The Unique Role Of Thrombin In Hemostasis

Thrombin holds a respected place in the coagulation mechanism for its multiplicity of function and the numerous reactions it mediates. The impact of thrombin is far reaching from the initial activation of the platelet system to the initiation of the fibrinolytic system and subsequent tissue repair. Prothrombin is the precursor to thrombin and can only be converted by the action of factor X, factor V, platelet factor 3, and calcium. Thrombin is generated in small concentrations through injury to the endothelial cells and proceeds to initiate a more enhanced coagulation mechanism. Once generated, thrombin is involved in the platelet release reaction as well as platelet aggregation. Secondarily, thrombin stimulates platelets to produce the platelet inhibitor, prostacyclin, or PGI2. With the coagulation system alerted, thrombin activates factors V and VIII, key cofactors in thrombus formation. Protein C, a naturally occurring inhibitor to coagulation, is also activated by thrombin. An additional product thrombomodulin which is secreted by endothelial cells amplifies protein C activity when complexed with thrombin.5 With respect to the fibrinogen degradation, thrombin plays a key role in negative feedback by converting plasmino-gen to plasmin to digest the soluble fibrin clot. This interplay of thrombin disposition and thrombin initiation of clot disposal is part of the biologic control of hemostasis. Once the clot is dissolved, thrombin plays a role in repairing tissue and wounds (Fig. 18.2).

Physiological Activators of Fibrinolysis

A critical link in the chain of hemostasis is the dissolution of fibrin clots, which usually occurs several hours after the stable clot is formed. In this way, blood flow is restored at the local levels and tissue healing is precipitated. The body provides naturally occurring or physiological activators that initiate this process. The key component in this reaction is plasminogen, a plasma enzyme synthesized in the liver with a half-life of 48 hours. Plasminogen is converted to plasmin, chiefly through the action of tissue plasminogen activator (tPA), a substance released through the activity of endothelial cell damage and the production of thrombin. Additional plasminogen activators include factor

XIIa, kallikrein, and high-molecular-weight kininogen. Once produced, plasmin, a potent enzyme, does not distinguish between fibrin and fibrinogen and works to digest both. Additionally, plasmin also hydrolyzes factors V and VIII, and if circulating in the plasma as pathological free plasmin, the damage to the coagulation system is significant, as clots are dissolved indiscriminately. Of interest is the fact that tPA has been synthesized by recombinant technology and is presently used as a pharmaceutical product during stroke episodes for fibrinolytic therapy. As a "clot-busting" drug, it has been effective in thrombotic strokes and if injected within a small time-frame can spare the patient serious stroke side effects. Another plasminogen activator is uroki-nase, a protease present in the urine and produced by the kidney. The physiological effect of urokinase is minimal in clot dissolution; however, like tPA it is a valuable commercial product used in thrombolytic therapy, for patients with heart attacks, strokes, and other throm-botic episodes.6 Streptokinase is an exogenous fibri-nolytic agent, produced when a bacterial cell product forms a complex with plasminogen, a pairing that converts plasminogen to plasmin. This toxic product results from infection with beta-hemolytic streptococci and is a dangerous byproduct if this bacterial strain develops into a systemic infection. It has the most activity on fibrinogen.

Naturally Occurring Inhibitors of Fibrinolysis

The balance of hemostasis is aided by those products that restrain fibrinolytic activity. These products, plasminogen activator inhibitor 1 (PAI-1) and alpha-2-antiplasmin, act upon different substrates in the fibri-

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