骨科损伤诱导的高凝状态和纤维蛋白溶解抑制的大鼠模型。
A rat model of orthopedic injury-induced hypercoagulability and fibrinolytic shutdown.
机构信息
From the Division of Trauma, Critical Care, and Acute Care Surgery, Department of Surgery (K.T.C., A.C.P., F.T.S., B.M.W., L.M., M.E.K.), and Department of Physiology and Biophysics (R.L.H.), University of Mississippi Medical Center, Jackson, Mississippi.
出版信息
J Trauma Acute Care Surg. 2020 Nov;89(5):926-931. doi: 10.1097/TA.0000000000002924.
BACKGROUND
Postinjury hypercoagulability occurs in >25% of injured patients, increasing risk of thromboembolic complications despite chemoprophylaxis. However, few clinically relevant animal models of posttraumatic hypercoagulability exist. We aimed to evaluate a rodent model of bilateral hindlimb injury as a preclinical model of postinjury hypercoagulability.
METHODS
Forty Wistar rats were anesthetized with isoflurane: 20 underwent bilateral hindlimb fibula fracture, soft tissue and muscular crush injury, and bone homogenate injection intended to mimic the physiological severity of bilateral femur fracture. Twenty sham rats underwent anesthesia only. Terminal citrated blood samples were drawn at 0, 6, 12, and 24 hours (n = 5 per timed group) for analysis by native thromboelastography in the presence and absence of taurocholic acid to augment fibrinolysis. Plasminogen activator inhibitor 1 and α-2 antiplasmin levels in plasma were assessed via enzyme-linked immunosorbent assay.
RESULTS
Injured rats became hypercoagulable relative to baseline by 6 hours based on thromboelastography maximal amplitude (MA) and G (p < 0.005); sham rats became hypercoagulable to a lesser degree by 24 hours (p < 0.005). Compared with sham animals, injured rats were hypercoagulable by MA and G within 6 hours of injury, remained hypercoagulable by MA and G through at least 24 hours (all p < 0.01), and showed impaired fibrinolysis by taurocholic acid LY30 at 12 hours (p = 0.019) and native LY30 at 24 hours (p = 0.045). In terms of antifibrinolytic mediators, α-2 antiplasmin was elevated in trauma animals at 24 hours (p = 0.009), and plasminogen activator inhibitor 1 was elevated in trauma animals at 6 hours (p = 0.004) and 12 hours (p < 0.001) when compared with sham.
CONCLUSIONS
Orthopedic injury in rodents induced platelet and overall hypercoagulability within 6 hours and fibrinolytic impairment by 12 to 24 hours, mimicking postinjury hypercoagulability in injured patients. This rodent model of orthopedic injury may serve as a preclinical testing ground for potential therapies to mitigate hypercoagulability, maintain normal fibrinolysis, and prevent thromboembolic complications.
背景
25%的受伤患者会出现创伤后高凝状态，尽管进行了化学预防，但仍会增加血栓栓塞并发症的风险。然而，目前仅有少数与临床相关的创伤后高凝状态的动物模型。本研究旨在评估双侧后肢损伤的啮齿动物模型，作为创伤后高凝状态的临床前模型。
方法
40 只 Wistar 大鼠用异氟烷麻醉：20 只大鼠行双侧后肢腓骨骨折、软组织和肌肉挤压伤，并注射骨匀浆，以模拟双侧股骨骨折的生理严重程度。20 只假手术大鼠仅接受麻醉。在存在和不存在牛磺胆酸以增强纤溶的情况下，通过原生血栓弹性描记术分析 0、6、12 和 24 小时（每个时间组 5 只）的终末枸橼酸盐血样。通过酶联免疫吸附试验评估血浆中纤溶酶原激活物抑制剂 1 和 α-2 抗纤溶酶的水平。
结果
与基线相比，受伤大鼠在 6 小时时通过血栓弹性描记术最大振幅（MA）和 G 变得高凝（p < 0.005）；假手术大鼠在 24 小时时高凝程度较低（p < 0.005）。与假手术动物相比，受伤大鼠在受伤后 6 小时内通过 MA 和 G 变得高凝，至少在 24 小时内通过 MA 和 G 保持高凝（均 p < 0.01），并且在 12 小时时通过牛磺胆酸 LY30（p = 0.019）和 24 小时时通过原生 LY30（p = 0.045）表现出纤溶受损。就抗纤维蛋白溶解介质而言，α-2 抗纤溶酶在创伤动物中于 24 小时升高（p = 0.009），纤溶酶原激活物抑制剂 1 在创伤动物中于 6 小时（p = 0.004）和 12 小时（p < 0.001）升高与假手术相比。
结论
在 6 小时内，啮齿动物的骨科损伤诱导血小板和整体高凝状态，并在 12 至 24 小时内诱导纤溶受损，模拟了受伤患者的创伤后高凝状态。这种骨科损伤的啮齿动物模型可能作为潜在治疗方法的临床前试验平台，以减轻高凝状态、维持正常纤溶和预防血栓栓塞并发症。
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