Clot retraction and fibrinolysis

In hemostasis, hemo referring to blood, and stasis meaning to stop—so hemostasis is the process where blood flow is stopped after there’s damage to a blood vessel.

Primary hemostasis involves the formation of a platelet plug at the site of an injured blood vessel, and secondary hemostasis involves the coagulation cascade which is where a protein net called a fibrin mesh forms over the platelet plug to reinforce it - forming a blood clot.

Now, anticoagulation occurs during primary and secondary hemostasis and helps regulate clot formation, whereas clot retraction and fibrinolysis occur after primary and secondary hemostasis are complete, and help a clot contract and degrade.

Anticoagulation prevents clots from growing too large and blocking blood flow to tissues supplied by the vessel. It also prevents clots from getting so big that small parts of the growing clot break off in the form of emboli. Depending on the location of the primary blood clot, these emboli may then cause a disruption in blood flow to organs like the heart or brain.

Now, the most important point of clot regulation is when a coagulation factor called thrombin is produced. Thrombin, or factor II, is a very important clotting factor, because it has multiple pro-coagulative functions. Think of thrombin as the accelerator on a car--the pedal that takes secondary hemostasis from 20 miles per hour to 100 miles per hour!

First, thrombin binds to receptors on platelets causing them to activate. Activated platelets change their shape to form tentacle-like arms that allow them to stick to other platelets. Second, thrombin activates two cofactors; factor V used in the common pathway, and factor VIII used in the intrinsic pathway.

Third, thrombin proteolytically cleaves fibrinogen or factor I, into fibrin or factor Ia which binds with other fibrin proteins to form a fibrin mesh. And finally, thrombin proteolytically cleaves stabilizing factor or factor XIII into factor XIIIa.

Factor XIIIa combines with a calcium ion cofactor to form cross links between the fibrin chains, further reinforcing the fibrin mesh. Since thrombin has so many jobs, it makes sense that it is the main target of two proteins that help with anticoagulation- protein C and antithrombin III.

Protein C is a circulating plasma protein produced in the liver along with a cofactor called protein S. Now both protein C and S interact with a protein called thrombomodulin, which is on the surface of intact endothelial cells, which line our blood vessels.

Now - let’s go back to an existing clot. When there’s a lot of thrombin around a damaged blood vessel, excess thrombin binds to thrombomodulin and it can no longer participate in the coagulation cascade.

So in a sense, the undamaged cells help ensure that the coagulation process is limited to the injury site. Furthermore, the thrombin-thrombomodulin complex binds to and activates protein C and S. The whole thing forms a complex that includes protein C, protein S, and thrombin-thrombomodulin. This protein complex proteolytically cleaves and inactivates active factor V, a cofactor for factor X in the common pathway, and VIII, a cofactor for factor IX in the intrinsic pathway. By inhibiting both the intrinsic and common pathway, coagulation slows down dramatically.

Now, a second anticoagulant is antithrombin III, sometimes just called antithrombin. Antithrombin is a protein made by the liver and released into the blood, and it binds both thrombin and factor X, both of which are in the common pathway. Excess thrombin can bind to antithrombin--similar to how it binds to thrombomodulin, and become unavailable.

Antithrombin also binds to excess active factor X, which is a pivotal coagulation protein that converts prothrombin into thrombin. Antithrombin also inhibits factors VII, IX, XI and XII--although with much less affinity. Antithrombin is also the target of an effective medication called heparin.

Heparin binds to antithrombin and increases its affinity for its target proteins, thus increasing its anticoagulant effects. So when individuals are given heparin the balance between coagulation and anticoagulation - tips in favor of anticoagulation.