Lyophilized platelets: Fifty years in the making
Lyophilized platelets: Fifty years in the making
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DOI：
10.1080/10731190600974962
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发表时间：
2007-01-01
期刊：
影响因子：
--
通讯作者：
Fischer, Thomas H.
中科院分区：
文献类型：
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作者：
Bode, Arthur P.;Fischer, Thomas H.
从Klein等人在20世纪50年代早期的工作开始，一直在共同努力应用冷冻干燥方法保存血小板，以便为出血患者提供稳定的可输注止血剂来止血。最初的尝试并没有保持血小板结构的完整性，并且被证明几乎没有临床益处。然而，已知通过各种交联剂的固定使得血小板能够在结构上完整地承受冻干应力，但（假定）功能性完全丧失。Read及其同事表明，固定和冻干血小板可对瑞斯托霉素诱导的凝集反应，因此设计了一种广泛接受的von Willebrands因子测定法，证明重组血小板很好地参与了主要止血中重要相互作用的体外模型。本综述记录了作者努力改进固定过程，使冻干和重组血小板保留止血所需的基本止血性能。所得到的产品已经证明了在血小板缺乏的动物模型中出血时间的校正或减少，包括Blajchman及其同事的血小板减少兔模型，东卡罗莱纳大学（ECU）的开胸手术的犬心肺转流模型，和猪创伤模型，北卡罗来纳州查佩尔山大学（UNC-CH）涉及放血和用血红蛋白完全血液交换，氧载体（HBOC）。此外，已经表明，固定过程杀死了掺入血小板悬浮液中的病毒和细菌，这表明最终材料确实可能是第一个真正无菌的细胞输注产品。临床效益的最初目标是防止武装部队人员战斗伤亡中的失血和低血容量性休克，对他们来说，血小板输注是最常见的。Entegrion Inc.正在承担商业利益。（以前称为Hemocellular Therapeutics Corporation）将该技术转移到用于生产Stasix（TM）的可规模化制造平台，Stasix（TM）是一种固定和冻干血小板的药物制剂，用于静脉内或局部使用，以阻止具有血小板相关出血素质的各种患者的活动性出血。从第一次尝试制备临床上有用的冻干血小板制剂到快速接近Stasix（TM）的临床试验已经花了50多年的时间;血小板的稳定是实现这一进步的关键。
Starting with the work of Klein et al. in the early 1950s, there has been a concerted effort to apply the process of freeze-drying for the preservation of platelets in order to provide hemorrhagic patients with a stable infusible hemostatic agent to stop bleeding. The original attempts did not preserve platelet structural integrity and proved to be of little clinical benefit. However, it was known that fixation by various cross-linking agents rendered platelets able to withstand structurally intact the stresses of lyophilization but with (assumed) complete loss of functionality. Read and coworkers showed that fixed and freeze-dried platelets could respond to ristocetin-induced agglutination, and thus devised a widely accepted assay for von Willebrands factor that demonstrated that reconstituted platelets participated well in this in vitro model of an important interaction in primary hemostasis. This review chronicles the efforts of the authors to refine the fixation process so that the freeze-dried and reconstituted platelets retain fundamental hemostatic properties necessary to stop bleeding. The resultant product has demonstrated correction or reduction of the bleeding times in animal models with platelet deficits including the thrombocytopenic rabbit model of Blajchman and coworkers, a canine cardiopulmonary bypass model of open-heart surgery at East Carolina University (ECU), and a porcine trauma model The University of North Carolina at Chapel Hill (UNC-CH) involving exsanguination and complete blood exchange with a hemoglobin-based oxygen carrier (HBOC). In addition, it has been shown that the fixation process kills viruses and bacteria spiked into the platelet suspension, indicating that the final material may indeed be the first truly sterile cellular transfusion product. The initial goal for clinical benefit is to prevent exsanguination and hypovolemic shock in combat casualties of armed services personnel, for whom platelet transfusions are most often unavailable. Commercial interests are being brought to bear by Entegrion Inc. (formerly known as Hemocellular Therapeutics Corporation) to transfer this technology to a scaleable manufacturing platform for the production of Stasix (TM), a pharmaceutical preparation of fixed and freeze-dried platelets for intravenous or topical use in the arrest of active hemorrhage in a wide variety of patients with a platelet-related bleeding diathesis. It has taken fifty+ years from the first attempt at making a clinically useful freeze-dried platelet preparation to get to the rapidly-approaching clinical trials of Stasix (TM); stabilization of the platelets has been the key to realizing this advance.