TY - JOUR

T1 - In vivo effect of rFVIII and rFVIIa in hemophilia A rats evaluated by the Tail Vein Transection Bleeding Model

AU - Stagaard, Rikke

AU - Øvlisen, Gabi Overgaard

AU - Klæbel, Julie Hviid

AU - Danielsen, Dennis

AU - Lund, Anne

AU - Elm, Torben

AU - Ley, Carsten Dan

N1 - Publisher Copyright: © 2022 International Society on Thrombosis and Haemostasis

PY - 2023

Y1 - 2023

N2 - Background: Preclinical bleeding models increase current hemophilia A (HA) knowledge and aid the development of new pharmacological treatments. There are several well-established mouse bleeding models, but limited options are available for rat models despite their high resemblance to human disease process. Objective: To provide a comprehensive description of the tail vein transection (TVT) bleeding model in HA rats and examine the correlation between in vivo pharmacological efficacy and global hemostatic assays. Methods: The TVT bleeding model was implemented in HA rats and used to perform dose-response studies with recombinant coagulation factors VIIa (rFVIIa) and VIII (rFVIII). After the TVT bleeding model, whole blood and plasma were collected from rats and evaluated with thrombin generation test (TGT) and rotational thromboelastometry (ROTEM). Results: Using the TVT bleeding model, the potency of rFVIII and rFVIIa treatments in HA rats were assessed, and the pharmacological windows established for rFVIII (≤15 U/kg) and rFVIIa (≤2.7 mg/kg). ED50 was estimated to be 1.75 U/kg for rFVIII and 0.37 mg/kg for rFVIIa, whereas complete normalization was observed with 15 U/kg and 2.7 mg/kg respectively. Furthermore, responses to rFVIII and rFVIIa in the TGT and ROTEM assays strongly correlated to in vivo pharmacological efficacy. Conclusion: The TVT bleeding model in HA rats is a useful tool to assess the pharmacodynamic effects of hemostatic compounds in vivo, and strongly correlates to results obtained with TGT and ROTEM in HA rats, adding further value to the HA rat model in preclinical research.

AB - Background: Preclinical bleeding models increase current hemophilia A (HA) knowledge and aid the development of new pharmacological treatments. There are several well-established mouse bleeding models, but limited options are available for rat models despite their high resemblance to human disease process. Objective: To provide a comprehensive description of the tail vein transection (TVT) bleeding model in HA rats and examine the correlation between in vivo pharmacological efficacy and global hemostatic assays. Methods: The TVT bleeding model was implemented in HA rats and used to perform dose-response studies with recombinant coagulation factors VIIa (rFVIIa) and VIII (rFVIII). After the TVT bleeding model, whole blood and plasma were collected from rats and evaluated with thrombin generation test (TGT) and rotational thromboelastometry (ROTEM). Results: Using the TVT bleeding model, the potency of rFVIII and rFVIIa treatments in HA rats were assessed, and the pharmacological windows established for rFVIII (≤15 U/kg) and rFVIIa (≤2.7 mg/kg). ED50 was estimated to be 1.75 U/kg for rFVIII and 0.37 mg/kg for rFVIIa, whereas complete normalization was observed with 15 U/kg and 2.7 mg/kg respectively. Furthermore, responses to rFVIII and rFVIIa in the TGT and ROTEM assays strongly correlated to in vivo pharmacological efficacy. Conclusion: The TVT bleeding model in HA rats is a useful tool to assess the pharmacodynamic effects of hemostatic compounds in vivo, and strongly correlates to results obtained with TGT and ROTEM in HA rats, adding further value to the HA rat model in preclinical research.

KW - animal models

KW - bleeding

KW - blood coagulation factors

KW - hemophilia A

KW - rats

U2 - 10.1016/j.jtha.2022.12.009

DO - 10.1016/j.jtha.2022.12.009

M3 - Journal article

C2 - 36696187

AN - SCOPUS:85153588691

VL - 21

SP - 1189

EP - 1199

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

SN - 1538-7933

IS - 5

ER -