Session: 330. Vascular Biology, Thrombosis, and Thrombotic Microangiopathies: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science
Objective: To assess the efficacy and safety of BAY 3389934, a novel short-lived, small molecule dual FIIa/Xa inhibitor, in reducing coagulopathy and protecting organ function in a baboon model of Staphylococcus aureus (S. aureus) sepsis.
Methods: The study employed a baboon model infused with heat-inactivated S. aureus (3.3 x 1010 bacteria/kg bw). Baboons were treated with BAY 3389934 (1-2 mg/kg bw, continuous IV infusion up to 8 hours post-bacterial challenge) starting at T0 (before) or 2 hours post-bacterial challenge. Various parameters, including markers of coagulation, fibrinolysis, organ function, and bleeding time, were assessed. Animals were kept in anesthesia for 9 hours and subsequently followed up to 48 hours after the start of bacterial challenge.
Results: S. aureus infusion induced robust activation of coagulation, as reflected by plasma levels of protease-serpin complexes (FXIIa-AT, Kal-AT, FXIa-AT, FVIIa-AT, and T-AT) and mirrored by fibrinogen and platelet consumption. S. aureus infusion led to organ dysfunction, as indicated by elevated vital signs, increased plasma ALT, total bilirubin, pancreatic amylase, plasma creatinine, and blood urea nitrogen, as well as histological evidence of kidney damage.
Treatment with BAY 3389934 significantly decreased the coagulation markers, blocking the activation of coagulation when given at T0 and strongly reducing it when given 2 hours after the challenge. Importantly, the treatment mitigated fibrinogen and platelet consumption without causing bleeding throughout the experiment. ROTEM analysis confirmed these findings.
Additionally, BAY 3389934 protected against organ dysfunction, as evidenced by reduced markers of liver (ALT), pancreas (amylase), and kidney (BUN, creatinine) damage, and decreased lactate levels. Histological analysis showed that the treatment prevented fibrin deposition in the kidney and lungs and necrosis of the kidney’s tubular epithelium.
Conclusion: In a model of sepsis-induced coagulopathy in baboons, the dual FIIa/Xa inhibitor BAY 3389934 reduced the hypercoagulable state strongly and protected from organ damage. Further studies are warranted to explore its full therapeutic potential in the treatment of sepsis-associated DIC.
Disclosures: Silasi: Bayer AG: Research Funding. Pfaff: Bayer AG: Current Employment. Heitmeier: Bayer AG: Current Employment. Lupu: Bayer AG: Research Funding.