Animal Models of Coagulopathy

Lammers, Daniel; Martin, Matthew J.

doi:10.1007/978-3-030-53606-0_45

Cited by 1 publication

(2 citation statements)

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“…While this reduced blood flow is expected to be sufficient for maintaining the hepatocyte-mediated rapid clearance of CT-001, the PK of CT-001 under traumatic shock remains to be experimentally defined. Large species, such as pigs, would be important TIC models for future studies 32 …”

Section: Discussionmentioning

confidence: 99%

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Rapid clearing CT-001 restored hemostasis in mice with coagulopathy induced by activated protein C

Sim¹,

Mallari²,

Bauzon³

et al. 2023

J Trauma Acute Care Surg

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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.

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Section: Discussionmentioning

confidence: 99%

“…Large species, such as pigs, would be important TIC models for future studies. 32 Current treatments for traumatic bleeding rely on damage control, blood product transfusions, and TXA. Additional pharmacological intervention to provide procoagulant activity could potentially improve patient outcomes.…”

Section: Acknowledgmentmentioning

confidence: 99%