Thrombogenesis

Sustained NF-kB activation, TNF-a, IL-1, proliferation, signals (M-CSF, G-CSF), chemotaxis (MCP-1), adhesion (VCAM-1, ICAM-1), thrombogenesis (TF)... 

It is remarkable that most of the data collected from the available SERMs are unanimous in reproducing an estrogen agonistic profile in venous thrombogenesis. The vast clinical experience acquired with tamoxifen confirms an augmented risk for both deep venous thrombosis and pulmonary embolism. This increase, however, did not presuppose increased mortality in the overview of randomized trials of adjuvant tamoxifen for early breast cancer, where the one extra death per 5000 woman-years of tamoxifen attributed to pulmonary embolus was not statistically significant (Early Breast Cancer Trialists Collaborative Group 1998). 

Scott, J., Thrombogenesis linked to atherogenesis at last Nature (London) 341, 22-23 (1989). 

Drugs that decrease the coagulability of blood, such as coumarins andhep-arin (A), are employed for the prophylaxis of thromboses. In addition, attempts are directed at inhibiting the aggregation of blood platelets, which are prominently involved in intra-arterial thrombogenesis (p. 148). For the therapy of thrombosis, drugs are used that dissolve the fibrin meshwork->fibrino-lytics (p. 146). 

The von Willebrandt s factor plays a key role in thrombogenesis. Lack of this factor causes thrombasthenia, a pathologically decreased platelet aggregation. Relative deficiency of the von Wille-Liillmann, Color Atlas of Pharmacology... 

Cigarette smoking is a major risk factor for coronary disease. It is associated with reduced levels of HDL, impairment of cholesterol retrieval, cytotoxic effects on the endothelium, increased oxidation of lipoproteins, and stimulation of thrombogenesis. Diabetes, also a major risk factor, is another source of oxidative stress. 

Dai W, Kloner RA. Relationship between cyclooxygenase-2 inhibition and thrombogenesis. J Cardiovasc Pharmacol Ther. 2004 9 51-59. 

Finally, aspirin has also been used to prevent thrombus formation in peripheral veins (deep vein thrombosis [DVT]), and aspirin is sometimes used as an adjunct or alternative to anticoagulants (heparin, warfarin) that are routinely used to treat DVTs.8 Aspirin can likewise be administered to prevent thromboembolism following surgical procedures such as coronary artery bypass, arterial grafts, endarterectomy, and valve replacement 45,78 By preventing platelet-induced thrombogenesis, aspirin helps maintain patency and prevent reocclusion of vessels following these procedures. 

Normal hemostasis is a balance between excessive and inadequate blood clotting. Overactive blood clotting is harmful because of the tendency for thrombus formation and occlusion of arteries and veins. Vessels may become directly blocked by the thrombus, or a portion of the thrombus may break off and create an embolism that lodges elsewhere in the vascular system. The tendency for excessive thrombus formation in the venous system is usually treated with anticoagulant drugs such as heparin and warfarin. Platelet inhibitors such as aspirin help prevent arterial thrombogenesis. Thrombolytic drugs (streptokinase, t-PA) that facilitate the dissolution of harmful clots may successfully reopen... 

Chan, J.K., McDonald, B.E., Gerrad, J.M., Bruce, V.M., Weaver, B.J., and Holub, B.J. 1993. Effect of dietary alpha-linolenic acid and its ratio to linoleic acid on platelet and plasma fatty acids and thrombogenesis. Lipids 28, 811-817. 

An overview of the main aspects of endothelial dysfunction as they relate to thrombogenesis and inflammation is important to provide a background of the factors affecting EMP release and their phenotype. A large number of reviews are available on this subject however, this section describes only the main features of EC perturbation and dysfunction as may be relevant to EMP. 

Procoagulcmt Activity. EMPs, similar to other MPs, have been demonstrated to readily induce thrombogenesis [5, 33]. In this regard, EMPs have been shown to be procoagulant in a TFrFVII-dependent manner [51]. In addition, they have been shown to elicit thrombin generation and to provide platelet factor 3 activity, as reviewed [5]. EMPs have also been shown to carry other important proteins such as PA-1 and vWF on their surface [56, 57]. 

The influence of NO in thrombogenesis, bacterial infection, angiogenesis, and the immune response suggest that its active release into the tissue surrounding a sensor may minimize the FBR. Sensor coatings that release NO could reduce the occurrence and severity of bacterial infection, minimize inflammation and collagen capsule formation, and promote the formation of new blood vessels, all of which would create a more favorable implant environment. Since NO is reactive (i.e., has a short half-life), the effects of NO would remain localized to the area from which it is released. 

Protein Adsorption. The development of medical implant polymers has stimulated interest in the use of ATR techniques for monitoring the kinetics of adsorption of proteins involved in thrombogenesis onto polymer surfaces. Such studies employ optical accessories in which an aqueous protein solution (93) or even ex - vivo whole blood (94-%) can be flowed over the surface of the internal reflection element (IRE), which may be coated with a thin layer of the experimental polymer. Modem FT-IR spectrometers are rapid - scanning devices, and hence spectra of the protein layer adsorbed onto the IRE can be computed from a series of inteiferograms recorded continuously in time, yielding ah effective time resolution of as little as 0.8 s early in the kinetic runs. Such capability is important because of the rapid changes in the composition of the adsorbed protein layers which can occur in the first several minutes (97). 

Polymer Adsorption. A review of the theory and measurement of polymer adsorption points out succinctly the distinquishing features of the behavior of macromolecules at solid - liquid interfaces (118). Polymer adsoiption and desorption kinetics are more complex than those of small molecules, mainly because of the lower diffusion rates of polymer chains in solution and the "rearrangement" of adsorbed chains on a solid surface, characterized by slowly formed, multi-point attachments. The latter point is one which is of special interest in protein adsoiption from aqueous solutions. In the case of proteins, initial adsoiption kinetics may be quite rapid. However, the slow rearrangement step may be much more important in terms of the function of the adsorbed layer in natural processes, such as thrombogenesis or biocorrosion / biofouling caused by cell adhesion. 

Studies have indicated that leukocytes play a critical role in the activation of coagulation in patients with septicemia and in animal models of acute lung injury (69). One study has presented direct evidence indicating the role of tissue factor expression on activated endothelial cells on in vivo thrombogenesis (70). 

Generation of procoagulant proteins and von Willebrand factor to activate thrombogenesis... 

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