Clot formation, structure, and fibrinolysis of plasma from pancreatic cancer patients.

Abstract

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.