Limiting Clotting : Fibrinolysis

Clots are temporary patches that must be removed once wound repair has begun. The fibrin clot is cleaved by the protein plasmin to fibrin degradation products (Fig. 1). [Note: Measurement of D-dimer, a fibrin degradation product containing two cross-linked D domains released by the action of plasmin, can be used to assess the extent of clotting .] Plasmin is a serine protease that is generated from plasminogen by plasminogen activators. Plasminogen, secreted by the liver into the circulation, binds to FIa and is incorporated into clots as they form. Tissue plasminogen activator (TPA, t-PA), made by vascular endothelial cells and secreted in an inactive form in response to FIIa, becomes active when bound to FIa–plasminogen. Bound plasmin and TPAa are protected from their inhibitors, α2-antiplasmin and plasminogen activator inhibitors, respectively. Once the fibrin clot is dissolved, plasmin and TPAa become available to their inhibitors. Therapeutic fibrinolysis in patients with an MI or an ischemic stroke can be achieved by treatment with commercially available TPA made by recombinant DNA techniques. Mechanical clot removal (thrombectomy) is also possible. [Note: Urokinase is a plasminogen activator (u-PA) made in a variety of tissues and originally isolated from urine. Streptokinase (from bacteria) activates both free and fibrin-bound plasminogen.]

Figure 1:  Fibrinolysis. [Note: Plasmin bound to fibrin is protected from its inhibitor.] TPA = tissue plasminogen activator; i = inactive; a = active; PAI = plasminogen activator inhibitor.
Plasminogen contains structural motifs known as “kringle domains” that mediate protein–protein interactions. Because lipoprotein (a) [Lp(a)] also contains kringle domains, it competes with plasminogen for binding to FIa. The potential to inhibit fibrinolysis may be the basis for the association of elevated Lp(a) with increased risk for cardiovascular disease.

مواضيع ذات صلة

Blood clotting (coagulation)

Platelet Plug Formation: Aggregation

Platelet Plug Formation: Activation

Platelet Plug Formation: Adhesion

Limiting Clotting : Inactivating proteins

Fibrin Meshwork Formation : Pathways

Fibrin Meshwork Formation : Formation of γ-carboxyglutamate residues

Fibrin Meshwork Formation :Role of phosphatidylserine and calcium

Fibrin Meshwork Formation: Proteolytic cascade

Blood Clotting : Overview

Biotechnology and Human Disease

Transgenic Animals