Fibrinogen-Coated Albumin Nanospheres Prevent Thrombocytopenia-Related Bleeding.
Fibrinogen-Coated Albumin Nanospheres Prevent Thrombocytopenia-Related Bleeding.
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DOI：
10.1667/rade-20-00016
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发表时间：
2020-08-01
影响因子：
3.4
通讯作者：
Chen BJ
中科院分区：
文献类型：
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作者：
Sung AD;Yen RC;Jiao Y;Bernanke A;Lewis DA;Miller SE;Li Z;Ross JR;Artica A;Piryani S;Zhou D;Liu Y;Vo-Dinh T;Hoffman M;Ortel TL;Chao NJ;Chen BJ
血小板减少症（TCP）可能导致严重和危及生命的出血。虽然这可以通过血小板输注来预防，但输血与潜在的并发症有关，并不总是有效（血小板难治性），并且并不总是可用。迫切需要合成替代品。我们评估了纤维蛋白原包被的纳米球（FCN）预防TCP相关出血的能力。FCN是由人血白蛋白聚合成100 nm的球体，并涂有纤维蛋白原。我们假设，FCNs将通过纤维蛋白原-GPIIb/IIIa相互作用与血小板结合，有助于TCP环境中的止血。我们使用两种小鼠模型来测试这些效果：在第一种模型中，BALB/c小鼠接受7.25戈伊全身照射（TBI）;在第二种模型中，低剂量TBI（7.0戈伊）与抗血小板抗体（抗CD 41）相结合，以诱导严重的TCP。两种模型中的死亡均归因于胃肠道或颅内出血。与单独7.0戈伊TBI相比，在7.0戈伊TBI中加入抗血小板抗体显著恶化TCP并增加死亡率。在两种模型中，与盐水对照相比，FCN显著改善了存活率，表明其改善了TCP相关的出血。此外，在抗体诱导TCP的隐静脉出血模型中，FCN缩短了出血时间。在FCN治疗后，没有血栓形成的临床或组织学结果或弥散性血管内凝血的实验室结果。为了支持安全性，荧光显微镜检查表明，只有在血小板被胶原蛋白激活时，FCN才能与血小板结合，从而将活性限制在内皮损伤区域。据我们所知，这是第一个证明在TCP相关出血中具有生存优势的生物合成药物。
Thrombocytopenia (TCP) may cause severe and life-threatening bleeding. While this may be prevented by platelet transfusions, transfusions are associated with potential complications, do not always work (platelet refractory) and are not always available. There is an urgent need for a synthetic alternative. We evaluated the ability of fibrinogen-coated nanospheres (FCNs) to prevent TCP-related bleeding. FCNs are made of human albumin polymerized into a 100-nm sphere and coated with fibrinogen. We hypothesized that FCNs would bind to platelets through fibrinogen-GPIIb/IIIa interactions, contributing to hemostasis in the setting of TCP. We used two murine models to test these effects: in the first model, BALB/c mice received 7.25 Gy total-body irradiation (TBI); in the second model, lower dose TBI (7.0 Gy) was combined with an anti-platelet antibody (anti-CD41) to induce severe TCP. Deaths in both models were due to gastrointestinal or intracranial bleeding. Addition of antiplatelet antibody to 7.0 Gy TBI significantly worsened TCP and increased mortality compared to 7.0 Gy TBI alone. FCNs significantly improved survival compared to saline control in both models, suggesting it ameliorated TCP-related bleeding. Additionally, in a saphenous vein bleeding model of antibody-induced TCP, FCNs shortened bleeding times. There were no clinical or histological findings of thrombosis or laboratory findings of disseminated intravascular coagulation after FCN treatment. In support of safety, fluorescence microscopy suggests that FCNs bind to platelets only upon platelet activation with collagen, limiting activity to areas of endothelial damage. To our knowledge, this is the first biosynthetic agent to demonstrate a survival advantage in TCP-related bleeding.