Amerikanische Gesellschaft für Hirudotherapie

A novel hirudin derivative inhibiting thrombin without bleeding for subcutaneous injection

Pharmacology study published in Thrombosis and Haemostasis (2016)

Zuletzt aktualisiert: June 18, 2026Geprüft von: ASH Editorial Board
Research article — evidence reviewArticle reference
Evidence: Observational studyArzneimittelentwicklungGenomik & ProteomikZhao B et al. · 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.

Publication typeComparative StudyJournal ArticleResearch Support, Non-U.S. Gov't
Indexed MeSH termsAnimalsAntithrombinsBlood CoagulationBlood Coagulation TestsChloridesCollagenDabigatranDisease Models, AnimalDose-Response Relationship, DrugEpinephrineFerric CompoundsHemorrhage

Zusammenfassung

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.

Warum dies für die Hirudotherapie relevant ist

This study designed and evaluated a novel direct thrombin inhibitor peptide (DTIP) using molecular simulation and homology modeling, with its C-terminus interacting with thrombin exosite I and N-terminus with the active site. DTIP interfered with thrombin-mediated coagulation in human, rat, and mouse plasma in vitro and, when administered subcutaneously to rats, showed dose-dependent extension of aPTT, PT, TT, and CT. DTIP prevented deep venous thrombosis, increased survival in a lethal pulmonary thromboembolism mouse model from 30% to 80% at 1.0 mg/kg, and induced significantly less bleeding than bivalirudin in rat tail transection assays. The abstract does not mention hirudin or any leech-derived source for DTIP, so a direct relevance to hirudotherapy or the leech secretome cannot be established from the abstract alone; these are preclinical findings from animal and in vitro models only, with no human studies reported.

Zitation

A novel hirudin derivative inhibiting thrombin without bleeding for subcutaneous injection.

Zhao B et al. · Thrombosis and Haemostasis, 2016

DOI

Verwandter klinischer Kontext

Erfahren Sie, wie diese Forschung mit der klinischen Praxis verknüpft ist

Drug PipelineDrug DevelopmentDirect Thrombin InhibitorsSpecies IdentificationTaxonomySalivary Gland SecretionHirudinAnticoagulation CompoundsBivalirudinOral AnticoagulantsHemostasisDermatological ApplicationsDermatologyOtolaryngologyPost-Thrombotic SyndromePulmonology

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