Gene Silencing - A Strategy for Anticoagulation during Mechanical Circulatory Support
James Tweddell, MD, Kyle W. Riggs, MD, Leah Rosenfeldt, BS, Richard S. Baker, BS, James Reagor, MS, Farhan Zafar, MD, Joseph Palumbo, MD.
Cincinnati Children's Hospital, Cincinnati, OH, USA.
Objectives: Therapies targeting Factor XII (fXII) may reduce thrombosis and inflammation associated with mechanical circulatory support without increasing surgical bleeding. We tested the capacity of a novel inhibitor of fXII synthesis to reduce thrombosis in a rabbit model of ECMO. Methods: Six rabbits were placed on ECMO for up to 4 hours through abdominal aorto-caval cannulation. Three rabbits were pretreated with a highly specific fXII antisense oligonucleotide “Gapmer” for 4 weeks prior to ECMO, while 3 control rabbits were not. Heparin was reversed with protamine within 10 minutes of ECMO initiation in all cases. Results: As expected, fXII Gapmer treatment significantly lowered fXII activity to ~5% of normal, but had no impact on other hemostatic parameters (i.e., prothrombin, factor XI, fibrinogen, platelets). Gapmer treated rabbits tended to have lower oxygenator pressure gradients (13mmHg [12-17mmHg] vs 130mmHg [19-180mmHg]) and longer duration of ECMO support (240min [220-240min] vs 127 [67-240min]) with less clot burden (0% clotted vs 66% clotted) than controls, all p>0.05. Consistent with a diminished thrombotic tendency, a trend toward less fibrinogen consumption was observed in the fXII Gapmer treated cohort. Conclusion: In a rabbit ECMO model, depletion of fXII appears to provide some protection from thrombotic complications. These results suggest that therapies targeting the contact activation pathway could limit thrombotic complications of ECMO, possibly decreasing the need for traditional anticoagulation, without additional bleeding risk.
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