Abstract Number: OC 48.3
Meeting: ISTH 2021 Congress
Background: Short term inhibition of fibrinolysis using tranexamic acid constitutes an important treatment for patients with inherited bleeding disorders. Targeted inhibition of plasminogen could provide an additional approach to reduce or prevent bleeding long-term.
Aims: To evaluate the efficacy of siRNA knockdown of plasminogen in hemophilia and von Willebrand disease models.
Methods: C57BL/6 FVIII-/- and VWF-/- mice were treated with an intravenous injection of lipid nanoparticle encapsulated plasminogen siRNA (siPLG), or luciferase siRNA (siLUC) control. Efficacy (bleeding time and blood loss) was evaluated in tail vein transection (TVT, FVIII-/- and VWF-/-) and saphenous vein puncture (SVP, FVIII-/-) models, 2-3 weeks following a single siRNA dose.
Results: Significant reduction in median blood loss (0.41 v 2.34uL/mg, p=0.008) and bleeding time (4.5 v 40.0 mins, p=0.04) was seen in FVIII-/- mice in the SVP model comparing siPLG (n=9) treated mice to siLUC (n=7) controls. In the SVP model, blood loss and bleeding time in siPLG treated FVIII-/- mice were similar to wild type controls. Preliminary results in the TVT model, showed a trend towards reduced mean bleeding time (26.0 v 41.8 mins, p=0.15) with no difference in blood loss (68.9 v 72.4, p=0.88) in FVIII-/- mice treated with siPLG (n=5) compared to siLUC (n=6). In VWF-/- mice, no difference was seen for median bleeding time (31.5 v 28.0 mins, p>0.99) or mean blood loss (74.3 v 73.0 mg, p=0.91) in the TVT model comparing siPLG (n=5) to siLUC treatment (n=6).
Conclusions: Despite what has been previously thought, targeted knockdown of plasminogen resulted in an improvement in the bleeding phenotype in an acute bleeding model in FVIII-/- mice. This treatment is expected to have a greater effect on long-term bleeding, where fibrinolysis contributes to re-bleeding risk. Further evaluation of this approach is ongoing in canine hemophilia models.
To cite this abstract in AMA style:Batty P, Strilchuk A, Nesbitt K, Yong A, Lillicrap D, Kastrup C. Therapeutic Knockdown of Plasminogen with siRNA in Hemophilia A and von Willebrand disease Mouse Models [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/therapeutic-knockdown-of-plasminogen-with-sirna-in-hemophilia-a-and-von-willebrand-disease-mouse-models/. Accessed November 29, 2021.
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