Rapid clearing CT-001 restored hemostasis in mice with coagulopathy induced by activated protein C.
J Trauma Acute Care Surg
; 96(2): 276-286, 2024 Feb 01.
Article
in En
| MEDLINE
| ID: mdl-37335129
ABSTRACT
BACKGROUND:
Activated protein C (APC) is one of the mechanisms contributing to coagulopathy, which is associated with high mortality. The counteraction of the APC pathway could help ameliorate bleeding. However, patients also transform frequently from a hemorrhagic state to a prothrombotic state at a later time. Therefore, a prohemostatic therapeutic intervention should take this thrombotic risk into consideration.OBJECTIVES:
CT-001 is a novel factor VIIa (FVIIa) with enhanced activity and desialylated N-glycans for rapid clearance. We assessed CT-001 clearance in multiple species and its ability to reverse APC-mediated coagulopathic blood loss.METHODS:
The N-glycans on CT-001 were characterized by liquid chromatography-mass spectrometry. Three species were used to evaluate the pharmacokinetics of the molecule. The potency and efficacy of CT-001 under APC pathway-induced coagulopathic conditions were assessed by coagulation assays and bleeding models.RESULTS:
The N-glycosylation sites of CT-001 had high occupancy of desialylated N-glycans. CT-001 exhibited 5 to 16 times higher plasma clearance in human tissue factor knockin mice, rats, and cynomolgus monkeys than wildtype FVIIa. CT-001 corrected the activated partial thromboplastin time and thrombin generation of coagulopathic plasma to normal in in vitro studies. In an APC-mediated saphenous vein bleeding model, 3 mg/kg of CT-001 reduced bleeding time in comparison with wildtype FVIIa. The correction of bleeding by CT-001 was also observed in a coagulopathic tail amputation severe hemorrhage mouse model. The efficacy of CT-001 is independent of the presence of tranexamic acid, and the combination of CT-001 and tranexamic acid does not lead to increased thrombogenicity.CONCLUSION:
CT-001 corrected APC pathway-mediated coagulopathic conditions in preclinical studies and could be a potentially safe and effective procoagulant agent for addressing APC-mediated bleeding.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tranexamic Acid
/
Blood Coagulation Disorders
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
J Trauma Acute Care Surg
Year:
2024
Document type:
Article