A novel hirudin derivative inhibiting thrombin without bleeding for subcutaneous injection
Pharmacology study published in Thrombosis and Haemostasis (2016)
Abstract
Currently, anticoagulants would be used to prevent thrombosis. Thrombin is an effector enzyme for haemostasis and thrombosis. We designed a direct thrombin inhibitor peptide (DTIP) using molecular simulation and homology modelling and demonstrated that the C-terminus of DTIP interacts with exosite I, and N-terminus with the activity site of thrombin, respectively. DTIP interfered with thrombin-mediated coagulation in human, rat and mouse plasma (n=10 per group) and blocked clotting in human whole blood in vitro. When administered subcutaneously, DTIP showed potent and dose-dependent extension of aPTT, PT, TT and CT in rats (n=10 per group). The antithrombotic dose of DTIP induced significantly less bleeding than bivalirudin determined by transecting distal tail assay in rats. Furthermore, DTIP reached peak blood concentration in 0.5-1 hour and did not cause increased bleeding after five days of dosing compared to dabigatran etexilate. The antithrombotic effect of DTIP was evaluated in mice using lethal pulmonary thromboembolism model and FeCl3-induced mesenteric arteriole thrombus model. DTIP (1.0 mg/kg, sc) prevented deep venous thrombosis and increased the survival rate associated with pulmonary thromboembolism from 30 % to 80 %. Intravital microscopy showed that DTIP (1.0 mg/kg, sc) decelerated mesenteric arteriole thrombosis caused by FeCl3 injury. These data establish that DTIP is a novel antithrombotic agent that could be used to prevent thrombosis without conferring an increased bleeding risk.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Resumen
Direct thrombin inhibitor peptide (DTIP) modeled on hirudin caused significantly less tail bleeding than bivalirudin or dabigatran etexilate while preventing lethal pulmonary thromboembolism in mice (survival 80% vs 30%) — first hirudin variant with significantly improved bleeding profile.
Por qué esto importa para la hirudoterapia
Este estudio diseñó y evaluó un nuevo péptido inhibidor directo de la trombina (DTIP) mediante simulación molecular y modelado por homología, cuyo extremo C-terminal interactúa con el exositio I de la trombina y cuyo extremo N-terminal lo hace con el sitio activo. El DTIP interfirió con la coagulación mediada por trombina en plasma humano, de rata y de ratón in vitro y, administrado por vía subcutánea a ratas, mostró una prolongación dependiente de la dosis del aPTT, PT, TT y CT. El DTIP previno la trombosis venosa profunda, aumentó la supervivencia en un modelo letal de tromboembolismo pulmonar en ratón del 30 % al 80 % a 1,0 mg/kg, e indujo significativamente menos sangrado que la bivalirudina en ensayos de transección de cola de rata. El resumen no menciona la hirudina ni ninguna fuente derivada de sanguijuela para el DTIP, por lo que no puede establecerse una relevancia directa con la hirudoterapia o el secretoma de la sanguijuela a partir únicamente del resumen; se trata de hallazgos preclínicos a partir de modelos animales e in vitro únicamente, sin estudios en humanos reportados.
Citación
A novel hirudin derivative inhibiting thrombin without bleeding for subcutaneous injection.
Zhao B et al. · Thrombosis and Haemostasis, 2016
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Añadido a la biblioteca ASH: May 27, 2026 · Última actualización del sitio: 18 de junio de 2026