Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets

Abstract

The glycoprotein P-selectin is a cell adhesion molecule of stimulated platelets and endothelial cells, which mediates the interaction of these cells with neutrophils and monocytes. It is a membrane component of cell storage granules, and is a member of the selectin family which includes E-selectin and L-selectin. P-selectin recognizes both lineage-specific carbohydrate ligands on monocytes and neutrophils, including the Lewis x antigen, sialic acid, and a protein component. In inflammation and thrombosis, P-selectin may mediate the interaction of leukocytes with platelets bound in the region of tissue injury and with stimulated endothelium. To evaluate the role of P-selectin in platelet-leukocyte adhesion in vivo, the accumulation of leukocytes within an experimental thrombus was explored in an arteriovenous shunt model in baboons. A Dacron graft implanted within an arteriovenous shunt is thrombogenic, accumulating platelets and fibrin within its lumen. These bound platelets express P-selectin. Here we show that antibody inhibition of leukocyte binding to P-selectin expressed on platelets immobilized on the graft blocks leukocyte accumulation and inhibits the deposition of fibrin within the thrombus. These results indicate that P-selectin is an important adhesion molecule on platelets, mediating platelet-leukocyte binding in vivo, that the presence of leukocytes in thrombi is mediated by P-selectin, and that these leukocytes promote fibrin deposition.

Platelet Activation in Cats with Hypertrophic Cardiomyopathy

“…These interactions can result in the development of a more stable platelet‐leukocyte complex as well as promoting the adhesion and recruitment of leukocytes to the endothelium. Recruitment of leukocytes to damaged endothelium by P‐selectin and the generation of leukocyte‐derived microparticles mediate the generation of fibrin 31. Studies in P‐selectin knockout mice showed prolonged bleeding times and increased hemorrhage in response to trauma, providing further evidence for the role of this selectin in hemostasis 32.…”

Tissue Plasminogen Activator (tPA) Deficiency Exacerbates Cerebrovascular Fibrin Deposition and Brain Injury in a Murine Stroke Model

“…Several vessels contained entrapped blood cells (eg, see venules in Figure 3A or the small microvessel in Figure 3E), possibly reflecting polymorphonuclear response (indicated by positive staining for polymorphonuclear markers; not shown) as reported previously. 27 Fibrin deposits and fibrin-rich thrombi were found occasionally after 24 hours of reperfusion in tPAϩ/ϩ wild-type 129/Sv and C57BL/6 mice in some venules, but most capillaries and other microvessels were negative for fibrin ( Figures 3G and 3H). Quantitative Western blot analysis for fibrin on 1-mm-thick TTC brain sections confirmed the immunohistological observations by demonstrating significant fibrin deposition in ischemic brain areas in tPAϪ/Ϫ mice versus barely detectable levels of fibrin in tPAϩ/ϩ wild-type control mixed-strain mice ( Figure 4C).…”

“…[17][18][19][20] Fibrin deposition in ischemic brain can be precipitated by procoagulant transformation of brain microvascular endothelium, [21][22][23]25 formation of a platelet plug, or leukocyte-endothelial interactions during reperfusion. 27 Previous studies have established a link between ischemic brain injury and reduced antithrombotic mechanisms in brain microcirculation in the presence of major stroke risk factors. 23,34,35 In humans, the antithrombotic factor protein C is protective in ischemic stroke.…”

Effects of Oxidized Low Density Lipoprotein, Lipid Mediators and Statins on Vascular Cell Interactions

“…Thus, a similar multistep model may apply to the highly efficient accumulation of PMN on surface-adherent platelets under flow. Indeed, rolling and arrest of PMN on activated platelets under flow requires the action of P-selectin and β 2 integrins, respectively (34)(35)(36)(37). Fibrinogen, a Mac-1 ligand (38, 39) which can bind to activated platelets via αIIbβ3 (40), has been implicated in platelet-PMN interactions in cell suspension or whole blood (41).…”