Evaluation of biomarkers for monitoring thrombogenic potential of FXaI16L

• Published in: Blood coagulation & fibrinolysis Vol. 31; no. 1; p. 16
• Main Authors: Bolt, Michael W, Hua, Fei, Brenneman, Karrie A, Graves, John E, Arkin, Steven, Criswell, Kay
• Format: Journal Article
• Language: English
• Published: England 01.01.2020
• Subjects: Animals; Anticoagulants - pharmacology; Anticoagulants - therapeutic use; Biomarkers - metabolism; Blood Coagulation Tests - methods; Factor Xa - pharmacology; Factor Xa - therapeutic use; Haplorhini; Humans; Mice; Rats; Rats, Wistar; Thrombosis - drug therapy
• ISSN: 1473-5733
• DOI: 10.1097/MBC.0000000000000866

: A zymogen-like activated factor X variant (FXa) is being developed for treating acute bleeding conditions. Activated factor V is an essential cofactor to FXa for activating prothrombin to thrombin. Thrombi/emboli formation was observed microscopically in FXa toxicity studies in animals. The objective of this research was to evaluate candidate biomarkers for FXa-induced thrombi/emboli formation to inform safety monitoring and dose-escalation decisions in FXa clinical trials. Effects of intravenous FXa administration on platelets, fibrinogen, activated partial thromboplastin time (aPTT), prothrombin time (PT), D-dimer, tissue factor pathway inhibitor, thrombin : antithrombin complex, antithrombin, and factor V, and protein C (PC) activities were evaluated in mice, rats, and monkeys. Mice had endogenous factor V activity 10× that of monkeys and were overly sensitive to FXa-induced thrombi/emboli formation. In monkeys, decreases in fibrinogen and prolongation in aPTT and PT emerged as potential biomarkers for impending FXa-induced thrombi/emboli formation, based on association of changes with microscopically observable thrombi/emboli (0-97 thrombi/emboli per monkey). PC decreases, measured by a clot-based assay, were also observed. A similar reduction in PC activity, when measured by clot-based assay, was observed in a phase 1 clinical trial. However, an in-vitro experiment with human plasma spiked with increasing concentrations of FXa indicated dose-dependent FXa-induced interference with clot-based assays and no depletion of PC or S by FXa in non-clot-based assays. Nonclinical biomarker studies identified fibrinogen, aPTT and PT as potential biomarkers for monitoring the clinical safety of FXa. Results of clot-based assays with FXa treatment should be interpreted with caution.