Fibrin deposition is frequently observed at inflamed sites. Limited efforts, however, have so far been made to shed light on the roles of blood coagulation in inflammation. Recent studies have increasingly revealed a close association of the blood coagulation system with inflammation and immune reactions; the coagulation factors can also work as inflammatory mediators or immune modulators, and that, vice versa, some inflammatory or immune stimuli are linked to blood coagulation. Here, the progress in the investigation of thrombin, factor Xa, tissue factor, factors of the kallikrein/kinin system and fibrinopeptide B are reviewed from the viewpoint of their roles, with an emphasis on the molecular basis, in inflammation (vascular permeability enhancement, leukocyte chemotaxis, mediator release, etc.) and immune reactions (T-cell proliferation, cytokine production, etc.). Evidence presented in this report suggests a network among blood coagulation, inflammation and immune reactions.
It has now been well documented that urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play a central role of fibrinolysis at cell surfaces. Further, the importance of this finding resides in various cellular regulation of fibrinolysis mediated by cell surface bound inhibitors and other fibrinolytic proteases. Other than those, members of a family of matrix metalloproteinases (MMP) either tightly or loosely bound to cell membranes are also intriguing in the efficient destraction of a surrounding extracellular matrix (ECM) when invasive tumor cells are spreading or tissues are remodeling. Plasminogen activators activate plasminogen as well as some members of latent MMPs. Thus, plasminogen activators and MMPs are thought to be functionally crossoverd at cell surfaces. Those local membrane structures such as adhesion plaque and invadopodia as well may be important biological architectures, where both the receptor, binding sites for plasminogen and other proteolytic enzymes are localized. The former is functioning not only for cell adhesion, but for cellular locomotion, being able to degrade ECM via the activation of membrane bound plasminogen. The latter appears to be organized when invasive tumor cell moves across pores of an ECM-coated invasion chamber by breaching out the proteins. Therefore, both are thought to be active parts of the cellular membrane (domains) being able to interact locally with an ECM area composed of a suprastructure of networks of various monomer types of glycoproteins, such as collagen type IV, proteoglycans and laminin. Here, I briefly describe the background of uPA/uPAR system at the level of cell and molecular biology and further hypothesize that interactions of the two structural domains are also essentially functional motifs; a driving force of the local hydorlysis of ECM and importance of uPA/uPAR dependent locomotion for invasive spread of tumor cell across basement membrane.
To investigate the serial changes of protein C after trauma, protein C activity and protein C antigen concentration were measured on the day of the injury and on the 1st, 3rd, and 5th days after admission. Seventy-six trauma patients after mild, moderate, and severe injury (Injury Severity Score of≤10, 11 to 24, and≥25, respectively) were the participants. The incidence of disseminated intravascular coagulation (DIC), multiple organ dysfunction syndrome (MODS) and the mortality rate were differed between the groups. On the day of the injury the moderate- and severe-injured patients had shown markedly low levels of protein C activity and protein C antigen concentration, but the levels had gradually increased to the normal range on the 5th day after the admission. When the patients were complicated with DIC, the protein C activity and the protein C antigen concentration showed significantly lower values than those for non-DIC patients. Further, the DIC patients were classified into subgroups of survivors and nonsurvivors. The protein C activity and the protein C antigen concentration decreased significantly in the nonsur-vivors compared with those in the survivors and the levels remained low throughout the studying period. In conclusion, protein C activity and protein C antigen concentration decrease after trauma, and the DIC enhances those decrease. Low levels of protein C in severely injured patients with DIC may have some role posttrauma MODS.
To determine reiationships between activation of haemostatic factors and severity of peripheral atherosclerosis and differences by site, an angiographic cross sectional survey was carried out on 74 men and 8 women with intermittent claudication or rest pain. Thirty five patients were classified as having aorto-iliac disease, 16 femoro-popliteal disease and 31 dual-site disease. Age, mean levels of haemostatic factors, and severity of disease did not differ significantly between the three groups. In all 82 patients, disease severity was correlated with plasma fibrinogen (r=-0.5629, p<0.05). Fibrinogen and thrombin-anti thrombin III complex (TAT) were associated with disease severity in the aorto-iliac disease (p<0.05), but not femoro-popliteal nor dual site disease. We conclude that elevated fibrinogen and activated coagulation pathway may be related the to extent of disease within the aorto-iliac arteries, more so than in the femoro-popliteal arteries.
A 51-year-old male patient with Behcet syndrome was found by venography to be complicated with superior vena cava syndrome. Flow cytometrical analysis revealed that the patient's platelet surface glycoprotein (GP) Ib and GPIX were decreased by 40 and 10%, respectively, after administration of 80, 000 U/body weight kg of urokinase. The decrease in the total platelet GPIb was confirmed by quantitative immunoblotting. The patient's plasma concentration of glycocalicin increased after administration of urokinase. In contrast, the patient's platelet surface GPIIb/IIIa were not changed after urokinase therapy. These results suggest that administration of urokinase caused proteolysis of the circulating platelet surface GPIb/IX molecules.