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How Clotting Factors Form a Fibrin Clot, Completing Hemostasis


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.jpgTo follow the laws of nature the cardiovascular system must pump enough blood with enough pressure throughout the body to provide its trillions of cells with what they need to live, grow, and work properly. But life is a dynamic process, for us as for our earliest ancestors. When we do things like run, jump, or climb, the effects of these same laws can result in injury to our blood vessels followed by bleeding when we trip and fall or bump and hurt ourselves. Clinical experience shows that, depending on location and severity, if the body can’t stop the bleeding fast enough it runs the risk of serious debility and even death. Thus, the body had to develop a mechanism to prevent disabling and life-threatening blood loss from blood vessel injury. This process is called hemostasis.

As I showed in a previous article, hemostasis involves mainly three almost simultaneous actions that take place upon blood vessel injury to stop the bleeding and allow healing to take place. These are; vasoconstriction, platelet aggregation, and activation of the clotting factors. But when it comes to preventing significant blood loss from blood vessel injury, the body faces another dilemma. A well-placed clot in a major blood vessel like an artery supplying blood to the brain, or the heart, or the lungs, can result in permanent debility and even instant death. In other words, hemostasis and the clots it forms must turn on only when it’s actually needed and must turn off and stay off when it’s not.

My last article looked at the role the injured blood vessel and the platelets play in helping to stop bleeding. I noted that normally the tissue that lines the inside of the blood vessel (endothelium) provides a chemical environment to maintain blood flow by keeping the muscle surrounding the blood vessel relatively relaxed and preventing the platelets from sticking to it and each other. Blood vessel injury and endothelial damage disrupt this chemical milieu, which triggers vasoconstriction and platelet aggregation to form a soft plug to fill the defect. This may be enough to stop the bleeding for some minor injuries, but many others require a stronger substance to fill the gap permanently. Let’s consider how activation of the clotting factors to form a fibrin clot completes the process of hemostasis.

The final products from activation of the clotting factors are long protein strands called fibrin. These fibrin strands consist of small identical fibrin molecules that are able to chemically bond with each other to form very large molecular chains. Like thousands of sticky threads, these long strands of fibrin attach to the platelet plug and wrap around it to form a molecular meshwork that entraps red blood cells and plasma to form a fibrin clot. Once the fibrin clot is large and strong enough to fill the defect in the blood vessel wall, the bleeding stops.

But where do the fibrin strands come from? After all, the muscle around the blood vessel is already in place, ready to contract and close it down to prevent further blood loss and help clot formation when the time is right. And the platelets are already in the blood that flows past the injured site, ready to stick to the vessel wall and to each other to form a plug when called for. So what about fibrin? Think about it! If long sticky fibrin strands were always present throughout the bloodstream, they would tend to attach to the walls of small blood vessels and block the flow of blood, which would result in multi-system organ failure and death. So, fibrin must somehow be in the blood and remain inactive until the right time.

In fact, the liver produces a protein called fibrinogen, also known as (clotting) Factor I. Fibrinogen remains in solution being prevented from becoming fibrin and joining together to form large insoluble strands by specific chemical groups at each end of the molecule. Platelets have receptors for fibrinogen and when activated, thousands of fibrinogen molecules attach to them. What causes the conversion of fibrinogen to fibrin and the formation of clot forming strands of fibrin is the presence of an enzyme called thrombin.

Thrombin removes the chemical groups at the ends of the fibrinogen molecule, thereby exposing bonding sites that allow the fibrin molecules to join together end to end to form the long insoluble strands needed for clotting. Thrombin also activates Factor XIII, which allows the fibrin strands to link up across each other as well, which significantly strengthens the clot.

But where does thrombin come from? Again, think about it! If thrombin quickly converts soluble fibrinogen into long insoluble strands of fibrin, resulting in clot formation, then if it were always present throughout the bloodstream, that would result in generalized clotting, multi-system organ failure, and death. In fact, the liver produces another protein called prothrombin, also known as (clotting) Factor II. Under the right set of circumstances an enzyme called prothrombinase forms and breaks two chemical bonds in prothrombin to convert it to thrombin which then goes on to convert fibrinogen to fibrin to form a fibrin clot.

But where does prothrombinase come from? Think about that too! If prothrombinase quickly converts prothrombin to thrombin which then quickly converts fibrinogen to fibrin, then if it were always present throughout the bloodstream that would result in generalized clotting, multi-system organ failure, and death. In fact, just as vasoconstriction and platelet aggregation take place due to changes in the chemical environment brought on by injury to the blood vessel, so too does activation of the clotting factors. Medical science has determined that there are two different pathways involved in the activation of the clotting factors to form prothrombinase.

One, called the Tissue Factor (extrinsic) pathway, works very quickly. With vessel damage, the blood, containing inactive Factor VII, comes in contact with Tissue Factor, a protein on the surface of the tissue that supports the blood vessel, and activates it into a protease, an enzyme that can break the chemical bonds within proteins. Activated Factor VII then breaks chemical bonds in Factor X to activate it, and when it joins to activated Factor V it forms prothrombinase.

The slower pathway, called the contact activation (intrinsic) pathway, takes place due to the direct contact of blood with the damaged tissue and involves other clotting factors. The contact first activates Factor XII, which becomes a protease that breaks chemical bonds to activate Factor XI. Activated Factor XI is also a protease that then activates Factor IX. Activated Factor IX, with the help of Factor VIII, then activates Factor X, which as noted above, joins with activated Factor V to form prothrombinase.

So, after blood vessel injury, whether prothrombinase comes about from either pathway, it then activates prothrombin into thrombin which then activates fibrinogen into fibrinand clot formation takes place. All of this together is known as the coagulation cascade.

It is the liver that produces most of the clotting factors. In fact, 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 would have made it impossible for our earliest ancestors to have lived long enough to reproduce. Evolutionary biologists seem to think that just showing how each of these factors could have come about from some other protein by a natural process (such as gene duplication) is enough to prove that the coagulation cascade itself came about solely by chance and the laws of nature.

But one can see that since each of these ten factors must be present so the two different pathways can work properly, this is preposterous notion. When comparing invertebrates to vertebrates, they speculate how intermediate organisms must have had intermediate systems with fewer clotting factors without accounting for the extremely high improbability of each new protein fitting perfectly into the right pathway. Since invertebrate circulations are low pressure systems they can seal their injuries by using a softer gel-like material, much like the platelet plugs, whereas for the high pressure systems of the vertebrates, it must have been serendipity that the final product (fibrin) had the exact physical properties to do the job.

Nowhere does evolutionary biology even mention how the high-pressure circulatory system of the vertebrate, which required this more sophisticated clotting mechanism in the first place, could have gradually developed within intermediate forms while the coagulation cascade was evolving as well.

But we’re not finished yet. Remember, to keep the blood flowing throughout the circulatory system, the body has to make sure that hemostasis only turns on when it’s actually needed and turns off and stays off when it’s not. Failure in this respect can lead to widespread clotting, multi-system organ failure, and death. My last article showed that it is the endothelium that provides a chemical environment to prevent the activation of vasoconstriction and platelet aggregation, the first two components of hemostasis. Next time we’ll look at what it takes to prevent activation of the clotting factors so the body can control the intricate process of hemostasis.

Image: Self-Portrait with a Bandaged Ear, by Vincent van Gogh [Public domain], via Wikimedia Commons.