor. This significantly improved the kinetics of fibrin formation in the hemophilia A mice and normalized their tail-bleeding time. P-sel-Ig treatment could become a new approach to sustained control of bleeding in hemophilia.

In inflamed venules, leukocytes use Pselectin glycoprotein ligand-1 (PSGL-1) to roll on P-selectin and E-selectin and to activate integrin ␣L␤2 (lymphocyte function-associated antigen-1, LFA-1) to slow rolling on intercellular adhesion molecule-1 (ICAM-1). Studies in cell lines have suggested that PSGL-1 requires its cytoplasmic domain to localize in membrane domains, to support rolling on Pselectin, and to signal through spleen tyrosine kinase (Syk). We generated "⌬CD" mice that express PSGL-1 without the cytoplasmic domain. Unexpectedly, neutrophils from these mice localized PSGL-1 normally in microvilli, uropods, and lipid rafts. ⌬CD neutrophils expressed less PSGL-1 on their surfaces because of inefficient export from the endoplasmic reticulum. Limited digestion of wild-type neutrophils with O-sialoglycoprotein endopeptidase was used to reduce the PSGL-1 density to that on ⌬CD neutrophils. At matched PSGL-1 densities, both ⌬CD and wild-type neutrophils rolled similarly on P-selectin. However, ⌬CD neutrophils rolling on P-selectin did not trigger Sykdependent activation of LFA-1 to slow rolling on ICAM-1. These data demonstrate that the PSGL-1 cytoplasmic domain is dispensable for leukocyte rolling on P-selectin but is essential to activate ␤2 integrins to slow rolling on ICAM-1. IntroductionDuring inflammation, leukocytes tether to and roll on the vessel wall. They then roll more slowly until they arrest. Finally, they crawl through or between endothelial cells into the underlying tissues. Interactions of selectins with glycosylated ligands mediate tethering and rolling. Interactions of ␤2 integrins with ligands, such as intercellular adhesion molecule-1 (ICAM-1), mediate slow rolling and arrest. 1,2 These interactions occur in blood flow, which exerts force on adhesive bonds that affects bond lifetimes. 3,4 Furthermore, engagement of adhesion receptors transmits signals that intersect with chemokine receptor signals to influence the adhesion cascade. 1 Binding of integrin cytoplasmic domains to signaling and cytoskeletal proteins is critical for integrin function. 1,5 Interactions of selectin cytoplasmic domains with cytosolic proteins also contribute to their adhesive properties. E-selectin and P-selectin are expressed on activated endothelial cells and/or platelets, whereas L-selectin is expressed on the microvilli of leukocytes. 2 The cytoplasmic domains of E-selectin and P-selectin interact with clathrin-coated pits. These interactions cluster E-selectin and P-selectin on the endothelial cell surface, enhancing leukocyte rolling under flow. 6,7 The cytoplasmic domain anchors L-selectin to the cytoskeleton by binding to ␣-actinin 8 and to the ezrin/radixin/ moesin (ERM) family. 9 Mutation of the ERM-binding site in the cytoplasmic domain shifts L-selectin out of microvilli onto the cell body of transfected cells and impairs tethering to L-selectin ligands under flow. 10 Removal of the ␣-actinin-binding site markedly impairs rolling of transfected cells on L-selectin ligands, and deletion of the cytoplas...

C-reactive protein on its own is a sensitive screening test for the presence of bacterial infections in cirrhosis and is also a useful marker to predict the likelihood of clinically significant bacterial infections in patients without overt infections.

HE4 concentrations may be elevated in CKD patients with no ovarian and lung cancer. Thus, HE4 results should be interpreted cautiously in women with renal disorders.