Clot retraction and fibrinolysis

Definitions & Key takeaways

After an injury to a blood vessel, primary and secondary hemostasis forms a blood clot to stop bleeding. After hemostasis, it follows another process called clot retraction, which stabilizes the clot by pulling together the wounded edges of the vessel. Next, fibrinolysis occurs, which is an enzymatic process during which blood clots are dissolved to clear the way for blood circulation.

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Introduction0:00–0:42

In hemostasis, hemo refers to blood, and stasis means 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 to regulate clot formation. Whereas clot retraction and fibrinolysis occur after primary and secondary hemostasis are complete and help a clot contract and degrade.

Clot regulation0:42–2:11

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 and form emboli.
Depending on the location of the primary blood clot, these embli may then cause a disruption in blood flow to organs like the heart and brain.
Now the most important part of this 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 procoagulative functions.
Think of Frombin as an accelerator on a car, the pedal that takes the 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 then change their shape to form tentacle-like arms that allow them to stick to other platelets.
Second, thrombin activates two cofactors, factor 5, used in the common pathway, and factor 8, used in the intrinsic pathway.
Third, thrombin proteolytically cleaves fibrinogen or factor 1 into fibrin or factor 1A, which binds other fibrin proteins to form a fibrin mesh.
And finally, thrombin proteolytically cleaves stabilizing factor or factor 13 into factor 13A. Factor 13A 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 has the main target of two proteins that help with anticoagulation, protein C and antithrombin 3.

Protein C2:11–3:20

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 to ensure that the coagulation process is limited to the injury site. And 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 5, a cofactor for factor 10 in the common pathway, and 8, a cofactor for factor 9 in the intrinsic pathway.
By inhibiting both the intrinsic and common pathway, coagulation slows down dramatically. Now, a second anticoagulant is antithrombin 3, sometimes just called antithrombin.

Antithrombin III3:20–4:16

Antithrombin is a protein made by the liver and released into the blood, and it binds to both thrombin and factor 10, 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 factor 10, which is a pivotal coagulation protein that converts prothrombin into thrombin.
Antithrombin also inhibits factors 79, 11, and 12, 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.
Now there are also some factors that prevent platelets from adhering to one another or to endothelial cells during primary hemostasis.

Platelet regulation4:16–4:51

Healthy, undamaged endothelial cells release nitric oxide and prostacyclin. These tiny molecules make activated platelets produce less thromboxane A2, which is a molecule that active platelets secrete to activate surrounding platelets.
Specifically, thromboxane A2 makes platelets express GP2B3A proteins on their membrane, and GP2B3A proteins bind to fibrinogen, which ultimately makes platelets stick to one another.

Clot retraction4:51–6:17

Now, within an hour or so after primary and secondary hemostasis creates a blood clot, platelets begin the process of clot retraction.
Activated platelets have proteins within them called actin and myosin, the same proteins found in muscle cells. These proteins are arranged in bundles called lamelopodia, and from the outside of the platelet, they look a bit like fingers poking through the platelet membrane.
A little bit creepy. Anyway, these lamalopodia are really important because they increase the surface area of the platelet, and that makes it easier for them to bind to the fibrin mesh as well as the endothelial lining of the blood vessel.
Now, platelets that are part of a clot typically have a surface protein called integrin alpha 2B beta 3, and when these receptors bind to fibrin in the presence of thrombin, it activates actin and myosin.
Actin and myosin slide along one another and it causes lamelopodia to contract. And since the cell surface integrines are both bound to fibrin, it pulls in on the fibrin mesh.
The fibrine mesh tightens in on all of the platelets in the clot, making the whole thing more rigid and contracted down.
When the clot contracts, it brings the edges of the wound closer together. When there's an open wound, the clot retraction pulls the two wound edges closer together, and the endothelial cells can divide and replace the lost tissue.
If the gap is too wide, it can get filled in with collagen, but this process takes longer and typically results in scarring.
Now, approximately 2 days after an injury, the blood clot is no longer needed since substantial healing has taken place.

Fibrinolysis6:17–7:11

At that point, it's time for the body to dissolve the blood clot through a process called fibrinolysis, which is the gradual degradation of the fibrin mesh.
To do this, a circulating protein produced by the liver called plasminogen gets converted by an enzyme called tissue plasminogen activator or TPA into its active form called plasmin.
Normally, healthy endothelial cells release only tiny amounts of TPA, but when they're exposed to coagulation factors, mainly factor 10 and thrombin, they start making lots of TPA.
But it's important that plasmin activity doesn't get out of hand either. So the endothelial cells also release plasminogen activator inhibitor 1 and antiplasmin, which are proteins that bind and sequester TPA and plasmin respectively.
It's all about always reaching that Zen balance of coagulation and anticoagulation. Now during an injury, more and more coagulation factors get activated and also more and more TPA gets released by endothelial cells, converting plasminogen into plasmin.

Plasmin7:11–7:53

Plasmin then acts as a protease, literally cutting fibrin into smaller pieces, allowing the trap red blood cells and platelets to float away, letting the clot dissolve.
Although TPA is the main activator of plasmin, a few other proteins activate plasmin as well, including coagulation factors 9A, 12A, calicreon, and protein C.
TPA is also used clinically. It's sometimes called a clot buster because it's used to dissolve blood clots that form in the lungs or in the brain.
OK, so as a quick recap, anticoagulation with protein C and S and antithrombin 3 prevents clots from getting too big during primary and secondary hemostasis.

Review7:53–8:23

Within an hour or so after primary and secondary hemostasis have created a blood clot, clot retraction begins to stabilize the clot and starts pulling together the wound edges.
Finally, there's the process of fibrinolysis, which is dependent upon the TPA which converts plasminogen into plasmin, an enzyme that cleaves fibrin and helps to dissolve the clot.