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Background <p>Locally acting antiplatelet and anticoagulant (APAC) is developed as an antithrombotic agent for administration during vascular interventions and in thrombo-inflammatory conditions. APAC has entered human studies as a dual inhibitor of von Willebrand factor-mediated platelet recruitment on collagen and thrombin generation. We aimed to assess safety and escalating intravenous (i.v.) doses of APAC on hemostasis using a large animal model.</p> Methods <p>We studied escalating APAC boluses (0.15–1.5&#xa0;mg/kg; <i>n</i> = 11) and their reversal in anesthetized pigs for pharmacodynamics using functional coagulation testing. In some experiments, aspirin (500&#xa0;mg) was co-administered with APAC, and protamine sulfate for reversal. Blood was repeatedly sampled for blood cell counts (CBC), activated partial thromboplastin time (APTT), prothrombin and thrombin time (PT, TT), thrombin generation (TG), activated clotting time (ACT), rotational thromboelastometry (ROTEM), and collagen-induced platelet aggregation (CIPA).</p> Results <p>APAC was well-tolerated, and CBC remained stable. APAC modestly inhibited CIPA at high doses, while APTT, TT and ACT, unlike PT, prolonged dose-dependently. The anticoagulant ED<sub>50</sub> doses of APAC and UFH showed similar range (0.54 vs. 0.43&#xa0;mg/kg), but UFH lasted longer and was less reversible by protamine. At 0.75&#xa0;mg/kg of APAC, TG was abolished, InTEM coagulation and clot formation times were prolonged <i>≥</i> 2.8-fold, maximum clot firmness was reduced to 8–45%, and amplitude to 35–80%. APAC effects were transient (T<sub>1/2</sub> APAC = 30&#xa0;min), and reversible by protamine.</p> Conclusions <p>Escalating i.v. doses of APAC were safe and provided modest platelet inhibition.Our results indicate that the dose-dependent anticoagulation effects of APAC can be monitored using conventional laboratory assays.</p>

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Escalating doses of intravenous APAC demonstrate antithrombotic effect in pigs

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月4日

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  • Zsuzsa Bagoly,
  • Annukka Jouppila,
  • Rita Orbán-Kálmándi,
  • Linda Lóczi,
  • Dóra Bomberák,
  • Zsófia Anna Kádár,
  • Ádám Deák,
  • Ádám Mátrai,
  • Ildikó Beke Debreceni,
  • János Kappelmayer,
  • Norbert Németh,
  • Riitta Lassila

摘要

Background

Locally acting antiplatelet and anticoagulant (APAC) is developed as an antithrombotic agent for administration during vascular interventions and in thrombo-inflammatory conditions. APAC has entered human studies as a dual inhibitor of von Willebrand factor-mediated platelet recruitment on collagen and thrombin generation. We aimed to assess safety and escalating intravenous (i.v.) doses of APAC on hemostasis using a large animal model.

Methods

We studied escalating APAC boluses (0.15–1.5 mg/kg; n = 11) and their reversal in anesthetized pigs for pharmacodynamics using functional coagulation testing. In some experiments, aspirin (500 mg) was co-administered with APAC, and protamine sulfate for reversal. Blood was repeatedly sampled for blood cell counts (CBC), activated partial thromboplastin time (APTT), prothrombin and thrombin time (PT, TT), thrombin generation (TG), activated clotting time (ACT), rotational thromboelastometry (ROTEM), and collagen-induced platelet aggregation (CIPA).

Results

APAC was well-tolerated, and CBC remained stable. APAC modestly inhibited CIPA at high doses, while APTT, TT and ACT, unlike PT, prolonged dose-dependently. The anticoagulant ED50 doses of APAC and UFH showed similar range (0.54 vs. 0.43 mg/kg), but UFH lasted longer and was less reversible by protamine. At 0.75 mg/kg of APAC, TG was abolished, InTEM coagulation and clot formation times were prolonged ≥ 2.8-fold, maximum clot firmness was reduced to 8–45%, and amplitude to 35–80%. APAC effects were transient (T1/2 APAC = 30 min), and reversible by protamine.

Conclusions

Escalating i.v. doses of APAC were safe and provided modest platelet inhibition.Our results indicate that the dose-dependent anticoagulation effects of APAC can be monitored using conventional laboratory assays.