# Escalating doses of intravenous APAC demonstrate antithrombotic effect in pigs

## TL;DR

This study shows that increasing doses of APAC safely reduce blood clotting in pigs, with effects that can be measured using standard tests.

## Contribution

The study demonstrates the safety and anticoagulant effects of escalating intravenous APAC doses in a large animal model.

## Key findings

- APAC was well-tolerated and did not significantly affect blood cell counts.
- APAC prolonged clotting times in a dose-dependent manner, similar to UFH but with faster reversal by protamine.
- At 0.75 mg/kg, APAC abolished thrombin generation and significantly reduced clot firmness.

## Abstract

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.

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).

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.

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.

The online version contains supplementary material available at 10.1186/s12959-025-00742-8.