A serpin with a finger in many PAI’s: PAI-1’s central function in thromboinflammation and cardiovascular disease

Gael B Morrow, Claire Whyte, Nicola J Mutch* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)
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Plasminogen activator inhibitor 1 (PAI-1) is a member of the serine protease inhibitor (serpin) superfamily. PAI-1 is the principal inhibitor of the plasminogen activators, tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Turbulence in the levels of PAI-1 tilts the balance of the haemostatic system resulting in bleeding or thrombotic complications. Not surprisingly there is strong evidence that documents the role of PAI-1 in cardiovascular disease. The more recent uncovering of the coalition between the haemostatic and inflammatory pathways have exposed a distinct role for PAI-1. The storm of proinflammatory cytokines liberated during inflammation, including IL-6 and TNFα, directly influence PAI-1 synthesis and increase circulating levels of this serpin. Consequently, elevated levels of PAI-1 are commonplace during infection and are frequently associated with a hypofibrinolytic state and thrombotic complications. Elevated PAI-1 levels are also a feature of metabolic syndrome, which is defined by a cluster of abnormalities including obesity, type 2 diabetes, hypertension and elevated triglyceride. Metabolic syndrome is in itself defined as a proinflammatory state associated with elevated levels of cytokines. In addition, insulin has a direct impact on PAI-1 synthesis bridging these pathways. This review describes the key physiological functions of PAI-1 and how these become perturbed during disease processes. We focus on the direct relationship between PAI-1 and inflammation and the repercussion in terms of an ensuing hypofibrinolytic state and thromboembolic complications. Collectively these observations strengthen the utility of PAI-1 as a viable drug target for treatment of various diseases.

Original languageEnglish
Article number653655
Number of pages13
JournalFrontiers in cardiovascular medicine
Publication statusPublished - 16 Apr 2021

Bibliographical note

NM and CW are funded by grants from the British Heart Foundation PG/15/82/31721 and PG/20/17/35050 and Friends of Anchor RS 2019 003 and Aberdeen Development Trust. GM,
CW, and NM were also funded by NHS Grampian Endowment Fund COV19-004.


  • PAI-1
  • Fibrinolysis
  • metabolic syndrome
  • obese
  • diabetes
  • thrombosis
  • inflammation


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