CAUTION: ENZYMES AT WORK: PART III: ANTI-CLOTTING

We live in a world made from matter.  Matter is made up of atoms and molecules that follow the laws of nature.  All life is made up of atoms and molecules that are organized into cells.  Our body has trillions of them.  Since our cells are made from matter they too must follow the laws of nature as well.  Everybody knows that when you get injured and bleed, the body tries to stop it by clotting.  And most people know that a clot which is blocking blood flow to a vital organ, like the brain, the lung or the heart muscle, can result in permanent debility and even death.  There are even some people who know that the clotting factors remain inactive until they are triggered by an injury to form a clot, so clotting normally gets turned on only when it is actually needed.  But, what most people do not understand or appreciate is that the body also has many different anti-clotting factors which work to prevent clotting when it’s not needed.  In other words, the body’s clotting mechanism is a delicate balance consisting of factors that are supposed to turn on when injury takes place and stay or turn off when clotting isn’t needed.  This is the reason why almost everybody doesn’t seem to know that when not resisted by some sort of innovation, the laws of nature do not bring about life, as evolutionary biologists would have us believe, but death.  Having both clotting and anti-clotting factors that work together in fine precision to keep the body alive is a good example of this.  But before you can understand and appreciate why this is so, you must first learn how clotting is actually done and how it can be slowed down or prevented.  So how does the body do it?  One of the most important set of molecules in the body is enzymes and their inhibitors.  Let’s first look at what enzymes are and what they do and then we’ll be able to better understand how they and their inhibitors help the body control clotting so it can survive within the laws of nature.

Enzymes

Enzymes are special molecules (mostly proteins) that are made in the cell which help other molecules undergo chemical reactions when they come in contact with each other.  When these reactions occur energy is either released or used up and different molecules are produced.  Every biochemical process in the body requires enzymes to work properly.

Molecules are made up of atoms joined together by chemical bonds.  There are very small molecules, like molecular oxygen, which is made up of two oxygen atoms joined together (O2) and water which is made up of two hydrogen atoms joined to one oxygen atom (H2O).  There are also slightly larger molecules, like glucose, a sugar that is made up of six atoms of carbon and oxygen joined to twelve atoms of hydrogen (C6 H12 O6).  And there are very large molecules, like carbohydrates, fats, and proteins, many of which are made up of hundreds or even thousands of atoms joined together. 

When molecules meet up with each other they sometimes react.  A reaction between molecules simply means that chemical bonds between atoms are created and destroyed.  This usually causes some of the atoms in the reacting molecules to change places with each other to form different molecules.  Enzymes help chemical bonds be destroyed in larger molecules to form smaller ones and be created between smaller molecules to make larger ones.  During this process energy may be released or used up.  At the end of the reaction the enzymes are not altered so they can continue to promote more reactions.  And, the total number of atoms present in the molecules that are produced at the end of the reaction is the same as there were in the molecules that reacted in the first place.  In other words, in a chemical reaction no new atoms are created or destroyed, just the bonds between them and this often results in the release or use of energy and the atoms involved changing partners to form different molecules.       

One important example of a chemical reaction that occurs within our cells involves how they get the energy they need from the chemical bonds within the glucose molecule.  Cellular respiration uses specific enzymes to help breakdown one glucose molecule (C6 H12 O6), in the presence of six oxygen molecules (6 O2), to release the energy the cell needs, while at the same time producing six carbon dioxide molecules (6 CO2) and six molecules of water (6 H2O).  Notice that the chemical reaction starts off with a total of six carbon atoms, twelve hydrogen atoms and eighteen oxygen atoms from one molecule of glucose (C6 H12 O6) and six molecules of oxygen gas (6 O2).  And it ends up with the same amount of carbon, hydrogen and oxygen atoms, but they make up the six molecules of carbon dioxide gas (6 CO2) and the six molecules of water (6 H2O) instead.

The laws of nature determine how fast specific molecules will react with each other.  But the addition of an enzyme makes this reaction take place much faster.  By speeding things up, enzymes help to produce many more new molecules, usually in the order of thousands or millions of times more, than what would normally happen at random.  This is why enzymes are called catalysts.  They help bring molecules together to react much faster than what would happen if they were dependent on the random forces of nature alone.    

If our body were to be left only to the random laws of nature the thousands of chemical reactions we need to help keep us alive would not take place fast enough and we would die.  Enzymes can catalyze chemical reactions because their specific chemical nature and shape allows them to bring specific molecules together to react in a specific way.  This is similar to how hormones have their specific effect(s) in the specific cells of specific target tissues by locking on to specific receptors (see prior articles entitled Caution: Hormones At Work).   It is also important to note here that the body also produces different proteins called enzyme inhibitors as well.  It is the specific chemical nature and shape of the enzyme inhibitor that enables it to bind to a specific type of enzyme and either slow down or totally block its metabolic effect.  Enzyme inhibition is one of the main ways the body is able to control many of its metabolic processes.

There are thousands of different enzymes in the body each of which have a specific effect on a specific molecule.  As noted above, it is the shape and chemical nature of the enzyme that determines which molecules it will work on and what type of reaction it will catalyze.  The first part of the chemical name of an enzyme usually indicates the specific molecule or class of molecules for which it catalyzes reactions.   And the last part of its name usually ends in “ase”.  For example, lactase is the enzyme that helps to breakdown lactose, a sugar in milk that is made up of one molecule of glucose joined to one molecule of galactose.  And a protease is a class of enzymes that helps to breakdown proteins which are made up of two or more amino acids joined together. 

The body often uses several specific enzymes in a specific order (pathway), in a chain reaction, to bring about what is needed for survival.  The first molecule undergoes a reaction catalyzed by the first enzyme, and one of the products of that reaction becomes the second molecule in the pathway.  The second molecule, in turn, undergoes a reaction catalyzed by the second enzyme, and one of the products of that reaction becomes the third molecule in the pathway.  The third molecule, in turn, undergoes a reaction catalyzed by the third enzyme, and one of the products becomes the fourth molecule in the pathway, and so on.  This process continues until the required molecule is produced so it can do what the body needs it to do.  Note, that if any one of the enzymes in the chemical pathway were to be missing or not working properly then not enough of the final product would be produced and life could hang in the balance. 

Finally, it is important to understand that since enzymes themselves are made up of hundreds, or thousands, of atoms chemically bonded together, their chemical stability and capacity to work properly can be affected by the laws of nature as well.  Things like temperature, hydrogen ion concentration and the body’s water content can affect the chemical structure of enzymes. When any of these three important parameters falls out of the normal range the enzymes in our body start to malfunction and so does our body.  Serious deviations can even result in death.  That is why our body must be able to control these three, and other vital parameters to allow us to survive within the laws of nature  (see prior articles called Caution: Hormones At Work.) 

For videos explaining enzymes and enzyme inhibition see:

How Enzymes Work

Enzyme Function and Inhibition

Now that we know what enzymes are and what they do let’s see how enzymes and  their inhibitors work to help the body control its clotting of blood.

Clotting

Experience tells us that injury to a blood vessel usually results in bleeding.  This takes place because the pressure that sustains blood flow throughout the body pushes blood out of the blood vessel when injury takes place.  Think of it like what happens to water when a pipe inside your home bursts.  The body normally responds to blood vessel injury with a process called hemostasis which ultimately forms a clot to stop blood loss.  The channel inside the blood vessel through which blood flows is called the lumen.  And the tissue that lines the lumen, and is in direct contact with blood, is called the endothelium.  When the endothelium is injured this activates hemostasis and the clotting mechanism needed to prevent major blood loss.  Hemostasis involves mainly three processes that take place almost simultaneously.  First, the smooth muscle surrounding the injured blood vessel contracts as much as possible to reduce the size of the lumen and facilitates clot formation.  Second, the platelets in the blood passing by the injured site begin to stick to the damaged endothelium and to each other, a process called platelet aggregation, to form a soft plug.  And third, the clotting factors in the blood become activated and attach to the platelet plug to form a fibrin clot to cover the defect, prevent further bleeding and allow healing to take place.  Most of the clotting factors are made in the liver but the platelets produce some of them too.  They must remain inactive until they are needed to stop blood loss from an injured blood vessel otherwise they may cause a blockage of blood flow to a vital organ, like the brain, the lung or the heart muscle, which can lead to sudden death. 

Factor I is fibrinogen which is activated by an enzyme called thrombin to become fibrin which ultimately forms the clot.  Thrombin also activates Factor XIII which helps to strengthen and stabilize the fibrin clot.  Thrombin is so good at what it does that it can be said that wherever it is present there is clotting and wherever it is not present there is not clotting.  Therefore the body must control the formation of thrombin or else there would be clotting everywhere.  Factor II is prothrombin which must be activated to become thrombin which then goes on to convert fibrinogen into fibrin to form a fibrous clot.  Prothrombin is converted into thrombin by prothrombinase, an enzyme which is made up of activated Factors V & X.  Once again one can see that the body must control the formation of prothrombinase or else it will quickly convert prothrombin into thrombin which will then convert fibrinogen into fibrin to form a fibrous clot.     

Medical science has determined that there seems to be two different chemical pathways involved in the formation of prothrombinase.  One pathway, 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.  This contact activates factor VII converting 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 many more clotting factors.  The contact first activates Factor XII which becomes a protease that breaks chemical bonds to activate Factor XIActivated Factor XI is also a protease that then activates Factor IXActivated Factor IX, with the help of Factor VIII then activates Factor X, which as noted above, joins with activated Factor V to form prothrombinase as well.  And from here prothrombinase activates prothrombin into thrombin which then activates fibrinogen into fibrin which results in clotting.  All of this together is known as the coagulation cascade.

To see a video that shows what is described above go to this link:

Coagulation Cascade Animation - Physiology of Hemostasis

To see a schematic diagram of what is described above go to this link:

Blood Clotting

Now that you understand how hemostasis and clotting takes place to prevent blood loss when blood vessel injury occurs, let’s look at how the body goes about controlling it to prevent clotting from taking place where and when it isn’t needed.

Anti-Clotting

The endothelium that lines the lumen does much more than just provide a barrier between the blood and the underlying tissue of the blood vessel.  The endothelium is directly involved in the prevention of hemostasis as well.  It sends out chemicals that help to relax the smooth muscle that surrounds the blood vessel and also prevents platelets from sticking to it and to each other as well.  This means that when blood vessel injury takes place, and the presence of these chemicals is greatly reduced, this allows smooth muscle contraction and platelet aggregation to take place.   

However, the endothelium also sends out anti-clotting factors that are involved in deactivating and neutralizing some of the clotting factors to prevent fibrin clot formation as well.  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.  By considering the chemical pathways of the coagulation cascade one can see that there are many places along the way that, if blocked to some degree, could limit or eliminate clot formation.

The liver produces a protein called antithrombin, which consists of more than 400 amino acids arranged in a specific order and is the body’s main inhibitor of thrombin.  It 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 changes 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 extent activated Factors IX and VII as well.  Since all 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.  Protein C is produced in the liver and like antithrombin, consists of more than 400 amino acids arranged in a specific order.  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, one can see 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 quick acting Tissue Factor pathway works by Factor VII becoming activated when it comes in contact with Tissue Factor after blood vessel damage occurs.  Another anti-clotting factor produced in normal endothelium is TFPI (Tissue Factor Pathway Inhibitor) 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. 

In summary, the clotting factors in the blood remain inactive until blood vessel injury takes place to turn on the coagulation cascade.  Meanwhile, the liver and the intact endothelium of the blood vessel combine to produce anti-clotting factors that together work to prevent or turn off clot formation.   It is this delicate balance of clotting and anti-clotting that allows the body, in normal circumstances, to stop bleeding when injured while at the same time allowing the blood to flow freely to the tissues.

Life And Death And The Laws Of Nature: Real Numbers Have Real Consequences

Both antithrombin and protein C consist of more than 400 amino acids bonded together in a specific order.  Since there are twenty different amino acids, this means that the probability of each one of these proteins coming into being at random is more than 1 chance in 20400 or 1 chance in 10520.   For those who believe that “given enough time anything can happen” it is sobering to realize that since there are 86,400 sec in a day (60 x 60 x 24) and 31,557,600 sec in a year (x 365.25), this means that the earth has existed for only 1.4 x 1017 sec (x 4.5 billion).  Moreover, if one assumes hypothetically that in every nanosecond (10-9 sec) of the earth’s existence a trillion (1012) different chemical reactions producing a protein with over 400 amino acids could have taken place then there would have only been 1.4 x 1038 of these reactions in the lifetime of the earth.   But a total of 10520 of these chemical reactions would have been needed to get just one molecule of either antithrombin or protein C.  It would seem that, in at least this hypothetical scenario, for just one molecule of either of these proteins to come into being one would have to wait until the earth was older by a factor of 10382.  Clearly, this is impossible and is why the liver cells, rather than relying on random chance and the laws of nature, use the instructions contained within the DNA in their nuclei to produce enough antithrombin and protein C to keep us alive.  But how much is enough and how is the production of antithrombin and protein C controlled?  This as yet is still a mystery. 

Recall, if our hominid ancestors hadn't had enough of any one of the clotting factors or it wasn't working properly, then excessive bleeding from dealing with the laws of nature, like friction, sheer, momentum and gravity, would have resulted in them not surviving long enough to reproduce.  But, clinical experience teaches that having too much of a good thing can result in debility and death as well.  Prothrombin 20210 is an inherited gene mutation that occurs in about 1% of the U.S. population in which the liver produces about 30% more prothrombin than normal.  Having too much prothrombin significantly increases the risk of clotting and the development of thromboembolic disease.  This happens when, in certain circumstances, clots form, usually in the leg veins.  These venous thrombi can then sometimes break off, becoming emboli, and travel through the veins to the right side of the heart and from there to the lungs.  Multiple pulmonary emboli can cause the quick onset of shortness of breath and chest pain which can easily lead to sudden death.  This occurs because, although the lungs may be bringing in enough oxygen, the blockage of the pulmonary arteries by the emboli prevents the oxygen from getting into bloodstream.  

Another mechanism that can cause increased clotting and thromboembolic disease is a deficiency in the amount, or function, of the anti-clotting factors.  Deficiencies of antithrombin, protein C and TFPI are relatively rare, while the total absence of any one of them is considered to be incompatible with life.  However, the commonest inherited condition that promotes clotting is Factor V Leiden.  This occurs in about 5% of the U.S. population and may be responsible for up to 30% of the cases of thromboembolic disease.  Recall, normal endothelium secretes thrombomodulin, which joins to thrombin to activate protein C.  Activated Protein C (APC) then deactivates Factors V and VIII, both of which are very important for clot formation.  However, the amino acid structure of Factor V Leidin is such that it is resistant to being broken down by APC.  The resulting increase in activated Factor V results in the accumulation of more thrombin than usual.  Having more thrombin, especially in the presence of other predisposing conditions, can often lead to venous thrombosis, and, less frequently, even arterial thrombosis.  

By reviewing the clinical significance of these conditions one can see why having enough properly working anti-clotting factors is just as important for survival as having enough clotting factors.  Hemostasis is a delicate balancing act in which a rise in the ratio of pro-clotting and anti-clotting factors can cause widespread clotting while a drop in this ratio can lead to widespread bleeding.

Points To Ponder

It was the extremely high improbability of any one of the thousands of biologically significant molecules, like the different clotting and anti-clotting factors, being formed by just chance and the laws of nature (never mind the need for the untold millions of each one of them to allow for life) that alerted scientists to there having to be an intelligent agent within the cells telling them how to make them.  This is what first motivated scientists to search for and find the DNA molecule and everything else connected to it that has been, and continues to be, discovered.  But, paradoxically, modern evolutionary biologists see all of the information packed into the DNA molecule and still conclude that it all came about by just chance and the laws of nature alone rather than “a mind at work” i.e. an intelligence.  In other words, scientists, using their ability to detect intelligence, recognized that there had to be an intelligent agent inside the cell instructing it on how and when to produce these complex and vital molecules, but after finding it concluded that this intelligent agent itself had come about by chance and the laws of nature alone.  Alternatively, many people now believe and teach that it was nature itself, as the intelligent agent that through evolution, brought about DNA and all of the innovations needed for life because that was what was needed.  They seem to forget that, by definition, evolution is a blind process which has no goals.

Clotting is a very intricate and complicated process involving several different clotting and anti-clotting factors each of which are made up of several hundred or a few thousand amino acids, without each of which human life would be impossible.  The clotting mechanism must turn on, work fast enough and have enough effect only when bleeding actually takes place.  Furthermore, if too much clotting takes place, or it happens where it is not needed, then blood flow can be seriously compromised and, depending on the blood vessel involved, can result in serious organ damage and even death.  In addition, clinical experience teaches that 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 life impossible for our hominid ancestors. 

Dr. Michael Behe has called a system where the absence of any one part renders it useless as being irreducibly complex.  It certainly looks like hemostasis in humans is irreducibly complex because if any one of the many clotting or anti-clotting factors is absent then life would be impossible.  However, as I have alluded to previously, having an irreducibly complex system does not automatically allow for survival.  As noted above, even if all of the clotting and anti-clotting factors are present, if any one of them is not being produced in the right amount or is not functioning properly, then serious bleeding or clotting leading to debility and death would be the result and our hominid ancestors could not have survived to reproduce. 

As you can see real numbers have real consequences when it comes to dealing with the laws of nature, like stopping bleeding from, or preventing inappropriate clotting within, a blood vessel.  For not just any amount of each of the clotting and anti-clotting factors is needed for survival.  It has to be the right amount and it has to work properly.  All clinical experience has borne this out.  Besides being irreducibly complex, systems that allow for life must also have a natural survival capacity.  By this I mean that each system must give the organism the capacity to survive by taking into account the laws of nature.  This usually involves having a knowledge of what is needed to keep the organism alive within the laws of nature and then being able to do what needs to be done.  The system the body uses to produce the clotting and anti-clotting factors seems to inherently know what is needed to get the job done and does it naturally.  

To hear evolutionary biologists tell it, all you have to do is show how each of the clotting and anti-clotting factors may have come about from some prior protein by a natural process, such as gene duplication, and that in and of itself should be sufficient to confirm that the coagulation cascade in humans came about solely by chance and the laws of nature alone.  But, this is a preposterous notion.  It’s like trying to explain how things like cruise control and autopilot came into being without taking into account the precise mechanisms that are involved to allow them to work properly.  For these innovations, like clotting and anti-clotting, did not develop within a vacuum and therefore should not be considered in isolation from what must have been going on within the intermediate organisms that led up to our hominid ancestors in the first place.  To do so, seems to be a tad simplistic, and frankly, unscientific. 

Given what we know about how life actually works and how easily it dies when clotting isn’t controlled it is evident that for the clotting and anti-clotting factors to have developed naturally within living organisms that could reproduce, would have required several simultaneous innovations.  What those innovations were and exactly how those intermediate organisms were able to control their clotting in these intermediate phases may never be known.  This is because further changes which may have come about have since gone by the wayside of evolution and we can only see what is present now.  This is one way to explain how clotting may have evolved without having to seriously consider the physiology of the now extinct intermediate organisms.  But this is not Science, where every aspect of the reverse engineering needed to come up with a plausible explanation should be explored before a theory is proclaimed to the public.  No, this is faux science and just wishful thinking.  It’s also how evolutionary biologists have been able convince themselves, and others, of the supposed irrelevance or even impossibility of irreducible complexity.  Some scientists have argued that the positions of intelligent design and irreducible complexity are arguments from ignorance which lack enough imagination.  I would submit that the concerns put forth above are based, not on ignorance, but on what we actually do know about how life actually works and how easily it dies.  But I wholeheartedly agree that, based on the current evolutionary theory of hemostasis, with no consideration of any of the factors mentioned above, that evolutionary scientists do indeed have very good imaginations.  Alas, we who believe that the design seen in nature is real, and not an illusion, are forced to limit our imaginings to what is already known about what it takes for life to survive within the laws of nature.    

The laws of nature have put up many obstacles to prevent life from existing.  Just as a car can die from not having enough gas for energy, or oil for seizing parts, or anti-freeze for engine overheating, so too, all physicians know that there are many different pathways to death.  If you really want to begin to understand how life came into existence, you first have to understand how easily it can become non-existent.  Did life really come about solely by random chemicals coming together to form cells, then simple organisms, and then complex ones like us?  In other words, without “a mind at work” to make it happen?  Do you think that innovations like cruise control and autopilot  just happened on their own?  No, when it comes to the origin of life it seems to me that Science still has a lot of explaining to do.  Meanwhile, as we wait for evolutionary biologists to admit the deficiencies in their theory our children and the whole world continue to be misled!


Be sure to catch all of the articles in Dr. Glicksman's series, "Beyond Irreducible Complexity."



Howard Glicksman M. D. graduated from the University of Toronto in 1978. He practiced primary care medicine for almost 25 yrs in Oakville, Ontario and Spring Hill, Florida. He now practices palliative medicine for a Hospice organization in his community. He has a special interest in how the ethos of our culture has been influenced by modern science’s understanding and promotion of what it means to be a human being.

Comments and questions about this article or any of the previous ones are welcome.

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Copyright 2015 Dr. Howard Glicksman. All rights reserved. International copyright secured.

July 2015