Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies.
Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies.
复制标题
酶促氧化的磷脂可恢复凝血因子缺乏时的凝血酶生成。
DOI：
10.1172/jci.insight.98459
复制
发表时间：
2018
期刊：
影响因子：
8
通讯作者：
Hall,
中科院分区：
文献类型：
--
作者：
Slatter,DavidA;Percy,CharlesL;Allen-Redpath,Keith;Gajsiewicz,JoshuaM;Brooks,NickJ;Clayton,Aled;Tyrrell,VictoriaJ;Rosas,Marcela;Lauder,SarahN;Watson,Andrew;Dul,Maria;Garcia-Diaz,Yoel;Aldrovandi,Maceler;Heurich,Meike;Hall,
止血缺陷使用凝血因子治疗;然而，凝块形成还需要促凝血磷脂（PL）表面。在这里，我们表明，先天免疫细胞衍生的酶促氧化磷脂（eoxPL）称为羟基二十碳四烯酸-磷脂（HETE-PL）恢复止血人类和小鼠的病理性出血条件。HETE-PL消除了小鼠血友病A中的失血，并增强了因子VIII-（FVIII-）、FIX-和FX-缺陷型人血浆中的凝血。体外循环（CPB）后患者血小板中HETE-PL减少。为了探索分子机制，在体外测试了eoxPL刺激单个分离的凝血因子/辅因子复合物的能力。HETE-PE和HETE-PC均能增强外源性肌腱酶（FVIIa/组织因子[TF]）、内源性肌腱酶（FVIIIa/FIXa）和凝血酶原酶（FVa/FXa），表明涉及脂肪酸部分的共同机制。在血浆中，9-、15-和12-HETE-PL比5-、11-或8-HETE-PL更有效，表明位置异构体特异性。凝血功能在较低的脂质/因子比下增强，与蛋白结合的更集中区域一致。表面等离子体共振证实了FIB和FX与HETE-PE的结合。HETE-PE增加膜曲率和厚度，但不增加表面电荷或均匀性，这可能表明阳离子/因子的可及性增加。总之，先天免疫衍生的eoxPL增强钙依赖性凝血因子功能，并提出了其在出血性疾病中的潜在效用。
Hemostatic defects are treated using coagulation factors; however, clot formation also requires a procoagulant phospholipid (PL) surface. Here, we show that innate immune cell–derived enzymatically oxidized phospholipids (eoxPL) termed hydroxyeicosatetraenoic acid–phospholipids (HETE-PLs) restore hemostasis in human and murine conditions of pathological bleeding. HETE-PLs abolished blood loss in murine hemophilia A and enhanced coagulation in factor VIII- (FVIII-), FIX-, and FX-deficient human plasma . HETE-PLs were decreased in platelets from patients after cardiopulmonary bypass (CPB). To explore molecular mechanisms, the ability of eoxPL to stimulate individual isolated coagulation factor/cofactor complexes was tested in vitro. Extrinsic tenase (FVIIa/tissue factor [TF]), intrinsic tenase (FVIIIa/FIXa), and prothrombinase (FVa/FXa) all were enhanced by both HETE-PEs and HETE-PCs, suggesting a common mechanism involving the fatty acid moiety. In plasma, 9-, 15-, and 12-HETE-PLs were more effective than 5-, 11-, or 8-HETE-PLs, indicating positional isomer specificity. Coagulation was enhanced at lower lipid/factor ratios, consistent with a more concentrated area for protein binding. Surface plasmon resonance confirmed binding of FII and FX to HETE-PEs. HETE-PEs increased membrane curvature and thickness, but not surface charge or homogeneity, possibly suggesting increased accessibility to cations/factors. In summary, innate immune-derived eoxPL enhance calcium-dependent coagulation factor function, and their potential utility in bleeding disorders is proposed.