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Effect of low and high dose melagatran and other antithrombotic drugs on platelet aggregation
Journal article   Peer reviewed

Effect of low and high dose melagatran and other antithrombotic drugs on platelet aggregation

Gerald Soslau, Aimee Ando, LaToya Floyd, Tom Hong, Lynn Mathew and Yvonne Yen
Journal of thrombosis and thrombolysis, v 25(2), pp 198-203
2008
DOI: https://doi.org/10.1007/s11239-007-0085-x
PMID: 17710375
Featured in Collection :   UN Sustainable Development Goals @ Drexel

Abstract

Article Cardiology Hematology Medicine Medicine & Public Health
Background Thrombin-induced aggregation of human platelets can be completely inhibited by melagatran, the bioactive form of ximelagatran, an oral direct thrombin inhibitor. Methods The potential of melagatran to differentially inhibit α- and γ-thrombins was tested with a synthetic thrombin substrate. Washed human platelets were also employed to determine if melagatran differentially inhibited α- and γ-thrombin-induced platelet aggregation at distinct platelet thrombin receptors. In vitro studies were conducted with washed human platelets to determine thrombin-induced aggregation responses in the presence of varying doses of the anti-thrombotic drugs: melagatran, argatroban, heparin, and hirudin. Results Melagatran rapidly inhibits the hydrolysis of a thrombin chromogenic substrate within 0–1 min with α-, β- and γ-thrombin being equally inhibited by high dose melagatran while α-thrombin was significantly more sensitive at low doses. The maximum level of melagatran inhibition of α- and γ-thrombin-induced platelet aggregation requires platelets to be pre-incubated with the drug for 10–30 min. Melagatran appears to have no direct effect on the PAR-1 receptor. It does appear to have a direct effect on the GPIbα thrombin receptor activity as well as the PAR-4 receptor. Inhibition of platelet aggregation is dose dependent, however, at low melagatran doses (0.01–0.04 nM) platelets aggregate at significantly ( P  < 0.05) higher levels. The lower the level of thrombin-induced aggregation that was observed with control samples (aggregations from 10% to 39%), corresponded with a higher observed melagatran-induced stimulation with drug-treated platelets. The range of stimulation varies between several hundred percent at ∼10% aggregation to around 20% at about 20–39% aggregation. Preliminary studies indicate that this in vitro stimulatory effect is abrogated in platelets derived from volunteers who took aspirin (81 mg/day) for 7 days. Three other anti-thrombotic drugs, argatroban, heparin and hirudin, were tested with low drug levels but none were found to consistently stimulate the reaction. Conclusions These results indicate that melagatran acts as both a direct thrombin inhibitor and indirectly by some interaction with the platelet membrane. While melagatran has been withdrawn from clinical use, its ability to differentially inhibit γ-thrombin/PAR-4 versus α-thrombin/PAR-1 at low doses may warrant it, or less toxic analogs to be used in the future for as yet unknown disease states involving PAR-4.

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Web of Science research areas
Cardiac & Cardiovascular Systems
Hematology
Peripheral Vascular Disease
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