Intravenously administered APAC, a dual AntiPlatelet AntiCoagulant, targets arterial injury site to inhibit platelet thrombus formation and tissue factor activity in mice

Nicole R Bonetti; Annukka S Jouppila; Seyed Soheil Saeedi Saravi; Brian C Cooley; Lisa Pasterk; Luca L Liberale; Sara Gobbato; Thomas F Lüscher; Giovanni G Camici; Riitta P Lassila; Jürg H Beer

doi:10.1016/j.thromres.2023.04.010

Intravenously administered APAC, a dual AntiPlatelet AntiCoagulant, targets arterial injury site to inhibit platelet thrombus formation and tissue factor activity in mice

Thromb Res. 2023 Aug:228:163-171. doi: 10.1016/j.thromres.2023.04.010. Epub 2023 Apr 25.

Affiliations

¹ Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland; Department of Internal Medicine, Cantonal Hospital Baden, Switzerland.
² Helsinki University Hospital Clinical Research Institute, Helsinki, Finland.
³ Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
⁴ Department of Pathology and Laboratory Medicine, Animal Surgery Core Lab, McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
⁵ Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
⁶ Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland; First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy.
⁷ Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland; Royal Brompton and Harefield Hospital Trusts and National Heart and Lung Institute, Imperial College, London, UK.
⁸ Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland; University Heart Center, University Hospital Zurich, Switzerland; Department of Research and Education, University Hospital Zurich, Switzerland.
⁹ Coagulation Disorders Unit, University of Helsinki and Departments of Hematology and Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland; Helsinki University, Faculty of Medicine, Research Program in Systems Oncology, Helsinki, Finland; Aplagon Ltd., Helsinki, Finland. Electronic address: riitta.lassila@kolumbus.fi.

PMID: 37331119
DOI: 10.1016/j.thromres.2023.04.010

Abstract

Introduction: Arterial thrombosis is the main underlying mechanism of acute atherothrombosis. Combined antiplatelet and anticoagulant regimens prevent thrombosis but increase bleeding rates. Mast cell-derived heparin proteoglycans have local antithrombotic properties, and their semisynthetic dual AntiPlatelet and AntiCoagulant (APAC) mimetic may provide a new efficacious and safe tool for arterial thrombosis. We investigated the in vivo impact of intravenous APAC (0.3-0.5 mg/kg; doses chosen according to pharmacokinetic studies) in two mouse models of arterial thrombosis and the in vitro actions in mouse platelets and plasma.

Materials and methods: Platelet function and coagulation were studied with light transmission aggregometry and clotting times. Carotid arterial thrombosis was induced either by photochemical injury or surgically exposing vascular collagen after infusion of APAC, UFH or vehicle. Time to occlusion, targeting of APAC to the vascular injury site and platelet deposition on these sites were assessed by intra-vital imaging. Tissue factor activity (TF) of the carotid artery and in plasma was captured.

Results: APAC inhibited platelet responsiveness to agonist stimulation (collagen and ADP) and prolonged APTT and thrombin time. After photochemical carotid injury, APAC-treatment prolonged times to occlusion in comparison with UFH or vehicle, and decreased TF both in carotid lysates and plasma. Upon binding from circulation to vascular collagen-exposing injury sites, APAC reduced the in situ platelet deposition.

Conclusions: Intravenous APAC targets arterial injury sites to exert local dual antiplatelet and anticoagulant actions and attenuates thrombosis upon carotid injuries in mice. Systemic APAC provides local efficacy, highlighting APAC as a novel antithrombotic to reduce cardiovascular complications.

Keywords: APAC; Anticoagulant; Antiplatelet; Thrombosis; Tissue factor.

MeSH terms

Animals
Anticoagulants / chemistry
Anticoagulants / pharmacology
Anticoagulants / therapeutic use
Carotid Artery Thrombosis* / drug therapy
Collagen / pharmacology
Fibrinolytic Agents / therapeutic use
Mice
Platelet Aggregation
Platelet Aggregation Inhibitors / pharmacology
Platelet Aggregation Inhibitors / therapeutic use
Thromboplastin
Thrombosis* / etiology
Vascular System Injuries*

Substances

Anticoagulants
Thromboplastin
Platelet Aggregation Inhibitors
Fibrinolytic Agents
Collagen