From Fibrinolysis to the Plasminogen–Plasmin System and Beyond: A Remarkable Growth of Knowledge, with Personal Observations on the History of Fibrinolysis

Abstract

Great advances have been made in our understanding of the fibrinolytic system from the initial discovery of proteolysis of fibrin by plasmin to the multifaceted and complex role of the plasminogen?plasmin (P?P) system. We now know that the P?P system is composed of several serine proteases and their inhibitors (serpins). This system is involved in many physiological functions, including embryogenesis, cell migration, and wound healing. They also play an important role in the pathogenesis of many diseases, including atherosclerosis, obesity, cancer, and even autoimmune disorders, and neuronal degeneration. Knowledge of their role in cancer enables their use as a prognostic factor. Therapeutic use of various forms of proteases derived from this system has been employed as thrombolytic agents. In addition, small molecules designed to inhibit many of the components of the P?P system are now available for clinical trial, aimed at treatment of these various disorders. The history of such remarkable development of our knowledge on fibrinolysis is reviewed in this article.

Emerging Risk Biomarkers in Cardiovascular Diseases and Disorders

“…P194Serum uric acid is independent predictor of decreased number of circulating proangiogenic progenitor cells in asymptomatic coronary artery disease patients [ 191 ], while P733regulatory B cells from patients with coronary artery disease display numerical and functional alterations, a novel immune defect in atherosclerosis [ 192 ]. Similarly, phospholipase A2 enzymes can predict ischemic events after acute coronary syndromes [ 193 ], while plasminogen-plasmin level is considered as an important biomarker of fibrinolysis [ 194 ]. Similarly, atrial fibrosis is a risk stratifier for atrial fibrillation [ 195 ], while mitogen-activated protein kinases [ 196 ] and intercellular adhesion molecule1 gene polymorphism are good markers of coronary heart diseases [ 197 ] mainly for atherosclerosis [ 196 ].…”

Breaking boundaries—coagulation and fibrinolysis at the neurovascular interface

“…The plasminogen activation (PA) system is an enzymatic cascade with key regulatory functions in fibrinolysis and degradation of extracellular matrix proteins (Syrovets and Simmet, 2004 ; Castellino and Ploplis, 2005 ; Kwaan, 2014 ). Plasminogen circulates in the blood as an inactive zymogen that is converted into active plasmin by tissue-type plasminogen activator (tPA) or urokinase-type plasminogen activator (uPA).…”

Spectrophotometric analysis of thrombolytic activity: SATA assay

“…Historically, fibrinolysis was discovered through many observations including the fact that blood collected by wet-cupping (several milliliters) might be clotted and then spontaneously dissolved in 12-24 hours. 36 Whole blood certainly possesses potency of lysing clot per se , and this potency originates from the natural blood thrombolytic agents. Thus, it is not of surprise that the control samples with zero concentration of active tPA exhibit clot lysis to some extents in all methods developed for thrombolytic activity measurement, including the developed SATA assay and the digested clot method.…”