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The Mechanism of Antifibrinolytic Action of Anionic Polyamidoamine Dendrimers

R. Aisina1, L. Mukhametova1,2, E. Ivanova1

1Lomonosov Moscow State University, Chemistry Faculty, Moscow, Russian Federation, 2Bauman Moscow State Technical University, Moscow, Russian Federation

Abstract Number: PB0767

Meeting: ISTH 2020 Congress

Theme: Fibrinolysis and Proteolysis » Thrombolytic Therapy

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 October 1, 2023.

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