APAC, a dual antiplatelet and anticoagulant - towards a local, vascular targeting antithrombotic
ISTH Academy. Lassila R. Jul 9, 2019; 264723; PB1534 Topic: Platelet Antagonists & Novel Therapeutics
Prof. Dr. Riitta Lassila
Prof. Dr. Riitta Lassila
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APAC, a Dual Antiplatelet and Anticoagulant: Towards a Local, Vascular Targeting Antithrombotic

R. Lassila1,2,3, A. Jouppila4
1Helsinki University Hospital, Comprehensive Cancer Center, Department of Hematology, Coagulation Disorders Unit and Laboratory Services, Helsinki, Finland, 2Helsinki University, Faculty of Medicine, Research Program in Oncology, Helsinki, Finland, 3Aplagon Ltd., Helsinki, Finland, 4Helsinki University Central Hospital Clinical Research Institute, Helsinki, Finland

Main Topic: Platelets and Megakaryocytes
Category: Platelet Antagonists & Novel Therapeutics

Background: APAC, developed as a mimic of heparin proteoglycans, has antiplatelet and anticoagulant action (collagen and thrombin) in several in vitro and vivo models (Semin Thromb Hemost, 2014). APAC alone inhibits both platelet and fibrin accumulation on collagen and tissue factor under a high shear rate (1000 1/s), and retained primary adhesion (Thromb Res, 2018). Moreover, APAC protects kidneys from ischemic reperfusion injury (Tuuminen et al. 2017).
Aims: We present APAC and its antithrombotic data on platelet aggregation and global coagulation in vitro, vascular targeting and antithrombotic role in vivo, including toxicology margins.
Methods: APAC was studied in platelet aggregation in response to collagen and ristocetin in whole blood (Multiplate), platelet-rich plasma (PRP) and in rotational thromboelastometry (ROTEM) compared with citrated blood and spiking. Porcine balloon and arterio-venous fistula sites were exposed to labelled APAC. Single and repeated dose toxicology of rodents and monkeys was assessed.
Results: APAC dose-dependently attenuates aggregation to collagen and ristocetin, unlike heparin, in citrated blood at 150 µg/mL by 58 ±15% (n=6) (mean ± SD) and by 25 ±2%, respectively. In PRP inhibition of collagen-induced aggregation was reached at 1 µg/mL by 55±31% to 30 µg/mL by 85±11% (n=9). APAC alone, also dose-dependently attenuated aggregation and ROTEM variables in whole blood. In ROTEM APAC alone (3-16 µg/mL) reduces INTEM, and acts as a broad platelet-dependent procoagulant. APAC co-localized with Von Willebrand Factor and laminin in porcine arterial injuries, but not with intact endothelium. Upon targeting vessels, APAC locally decreased platelet accumulation and overt thrombosis in a rat model of anastomosis, but retained at anastomosis sites despite high shear blood flow. Single and multiple (7-14 d) doses (3-20 mg/kg in monkeys and rodents) indicate wide safety without accumulation.
Conclusions: With APAC's unique profile, local integration and inhibition of platelet-mediated thrombosis may benefit vascular interventions.

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