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 While melagatran has been withdrawn from clinical use, its ability to differentially inhibit γ-thrombin/PAR-4 versus α-thrombin/PAR-1 at low doses may warrant it, or less toxic analogs to be used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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We would like to thank Dr Christer Mattsson for his advice and support in these studies. The work was supported by a grant from AstraZeneca.
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Soslau, G., Ando, A., Floyd, L. et al. Effect of low and high dose melagatran and other antithrombotic drugs on platelet aggregation. J Thromb Thrombolysis 25, 198–203 (2008). https://doi.org/10.1007/s11239-007-0085-x
- In vitro
- Platelet aggregation