Tissue-type plasminogen activator-mediated plasminogen activation and contact activation, implications in and beyond...

Due to its discovery as initiator of fibrinolysis and its well-studied activation by fibrin, tissue-type plasminogen activator (tPA) and the fibrinolytic system are generally associated with the dissolution of blood clots. However, it has been demonstrated over the years that (i) tPA can be activated by multiple proteins, (ii) plasmin has many substrates other than fibrin and (iii) tPA and plasmin have biological functions independent of fibrin and distinct from their role in blood clot lysis. We here review the data with respect to the activation of tPA by fibrin and its multiple other cofactors, in relation to tPA's role in pathophysiology, notably fibrinolysis and amyloidosis, with emphasis on Alzheimer's disease. We demonstrate a common structural element, termed cross-β structure, in misfolded proteins that is causal to tPA activation. The implications for protein misfolding diseases that are known to be associated with the deposition of amyloid and for diseases for which this has not (yet) been established are discussed.