SummaryP-selectin is a 140 kD protein found in the α-granules of platelets and the Weibel-Palade bodies of endothelial cells. On cell activation it is expressed on the cell surface and also secreted into plasma. Whether the circulating soluble P-selectin (sP-selectin) originates from platelets, endothelial cells, or both, is not known. We studied the level of sP-selectin in diseases with different platelet counts, with or without evidence of endothelial cell activation. Endothelial cell activation was confirmed by the detection of sE-selectin and EDl-fibronectin. A significant positive correlation between platelet count and sP-selectin concentration was observed in healthy controls, and in patients with thrombocytopenia due to bone marrow aplasia, or with thrombocytosis (r = 0.85; n = 47; p <0.001). In patients with idiopathic thrombocytopenic purpura (ITP) the sP-selectin concentration was 110 ± 39 ng/ml (n = 10), compared to 122 ± 38 ng/ml in healthy controls (n = 26). However, their mean platelet count was lower (58 X 109/1 versus 241 X 109/1 in the control group). Accordingly, the levels of sP-selectin expressed per platelet increased to significantly higher levels (2.0 ± 1.2 versus 0.6 ± 0.2 fg/platelet in the control group-; p <0.0001). This suggests increased platelet turnover in patients with ITP. High levels of sP-selectin were found in patients with sepsis (398 ± 203 ng/ml; n = 15) and with thrombotic thrombocytopenic purpura (TTP; 436 ± 162 ng/ml; n = 12). Compared with patients with ITP, the concentration of sP-selectin per platelet was higher in patients with sepsis (4.8 ± 4.3 fg/platelet; p <0.005) or TTP (17.1 ± 9.5 fg/platelet; p <0.001). Endothelial cells are very likely to be the source in these patients and the presence of endothelial cell activation was confirmed by increased levels of circulating E-selectin and ED 1 -fibronectin.This study suggests that platelets are the major source of circulating sP-selectin in healthy individuals. Endothelial cell activation is associated with an increased sP-selectin concentration per platelet.

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The alternatively spliced and highly conserved EIIIA domain of fibronectin (FN) is included in most FN of the extracellular matrix in embryos. In adults, both extracellular matrix and plasma FN essentially lack EIIIA. In diverse inflammatory situations however, EIIIA is specifically included by regulated RNA splicing. In atherosclerotic lesions, FN, including the EIIIA domain (EIIIA-FN), is abundant, whereas FN in the flanking vessel wall lacks EIIIA. Lesional EIIIA-FN is localized with endothelial cells and macrophage foam cells. To directly test the function of EIIIA-FN, we generated EIIIA-null (EIIIA ؊/؊ ) mice that lack the EIIIA exon and crossed them with apolipoprotein E (ApoE)-null (ApoE ؊/؊ ) mice that develop arterial wall lesions. Compared with ApoE ؊/؊ controls, EIIIA ؊/؊ ApoE ؊/؊ mice had significantly smaller lesions throughout the aortic tree. EIIIA-FN was increased in ApoE ؊/؊ plasma, and total plasma cholesterol was reduced in EIIIA ؊/؊ ApoE ؊/؊ mice, specifically in large lipoprotein particles, suggesting a functional role for plasma EIIIA- IntroductionFibronectins (FNs) are best known as a family of ligands for the integrin family of adhesion and signaling receptors. [1][2][3][4] FNs are essential for heart and blood vessel development, 5,6 and their polymerization regulates extracellular matrix (ECM) composition and organization. 7 FN variants are generated from a single gene by alternative RNA splicing of the V, EIIIA, and EIIIB segments, which are also known as CS-1, ED-A, and ED-B segments, respectively, 8 and the (V ϩ C) region. 9 EIIIA and EIIIB are type III repeats that are included or excluded from the FN monomer. Gene targeting experiments have shown that plasma FN, which lacks EIIIA and EIIIB, but includes V/CS-1, reduces brain injury by promoting neuronal survival 10 and also functions in thrombus growth and stability. 11 EIIIA-containing fragments are present in synovial fluid in arthritis 12 and in plasma of patients with vascular 13 and pulmonary injury. 14 EIIIA peptide can induce expression of proinflammatory cytokines interleukin 1␣ (IL-1␣) and IL-1␤, and matrix metalloproteinases. 15 High-sequence conservation of EIIIA and EIIIB (Ͼ 95% among mammals) and regulated expression [16][17][18] suggest that they are functional. In vitro, EIIIA-FN mediates wound healing in liver by inducing stellate cells to differentiate into myofibroblasts, which promote fibrosis. 19,20 EIIIA-FN is also up-regulated during cutaneous wound healing 21 and may have a functional role. 22 Skin fibroblasts respond to EIIIA-FN in vitro by differentiating to a fibrotic phenotype. 23 EIIIA-FN is also secreted by infiltrating leukocytes and deposited in the myocardium of rejecting cardiac allografts. 24 FN alternative exons have also been shown to be binding sites for integrins. The alternative V/CS-1 segment is a binding site for leukocyte integrins ␣4␤1 and ␣4␤7. 25,26 Of particular interest, the alternative EIIIA domain is a ligand for leukocyte integrins: ␣9␤1 and ␣4␤1. 27 In the chronic inflammation tha...