Plasminogen activator inhibitor 1 and venous thrombosis in pancreatic cancer.

Yohei Hisada, Kenison B Garratt, Anaum Maqsood, Steven P Grover, Tomohiro Kawano, Brian C Cooley, Jonathan Erlich, Florian Moik, Matthew J Flick, Ingrid Pabinger, Nigel Mackman, Cihan Ay

Blood advances 2021 Jan 26

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Pancreatic cancer patients have a high risk of venous thromboembolism (VTE). Plasminogen activator inhibitor 1 (PAI-1) inhibits plasminogen activators and increases the risk of thrombosis. PAI-1 is expressed by pancreatic tumors and human pancreatic cell lines. However, to date, there are no studies analyzing the association of active PAI-1 and VTE in pancreatic cancer patients. We investigated the association of active PAI-1 in plasma and VTE in pancreatic cancer patients. In addition, we determined if the presence of human pancreatic tumors expressing PAI-1 impairs venous thrombus resolution in mice. Plasma levels of active PAI-1 in patients with pancreatic cancer and mice bearing human tumors were determined by enzyme-linked immunosorbent assay. We measured PAI-1 expression in 5 different human pancreatic cancer cell lines and found that PANC-1 cells expressed the highest level. PANC-1 tumors were grown in nude mice. Venous thrombosis was induced by complete ligation of the inferior vena cava (IVC). Levels of active PAI-1 were independently associated with increased risk of VTE in patients with pancreatic cancer (subdistribution hazard ratio per doubling of levels: 1.39 [95% confidence interval, 1.09-1.78], P = .007). Mice bearing PANC-1 tumors had increased levels of both active human and active mouse PAI-1 and decreased levels of plasmin activity. Importantly, mice bearing PANC-1 tumors exhibited impaired venous thrombus resolution 8 days after IVC stasis compared with nontumor controls. Our results suggest that PAI-1 contributes to VTE in pancreatic cancer. © 2021 by The American Society of Hematology.

Citation

Yohei Hisada, Kenison B Garratt, Anaum Maqsood, Steven P Grover, Tomohiro Kawano, Brian C Cooley, Jonathan Erlich, Florian Moik, Matthew J Flick, Ingrid Pabinger, Nigel Mackman, Cihan Ay. Plasminogen activator inhibitor 1 and venous thrombosis in pancreatic cancer. Blood advances. 2021 Jan 26;5(2):487-495