Improving long circulation and procoagulant platelet targeting by engineering of hirudin prodrug
Research article published in International journal of pharmaceutics (2020)
Abstract
To reduce systemic bleeding risks during anticoagulant treatment, a new concept named "precise anticoagulation" was proposed to localize the effects of anticoagulants via the targeted delivery of prodrugs to the coagulation site. In this study, the fusion protein Annexin V-hirudin 3-ABD (hAvHA) was constructed to achieve the prolonged circulation and targeted delivery of hirudin to coagulation sites. hAvHA was inactive as a prodrug, and it could bind to albumin during circulation. The drug was quickly activated via factor Xa-mediated cleavage once coagulation occurred, and hirudin was efficiently released to exert antithrombin activity in vitro. The hAvHA protein could be activated in mouse blood and exert significant anticoagulation effects. The results of FITC labeling illustrated that hAvHA bound to procoagulant platelets, suggesting the Annexin V modification permits targeted delivery to sites of thrombosis. hAvHA bound to albumin in vitro with an equilibrium dissociation constant of 8 pM, suggesting the ABD modification permitted prolonged circulation in vivo. Moreover, the bleeding time was much shorter in hAvHA-treated mice than in hirudin-treated mice. Therefore, our results suggested that that hAvHA is a potential and promising anticoagulant in vivo.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Resumen
Improving long circulation and procoagulant platelet targeting by engineering of hirudin prodrug.
Por qué esto importa para la hirudoterapia
Este estudio construyó una proteína de fusión, Annexin V-hirudina 3-ABD (hAvHA), como un profármaco diseñado para localizar la actividad anticoagulante de la hirudina en los sitios de trombosis. El profármaco se une a la albúmina para prolongar la circulación, se activa por la escisión mediada por el factor Xa en los sitios de coagulación y libera hirudina para inhibir la trombina; en ratones, hAvHA produjo una anticoagulación significativa con tiempos de sangrado más breves que la hirudina libre. Esto es relevante para ASH porque diseña la hirudina —el anticoagulante distintivo de la sanguijuela— como un terapéutico dirigido con una seguridad potencialmente mejorada. Matiz: el trabajo es preclínico (in vitro y modelos en ratones) y no involucra sanguijuelas vivas ni hirudoterapia.
Citación
Improving long circulation and procoagulant platelet targeting by engineering of hirudin prodrug
Han H et al. · International journal of pharmaceutics, 2020
Contexto clínico relacionado
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Añadido a la biblioteca ASH: May 27, 2026 · Última actualización del sitio: 18 de junio de 2026