Thrombolysis and Physiological Anticoagulation

Once a blood clot has formed and has served its purpose it needs to be broken down and removed. This is the job of the thrombolytic system. However, the thrombolytic system has a more far reaching role than simply clot clear up and is vital in preventing overzealous activation of the coagulation system, as well as limiting its action when it does engage.

The cast of the thrombolytic and anticoagulation system has several principal members.

Protein C Protein C degrades activated factor V and factor VIII. It is synthesised by the liver.
Protein S Protein S is a cofactor to protein C. It also binds to cells that are undergoing apoptosis and marks the membrane-bound packets they release during apoptosis for phagocytosis.
Antithrombin III Antithrombin III inhibits factors II, IX, X, XI and XII and therefore targets the intrinsic pathway and thrombin. It is assisted by heparan sulphate.
Tissue factor plasma inhibitor Tissue factor plasma inhibitor opposes factor Xa and the tissue factor - factor VIIa complex and prevents low levels of these active factors from precipitating an excessive clotting response.
Plasminogen When converted into its active form, plasminogen can lyse fibrin and von Willebrand factor. The former ability allows it to destroy blood clots, a property that the other anticoagulant proteins lack.
Tissue plasminogen activator Tissue plasminogen activator (tPA) is synthesised by endothelial cells and converts plasminogen into plasmin.
Urokinase Urokinase is also able to activate plasminogen.
Prostacylin Prostacyclin is an inhibitor of platelet activation and therefore also helps to limit blood clotting.

Minor activation of the coagulation cascade is likely to be rapidly controlled by background activity of protein C, tissue factor plasma inhibitor and antithrombin III. Only when the magnitude of the procoagulant stimulus is sufficiently great will the cascade be driven with enough power to overcome this basal opposition. Thus, clotting only occurs when it is really needed.

Among the various activities in which endothelial cells engage when they are damaged is the release of plasminogen. This plasminogen becomes trapped in the fibrin network of the blood clot. Initially the procoagulant stimulus swamps any action of plasminogen but the injured endothelial cells slowly release tissue plasminogen activator such that a few days after the clot has formed and coagulation ceased, the levels of tPA and plasmin have attained a sufficient concentration to be able to lyse the clot. In other words, the clot includes at the time of its creation the agent that will be needed to destroy the haemostatic plug once it has served its purpose.

Protein C is activated by thrombin that has not been caught up in the fray of forming the blood clot and has instead been bound by thrombomodulin. When complexed with thrombomodulin, this spare thrombin gains the ability to activate protein C.

The formation of a blood clot seals the defect in the wall of the blood vessel. This isolates the blood from the underlying subendothelial tissues and restores laminar flow and therefore removes the pro-coagulant stimulus. This shifts the balance in favour of anticoagulant agents such as protein C, which can then neutralise the remaining clotting activity and bring the process to a halt at the right time.

Abnormal Resolution of a Blood Clot

The fibrinolytic system will usually ensure that once a blood clot has served its purpose it will be removed entirely. As with other tidying up operations in the body, macrophages are involved in the sweeping up, this time to remove the entrapped platelets, dead erythrocytes and breakdown products of the fibrin network. In parallel with the removal of the blood clot the surviving nearby endothelial cells replace those that were lost in the injury. The result should be a fully healed blood vessel that is regenerated rather than just repaired.

Some blood clots, particularly those that occlude a blood vessel, undergo recanalisation as part of the regeneration. During the course of the breakdown of the blood clot, small capillary channels are formed within it by endothelial cells that have proliferated from the wall of the affected blood vessel. These small capillaries constitute a form of bypass through the clot.

Occasionally the clot fails to undergo complete resolution, possibly due to the size of the clot or defective fibrinolytic systems. In these circumstances there may be either partial removal of the clot by the usual pathways while the remainder undergoes organisation into a fibrotic mass that is then covered by endothelial cells to form a permanent bulge in the wall of the blood vessel. Alternatively the entire clot may become fibrotic and the lumen of the blood vessel permanently occluded and obliterated.

Damage to a blood vessel is usually associated with injury to the surrounding tissue. It is therefore biologically beneficial if the haemostatic pathway can interact with the inflammatory and wound healing pathways. Platelets are the principle mediators that allow haemostasis to signal other repair mechanisms. Their alpha granules contain various growth factors, including the sensibly named platelet derived growth factor, that stimulate macrophages, fibroblasts and endothelial cells to initiate repair mechanisms.

A haematoma is a blood clot that is formed outside the circulation. It may either be healed by complete removal and resolution (using fibrinolysis and macrophage clear up), or undergo fibrosis, with our without calcification, either in whole or in part.