Thrombosomes: a platelet-derived hemostatic agent for control of noncompressible hemorrhage
Thrombosomes: a platelet-derived hemostatic agent for control of noncompressible hemorrhage
复制标题
DOI：
10.1111/trf.12043
复制
发表时间：
2013-01-01
期刊：
影响因子：
2.9
通讯作者：
Tandon, Narendra
中科院分区：
文献类型：
--
作者：
Fitzpatrick, G. Michael;Cliff, Richard;Tandon, Narendra
背景在美国，不受控制的出血是导致战斗中80%的潜在存活死亡和超过40%的65岁以下年龄组早期死亡的原因。向急救人员提供易于使用的可输注止血剂可以显著降低这些死亡率。我们报告了一个不溶性冻干血小板衍生的止血剂稳定与海藻糖和聚蔗糖之前和过程中lyophily.Study设计和方法表征，包括确定颗粒人口的大小范围，表面标志物表达GPIIb，GPIIbIIIa，和膜联蛋白V的结合。通过聚集、血栓弹力图和凝血酶生成评估功能。在健康新西兰白色兔（NZWR）中使用铟111标记的血栓体建立药代动力学、生物分布和免疫原性，在血小板减少的NZWR中的功效，以及在NZWR、犬和非人灵长类动物中的安全性。（再水化颗粒的98.71%+/-0.18）、GPIb表达降低（47.77%+/-6.65）和膜联蛋白V结合（86.05%+/-2.65）。除缓冲液中的凝血酶外，所有激动剂的聚集结论我们的体外表征研究结合临床前动物安全性和有效性研究证明了血栓小体在生产、维持止血功能、高剂量浓度下的安全性以及在损伤部位提供有效止血剂的潜力。
Background Uncontrolled hemorrhage is responsible for similar to 80% of the potentially survivable deaths in combat and over 40% of early mortality in the under 65 age group in the United States. Providing an easily used infusible hemostatic agent to first responders could significantly reduce these fatalities. We report on an infusible lyophilized platelet-derived hemostatic agent stabilized with trehalose and polysucrose prior to and during lyophilization.Study Design and Methods Characterization included determining the particle population size range, surface marker expression GPIb, GPIIbIIIa, and Annexin V binding. Function was assessed by aggregation, thromboelastography, and thrombin generation. Pharmacokinetics, biodistribution, and immunogenicity established using Indium111 labeled Thrombosomes in healthy New Zealand white rabbits (NZWRs), efficacy in thrombocytopenic NZWR, and safety in NZWRs, canines, and nonhuman primates.Results Thrombosomes retained GPIIbIIIa expression (98.71%+/- 0.18 of the rehydrated particles), a reduced expression of GPIb (47.77%+/- 6.65), and Annexin V binding (86.05%+/- 2.65). Aggregation to all agonists except thrombin in buffer (78.15%+/- 2.5) was 80% in the thrombocytopenic ear bleed model.Conclusion Our in vitro characterization studies in conjunction with preclinical animal safety and efficacy studies demonstrated lot consistency in manufacturing, maintenance of hemostatic functions of Thrombosomes, safety at high dose concentrations, and the potential to provide an effective hemostatic agent at the site of injury.