Abstract Number: OC 05.2
Meeting: ISTH 2020 Congress
Theme: Coagulation and Natural Anticoagulants » Animal Models in Thrombosis and Hemostasis
Background: Extracorporeal membrane oxygenation (ECMO) is a lifesaving therapy for many pediatric patients but requires anticoagulation due to contact activation of blood. Despite the use of unfractionated heparin (UFH), significant thrombotic and hemorrhagic complications are common and contribute to mortality. A more selective anticoagulation strategy might provide similar thromboprevention while improving hemostasis compared to UFH.
Aims: Thromboprevention and hemorrhage in a high-fidelity piglet model of pediatric venoarterial ECMO were compared between the standard of care (UFH) and RB006, a novel and highly specific RNA aptamer-based factor IXa (FIXa) inhibitor.
Methods: Ten Yorkshire piglets weighing 4-5kg were anesthetized and cannulated via R carotid and jugular to venoarterial ECMO for 12hrs. Five piglets were treated with a single dose of RB006 (target plasma concentration 0.5uM) at cannulation, and five control piglets were treated with UFH infusion titrated to a goal ACT of 180-220s. Arterial blood gas (ABG) analysis and ACT were performed hourly. Primary outcomes were ECMO flows and blood transfusions to maintain hematocrit >20%. Clinical bleeding and oxygenator clot burden were documented by photography and electron microscopy.
Results: All 10 circuits remained patent with excellent flows throughout the 12-hour run. RB006 transfusion requirements were significantly less than UFH (3.9 mLs/kg vs. 47.4mLs/kg, p=0.0061). Consistent with clinical experience, all 5 UFH control animals slowly bled from instrumentation sites, while RB006 animals were hemostatic after cannulation. A few small macroscopic clots were visible on all 10 oxygenators at run completion, and SEM revealed significant adherent microscopic clot on 2/3 UFH and 0/3 RB006 oxygenators, with minimal foci of clot on the remainder.
Conclusions: Inhibition of the final step of the contact pathway with a novel RNA aptamer inhibitor of FIXa represents a rational approach to anticoagulation in a piglet model of pediatric ECMO. Its use greatly improved hemostasis while providing similar thromboprevention compared to the standard of care.
[LEFT: Circuit schematic. TOP RIGHT: Mean flows for 12hr run, ideal flows in gray box. BOTTOM RIGHT: Scanning EM comparison of oxygenator clot burden. ]
[LEFT: Mean transfusion volume to maintain hematocrit >20%, p = 0.0061. RIGHT: Bleeding at instrumentation sites at conclusion of 12hr run.]
To cite this abstract in AMA style:
Reed C, Bonadonna D, McDaniel G, Otto J, Frederiksen J, Chabata C, Sullenger B, Tracy E. A Novel Contact Pathway Inhibitor Improves Hemostasis and Maintains Circuit Patency in a Piglet Model of Pediatric ECMO [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/a-novel-contact-pathway-inhibitor-improves-hemostasis-and-maintains-circuit-patency-in-a-piglet-model-of-pediatric-ecmo/. Accessed March 3, 2021.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/a-novel-contact-pathway-inhibitor-improves-hemostasis-and-maintains-circuit-patency-in-a-piglet-model-of-pediatric-ecmo/