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Clotting: Controlling the System


Editor’s note: Physicians have a special place among the thinkers who have elaborated the argument for intelligent design. Perhaps that’s because, more than evolutionary biologists, they are familiar with the challenges of maintaining a functioning complex system, the human body. With that in mind, Evolution News & Views is delighted to present this series, “The Designed Body.” For the complete series, see here. Dr. Glicksman practices palliative medicine for a hospice organization.

the-designed-body4.jpgThe human body is made up of matter and must follow the laws of nature. Since blood is under pressure as it circulates throughout the body, these laws cause bleeding when blood vessel damage takes place. It’s just like what happens when a water pipe bursts in the home. To prevent serious injury or death, the body had to come up with a mechanism that could apply a substance strong enough to stop the blood loss.

This innovation is called hemostasis and involves three actions; vasoconstriction, platelet aggregation, and activation of the clotting factors. Hemostasis ultimately forms a fibrin clot, stops the bleeding, and allows healing to take place. However, since heart attacks and strokes occur due to clotting, the body must be able to control hemostasis so that it only turns on when it’s needed and turns off and stays off when it’s not. In other words, controlled hemostasis is a delicate balance between the forces that promote and prevent clotting.

It is the endothelium, lining the inner surface of the blood vessel, that provides a chemical environment to prevent vasoconstriction and platelet aggregation. When blood vessel and endothelial damage takes place, this changes the milieu and allows these first two components of hemostasis to swing into action. My last article in this series explained how activation of the clotting factors to form a fibrin clot takes place. We will now look at the anti-clotting mechanisms the body uses to control hemostasis.

To understand how the anti-clotting mechanisms work, it’s important to review how activating the clotting factors, most of which are produced in the liver and are dissolved in the blood, produces a fibrin clot. Fibrinogen, which attaches to binding sites on the platelet plug, must be activated by an enzyme called thrombin to become fibrin. Thrombin also activates Factor XIII which helps to strengthen and stabilize the fibrin clot. Thrombin comes about from the activation of prothrombin by prothrombinase which is an enzyme made up of activated Factors V and X. Prothrombinase, which converts prothrombin into thrombin, which then converts fibrinogen into fibrin, is the key to fibrin clot formation.

Medical science has determined that there are two chemical pathways for the production of prothrombinase. One is called the Tissue Factor Pathway. This pathway involves activation of Factor VII which, with blood vessel injury, comes in contact with Tissue Factor, a protein on the surface of the tissue that supports the blood vessel. Activated Factor VII activates Factor X, which joins activated Factor V to form prothrombinase.

The other pathway is called the Contact Activation Pathway. This takes place due to direct contact of blood with the damaged tissue and involves other clotting factors. The contact first activates Factor XII, which activates Factor XI, which activates Factor IX, which with the help of Factor VIII, activates Factor X. Activated Factor X then joins activated Factor V to form prothrombinase.

The combination of events involving the clotting factors when blood vessel injury takes place that results in the formation of a fibrin clot is called the coagulation cascade. Now that you understand how clotting takes place we can look at the anti-clotting mechanisms that the body uses to control hemostasis.

In the same way it provides a chemical environment to prevent vasoconstriction and platelet aggregation, normal endothelium sends out anti-clotting factors that deactivate and neutralize some of the clotting factors to prevent fibrin clot formation. So, when the endothelium is disrupted by injury, the loss of these anti-clotting factors removes the inhibition of the powerful coagulation cascade and clot formation is allowed to take place. Also, since the vessel walls on either side of the injury still have an intact endothelium, this usually prevents activation of the clotting factor in either direction from the injury site. In this way, fibrin clot formation is usually limited to mainly the site of blood vessel injury.

The liver produces a protein called antithrombin,which is the body’s main inhibitor of thrombin. Antithrombin works by chemically entrapping thrombin, like a fly in a spider web. This makes thrombin unavailable to convert fibrinogen into fibrin and prevents clotting. However, normal endothelium produces a chemical called heparan sulfate which, when it attaches to antithrombin, makes it change its shape in a way that enhances its ability (by more than a thousand fold) to bind thrombin. Antithrombin also blocks activated Factor X and to a lesser degree activated Factors IX and VII. Since all of these clotting factors are needed in the chain reaction that produces thrombin, one can see that the combination of antithrombin (made in the liver) and heparan sulfate (made in the endothelium) work well together to prevent clot formation.

Another chemical produced by intact endothelium is thrombomodulin. Thrombomodulin attaches to thrombin and together they activate protein C,which is also produced in the liver. Activated protein C (APC) is a protease which breaks specific chemical bonds and neutralizes activated Factors V and VIII. Since both of these clotting factors are needed for the coagulation cascade to work properly, it’s apparent that the combination of protein C(made in the liver) and thrombomodulin (made in the endothelium) also work well together to prevent clotting.

Recall from above, that the Tissue Factor pathwayworks because Factor VII is activated when it comes in contact with Tissue Factor after blood vessel damage occurs. Another anti-clotting factor produced in normal endothelium is Tissue Factor Pathway Inhibitor (TFPI), which works to prevent clotting by attaching to activated Factor X and deactivating it. This complex is then able to attach to activated Factor VII and deactivate it as well.

So, in summary, the clottingfactors in the blood remain inactive until blood vessel injury takes place to turn on the coagulation cascade. Meanwhile, the liver and the endothelium combine to produce anti-clotting factors that together work to turn off hemostasis and allow it to stay off when it’s not needed. It is this delicate balance of clotting and anti-clotting factors that allows the body to normally be able to stop bleeding when injured, while at the same time allowing blood to flow freely to the tissues. Moreover, the total absence of fibrinogen, or prothrombin, or Tissue Factor, or Factor V, or Factor VII, or Factor VIII, or Factor IX, or Factor X, or Factor XI, or Factor XIII, or antithrombin, or protein C or TFPI would have made it impossible for our earliest ancestors to live long enough to reproduce.

Michael Behe has described a system where the absence of any one part renders it non-functional as being irreducibly complex. It certainly looks like hemostasis is irreducibly complex, because if any one of the many clotting or anti-clotting factors were absent life would be impossible.

However, as I have stated before, having an irreducibly complex system does not automatically allow for survival. The body must follow the laws of nature, and when it comes to hemostasis, these laws demand that there be enough platelets and clotting and anti-clotting factors present and that they work fast and well. Evolutionary biologists may imagine how each of these factors came into being but clinical experience shows that when it comes to hemostasis and survival, real numbers have real consequences. That’s what we’ll look at next time.

Image: Time the Physician, by Eleanor Fortescue-Brickdale [Public domain], via Wikimedia Commons.