In vivo efficacy of platelet-delivered, high specific activity factor VIII variants
In vivo efficacy of platelet-delivered, high specific activity factor VIII variants
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DOI：
10.1182/blood-2010-06-293308
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发表时间：
2010-12-23
期刊：
影响因子：
20.3
通讯作者：
Poncz, Mortimer
中科院分区：
文献类型：
--
作者：
Greene, Teshell K.;Wang, Cheng;Poncz, Mortimer
异位表达的人无B区(HB)因子8(F8)在几种损伤模型中改善了血友病A鼠的止血作用。然而，在皮肤出血模型和提睾肌激光小动脉/小静脉损伤模型中，血小板衍生(P)hBF8的疗效都存在局限性，包括增加血栓栓塞率。我们现在讨论具有增强活性的F8变体，抗灭活的F8(IR8)和犬(C)BF8是否会改善凝血效果。在转基因和慢病毒小鼠模型中，pIR8的表达水平与phBF8相当，而pcBF8的表达水平仅为约30%。在皮肤出血和FeCl3颈动脉模型中，两种变异体都比hBF8更有效。然而，在提睾肌损伤模型中，只有pcBF8更有效，显著减少了血栓栓塞率。由于F8的抑制剂储存在血小板颗粒中，而IR8不受von Willebrand因子结合的保护，我们还测试了pIR8在面对抑制剂时是否有效，发现pIR8对抑制剂具有保护作用。总之，具有高比活性的pF8变体在控制出血方面更有效，但这种改善的疗效在出血模型之间是不一致的，可能反映了所研究的F8变体比活性增加的潜在机制(S)。(血。2010；116(26)：6114-6122)
Ectopically expressed, human B-domainless (hB) factor 8 (F8) in platelets improves hemostasis in hemophilia A mice in several injury models. However, in both a cuticular bleeding model and a cremaster laser arteriole/venule injury model, there were limitations to platelet-derived (p) hBF8 efficacy, including increased clot embolization. We now address whether variants of F8 with enhanced activity, inactivation resistant F8 (IR8) and canine (c) BF8, would improve clotting efficacy. In both transgenic and lentiviral murine model approaches, pIR8 expressed at comparable levels to phBF8, but pcBF8 expressed at only approximately 30%. Both variants were more effective than hBF8 in cuticular bleeding and FeCl3 carotid artery models. However, in the cremaster injury model, only pcBF8 was more effective, markedly decreasing clot embolization. Because inhibitors of F8 are stored in platelet granules and IR8 is not protected by binding to von Willebrand factor, we also tested whether pIR8 was effective in the face of inhibitors and found that pIR8 is protected from the inhibitors. In summary, pF8 variants with high specific activity are more effective in controlling bleeding, but this improved efficacy was inconsistent between bleeding models, perhaps reflecting the underlying mechanism(s) for the increased specific activity of the studied F8 variants. (Blood. 2010; 116(26):6114-6122)