Abstract Number: PB0767
Meeting: ISTH 2020 Congress
Background: Polyamidoamine (PAMAM) dendrimers are a new class of monodisperse polymers used for systemic drug delivery. A key enzyme in the fibrinolysis system, plasmin, dissolving clot fibrin, is formed upon plasminogen activation by tissue plasminogen activator (tPA) and urokinase (uPA). Native Glu-plasminogen (Glu-Pg) adopts closed conformation in the presence of Cl–. Glu-Pg without Cl– and Lys-Pg adopt relaxed conformation. We recently discovered that anionic PAMAM dendrimers inhibit Glu-Pg activation by tPA.
Aims: Clarify the mechanism of the inhibitory effect of PAMAM-COOH dendrimers on the fibrinolysis system activity.
Methods: The concentration effects of dendrimers on intrinsic activities of plasmin, tPA and uPA, on fluorescent spectra of Glu-Pg and Lys-Pg, on the plasminogen activation rate with tPA and uPA, and on plasma clots lysis induced by two activators were studied.
Results: With increasing generation (G1.5-G3.5) and concentration of dendrimers, amidolytic activity of plasmin practically did not change, while tPA and uPA lost intrinsic activity by a maximum of 13 and 30%, respectively, at 300 µM dendrimer G3.5. The fluorescence spectrum peak (340 nm) of Glu-Pg and Lys-Pg (λexc 280 nm) decreased with increasing dendrimers concentration of both in the absence and in the presence of Cl–. Consequently, dendrimers and Cl–, binding to different centers of Glu-Pg, independently change the conformation of open and relaxed forms of zymogen. Sharp decrease in the Glu-Pg activation rate with tPA and uPA was caused by G2.5 and G3.5 dendrimers (by 95-99% at 300 µM derdrimers), and the additing 60 µM soluble fibrin weakened the inhibitory effect of dendrimers. Plasma clot lysis induced by tPA and uPA was inhibited by dendrimers to a lesser extent than Glu-Pg activation.
Conclusions: Mechanism of antifibrinolytic action of PAMAM-COOH dendrimers consists mainly in changing the Glu-Pg conformation and, partially, in reducing the tPA and uPA activity after their binding to dendrimers.
To cite this abstract in AMA style:Aisina R, Mukhametova L, Ivanova E. The Mechanism of Antifibrinolytic Action of Anionic Polyamidoamine Dendrimers [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/the-mechanism-of-antifibrinolytic-action-of-anionic-polyamidoamine-dendrimers/. Accessed March 3, 2021.
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