Key result
Tipiracil hydrochloride dramatically inhibited thrombosis without inducing significant bleeding in mice, demonstrating a lower bleeding risk compared with aspirin and clopidogrel.
Why the study?
Current antiplatelet medications increase the risk of bleeding, creating a clinical need for novel mechanism-based antiplatelet drugs.
Does tipiracil hydrochloride attenuate thrombosis without increasing bleeding risk in mouse models?
Does tipiracil hydrochloride attenuate thrombosis without increasing bleeding risk in mouse models?
Tipiracil hydrochloride, a selective TYMP inhibitor, effectively attenuates thrombosis without increasing bleeding risk in preclinical mouse models, suggesting its potential as a novel antithrombotic therapy.
Hypothesis-generating for TYMP inhibition as a low-bleeding antithrombotic; leaves open translation to human trials.
OBJECTIVE: Current antiplatelet medications increase the risk of bleeding, which leads to a clear clinical need in developing novel mechanism-based antiplatelet drugs. TYMP (Thymidine phosphorylase), a cytoplasm protein that is highly expressed in platelets, facilitates multiple agonist-induced platelet activation, and enhances thrombosis. Tipiracil hydrochloride (TPI), a selective TYMP inhibitor, has been approved by the Food and Drug Administration for clinical use. We tested the hypothesis that TPI is a safe antithrombotic medication. Approach and Results: By coexpression of TYMP and Lyn, GST (glutathione S-transferase) tagged Lyn-SH3 domain or Lyn-SH2 domain, we showed the direct evidence that TYMP binds to Lyn through both SH3 and SH2 domains, and TPI diminished the binding. TYMP deficiency significantly inhibits thrombosis in vivo in both sexes. Pretreatment of platelets with TPI rapidly inhibited collagen- and ADP-induced platelet aggregation. Under either normal or hyperlipidemic conditions, treating wild-type mice with TPI via intraperitoneal injection, intravenous injection, or gavage feeding dramatically inhibited thrombosis without inducing significant bleeding. Even at high doses, TPI has a lower bleeding side effect compared with aspirin and clopidogrel. Intravenous delivery of TPI alone or combined with tissue plasminogen activator dramatically inhibited thrombosis. Dual administration of a very low dose of aspirin and TPI, which had no antithrombotic effects when used alone, significantly inhibited thrombosis without disturbing hemostasis. CONCLUSIONS: This study demonstrated that inhibition of TYMP, a cytoplasmic protein, attenuated multiple signaling pathways that mediate platelet activation, aggregation, and thrombosis. TPI can be used as a novel antithrombotic medication without the increase in risk of bleeding.
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Belcher et al. (2020) studied Thrombosis. Tipiracil hydrochloride (TPI) vs. Aspirin and clopidogrel was evaluated on Thrombosis and bleeding. Tipiracil hydrochloride dramatically inhibited thrombosis without inducing significant bleeding in mice, demonstrating a lower bleeding risk compared with aspirin and clopidogrel.
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