Fibrinolytic compromise by simultaneous administration of site-directed inhibitors of thrombin

Newly developed synthetic and recombinant thrombin inhibitors possess strong anticoagulant effects. Despite these effects, interactions of these agents with enzymes in the fibrinolytic network result in the modulation of such proteases as t-PA, u-PA and streptokinase. The inhibitory spectrum of several thrombin inhibitors [D-Phe-Pro-Arg-H(GYKI 14166), D-MePhe-Pro-Arg-H(GYKI 14766), Boc-D-Phe-Pro-Arg-H (GYKI 14451), Ac-D-Phe-Pro-boroArg-OH (DuP 714), recombinant hirudin (r-Hir) and unfractionated porcine mucosal heparin complexed with antithrombin III (Heparin/AT-III)] was studied towards various serine proteases such as tissue plasminogen activator (t-PA), plasmin, plasminogen/streptokinase complex, urokinase and kallikrein. Aprotinin was also studied in the same systems as the thrombin inhibitors. All four tripeptide derivatives were found to inhibit t-PA, plasmin and plasminogen/streptokinase complex at micromolar concentrations (IC50: 0.57 mM-3.3 microM). Boc-D-Phe-Pro-Arg-H and Ac-D-Phe-Pro-boroArg-OH also inhibited urokinase, while Ac-D-Phe-Pro-boroArg-OH inhibited kallikrein as well (IC50: 0.15 mM-16 microM). In contrast, r-Hir and Heparin/AT-III did not inhibit any of these enzymes at millimolar concentrations (IC50 > or = 1 mM). Aprotinin inhibited plasmin, plasminogen/streptokinase complex and kallikrein at micromolar concentrations (IC50: 3.1-0.85 microM). In a rabbit thrombolysis model, where pre-formed clots are lysed by streptokinase, simultaneous administration of D-MePhe-Pro-Arg-H or Ac-D-Phe-Pro-boroArg-OH, at concentrations approximately 1 mumol/kg, i.v. resulted in complete inhibition of the fibrinolytic process. Aprotinin at 0.1 mumol/kg, i.v. produced similar inhibition. These results demonstrate that thrombin inhibitors may exert significant antiprotease actions against various fibrinolytic enzymes.

Resumen tomado de PubMed (NCBI) para el registro citado, en el idioma original. La versión de referencia es la de la publicación original.

El resumen se deja sin traducir para conservar la redacción original de los autores.

Synthetic tripeptide thrombin inhibitors inhibited t-PA, plasmin and, for some, urokinase or kallikrein at micromolar concentrations; two abolished streptokinase thrombolysis in rabbits, while recombinant hirudin and heparin/antithrombin III inhibited none of these fibrinolytic enzymes.

Explore cómo esta investigación se conecta con la práctica clínica

Más estudios revisados por pares en la categoría «Farmacología salival».

• Novel Leech Antimicrobial Peptides — Hirunipins — Kumar et al. (2025)
• Leech Salivary Proteome and Transcriptome: 434 Deduced Protein Sequences — Liu Z, Tong X, Su Y, et al. (2019)
• Medicinal Leech Draft Genome — Anticoagulant Gene Survey — Kvist S, Manzano-Marín A, de Carle D, Trontelj P, Siddall ME (2020)
• Effects of hirudotherapy on liver functions, lipid profile, and insulin sensitivity in rats with metabolic syndrome — Bilden A et al. (2026)
• Efficacy and Safety of Hirudotherapy for Improving Sperm Quality Parameters in Male Infertility: A Randomized Controlled Trial — Abtahi-Forooshani M et al. (2026)
• Medicinal leeches and hirudotherapy — Gödekmerdan A et al. (2011)
• PEROXIDATION OF SALIVA LIPIDS IN PATIENTS WITH POSTCOVID SYNDROME DURING HIRUDOTHERAPY — Serikbayeva S et al. (2024)
• Medicinal leech therapy in pain syndromes: a narrative review — Koeppen D, Aurich M, Rampp T (2014)
• Leech therapy in the treatment of a penile haematoma in a stallion — Nowicki A, Jaworska J, Baranski W (2021)
• Leech therapy (Hirudo medicinalis) attenuates testicular damages induced by testicular ischemia/reperfusion in an animal model — Davoodi F et al. (2021)

Ver toda la investigación analizada por la ASH →