Zhao Liangliang, Bi Yayan, Kou Junjie, Shi Jialan, Piao Daxun
Department of Colorectal Surgery, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China.
Department of Medicine, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China.
J Exp Clin Cancer Res. 2016 Mar 25;35:54. doi: 10.1186/s13046-016-0328-9.
Colon cancer is invariably accompanied by altered coagulation activity; however, the precise role of phosphatidylserine (PS) in the hypercoagulable state of colon cancer patients remains unclear. We explored the exposure of PS on platelets and microparticles (MPs), and evaluate its role in procoagulant activity in colon cancer patients.
PS-positive platelets and MPs, mainly from platelets and endothelial cells, were detected by flow cytometry and confocal microscopy, and their procoagulant activity was assessed with purified coagulation complex assays, clotting time, and fibrin turbidity.
Plasma levels of PS-positive platelets increased gradually from stage I to IV and were higher in all stages of the patients than in the healthy control, while PS-positive platelet-derived MPs only increased significantly in stage III/IV patients. Meanwhile, PS-positive MPs and endothelial-derived MPs in stage II/III/IV patients were markedly higher than ones in controls but no difference with stage I. Tissue factor positive MPs were higher in all 4 stages of colon cancer patients than in the healthy control. Platelets and MPs from the patients demonstrated significantly enhanced intrinsic/extrinsic FXa and thrombin generation, greatly shortened coagulation time, and increased fibrin formation. Combined treatment with PS antagonist lactadherin, strongly prolonged the coagulation time and reduced fibrin formation by inhibiting factor tenase and prothrombinase complex activity. In contrast, pretreatment with anti tissue factor antibody played a lesser role in suppression of procoagulant activity.
Our results suggest that PS-positive platelets and MPs contribute to hypercoagulability and represent a potential therapeutic target to prevent coagulation in patients with colon cancer.
结肠癌总是伴有凝血活性改变；然而，磷脂酰丝氨酸（PS）在结肠癌患者高凝状态中的确切作用仍不清楚。我们探讨了PS在血小板和微粒（MPs）上的暴露情况，并评估其在结肠癌患者促凝活性中的作用。
通过流式细胞术和共聚焦显微镜检测主要来自血小板和内皮细胞的PS阳性血小板和MPs，并用纯化的凝血复合物测定、凝血时间和纤维蛋白浊度评估其促凝活性。
PS阳性血小板的血浆水平从I期到IV期逐渐升高，且在患者的所有阶段均高于健康对照，而PS阳性血小板衍生的MPs仅在III/IV期患者中显著增加。同时，II/III/IV期患者的PS阳性MPs和内皮衍生的MPs明显高于对照组，但与I期无差异。组织因子阳性MPs在结肠癌患者的所有4个阶段均高于健康对照。患者的血小板和MPs表现出显著增强的内源性/外源性FXa和凝血酶生成，凝血时间大大缩短，纤维蛋白形成增加。与PS拮抗剂乳黏素联合治疗可通过抑制因子X酶和凝血酶原酶复合物活性，显著延长凝血时间并减少纤维蛋白形成。相比之下，用抗组织因子抗体预处理在抑制促凝活性方面作用较小。
我们的结果表明，PS阳性血小板和MPs促成高凝状态，是预防结肠癌患者凝血的潜在治疗靶点。
