From the Department of Laboratory Medicine (D.R.P., A.T., M.L., B.Y.M., L.R.V., S.P.), University of California, San Francisco, San Francisco, CA; Department of Surgery (B.M., M.A.S.), Oregon Health & Science University, Portland, Oregon; and Department of Pediatrics (A.N.), University of California San Francisco, San Francisco, California.
J Trauma Acute Care Surg. 2020 Dec;89(6):1068-1075. doi: 10.1097/TA.0000000000002890.
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.
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.
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.
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.
出血性休克（HS）和创伤可导致创伤性内皮病，其特征为内皮功能障碍、炎症和异常凝血。促凝血酶原复合物（Kcentra）是一种凝血酶原浓缩物，已被证明可减轻 HS 小鼠模型中的肺血管渗漏。我们在 HS 大鼠模型中研究了 Kcentra 的作用，以达到相关的生理终点。
对接受 IV 级脾损伤并控制性出血 60 分钟的大鼠进行复苏，输注以下液体：（1）乳酸林格氏液（LR），（2）LR + 20 IU/kg Kcentra，（3）LR + 50 IU/kg Kcentra，（4）大鼠新鲜冷冻血浆（RFFP），或（5）人新鲜冷冻血浆（HFFP）。采集血液以监测代谢和凝血功能。评估大鼠肺脏以评估肺损伤和通透性。
用 LR 复苏的动物肺血管通透性显著增加（假手术组：407.9±122.4；休克+LR 组：2040±1462）。RFFP（606.5±169.3）复苏降低了渗漏；然而，用 Kcentra（HS+Kcentra[20 IU/kg]：1792±903.4，HS+Kcentra[50 IU/kg]：1876±1103）和 HFFP（1450±533.2）治疗对通透性没有显著影响。Kcentra 适度改变了凝血参数。代谢指标，如乳酸、pH 值和碱缺失，用 RFFP 和 HFFP 恢复到基线水平，但 Kcentra 或 LR 不行。
Kcentra 没有改变肺血管通透性，但适度增加了受伤大鼠的凝血潜能。这表明，在大鼠中可能存在人类产品的异种反应，并且 Kcentra 对血管稳定性的影响可能与其调节凝血的能力不同。我们的数据表明，用于测试人类来源的血液制品在动物模型中的功效的体内临床前试验中选择和使用的物种非常重要，这是交流这些结果的主要动力。
