Vascular cell adhesion molecule-1 (VCAM-1) is a protein expressed on the surface of activated endothelial cells and expressed in early atherosclerosis. Because part of the protein is shed in the circulation and can be detected in peripheral plasma [soluble (s) VCAM-1], we hypothesized that sVCAM-1 may be a circulating marker of the presence and severity of atherosclerosis in humans. We selected 11 patients with essential hypertension plus peripheral vascular disease (PVD) and matched them for age, gender, body mass index, and smoking habits with 11 patients with uncomplicated essential hypertension (UH) and 11 healthy controls. We evaluated plasma concentrations of sVCAM-1 along with those of the soluble form of two other endothelial leukocyte adhesion molecules [sE-selectin and s-intercellular adhesion molecule-1 (sICAM-1)] and other markers of endothelial dysfunction/ damage [s-thrombomodulin, plasminogen activator inhibitor type I, and von Willebrand factor (vWF)]. We also measured insulin, glucose, fibrinogen, total and HDL cholesterol, and the urinary albumin excretion (UAE), which may also be related to atherosclerosis. Results of these assays were related to the echographic assessment of the maximum intima-media thickness (IMTmax) at the carotid bifurcation, as an index of atherosclerosis in the carotids. PVD patients had a clearly elevated IMTmax [2.7 (1.1-3.1) mm, median (range)] compared with both UH patients [1.2 (0.8-2.4) mm] and controls [1 (0.6-2) mm]. sVCAM-1 was clearly higher in PVD patients [990 (273-1808) ng/mL, median (range)] versus 340 (236-975) ng/mL in UH and 386 (204-835) ng/mL in controls, and it separated clinical categories better than sICAM-1, vWF, glucose, insulin, UAE, triglycerides, or total, LDL or HDL cholesterol, sVCAM-1 was also the best biohumoral correlate of IMTmax (R = .59; P < .001) in univariate analysis. Because many of the biohumoral variables assessed were mutually intercorrelated, they were entered in a multivariate analysis to assess their contribution in explaining IMTmax variability. sVCAM-1 remained the only independent predictor of IMTmax and totally abolished the contribution of other variables to IMTmax variability. Thus, sVCAM-1 is a good biohumoral correlate of overt atherosclerosis, independent of underlying hypertension, and may be an in vivo marker of endothelial activation. Its potential value as a surrogate for global risk assessment and its behavior in intervention studies remain to be determined.

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The patterns of degradation and the influence of factor XIII polymerization on fibrin stability were examined in vitro following incubation with leukocyte elastase. In vivo experiments, various factor XIII-polymerized fibrin clots were implanted subcutaneously in mice to evaluate the stability of clots in the extravascular space. Both in vitro and in vivo lysis proceeded faster with nonpolymerized fibrin and was not influenced by the presence of cross-linked alpha 2-plasmin inhibitor. In vivo lysis of implanted clots was prevented by elastatinal, powerful elastase inhibitor, suggesting that granulocyte elastase is chiefly responsible for clot lysis in the extravascular space. To further extend investigations on the mechanisms of fibrinolysis in tissues, we evaluated fibrin and its degradation products in the synovial space. Expression of factor XIII in synovial cells and activities of coagulation factors, fibrinolytic enzymes, and inhibitors were investigated in the synovial fluid of rheumatoid arthritis patients. Immunohistochemical analysis showed deposits of insoluble fibrin on synovial membranes and pannus to an extent related to the progression of the disease. Factor XIII was expressed by fibroblasts and macrophages in the early stages of the disease, whereas in advanced stages factor XIII staining was associated with fibrin. The reduction of certain coagulation factors and high level of thrombin-antithrombin complexes in synovial fluid show a steady activation of the coagulation cascade. The evaluation of fibrinogen degradation products and the pattern of degradation of synovial fibrin(ogen) suggest the participation of leukocyte elastase in fibrin(ogen) lysis in synovial tissue of rheumatoid arthritis.