Wang Yongzhi, Zhang Su, Luo Lingtao, Norström Eva, Braun Oscar Ö, Mörgelin Matthias, Thorlacius Henrik
Department of Clinical Sciences, Section for Surgery, Lund University, Malmö, Sweden.
Department of Laboratory Medicine, Section of Clinical Chemistry, Lund University, Malmö, Sweden.
J Cell Physiol. 2018 Feb;233(2):1051-1060. doi: 10.1002/jcp.25959. Epub 2017 Jun 6.
Sepsis is associated with dysfunctional coagulation. Recent data suggest that platelets play a role in sepsis by promoting neutrophil accumulation. Herein, we show that cecal ligation and puncture (CLP) triggered systemic inflammation, which is characterized by formation of IL-6 and CXC chemokines as well as neutrophil accumulation in the lung. Platelet depletion decreased neutrophil accumulation, IL-6, and CXC chemokines formation in septic lungs. Depletion of platelets increased peak thrombin formation and total thrombin generation (TG) in plasma from septic animals. CLP elevated circulating levels of platelet-derived microparticles (PMPs). In vitro generated PMPs were a potent inducer of TG. Interestingly, in vitro wild-type recombinant annexin V abolished PMP-induced thrombin formation whereas a mutant annexin V protein, which does not bind to phosphatidylserine (PS), had no effect. Administration of wild-type, but not mutant annexin V, significantly inhibited thrombin formation in septic animals. Moreover, CLP-induced formation of thrombin-antithrombin complexes were reduced in platelet-depleted mice and in animals pretreated with annexin V. PMP-induced TG attenuated in FXII- and FVII-deficient plasma. These findings suggest that sepsis-induced TG is dependent on platelets. Moreover, PMPs formed in sepsis are a potent inducer of TG via PS exposure, and activation of both the intrinsic and extrinsic pathway of coagulation. In conclusion, these observations suggest that PMPs and PS play an important role in dysfunctional coagulation in abdominal sepsis.
脓毒症与凝血功能障碍有关。最近的数据表明，血小板通过促进中性粒细胞聚集在脓毒症中发挥作用。在此，我们表明盲肠结扎和穿刺（CLP）引发全身炎症，其特征是白细胞介素-6（IL-6）和CXC趋化因子的形成以及肺中中性粒细胞的聚集。血小板减少可降低脓毒症肺中中性粒细胞的聚集、IL-6和CXC趋化因子的形成。血小板减少会增加脓毒症动物血浆中凝血酶峰值形成和总凝血酶生成（TG）。CLP可提高循环中血小板衍生微粒（PMPs）的水平。体外生成的PMPs是TG的有效诱导剂。有趣的是，体外野生型重组膜联蛋白V可消除PMP诱导的凝血酶形成，而不与磷脂酰丝氨酸（PS）结合的突变型膜联蛋白V蛋白则无此作用。给予野生型而非突变型膜联蛋白V可显著抑制脓毒症动物体内的凝血酶形成。此外，在血小板减少的小鼠和用膜联蛋白V预处理的动物中，CLP诱导的凝血酶-抗凝血酶复合物的形成减少。在缺乏因子XII（FXII）和因子VII（FVII）的血浆中，PMP诱导的TG减弱。这些发现表明，脓毒症诱导的TG依赖于血小板。此外，脓毒症中形成的PMPs通过PS暴露以及凝血内源性和外源性途径的激活，是TG的有效诱导剂。总之，这些观察结果表明，PMPs和PS在腹部脓毒症的凝血功能障碍中起重要作用。
