Risman Rebecca A, Milman Noam, Ali Sinan Hajer, Tutwiler Valerie
Department of Biomedical Engineering, Rutgers University, New Brunswick, USA.
J Thromb Thrombolysis. 2025 Jul 14. doi: 10.1007/s11239-025-03118-x.
Pancreatic cancer (PC) has the highest risk of venous thromboembolisms amongst all cancer types. If not degraded through a process known as fibrinolysis, thrombi will continue to restrict blood flow and the transport of nutrients to downstream organs, which can lead to heart attack or stroke. While PC patients are known to be hypercoagulable and thus have an elevated thrombosis risk, the mechanism behind this behavior is not fully understood. We aimed to characterize alterations in clotting and fibrinolytic profiles in PC patients compared to healthy controls. Human blood plasma was collected from PC patients and healthy donor controls following institutional review board approval. We used kinetic turbidity to define the rates/timing of blood clot formation/degradation. Confocal and scanning electron microscopy were used to probe the effect PC has on fibrin network structure. Concentrations of proteins for clotting/fibrinolytic pathways were measured using ELISAs. PC patients were hypercoagulable compared to healthy donors with heightened fibrinogen concentration. A subset of patients were hypofibrinolytic, while most had similar fibrinolytic profiles to healthy. A comprehensive analysis revealed that delayed lysis in this subset was only present in patients with diabetes and/or COVID-19 due delayed clotting and, notably, elevated plasminogen activator inhibitor (PAI-1). In the general PC population, an extended PTT correlated with thicker fiber diameters while faster clotting resulted in smaller network pore size but was not correlated with lysis rate. Healthy, pooled plasma spiked with relevant concentrations of PAI-1 showed no difference in clot structure and comparable delays in lysis to patients. PAI-1, rather than network structure or other clotting/fibrinolytic factors, played a more significant role in hypofibrinolysis. PAI-1 inhibitors could be a prospective target for development of improved therapeutics to prevent restricted fibrinolysis.
在所有癌症类型中，胰腺癌（PC）发生静脉血栓栓塞的风险最高。如果血栓不能通过一种称为纤维蛋白溶解的过程降解，它将继续限制血液流动以及营养物质向下游器官的输送，这可能导致心脏病发作或中风。虽然已知PC患者具有高凝性，因此血栓形成风险升高，但其背后的机制尚未完全了解。我们旨在描述PC患者与健康对照相比凝血和纤维蛋白溶解谱的变化。在获得机构审查委员会批准后，从PC患者和健康供体对照中采集人血浆。我们使用动力学浊度法来确定血液凝固/降解的速率/时间。共聚焦和扫描电子显微镜用于探究PC对纤维蛋白网络结构的影响。使用酶联免疫吸附测定法测量凝血/纤维蛋白溶解途径的蛋白质浓度。与健康供体相比，PC患者具有高凝性，纤维蛋白原浓度升高。一部分患者纤维蛋白溶解功能减退，而大多数患者的纤维蛋白溶解谱与健康人相似。综合分析表明，这一亚组患者的纤溶延迟仅出现在患有糖尿病和/或新冠肺炎的患者中，原因是凝血延迟，尤其是纤溶酶原激活物抑制剂（PAI-1）升高。在一般PC人群中，活化部分凝血活酶时间延长与纤维直径变粗相关，而凝血速度加快导致网络孔径变小，但与纤溶速率无关。加入相关浓度PAI-1的健康混合血浆在凝块结构上没有差异，纤溶延迟情况与患者相当。PAI-1而非网络结构或其他凝血/纤维蛋白溶解因子在纤维蛋白溶解功能减退中起更重要作用。PAI-1抑制剂可能是开发改善治疗方法以防止纤维蛋白溶解受限的一个潜在靶点。
