The role of inflammation in cardiovascular disease and especially in thrombogenesis has become increasingly recognized as an important component of the overall disease process. Plaque rupture promotes activation of the inflammatory response and increased expression of tissue factor (TF), which in turn acts as one of the major initiators of extrinsic coagulation. It is becoming apparent that the expression of TF on endothelial cells, underlying smooth muscle cells and monocytes is regulated, in part, by proinflammatory cytokines including tumor necrosis factor and IL-1. In addition to initiating coagulation, interaction of TF with the adhesion molecule, P-selectin, has been demonstrated to accelerate the rate and extent of fibrin formation and deposition. P-selectin is expressed on activated platelets and endothelium and serves as the receptor for the endogenous ligand, P-selectin glycoprotein-1 (PSGL-1), expressed on various leukocytic cell types. In addition to mediating transient interactions between endothelial cells and leukocytes, P-selectin has been reported to mediate adherence of platelets to monocytes and neutrophils via specific interaction with PSGL-1. P-selectin is rapidly cleaved off the surface of the platelet membrane and appears in the circulation as a soluble form, which has been reported to be elevated in patients with acute coronary syndromes including unstable angina and non-Q-wave myocardial infarction. This review will focus on the role of cytokines in mediating TF expression and also explore the significance of the relationship between P-selectin and tissue factor in thrombus generation. In addition, possible pharmacological mechanisms to interrupt this disease process will be discussed.
These data suggest that P-selectin is involved in processes leading to cell migration and proliferation associated with vascular remodeling, presumably by mediating leukocyte recruitment and the interaction between platelets and leukocytes.
Restenosis is the reobstruction of an artery following interventional procedures such as balloon angioplasty or stenting. Local pharmacotherapeutic approaches using controlled release systems are under investigation to inhibit the regional pathophysiologic process of restenosis. We have been investigating biodegradable nanoparticles (100 +/- 39 nm in diameter, mean +/- sd) for the local intra-arterial drug delivery. The purpose of this study was to investigate nanoparticle surface modifications (see Table 1) to enhance their arterial uptake. The PLGA (polylactic polyglycolic acid copolymer) nanoparticles were formulated by an oil-in-water emulsion solvent evaporation technique using a 2-aminochromone (U-86983, Upjohn and Pharmacia) (U-86) as a model antiproliferative agent. The various formulations of nanoparticles were evaluated for the arterial wall uptake by using an ex-vivo dog femoral artery model. The selected formulations were then tested in vivo in acute dog femoral artery and pig coronary artery models. The nanoparticles surface modified with a cationic compound, didodecyldimethylammonium bromide (DMAB), demonstrated 7-10-fold greater arterial U-86 levels compared to the unmodified nanoparticles in different ex-vivo and in-vivo studies. The mean U-86 levels were 10.7 +/- 1.7 microg/10 mg (dog) and 6.6 +/- 0.6 microg/10 mg (pig) in the artery segments ( approximately 2 cm) which were infused with the nanoparticles. The pig coronary studies further demonstrated that the infusion of nanoparticles with higher U-86 loading reduced the arterial U-86 levels, whereas increasing the nanoparticle concentration in the infusion solutions increased the arterial U-86 levels. The biodistribution studies in pigs following coronary arterial administration of nanoparticles demonstrated disposition of U-86 in the myocardium and distally in the liver and the lung. The mechanism of enhanced arterial uptake of the DMAB surface modified nanoparticles seems to be due to the alteration in the nanoparticle surface charge. The unmodified nanoparticles had a zeta potential of -27.8 +/- 0.5 mV (mean +/- sem, n = 5), whereas the DMAB modified nanoparticles demonstrated a zeta potential of +22.1 +/- 3.2 mV (mean +/- sem, n = 5). The adsorption of DMAB to the nanoparticle surface followed the Freundlich isotherm with binding capacity k = 28.1 microg/mg and affinity constant p = 2. 33. In conclusion, surface modified nanoparticles have potential applications for intra-arterial drug delivery to localize therapeutic agents in the arterial wall to inhibit restenosis.
SummaryAn in vivo thromboplastin (TP)-induced venous stasis thrombosis model in rabbits was used to compare the efficacy of standard heparin with the selective factor Xa inhibitors, recombinant tick anticoagulant peptide (rTAP) and recombinant antistasin (rATS), in prophylactic prevention of thrombus formation. Heparin significantly reduced TP-induced clot formation at doses of 55 and 100 U kg−1 h−1 yielding clot weights of 9 ± 4 and 6 ± 2%, respectively. Clot formation was significantly decreased by i.v. infusions of rTAP at doses of 21, 37 and 64 Μg kg−1 min−1 resulting in normalized clot weights of 13 ± 3, 8 ± 2 and 2 ± 1%, respectively. rATS was approximately 10-fold more potent than rTAP, reducing normalized clot weights to 16 ± 5, 2 ± 1 and 1 ± 0.8% at rATS doses of 1.25, 2.5 and 5.0 Μg kg−1 min−1, respectively. These data suggest that factor Xa-mediated inhibition of coagulation with rTAP and rATS is as effective as conventional anticogulant treatment with heparin in preventing venous thrombosis.
This year approximately 1.5 million Americans will undergo a myocardial infarction (MI). Of those who make it to the hospital (approximately 1.2 million), only about 20% will receive thrombolytic therapy. Multiple factors contribute to this dismaying figure, but most of them are risk/benefit-related. Moreover, of those receiving lytic therapy, the coronary arteries of as many as one-third may not reopen, and of those that do undergo coronary thrombolysis, an unacceptable fraction will experience reocclusion acutely. Thus, despite significant progress, major challenges for antithrombotic and thrombolytic therapy remain. Promising results with aspirin provide some hope that the figures above can be altered favorably. Efforts are under way in industry and academia to develop drugs to accomplish one or more of the following: lower the incidence of MI, prevent the development of unstable angina or retard its progression to frank MI, increase the inclusion window for lytic therapy, raise the percentage of patients undergoing successful thrombolysis, and maintain coronary patency. During the period that thrombolytic agents have come into vogue important advances have been made in our understanding of platelet function, coagulation, and the endogenous fibrinolytic system. These have spurred the development of novel drugs, such as platelet fibrinogen receptor antagonists, plasminogen activators, and inhibitors of factor IIa (thrombin) and XIIIa. Evaluation of these agents for their antithrombotic or profibrinolytic activity requires relevant animal models of thrombosis. Despite appropriate concerns about their clinical relevance, these models bridge the wide gap between test tube assays of aggregation or coagulation and humans.
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