创伤性脑损伤后产生的微囊泡通过二磷酸腺苷受体诱导血小板功能障碍。
Microvesicles generated following traumatic brain injury induce platelet dysfunction via adenosine diphosphate receptor.
机构信息
From the Department of Surgery (G.E.M., A.P., R.M., R.V., L.A.F., T.A.P., A.T.M., C.C.C., M.D.G.), University of Cincinnati, Cincinnati, Ohio.
出版信息
J Trauma Acute Care Surg. 2019 Apr;86(4):592-600. doi: 10.1097/TA.0000000000002171.
BACKGROUND
Traumatic brain injury (TBI) can result in an acute coagulopathy including platelet dysfunction that can contribute to ongoing intracranial hemorrhage. Previous studies have shown adenosine diphosphate (ADP)-induced platelet aggregation to be reduced after TBI. In addition, circulating microvesicles (MVs) are increased following TBI and have been shown to play a role in post-TBI coagulopathy and platelet function. We hypothesized that post-TBI MVs would affect platelet aggregation in a murine head injury model.
METHODS
Moderate TBI was performed using a weight-drop method in male C57BL6 mice. Whole blood, plasma, MVs, and MV-poor plasma were isolated from blood collected 10 minutes following TBI and were mixed separately with whole blood from uninjured mice. Platelet aggregation was measured with Multiplate impedance platelet aggregometry in response to ADP. The ADP P2Y12 receptor inhibitor, R-138727, was incubated with plasma and MVs from TBI mice, and platelet inhibition was again measured.
RESULTS
Whole blood taken from 10-minute post-TBI mice demonstrated diminished ADP-induced platelet aggregation compared with sham mice. When mixed with normal donor blood, post-TBI plasma and MVs induced diminished ADP-induced platelet aggregation compared with sham plasma and sham MVs. By contrast, the addition of post-TBI MV-poor plasma to normal blood did not change ADP-induced platelet aggregation. The observed dysfunction in post-TBI ADP platelet aggregation was prevented by the pretreatment of post-TBI plasma with R-138727. Treatment of post-TBI MVs with R-138727 resulted in similar findings of improved ADP-induced platelet aggregation compared with nontreated post-TBI MVs.
CONCLUSION
Adenosine diphosphate-induced platelet aggregation is inhibited acutely following TBI in a murine model. This platelet inhibition is reproduced in normal blood by the introduction of post-TBI plasma and MVs. Furthermore, observed platelet dysfunction is prevented when post-TBI plasma and MVs are treated with an inhibitor of the P2Y12 ADP receptor. Clinically observed post-TBI platelet dysfunction may therefore be partially explained by the presence of the ADP P2Y12 receptor within post-TBI MVs.
LEVEL OF EVIDENCE
Level III.
背景
创伤性脑损伤（TBI）可导致急性凝血病，包括血小板功能障碍，这可能导致持续的颅内出血。先前的研究表明，TBI 后二磷酸腺苷（ADP）诱导的血小板聚集减少。此外，TBI 后循环微泡（MVs）增加，并已证明其在 TBI 后凝血病和血小板功能中起作用。我们假设 TBI 后 MV 会影响小鼠颅脑损伤模型中的血小板聚集。
方法
使用重物下落法在雄性 C57BL6 小鼠中进行中度 TBI。在 TBI 后 10 分钟采集血液，分离全血、血浆、MVs 和 MV 贫血浆，并分别与未受伤小鼠的全血混合。用 Multiplate 阻抗血小板聚集仪测量 ADP 诱导的血小板聚集。将 ADP P2Y12 受体抑制剂 R-138727 与 TBI 小鼠的血浆和 MVs 孵育，再次测量血小板抑制率。
结果
与假手术小鼠相比，从 TBI 后 10 分钟采集的全血显示 ADP 诱导的血小板聚集减少。当与正常供体血液混合时，与假手术血浆和假手术 MVs 相比，TBI 后血浆和 MVs 诱导的 ADP 诱导的血小板聚集减少。相比之下，将 TBI 后 MV 贫血浆添加到正常血液中不会改变 ADP 诱导的血小板聚集。用 R-138727 预处理 TBI 后血浆可预防 TBI 后 ADP 诱导的血小板聚集功能障碍。与未处理的 TBI 后 MVs 相比，用 R-138727 处理 TBI 后 MVs 可导致 ADP 诱导的血小板聚集得到改善。
结论
在小鼠模型中，TBI 后急性抑制 ADP 诱导的血小板聚集。在正常血液中，通过引入 TBI 后血浆和 MVs 可重现这种血小板抑制作用。此外，当用 P2Y12 ADP 受体抑制剂处理 TBI 后血浆和 MVs 时，观察到的血小板功能障碍得到预防。因此，临床上观察到的 TBI 后血小板功能障碍可能部分归因于 TBI 后 MVs 中存在 ADP P2Y12 受体。
证据水平
III 级。
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