Modulating Platelet Function With Selective Thrombin Inhibitors

Verstraete, Marc

doi:10.1159/000217287

Cited by 11 publications

(14 citation statements)

References 17 publications

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“…After 30 min at 37°C, hirudin (0.5 unit/ml) was added to inactivate thrombin (14), and the platelet suspension was mixed with an equal volume of monocyte medium (PT medium); 2 ml of PT medium was transferred onto 2 ϫ 10 6 monocytes seeded in 10 ϫ 35-mm dishes (final platelet density, 10 8 /ml). After 1 h of incubation at 37°C, the supernatant was collected, centrifuged at 13,000 ϫ g for 3 min, and either used in autocrine/paracrine stimulation experiments (MPT medium) or extracted to determine the ABA content.…”

Section: Determination Of Intracellular Camp ([Camp] I ) and [Cadpr] mentioning

confidence: 99%

Abscisic Acid Released by Human Monocytes Activates Monocytes and Vascular Smooth Muscle Cell Responses Involved in Atherogenesis

Magnone

Bruzzone²,

Guida³

et al. 2009

Journal of Biological Chemistry

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Abscisic acid (ABA) is a phytohormone recently identified as a new endogenous pro-inflammatory hormone in human granulocytes. Here we report the functional activation of human monocytes and vascular smooth muscle cells by ABA. Incubation of monocytes with ABA evokes an intracellular Ca 2؉ rise through the second messenger cyclic ADP-ribose, leading to NF-B activation and consequent increase of cyclooxygenase-2 expression and prostaglandin E 2 production and enhanced release of MCP-1 (monocyte chemoattractant protein-1) and of metalloprotease-9, all events reportedly involved in atherogenesis. Moreover, monocytes release ABA when exposed to thrombin-activated platelets, a condition occurring at the injured vascular endothelium; monocyte-derived ABA behaves as an autocrine and paracrine pro-inflammatory hormone-stimulating monocyte migration and MCP-1 release, as well as vascular smooth muscle cells migration and proliferation. These results, and the presence of ABA in human arterial plaques at a 10-fold higher concentration compared with normal arterial tissue, identify ABA as a new signal molecule involved in the development of atherosclerosis and suggest a possible new target for anti-atherosclerotic therapy. ABA2 is an isoprenoid phytohormone regulating several physiological functions in Metaphyta, including response to abiotic stress (1), and in lower Metazoa, where ABA mediates temperature-induced oxygen consumption and water filtration in sponges (2) Monocytes play a key role in both inflammation and immunity by performing antigen presentation, phagocytosis, and immunomodulation through the production of various cytokines and growth factors (6). In atherosclerosis, a chronic immune inflammatory disease, the interaction between monocytes, platelets, and injured luminal endothelium is a crucial event leading to the atherosclerotic lesion of the arterial intima (7,8). Platelets trigger atherogenesis through adhesion to damaged endothelial cells and release of pro-inflammatory mediators, recruiting circulating monocytes to the site of the lesion (9). Monocytes attach to and penetrate the vessel wall, where they undergo transformation into macrophages and eventually into foam cells (10). At the site of the atherosclerotic lesion, monocytes/macrophages, platelets, and endothelial cells release chemoattractants, growth factors, and cytokines, which stimulate VSMC proliferation and migration into the sub-endothelium. Thrombus organization, extracellular matrix synthesis, and VSMC proliferation eventually lead to the development of the atheromatous plaque (7-10). Here we investigate the effect of ABA on human monocytes and VSMC and its possible role in the activation of cell responses known to be responsible for atherogenesis.

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Section: Determination Of Intracellular Camp ([Camp] I ) and [Cadpr] mentioning

confidence: 99%

Abscisic Acid Released by Human Monocytes Activates Monocytes and Vascular Smooth Muscle Cell Responses Involved in Atherogenesis

Magnone

Bruzzone²,

Guida³

et al. 2009

Journal of Biological Chemistry

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“…GYKI-14766 (5) (efegatran, Ki ¼ 1.2 nM) is in clinical trials and is administered parenterally. 40,41 CVS-1123 (6) is orally administered and is also in clinical trials. 39 Ketocarboxamides (7) (Ki ¼ 0.48 nM) 42,43 also shows high affinity for the enzyme.…”

Section: B Reversible Covalent Thrombin Inhibitorsmentioning

confidence: 99%

Progress in the design of low molecular weight thrombin inhibitors

2005

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Intravascular thrombosis and its complication, embolism, is a leading cause of morbidity and mortality throughout the world. Past few decades have seen a great deal of progress in the development of antithrombotic agents, though the current treatment options are limited to heparin, LMW heparins, and warfarin. Detailed understanding of the biochemical and biophysical mechanisms of activation and regulation of blood coagulation have helped in developing specific inhibitors of enzymes, especially thrombin, within the coagulation cascade. Thrombin plays a central role in the coagulation cascade and so has become the primary target for the development of antithrombotic drugs. The review covers the main pharmacological aspects of haemostasis and thrombosis and provides an update on low molecular weight thrombin inhibitors along with the limitations of the prevalent antithrombotic agents. Recent developments in small molecule inhibitors of Protease Activated Receptor-1 (PAR-1) which can be helpful for the treatment of thrombotic and vascular proliferative disorders, have also been discussed.

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“…In PRP there is an extra effect on platelet activation by traces of thrombin during the lag phase [3,32].…”

Section: Thrombin Generation As a Pharmacological Probementioning

confidence: 99%

On the Coagulation of Platelet-Rich Plasma

Béguin

Keularts²

1999

Pathophysiol Haemos Thromb

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Thrombin formation and blood platelet reactions are intimately linked in haemostasis and in thrombosis. In vivo, procoagulant phospholipids required for the coagulation mechanism are mainly provided by activated platelets, and thrombin is the most potent platelet activator. To study these interactions, an ancient tool of coagulation physiology, the thrombin generation test, was revived and the results obtained were reviewed. The amount of thrombin activity that develops, expressed as the endogenous thrombin potential (the area under the thrombin generation curve), is influenced by the clotting factors (except XII and XIII), the activated protein C system and natural inhibitors on the one hand and by platelet activity on the other. The platelet reactions that we found to be involved are induced by thrombin via glycoprotein (GP) IIb/IIIa activation and by fibrin via interaction with GPIb. von Willebrand factor is crucial in both reactions and therefore an obligatory factor for normal thrombin generation in the presence of platelets. All antithrombotics, be it anticoagulants (e.g. OAC, all heparins or hirudin) or antiplatelet drugs (aspirin, GPIIb/IIIa blockers) diminish thrombin generation.

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Modulating Platelet Function With Selective Thrombin Inhibitors

Cited by 11 publications

References 17 publications

Abscisic Acid Released by Human Monocytes Activates Monocytes and Vascular Smooth Muscle Cell Responses Involved in Atherogenesis

Abscisic Acid Released by Human Monocytes Activates Monocytes and Vascular Smooth Muscle Cell Responses Involved in Atherogenesis

Progress in the design of low molecular weight thrombin inhibitors

On the Coagulation of Platelet-Rich Plasma

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