Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety. Full citations for publications not cited fully within the specification are set forth at the end of the specification.
Thrombotic cardiovascular complications represent the leading cause of death among patients with end-stage renal disease (ESRD) and account for more than half of death in such patients. The well-documented high mortality rate in ESRD is especially prominent in patients on dialysis. Since the cardiovascular death rate in dialysis patients is unaccepted high (almost 40-fold higher than in the general population), great scientific interest has gathered on this topic and intense efforts aim 1n attenuating this phenomenon. In addition, vascular-access thrombotic events in hemodialysis patients constitute a major morbidity cause. However, although spectacular achievements have been accomplished in reducing cardiovascular death and thrombotic events in the general population through better control of traditional risk factors, no such trend has been detected for patients with ESRD and results are far from optimal. This might be due to the fact that traditional risk factors (such as hypertension and hyperlipidemia) are less predictive of thrombotic events in ESRD patients than in the general population, while markers of inflammation predict all cause and cardiovascular mortality in hemodialysis patients, underlining the significant role of inflammation in the atherothrombotic process.
Inflammation and thrombosis are linked in certain clinical models. Biomaterials are known inflammatory agonists and induce leukocytes and complement activation [15-19]. Neutrophils and complement are key mediators of innate immunity and play a pivotal role in the inflammatory response to various stimuli [20]. Thus, chronic hemodialysis in ESRD patients is considered as a major contributor for atherosclerosis through chronic inflammatory activation [21, 22]. In addition, TF extrinsic pathway plays the main in vivo role for coagulation triggering [23]. However, the mechanisms of TF regulation in coagulant process in such patients remain elusive. Different inflammatory agonists are responsible for TF induction in monocytes and activated endothelial cells. Recently it has been reported that neutrophils are able to produce functional TF through C5a/C5aR, thus suggesting that this novel pathway may be implicated in different clinical models [24].
As can be seen from the foregoing discussion, cardiovascular and/or vascular-access thrombotic events are very prominent in ESRD patients, especially those on dialysis. Although several mechanisms have been proposed, no substantial progress in reducing morbidity and mortality has been accomplished. Thus, there is a need in the art to identify and develop new methods for alleviating these unwanted and dangerous side-effects of hemodialysis and other extracorporeal treatments. This invention addressed those needs.
USPTO Backgrounds
USPTO Backgrounds