Enhanced Procoagulant Activity on Blood Cells after Acute Ischemic Stroke

The role of phosphatidylserine (PS)-mediated procoagulant activity (PCA) in stroke remains unclear. To ascertain this role, early dynamic evolution of PS exposure on blood cells and released microparticles (MPs) and the corresponding PCA were evaluated in patients with acute ischemic stroke (AIS). Flow cytometry analyses revealed that initial levels of PS exposure on erythrocyte, platelet, and leukocyte were 2.40-, 1.36-, and 1.38-fold higher, respectively, in AIS than the risk factor-matched (RF) controls. Concomitantly, total PS+ MPs were increased in AIS (1949 +/- 483/mu l) compared with the RF group (1674 +/- 387/mu l; P = 0.019) and healthy controls (1052 +/- 179/mu l; P < 0.001). Specifically, PS+ erythrocytes gradually increased within 1 week. PS+ platelets and MPs peaked at 24 h and declined at 7 days, while PS+ leukocytes were markedly elevated at 24 h. Further, PS exposure on blood cells and MPs in stroke resulted in shortened clotting time with an accompanying increase in FXa and thrombin formation significantly. Treatment with lactadherin, a PS antagonist, delayed the coagulation time by approximately 20 % and blocked the generation of FXa and thrombin by about 50 %. Furthermore, initial counts of PS+ platelets and platelet MPs significantly correlated with stroke severity. Thrombin generation promoted by platelets and MPs at 12 h was significantly higher in patients with cardioembolism than in patients without. The thrombophilic susceptibility of AIS patients can be partly ascribed to PS exposure on blood cells and the release of MPs. Our studies identify PS exposure as a potentially novel therapeutic target in the treatment of AIS.

磷脂酰丝氨酸（PS）介导的促凝血活性（PCA）在脑卒中中的作用仍不明确。为了确定这一作用，我们对急性缺血性脑卒中（AIS）患者血细胞和释放的微粒（MPs）上PS暴露的早期动态演变以及相应的PCA进行了评估。流式细胞术分析显示，AIS患者红细胞、血小板和白细胞上PS的初始暴露水平分别比危险因素匹配（RF）的对照组高2.40倍、1.36倍和1.38倍。同时，与RF组（1674 ± 387/μl；P = 0.019）和健康对照组（1052 ± 179/μl；P < 0.001）相比，AIS患者的总PS⁺ MPs增加（1949 ± 483/μl）。具体而言，PS⁺红细胞在1周内逐渐增加。PS⁺血小板和MPs在24小时达到峰值，并在7天下降，而PS⁺白细胞在24小时显著升高。此外，脑卒中时血细胞和MPs上的PS暴露导致凝血时间缩短，同时伴有显著的FXa和凝血酶形成增加。用PS拮抗剂乳黏素治疗可使凝血时间延迟约20%，并使FXa和凝血酶的产生减少约50%。此外，PS⁺血小板和血小板MPs的初始计数与脑卒中严重程度显著相关。心源性栓塞患者在12小时时由血小板和MPs促进的凝血酶生成显著高于无此情况的患者。AIS患者的血栓形成倾向可部分归因于血细胞上的PS暴露和MPs的释放。我们的研究确定PS暴露是AIS治疗中一个潜在的新治疗靶点。