We appreciate the summary and interpretation of the findings of our NASHFit Trial by Zanetto et al.[1] This was the first study investigating how exercise can mitigate thrombotic risk in patients with NASH. We found that the plasma level of plasminogen activator inhibitor (PAI)-1 was significantly decreased following 20 weeks of exercise training, independent of obesity or body composition. These findings are important because patients with NASH have increased rates of thromboembolism.[2] Decreasing PAI-1, which is abnormal and leads to impaired fibrinolysis (clot breakdown) in NASH, would be expected to lessen thromboembolism and its subsequent morbidity and mortality.
PAI-1 is an established biomarker of thrombotic complications across multiple populations, including those with metabolic disease. In patients with NASH, there is a large body of evidence demonstrating increased PAI-1 level in a dose-dependent fashion across all disease stages.[3] We previously demonstrated that PAI-1 level was much greater in liver transplant candidates with NASH cirrhosis and that PAI-1 level normalizes within 1 week following transplantation.[4] However, our study was underpowered to detect an association between PAI-1 and thromboembolism. To date, we are unaware of any prospective studies linking PAI-1 to thrombotic events exclusively in patients with NASH.
In this letter, Zanetto et al. provide new evidence to support PAI-1 as a biomarker of thromboembolism in NASH. In their post hoc analysis of 26 patients with NASH cirrhosis, PAI-1 level was significantly greater in the 5 patients who developed venous thromboembolism, independent of other components of the fibrinolytic system. Although interpretation of these results needs to be performed cautiously given the relatively small sample size consisting largely of male patients with decompensated cirrhosis, the findings are nonetheless promising and provide additional evidence linking impaired fibrinolysis to thrombotic events in NASH. We look to future prospective studies to validate these findings and confirm that PAI-1 remains a relevant thrombotic biomarker in patients with NASH across all stages of disease.
Footnotes
CONFLICT OF INTEREST
Dr. Stine received grants from Novo Nordisk, Noom, Inc., AstraZeneca and Grifols.
REFERENCES
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