Fibrinolysis and the control of blood coagulation

Abstract

Fibrin plays an essential role in hemostasis as both the primary product of the coagulation cascade and the ultimate substrate for fibrinolysis. Fibrinolysis efficiency is greatly influenced by clot structure, fibrinogen isoforms and polymorphisms, the rate of thrombin generation, the reactivity of thrombus-associated cells such as platelets, and the overall biochemical environment. Regulation of the fibrinolytic system, like that of the coagulation cascade, is accomplished by a wide array of cofactors, receptors, and inhibitors. Fibrinolytic activity can be generated either on the surface of a fibrin-containing thrombus, or on cells that express profibrinolytic receptors. In a widening spectrum of clinical disorders, acquired and congenital defects in fibrinolysis contribute to disease morbidity, and new assays of global fibrinolysis now have potential predictive value in multiple clinical settings. Here, we summarize the basic elements of the fibrinolytic system, points of interaction with the coagulation pathway, and some recent clinical advances.

Blood–Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke

“…The resulting fragments are typically cleared by proteases or by the kidney and liver 110. DM is associated with diminished fibrinolytic capacity, increased coagulability, and increased concentration in blood of PAI‐1 111.…”

The evolution of recombinant thrombolytics: Current status and future directions

“…Plasmin restores the vascular patency by proteolysis of insoluble fibrin into fibrin degradation products leading to the dissolution of blood clots. 14 …”

“…17 Upon activation by thrombin, the thrombin-activated fibrinolysis inhibitor (TAFI) (a non-serpin inhibitor) downregulates thrombolysis by removing the C-terminal lysine residues essential for plasminogen binding to fibrin. 14 …”

“…123 Deletion or substitution of the Lys 11 residue abolished its activator function. 124 Substitution of Lys 11 , Asp 13 , and Asp 14 with Ala results in a mutated SAK that binds plasmin (ogen) but does not activate soluble plasminogen. Similarly, substitutions of Glu 46 , Lys 50 , Glu 65 and Asp 69 with alanine yielded mutants with impaired activation ability.…”

“…They are specific, fastacting inactivators of the serine protease inhibitor (SERPIN) superfamily. 14 The main physiological inhibitors of the plasminogen activators are plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2). 18 The primary plasmin inhibitor in circulation is a2-antiplasmin (a2-PI).…”