Abstract 11269: Recombinant Soluble Thrombomodulin in Prolonged Porcine Cardiac Arrest

Abstract

Introduction: Sudden Cardiac Arrest (CA) affects more than 400,000 people per year in the United States. Although a third of these patients survive to hospital admission, another 60-70% go on to die due to failed recovery of vital organ function. Microvascular thrombosis has been suggested as a potential contributor to prolonged organ dysfunction, but no antithrombotic therapies have been shown to be beneficial and coagulofibrinolytic abnormalities in prolonged CA remain poorly understood. Objectives: To establish key biomarkers of porcine coagulation and fibrinolysis in the setting of prolonged CA and cardiopulmonary resuscitation (CPR) and test the ability of ART-123 (recombinant human thrombomodulin alpha) to reverse these abnormalities. Methods: 15 pigs (n=5 per group) underwent 8 minutes of no-flow CA followed by 50 minutes of mechanical CPR. Animals were randomized to receive saline or ART-123 (~1mg/kg) pre-arrest (5 minutes prior to ventricular fibrillation) or post-arrest (2 minutes after initiation of CPR). Results: Robust and ongoing activation of coagulation and fibrinolysis were detected throughout the resuscitation. After 50 minutes of CPR, plasma tests suggested consumptive coagulopathy, while whole blood testing (thromboelastography) indicated a persistent hypercoagulable state. ART-123 had a clear anticoagulant effect irrespective of timing (TAT complexes 381±25 vs. 238±18 vs. 226±12, p<0.01, and d-dimer 4.86±0.54 vs. 2.39±0.2 vs. 2.46±0.21 for vehicle, pre-arrest, post-arrest, p = 0.05). A pro-fibrinolytic effect was also observed, but only when the drug was given before no-flow, with a significant increase in levels of free endogenous tPA (1.2±0.12 vs. 3.29±0.29 vs. 1.72±0.3, p < 0.001) and corresponding suppression of free PAI-1 (0.59±0.15 vs. 0.14±0.01 vs. 0.41±0.09, p < 0.001). Conclusion: Our porcine CA model provides an excellent platform for evaluating antithrombotic interventions. Plasma testing after prolonged CA/CPR suggests consumptive coagulopathy, although TEG indicates a persistent hypercoagulable state. ART-123 given before no-flow or just after CPR demonstrates antithrombotic effects, although the specific modes of action depending on the timing of administration.