Distinct Pathogenesis of Pancreatic Cancer Microvesicle–Associated Venous Thrombosis Identifies New Antithrombotic Targets In Vivo
Distinct Pathogenesis of Pancreatic Cancer Microvesicle–Associated Venous Thrombosis Identifies New Antithrombotic Targets In Vivo
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DOI：
10.1161/atvbaha.117.310262
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发表时间：
2018-02
期刊：
影响因子：
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通讯作者：
K. Stark;I. Schubert;U. Joshi;B. Kilani;P. Hoseinpour;M. Thakur;Petra Grünauer;S. Pfeiler;Tobias Schmidergall;Sven Stockhausen;Markus Bäumer;S. Chandraratne;Marie-Luise von Brühl;M. Lorenz;R. Coletti;S. Reese;I. Laitinen;S. Wörmann;H. Algül;C. Bruns;J. Ware;N. Mackman;B. Engelmann;S. Massberg
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文献类型：
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作者：
K. Stark;I. Schubert;U. Joshi;B. Kilani;P. Hoseinpour;M. Thakur;Petra Grünauer;S. Pfeiler;Tobias Schmidergall;Sven Stockhausen;Markus Bäumer;S. Chandraratne;Marie-Luise von Brühl;M. Lorenz;R. Coletti;S. Reese;I. Laitinen;S. Wörmann;H. Algül;C. Bruns;J. Ware;N. Mackman;B. Engelmann;S. Massberg
目的-癌症患者发生深静脉血栓形成（DVT）和静脉血栓栓塞的风险很高，这是该人群死亡的主要原因。然而，目前还不清楚恶性肿瘤如何驱动血栓前级联反应最终导致DVT。方法和结果-在这里，我们讨论了恶性DVT与非恶性DVT相比的病理生理学，并重点关注肿瘤微泡作为预防癌症相关DVT的潜在靶点的作用。我们发现胰腺癌细胞释放的微泡（胰腺肿瘤衍生的微泡[pcMV]）促进小鼠腔静脉血流受限模型中的血栓形成。这取决于pcMV和宿主组织因子对凝血的协同激活。与由先天免疫细胞引发和传播的非恶性DVT不同，pcMV触发的血栓形成在很大程度上不依赖于髓系白细胞或血小板。相反，我们确定磷脂磷脂酰乙醇胺的外化作为一个主要的机制控制血栓前活动的pcMV。破坏X因子的磷脂酰乙醇胺依赖性激活可抑制PCV诱导的DVT，而不引起止血变化。结论：总之，我们在这里表明，与先天性免疫细胞促进的非恶性DVT的病理生理学与pcMV相关的实验性DVT明显不同，因此适用于不同的抗血栓形成策略。将磷脂酰乙醇胺靶向于肿瘤微囊泡可能是预防癌症相关DVT而不引起出血并发症的新策略。
Objective— Cancer patients are at high risk of developing deep venous thrombosis (DVT) and venous thromboembolism, a leading cause of mortality in this population. However, it is largely unclear how malignant tumors drive the prothrombotic cascade culminating in DVT. Approach and Results— Here, we addressed the pathophysiology of malignant DVT compared with nonmalignant DVT and focused on the role of tumor microvesicles as potential targets to prevent cancer-associated DVT. We show that microvesicles released by pancreatic adenocarcinoma cells (pancreatic tumor–derived microvesicles [pcMV]) boost thrombus formation in a model of flow restriction of the mouse vena cava. This depends on the synergistic activation of coagulation by pcMV and host tissue factor. Unlike nonmalignant DVT, which is initiated and propagated by innate immune cells, thrombosis triggered by pcMV was largely independent of myeloid leukocytes or platelets. Instead, we identified externalization of the phospholipid phosphatidylethanolamine as a major mechanism controlling the prothrombotic activity of pcMV. Disrupting phosphatidylethanolamine-dependent activation of factor X suppressed pcMV-induced DVT without causing changes in hemostasis. Conclusions— Together, we show here that the pathophysiology of pcMV-associated experimental DVT differs markedly from innate immune cell–promoted nonmalignant DVT and is therefore amenable to distinct antithrombotic strategies. Targeting phosphatidylethanolamine on tumor microvesicles could be a new strategy for prevention of cancer-associated DVT without causing bleeding complications.