Fibrinolysis

Ok, so now we have a basic understanding of how platelets form a plug, and how the cascade forms a clot. After the clot is formed and the bleeding has stopped, the coagulation cascade needs to stop and the clot needs to be removed.

First let’s talk about how the cascade is slowed down and stopped. There are a few main players.

Antithrombin (AT):
Antithrombin and antithrombin 3 (AT3) are used interchangeably. Antithrombin is produced in the liver and accounts for a majority of antithrombotic activity. It inhibits thrombin, and factors 10a, 9a, 11a, and 12a. If you look back to our cascade diagram, you will see this shuts down factors in the intrinsic pathway and the common pathway.

Protein C:
Protein C inactivates factors 5a and 8a. Factors 5a and 8a upregulate the cascade so neutralizing these greatly slows down the cascade.  What activates Protein C?

Protein C is actually activated by thrombin but only after thrombin has been bound to the endothelial cell receptor thrombomodulin. Thrombomodulin changes thrombin from a procoagulant to an anticoagulant. Thrombin plays for both teams! Protein C is basically waiting and ready to slow the clotting process down once called upon, and oddly and efficiently enough, it’s activated by the same protein (thrombin) that upregulates the cascade! Protein S is a cofactor of Protein C, and Protein C will not operate correctly without it. Protein C is also vitamin K dependent.

Ok so we know how things are slowed down but how does fibrinolysis work, how is fibrin broken down?

Fibrin is broken down by the activated form of plasminogen which is plasmin. Plasminogen which freely floats in the bloodstream (just like other inactivated factors), is activated by tissue plasminogen activator (TPA) which is released from damaged endothelial cells. What if TPA activates too much plasminogen and plasmin starts breaking down the clot too soon?

α2-antiplasmin, an inhibitor of plasmin and the fibrinolytic system helps to regulate fibrinolysis. It binds plasmin and prevents plasmin from binding to fibrin. It is released from platelet granules, and in rare cases when missing causes a bleeding disorder. This makes sense because if plasmin is not kept in check, it will break down the clot too early.

TPA will also only activate plasminogen under certain circumstances, one of them being plasminogen bound to fibrin. All of the fibrinolytic players are highly regulated to only breakdown the clot once the injury is repaired. Once fibrin is broken down into smaller fragments D, E, X and, Y, fixed macrophages (macrophages that stay in a specific area of the body) remove the fragments. Job finished!

D-Dimer:
D-Dimer is a stabilized fibrin degradation product that consists of two D fragments and an E fragment crosslinked together. It can be tested for in the chemistry department and is mainly used to rule out thrombosis. D-dimer is not usually present in normal serum and its presence can indicate a clotting problem.