PB0579 - The Influence of Plasma Prekallikrein Oligonucleotide Antisense Therapy on Coagulation and Fibrinolysis Assays

Background: Congenital prekallikrein deficiency has been associated with increased risk of thrombosis in a few uncontrolled studies. Prekallikrein levels were reduced by 60-65% in a recent phase 2 study with prekallikrein oligonucleotide antisense therapy (donidalorsen) for hereditary angioedema (HAE).

Aims: To estimate the effects of plasma prekallikrein reduction on coagulation and fibrinolysis.

Methods: Plasma samples were obtained from 16 HAE patients treated with donidalorsen and six patients with placebo. Informed consent was obtained from all participants and the study was approved by a recognized medical ethics committee. Calibrated automated thrombogram (CAT), clot lysis time (CLT), high-molecular-weight kininogen activity, factor XI activity, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complexes, D-dimer, plasminogen activity, plasmin-α2-antiplasmin complexes, and α2-antiplasmin activity were measured before and after four months of treatment.

Results: No significant changes following donidalorsen treatment were observed between baseline and follow-up: CAT lag time 3.0 min and 3.0 min, CAT peak thrombin concentration 109% and 129%, CAT endogenous thrombin potential 98% and 108%, factor XI activity 110% and 115%, F1+2 levels 251 pMol/L and 161 pMol/L, thrombin-antithrombin complexes 2.6 µg/L and 1.9 µg/L, high-molecular-weight kininogen activity 87% and 93%, CLT with carboxypeptidase inhibitor 92% and 99%, CLT without carboxypeptidase inhibitor 87% and 93%, D-dimer levels 0.65 µg/L and 0.36 µg/L, plasminogen activity 116% and 125%, plasmin-α2-antiplasmin complexes 533 ng/mL and 328 ng/mL, and α2-antiplasmin activity 122% and 127%, respectively. There were also no differences between donidalorsen and placebo treatment.

Conclusion(s): Reduction of plasma prekallikrein by oligonucleotide antisense therapy in HAE patients does neither affect thrombin formation nor fibrinolytic activity. Our data show that that partial plasma prekallikrein reduction does not cause a procoagulant state and thereby suggest that it does not influence thrombotic risk.
(Funded by Ionis Pharmaceuticals, Inc.; ISIS 721744-CS2, ClinicalTrials.gov number: NCT04030598.)