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Thrombin Inhibition (thrombin + inhibition)

Distribution by Scientific Domains

Medical Sciences	80%

Selected Abstracts

Current Update on Glycoprotein IIb-IIIa and Direct Thrombin Inhibition in Percutaneous Coronary Intervention for Non-ST Elevation Acute Coronary Syndromes: Balancing Bleeding Risk and Antiplatelet Efficacy

JOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 2 2008
ANDREW T. KWA M.D.
Appropriate pharmacologic treatment for patients with acute coronary syndromes (ACS) remains a matter of controversy. Additionally, a substantial gap exists between recommended guidelines and current clinical practice. Questions remain regarding which antiplatelet/antithrombotic treatment strategies are appropriate for individual patients, based on their risk. We explore the role of glycoprotein IIb-IIIa inhibitors and the direct thrombin inhibitor bivalirudin in ACS patients, and consider the difficulties involved in reducing ischemic events while limiting bleeding risks. In patients with ACS who are undergoing percutaneous coronary intervention, high levels of microembolization and myocardial necrosis are potential risk factors for adverse long-term outcomes. Intensive antiplatelet/antithrombotic regimens may substantially affect these factors. Determination of risk levels, with the goal of targeting aggressive antithrombotic and interventional therapies to patients at higher risk, will help physicians choose appropriate pharmacologic therapy for patients with ACS. [source]

The effects of vasoactive agents, platelet agonists and anticoagulation on thrombelastography

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 9 2007
J. Kawasaki
Background:, Platelet activation is a critical step in primary hemostasis and clot formation. We tested a hypothesis that platelet stimulating effects of vasoactive agents or platelet agonists could be shown using thrombelastography (TEG®) as faster onset or increased clot strength. We further examined if TEG® could be modified to evaluate activated platelets as a reversal of anticoagulation in the presence of partial thrombin inhibition. Methods:, Blood samples were obtained from 126 non-cardiac surgical patients. Effects of vasoactive agents on TEG® and aggregometry were examined using epinephrine, norepinephrine, vasopressin, desmopressin acetate, milrinone and olprinone (Experiment I). Platelet agonists (epinephrine, ADP and collagen) were separately tested on TEG® (Experiment II). Effects of platelet agonists (ADP and collagen) on TEG® under anticoagulation in the absence or presence of abciximab were studied (Experiment III). We also tested antiplatelet effects of milrinone and olprinone in the presence of anticoagulants on TEG® (Experiment IV). Results:, Neither vasoactive agents nor platelet agonists affected TEG® or aggregometry results except for milrinone and olprinone on aggregometry (Experiment I, II). Platelet agonists facilitated clotting in the presence of anticoagulants (Experiment III). Abciximab-treated platelets still exhibited procoagulant effects in the presence of heparin, while not in the presence of argatroban (Experiment III). Platelet inhibition on the modified TEG® was more extensive with milrinone than olprinone, and it was dose dependent (Experiment IV). Conclusion:, Modified TEG® using heparin or argatroban might delineate the procoagulant effects of platelets by adding platelet specific agonist. [source]

Complementary roles of platelets and coagulation in thrombus formation on plaques acutely ruptured by targeted ultrasound treatment: a novel intravital model

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2009
M. J. E. KUIJPERS
Summary.,Background:,Atherothrombosis is a major cause of cardiovascular events. However, animal models to study this process are scarce. Objectives:,We describe the first murine model of acute thrombus formation upon plaque rupture to study atherothrombosis by intravital fluorescence microscopy. Methods:,Localized rupture of an atherosclerotic plaque in a carotid artery from Apoe,/, mice was induced in vivo using ultrasound. Rupture of the plaque and formation of localized thrombi were verified by two-photon laser scanning microscopy (TPLSM) in isolated arteries, and by immunohistochemistry. The thrombotic reaction was quantified by intravital fluorescence microscopy. Results:,Inspection of the ultrasound-treated plaques by histochemistry and TPLSM demonstrated local damage, collagen exposure, luminal thrombus formation as well as intra-plaque intrusion of erythrocytes and fibrin. Ultrasound treatment of healthy carotid arteries resulted in endothelial damage and limited platelet adhesion. Real-time intravital fluorescence microscopy demonstrated rapid platelet deposition on plaques and formation of a single thrombus that remained subocclusive. The thrombotic process was antagonized by thrombin inhibition, or by blocking of collagen or adenosine diphosphate receptor pathways. Multiple thrombi were formed in 70% of mice lacking CD40L. Conclusions:,Targeted rupture of murine plaques results in collagen exposure and non-occlusive thrombus formation. The thrombotic process relies on platelet activation as well as on thrombin generation and coagulation, and is sensitive to established and novel antithrombotic medication. This model provides new possibilities to study atherothrombosis in vivo. [source]

Both ADP and Thrombin Regulate Arteriolar Thrombus Stabilization and Embolization, but Are Not Involved in Initial Hemostasis as Induced by Micropuncture

MICROCIRCULATION, Issue 3 2007
Miriam A. Van Gestel
ABSTRACT Objective: Thrombosis and embolization are main causes of morbidity and mortality. Up to now, the relative importance of mediators involved is only partly known. It was the aim of this study to investigate the involvement of ADP and thrombin in subsequent phases of arteriolar hemostasis and thromboembolism in vivo. Methods: Rabbit mesenteric arterioles were punctured, which induced bleeding, hemostasis, and subsequent thromboembolism. This reaction as well as the activation state of platelets involved ([Ca2 +]i), was monitored in real time by intravital (fluorescence) microscopy. Results: Neither inhibition of thrombin formation or thrombin activity nor blockade of platelet ADP receptors P2Y1 and P2Y12 influenced the initial hemostatic reaction: in all experiments initial bleeding was stopped by a primary thrombus within 2,3 s. On the other hand, both thrombin inhibition and P2Y1 blockade increased rebleeding frequency, which indicates reduced thrombus stability in the long term. Finally, inhibition of either thrombin or ADP (via both receptors) reduced aggregate formation during the embolization phase by at least 90%. While most participating platelets exhibited a transient increase in [Ca2 +]i during embolization, an increased percentage of platelets showed no calcium response at all during P2Y1 blockade, which was accompanied by reduced platelet,platelet interaction strength. Conclusions: Whereas thrombin and ADP are not involved in the initial hemostatic reaction, both substances appear to be essential to prevent rebleedings in the long term. During subsequent embolization, ADP (via both receptors) and small amounts of thrombin are involved in platelet activation. [source]

Structure of human factor VIIa/tissue factor in complex with a peptide-mimetic inhibitor: high selectivity against thrombin by introducing two charged groups in P2 and P4

ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 2 2005
Shojiro Kadono
The crystal structure of human factor VIIa/soluble tissue factor (FVIIa/sTF) in complex with a highly selective peptide-mimetic FVIIa inhibitor which shows 1670-fold selectivity against thrombin inhibition has been solved at 2.6,Å resolution. The inhibitor is bound to FVIIa/sTF at the S1, S2 and S3 sites and at the additional S1 subsite. Two charged groups, the amidino group in P2 and the carboxylate group in P4, form ionic interactions with Asp60 and Lys192 of FVIIa, respectively. Structural comparisons between factor VIIa and thrombin show that thrombin has oppositely charged residues, Lys60F and Glu192, in the S2 site and the S1 subsites, respectively. These data suggest that the utilization of the differences of charge distribution in the S2 site and the S1 subsites between FVIIa and thrombin is critical for achieving high selectivity against thrombin inhibition. These results will provide valuable information for the structure-based drug design of specific inhibitors for FVIIa/TF. [source]