PB1082 - Comprehensive coagulation activity assessments of escalating doses of intravenous APAC, a heparin proteoglycan mimic, in pigs

Tuesday, June 27, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Annukka Jouppila, MSc

Research Scientist
Clinical Research Institute HUCH
Helsinki, Uusimaa, Finland

Co-Author(s)

Zsuzsa Bagoly, MD, PhD

Professor (Associate)
Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Debrecen, Hajdu-Bihar, Hungary

Co-Author(s)

Rita Orbán-Kálmándi

Junior research fellow
Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Debrecen, Hajdu-Bihar, Hungary
Linda Lóczi

PhD Student
Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Debrecen, Hajdu-Bihar, Hungary
DB

Dóra Bomberák

PhD Student
Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Debrecen, Hajdu-Bihar, Hungary
�D

Ádám Deák

Professor Assistant
Department of Operative Techniques and Surgical Research, University of Debrecen, Debrecen, Hungary
Debrecen, Hajdu-Bihar, Hungary
�M

Ádám Mátrai

PhD Student
Department of Operative Techniques and Surgical Research, University of Debrecen, Debrecen, Hungary
Debrecen, Hajdu-Bihar, Hungary
NN

Norbert Németh

Professor
Department of Operative Techniques and Surgical Research, University of Debrecen, Debrecen, Hungary
Debrecen, Hajdu-Bihar, Hungary
Riitta Lassila, MD, PhD (she/her/hers)

Professor of Coagulation Medicine
Helsinki University Hospital, Coagulation Disorders Unit, Department of Haematology, Comprehensive Cancer Centre, and Research Program Unit in System Oncology, University of Helsinki, Helsinki, Finland
Helsinki, Uusimaa, Finland

Background: Vascular injury targeting APAC is a locally acting dual antiplatelet and anticoagulant. APAC mimics naturally occurring heparin proteoglycans and has entered clinical studies. APAC inhibits collagen-induced platelet aggregation (CIPA) and reduces platelet accumulation and fibrin formation on thrombogenic surfaces. APAC is anti-inflammatory, inhibits atherothrombosis and consequences of thrombotic occlusion in several animal models.

Aims: To assess impact on coagulation activity by clinically relevant escalating bolus doses of IV-APAC in pigs.

Methods: We administered APAC (0.25 – 1.5 mg/Kg, n=11) and assessed clinical coagulation biomarker responses in plasma and blood. ASA and APAC were also co-administered, and protamine sulfate was studied as an antidote. We assessed blood cell counts (CBC), activated clotting time (ACT) and rotational thromboelastometry (ROTEM) in blood, and activated partial thromboplastin time (APTT), thrombin time (TT), and thrombin generation (TG) in plasma, and CIPA in platelet-rich plasma.

Results: CBC remained unaltered, although platelet count reduced 10%. Hemostasis stayed intact up on total APAC infusion of 2.75 mg/Kg. APAC dose-dependently prolonged APTT, TT and ACT. At > 0.5 mg/Kg of APAC, APTT and TT reached maximum, TG was abolished, while InTEM clotting time (CT) and clot formation time (CFT) were prolonged by 40-80%. At 0.75 mg/Kg, APAC prolonged CT and CFT by >2.8-fold and reduced MCF to 8-45%. CIPA was modestly inhibited with APAC and co-administered ASA. Protamine reversed APAC. Overall, APAC effects were transient and normalized after 75 min, despite the escalated dosing.

Conclusion(s): The antiplatelet effects of APAC are modest in porcine, unlike in human blood, but the anticoagulant effect appears similar. APAC dose-dependently prolonged coagulation times and inhibited intrinsic pathway and thrombin-triggered blood coagulation. Protamine could be used as an antidote for APAC. At the escalated dose regimen, the systemic effects of APAC were transient.