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. 35.19). [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 (see Fig. 35.12).] 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.]
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 (see p. 236).
IV. PLATELET PLUG FORMATION
Platelets (thrombocytes) are small, anucleate fragments of megakaryocytes that adhere to exposed collagen of damaged endothelium, get activated, and aggregate to form a platelet plug (Fig. 35.20; also see Fig. 35.1). Formation of the platelet plug is referred to as primary hemostasis because it is the first response to bleeding. In a normal adult, there are 150,000–450,000 platelets per µl of blood. They have a life span of up to 10 days, after which they are taken up by the liver and spleen and destroyed. Clinical laboratory tests to measure platelet number and activity are available.
A. Adhesion