TY - JOUR
T1 - The effects of human prothrombin complex concentrate on hemorrhagic shock-induced lung injury in rats
T2 - Implications for testing human blood products in rodents
AU - Potter, Daniel R.
AU - Trivedi, Alpa
AU - Lin, Maximillian
AU - Miyazawa, Byron Y.
AU - Vivona, Lindsay R.
AU - McCully, Belinda
AU - Nair, Alison
AU - Schreiber, Martin A.
AU - Pati, Shibani
N1 - Funding Information:
Conflicts of interest: Dr. Schreiber is a consultant for CSL Behring and has received funding to study Kcentra in a trauma clinical trial unrelated to this study. Dr. Pati has received funding from CSL Behring to study Kcentra in a preclinical study of TBI unrelated to this study. Sources of Funding: This project was funded by the US Department of Defense Award (MS): W81XWH-17-2-0066, Log number: DM160342. The remaining authors have no conflicts of interests to disclose.
Publisher Copyright:
© Wolters Kluwer Health, Inc. All rights reserved.
PY - 2020/12
Y1 - 2020/12
N2 - BACKGROUND Hemorrhagic shock (HS) and trauma can result in an endotheliopathy of trauma, characterized by endothelial compromise, inflammation, and aberrant coagulation. Kcentra, a prothrombin concentrate, has been demonstrated to mitigate pulmonary vascular leak in a murine model of HS. We investigated the effects of Kcentra in a rat model of HS, to achieve physiologic endpoints of relevance. METHODS Rats subjected to a grade intravenous splenic injury and controlled hemorrhage for 60 minutes were resuscitated with shed volumes of (1) Lactated Ringer's (LR) solution, (2) LR + 20 IU/kg Kcentra, (3) LR + 50 IU/kg Kcentra, (4) rat fresh frozen plasma (RFFP), or (5) human fresh frozen plasma (HFFP). Blood was harvested for monitoring metabolic and coagulation function. Rat lungs were evaluated for lung injury and permeability. RESULTS Animals resuscitated with LR displayed a significant increase in pulmonary vascular permeability (sham, 407.9 ± 122.4; shock + LR, 2040 ± 1462). Resuscitation with RFFP (606.5 ± 169.3) reduced leak; however, treatment with Kcentra (HS + Kcentra [20 IU/kg]: 1792 ± 903.4, HS + Kcentra [50 IU/kg]: 1876 ± 1103), and HFFP (1450 ± 533.2) had no significant effect on permeability. Kcentra modestly altered clotting parameters. Metabolic measures, such as lactate, pH, and base deficit, were restored to baseline levels by both RFFP and HFFP, but not Kcentra or LR. CONCLUSION Kcentra did not alter pulmonary vascular permeability, but modestly increased clotting potential in injured rats. This suggests that there may be a xenogenic reaction of human products in rats and that the effects of Kcentra on vascular stability may be distinct from its ability to modulate clotting. Our data indicate that the species chosen and utilized for in vivo preclinical testing of human derived blood products is of critical importance in determining their efficacy in animal models and is the primary impetus to communicate these results.
AB - BACKGROUND Hemorrhagic shock (HS) and trauma can result in an endotheliopathy of trauma, characterized by endothelial compromise, inflammation, and aberrant coagulation. Kcentra, a prothrombin concentrate, has been demonstrated to mitigate pulmonary vascular leak in a murine model of HS. We investigated the effects of Kcentra in a rat model of HS, to achieve physiologic endpoints of relevance. METHODS Rats subjected to a grade intravenous splenic injury and controlled hemorrhage for 60 minutes were resuscitated with shed volumes of (1) Lactated Ringer's (LR) solution, (2) LR + 20 IU/kg Kcentra, (3) LR + 50 IU/kg Kcentra, (4) rat fresh frozen plasma (RFFP), or (5) human fresh frozen plasma (HFFP). Blood was harvested for monitoring metabolic and coagulation function. Rat lungs were evaluated for lung injury and permeability. RESULTS Animals resuscitated with LR displayed a significant increase in pulmonary vascular permeability (sham, 407.9 ± 122.4; shock + LR, 2040 ± 1462). Resuscitation with RFFP (606.5 ± 169.3) reduced leak; however, treatment with Kcentra (HS + Kcentra [20 IU/kg]: 1792 ± 903.4, HS + Kcentra [50 IU/kg]: 1876 ± 1103), and HFFP (1450 ± 533.2) had no significant effect on permeability. Kcentra modestly altered clotting parameters. Metabolic measures, such as lactate, pH, and base deficit, were restored to baseline levels by both RFFP and HFFP, but not Kcentra or LR. CONCLUSION Kcentra did not alter pulmonary vascular permeability, but modestly increased clotting potential in injured rats. This suggests that there may be a xenogenic reaction of human products in rats and that the effects of Kcentra on vascular stability may be distinct from its ability to modulate clotting. Our data indicate that the species chosen and utilized for in vivo preclinical testing of human derived blood products is of critical importance in determining their efficacy in animal models and is the primary impetus to communicate these results.
KW - Blood products
KW - animal model development
KW - endothelial permeability
KW - four factor prothombin complexes
KW - hemorrhagic shock
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U2 - 10.1097/TA.0000000000002890
DO - 10.1097/TA.0000000000002890
M3 - Article
C2 - 32697449
AN - SCOPUS:85096815824
SN - 2163-0755
VL - 89
SP - 1068
EP - 1075
JO - Journal of Trauma and Acute Care Surgery
JF - Journal of Trauma and Acute Care Surgery
IS - 6
ER -