The Direct Thrombin Inhibitors Dabigatran and Lepirudin Inhibit GPIbalpha-Mediated Platelet Aggregation

The direct thrombin inhibitor (DTI) dabigatran is a non-vitamin K antagonist oral anticoagulant for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. In addition to its anti-thrombotic efficacy, dabigatran has been suggested to exert some pro-thrombotic effect due to fostering the ligation of thrombin to its high affinity platelet receptor glycoprotein (GP) Ibα in patients with atrial fibrillation. On the other hand, we provided evidence that a member of another class of DTIs, lepirudin, stimulates the inhibitory cyclic guanosine monophosphate (cGMP)/soluble guanylate cyclase pathway in human platelets. Here, we investigated the effect of lepirudin and dabigatran spiked to platelets from healthy volunteers on GPIbα-mediated platelet aggregation and agglutination. Ristocetin/von Willebrand factor (vWF)-induced aggregation of platelets in the presence or absence of plasma was significantly inhibited by lepirudin, dabigatran and D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK). However, ristocetin/vWF-mediated platelet agglutination and binding of vWF to platelets were not affected by the DTIs. The anti-aggregatory effect was confirmed by using the GPIbα-specific agonist echicetin beads for human and murine platelets. DTIs diminished echicetin beads-induced Syk Y352 phosphorylation (used here as readout for an early signal occurring during echicetin-induced platelet aggregation), but did not inhibit adenosine diphosphate- or thromboxane A2-induced platelet aggregation. Thrombin was not generated in response to ristocetin/vWF or echicetin beads and therefore did not explain the inhibitory effect of the DTIs. Therapeutic concentration of lepirudin and dabigatran did not affect significantly platelet vasodilator-stimulated phosphoprotein S239 phosphorylation or cGMP and cyclic adenosine monophosphate levels. These data suggest that the DTIs, lepirudin and dabigatran, impair platelet activation measured during platelet aggregation induced by ristocetin/vWF or echicetin beads.

Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.

Direct thrombin inhibitors lepirudin and dabigatran inhibit ristocetin/vWF-induced platelet aggregation through GPIbalpha, with implications for an under-appreciated antiplatelet mechanism beyond thrombin inhibition.

Leech-derived molecules this paper discusses, each with a full profile in the ASH compound registry:

Explore cómo esta investigación se conecta con la práctica clínica

More peer-reviewed studies in Desarrollo de fármacos.

• Novel Leech Antimicrobial Peptides — Hirunipins — Kumar et al. (2025)
• Medicinal Leech Genome Assembly — Anticoagulant Gene Catalog — Kvist et al. (2020)
• Effects of hirudotherapy on liver functions, lipid profile, and insulin sensitivity in rats with metabolic syndrome — Bilden A et al. (2026)
• Hirudotherapy in Medicine and Dentistry — Jha K et al. (2015)
• Medicinal leech therapy (hirudotherapy): a brief overview — Singh A (2010)
• HIRUDOTHERAPY IN PRESBYACUZIS PRAECOX IN CLEAN-UP WORKERS AFTER THE CHORNOBYL ACCIDENT DURING THE POST-CATASTROPHE YEARS — Zabolotnyi D, Mishchanchuk N (2019)
• Investigation of oxidant-antioxidant status in patients treated with hirudotherapy: an experimental study — Sarikan I, Savas H (2024)
• Leech therapeutic applications — Abdualkader A et al. (2013)
• Non-Occlusive Mesenteric Ischemia Due to Hirudotherapy: A Case Report — Akalın Ç, Ekmen N (2020)
• Leech therapy: a history — Hyson J (2005)

Browse all ASH-analysed research →