The plasmin–antiplasmin system: structural and functional aspects

Abstract

The plasmin-antiplasmin system plays a key role in blood coagulation and fibrinolysis. Plasmin and α(2)-antiplasmin are primarily responsible for a controlled and regulated dissolution of the fibrin polymers into soluble fragments. However, besides plasmin(ogen) and α(2)-antiplasmin the system contains a series of specific activators and inhibitors. The main physiological activators of plasminogen are tissue-type plasminogen activator, which is mainly involved in the dissolution of the fibrin polymers by plasmin, and urokinase-type plasminogen activator, which is primarily responsible for the generation of plasmin activity in the intercellular space. Both activators are multidomain serine proteases. Besides the main physiological inhibitor α(2)-antiplasmin, the plasmin-antiplasmin system is also regulated by the general protease inhibitor α(2)-macroglobulin, a member of the protease inhibitor I39 family. The activity of the plasminogen activators is primarily regulated by the plasminogen activator inhibitors 1 and 2, members of the serine protease inhibitor superfamily.

Coagulation factor XIIIa is inactivated by plasmin

“…Physiologically, tPA is present in the blood at ;70 pM; however, therapeutic tPA is typically administered either IV, leading to systemic blood concentrations of ;50 nM, 24 or locally into clots from intravascular catheters at ;400 nM. 19 In our experiments, FXIII-A 2 * was degraded during clot formation under thrombolytic conditions, at 50 nM tPA. This mechanism may contribute to hemorrhaging associated with thrombolytic therapy.…”

“…However, the rate of cleavage of FXIII-A 2 * in plasma was slower than the estimated half-life of FXIII-A 2 *, likely due to the presence of competing substrates such as fibrin 18 and inhibitors of plasmin such as a 2 -antiplasmin. 19 Notably, however, during normal clot formation, FXIII-A 2 * appeared to reach its full potential in cross-linking fibrin before it was inactivated, but fibrin was not cross-linked when added to reactions following FXIII-A 2 * inactivation. Thus, this mechanism may prevent FXIII-A 2 * from aberrantly cross-linking fibrin and other proteins in blood vessels.…”

Urokinase-type Plasminogen Activator (uPA) and its Receptor (uPAR) Promote Neurorepair in the Ischemic Brain

“…uPA is assembled by an amino terminal epidermal growth factor (EGF)-like domain that contains the uPAR binding residues, a kringle domain and a carboxy-terminal proteolytic domain [5] . The first two regions form the amino terminal fragment (ATF), which contains the interaction site with the receptor but lacks the enzymatic activity.…”

Proteolytic clearance of extracellular α-synuclein as a new therapeutic approach against Parkinson disease

“…It is derived from its inactive form, plasminogen, by tissue type plasminogen activator (tPA) or urokinase plasminogen activator (uPA). 63 Although plasmin is synthesized mainly in the liver, it has also been detected in the CNS and is mainly expressed in neurons and astrocytes. enzymes responsible for the degradation of aggregation-prone proteins and efforts to find them and so regulate them directly or indirectly should aid the elucidation of the pathogenesis of many neurodegenerative diseases and hence help the development of therapeutic strategies of them.…”