Trauma-targeted delivery of tranexamic acid improves hemostasis and survival in rat liver hemorrhage model.
Trauma-targeted delivery of tranexamic acid improves hemostasis and survival in rat liver hemorrhage model.
复制标题
DOI：
10.1111/jth.14552
复制
发表时间：
2019-10
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
创伤性出血和凝血功能障碍仍然是导致死亡的主要原因。这种凝血功能障碍通常导致高纤溶表型，其中止血凝块由于组织纤溶酶原激活物（tPA）活性上调而变得不稳定。氨甲环酸（TXA）是一种合成的tPA抑制剂，已成为缓解纤维蛋白溶解的有前景的药物。TXA被美国食品和药物管理局批准用于治疗月经和产后出血，并在创伤治疗中显示出前景。然而，新出现的报道也暗示了TXA对脱靶全身性凝血病、血栓栓塞并发症和神经病变的影响。我们假设有针对性地将TXA输送到创伤损伤部位可以选择性地发挥其凝块稳定作用，从而改善止血和生存，同时避免脱靶效应。为了验证这一点，我们使用脂质体作为模型递送载体，用纤维蛋白原模拟肽修饰其表面，用于锚定创伤相关凝块中的活性血小板，并在其中封装TXA。在体外大鼠血液和体内大鼠肝损伤模型中，对负载txa的创伤靶向纳米囊泡（T-tNVs）进行了评价。负载TXA的对照（非靶向）纳米囊泡（tnv）、游离TXA或生理盐水作为对照组进行研究。我们的研究表明，在体外，t - tnv可以在tpa添加的大鼠血液中抵抗裂解。在体内，t - tnv维持了大鼠肝出血模型的全身安全性，显著减少了失血量，提高了生存率。对安乐死大鼠切除组织的死后评估证实了t - tnv的全身安全性和创伤靶向活性。总的来说，这些研究确立了靶向给药TXA在安全的损伤部位选择性增强和止血凝块稳定方面的潜力，以提高创伤患者的生存率。
Trauma-associated hemorrhage and coagulopathy remain leading causes of mortality. Such coagulopathy often leads to a hyperfibrinolytic phenotype where hemostatic clots become unstable because of upregulated tissue plasminogen activator (tPA) activity. Tranexamic acid (TXA), a synthetic inhibitor of tPA, has emerged as a promising drug to mitigate fibrinolysis. TXA is US Food and Drug Administration-approved for treating heavy menstrual and postpartum bleeding, and has shown promise in trauma treatment. However, emerging reports also implicate TXA for off-target systemic coagulopathy, thromboembolic complications, and neuropathy. We hypothesized that targeted delivery of TXA to traumatic injury site can enable its clot-stabilizing action site-selectively, to improve hemostasis and survival while avoiding off-target effects. To test this, we used liposomes as a model delivery vehicle, decorated their surface with a fibrinogen-mimetic peptide for anchorage to active platelets within trauma-associated clots, and encapsulated TXA within them. The TXA-loaded trauma-targeted nanovesicles (T-tNVs) were evaluated in vitro in rat blood, and then in vivo in a liver trauma model in rats. TXA-loaded control (un-targeted) nanovesicles (TNVs), free TXA, or saline were studied as comparison groups. Our studies show that in vitro, the T-tNVs could resist lysis in tPA-spiked rat blood. In vivo, T-tNVs maintained systemic safety, significantly reduced blood loss and improved survival in the rat liver hemorrhage model. Postmortem evaluation of excised tissue from euthanized rats confirmed systemic safety and trauma-targeted activity of the T-tNVs. Overall, the studies establish the potential of targeted TXA delivery for safe injury site-selective enhancement and stabilization of hemostatic clots to improve survival in trauma.
登录
查看更多内容
影响因子：
4.8
作者：
Cierniewski, CS;Byzova, T;Plow, EF
通讯作者：
Plow, EF
影响因子：
2.4
作者：
Chen, JM;López, KA
通讯作者：
López, KA
影响因子：
8
作者：
Bozzuto G;Molinari A
通讯作者：
Molinari A
DOI：
10.1002/wnan.1464
发表时间：
2017-11
期刊：
Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology
影响因子：
--
作者：
Sen Gupta A
通讯作者：
Sen Gupta A
影响因子：
7.5
作者：
Baylis JR;Chan KY;Kastrup CJ
通讯作者：
Kastrup CJ