Functional plasminogen activator inhibitor 1 is retained on the activated platelet membrane following platelet activation.

Morrow, Gael B.; Whyte, Claire S.; Mutch, Nicola J.

Abstract

Platelets harbor the primary reservoir of circulating plasminogen activator inhibitor 1 (PAI-1), but the reportedly low functional activity of this pool of inhibitor has led to debate over its contribution to thrombus stability. Here we analyze the fate of PAI-1 secreted from activated platelets and examine its role in maintaining thrombus integrity. Activation of platelets results in translocation of PAI-1 to the outer leaflet of the membrane, with maximal exposure in response to strong dual agonist stimulation. PAI-1 is found to co-localize in the 'cap' of phosphatidylserine-exposing platelets with its co-factor, vitronectin, and fibrinogen. Inclusion of tirofiban or Gly-Pro-Arg-Pro significantly attenuated exposure of PAI-1, indicating a crucial role for integrin αIIbb3 and fibrin in delivery of PAI-1 to the activated membrane. Separation of platelets post stimulation into soluble and cellular components revealed the presence of PAI-1 antigen and activity in both fractions, with approximately 40% of total platelet-derived PAI-1 remaining associated with the cellular fraction. Using a variety of fibrinolytic models, we found that platelets produce a strong stabilizing effect against tissue plasminogen activator (tPA)-mediated clot lysis. Platelet lysate, as well as soluble and cellular fractions, stabilize thrombi against premature degradation in a PAI-1-dependent manner. Our data show for the first time that a functional pool of PAI-1 is anchored to the membrane of stimulated platelets and regulates local fibrinolysis. We reveal a key role for integrin αIIbb3 and fibrin in delivery of PAI-1 from platelet α-granules to the activated membrane. These data suggest that targeting platelet-associated PAI-1 may represent a viable target for novel profibrinolytic agents.

Citation

MORROW, G.B., WHYTE, C.S. and MUTCH, N.J. 2020. Functional plasminogen activator inhibitor 1 is retained on the activated platelet membrane following platelet activation. Haematologica [online], 105(12), pages 2824-2833. Available from: https://doi.org/10.3324/haematol.2019.230367

• Journal Article Type: Article
• Acceptance Date: Nov 21, 2019
• Online Publication Date: Nov 28, 2019
• Publication Date: Dec 31, 2020
• Deposit Date: Aug 7, 2023
• Publicly Available Date: Aug 15, 2023
• Journal: Haematologica
• Print ISSN: 0390-6078
• Electronic ISSN: 1592-8721
• Publisher: Ferrata Storti Foundation
• Peer Reviewed: Peer Reviewed
• Volume: 105
• Issue: 12
• Pages: 2824-2833
• DOI: https://doi.org/10.3324/haematol.2019.230367
• Keywords: PAI-1; Platelets; Thrombus; Hemostasis; Vessel injury; Hematology
• Public URL: https://rgu-repository.worktribe.com/output/2034907