- Education and Science»
- Life Sciences
Blood Coagulation Pathway (Stepwise with Pictures)
It is very common experience to find the blood ooze out from a cut after an injury.
Say injuring a finger with a knife while peeling a potato. You do apply ice cubes or pressure to stop bleeding but finally the bleeding automatically stops by itself after some time.
Naturally the question arises how does it stop?
This is the article where I will explain that bodys 'mechanism' which is responsible to stop bleeding from a cut.
To begin with, let us first draw an outline of the things that take place when we meet an injury, say when we cut our hand.
Once there is a cut then the bleeding starts from the damaged blood vessels. This is an obvious observation.
But soon a ‘series of events’ is initiated (which I will discuss in detail below) for which a clot is formed which ultimately it seals off the damaged blood vessel.
The ‘series of events’ which I mentioned above is quite cumbersome to deal with at the beginning when we first learn it but later on it becomes very easy with practice.
Fortunately in this article I will share an interesting trick that will make this hectic pathway lot easy.
Before we begin I would like to describe the structure of the blood vessel in short so that it becomes easy to understand the pathway.
Do you find the coagulation pathway difficult to memorize?
The structure of blood vessel
- A blood vessel has the shape of a cylinder through which the blood in our body flows.
- The wall of a blood vessel is made up of flattened cells called endothelial cells. Normally this wall prevents the blood from leaking out of the circulation unless some injury occurs.
- Outside the endothelial cell lining is the collagen lining which is a strong fibrous insoluble protein. It needs to be mentioned that normally the blood does not come in contact with the collagen layer.
What happens when an injury occurs?
- When there is an injury then the wall of the blood vessel gets damaged (including the endothelial layer) and the blood comes in contact with the collagen.
- This causes the platelets (which is a small disc shaped cell without nucleus) present in the blood to attach with the collagen and change their shape which causes them to get activated.
- Activated platelets release their granular contents which makes their surface sticky. These granules further activate new platelets which also start getting sticky. Now these sticky platelets attach to each other and together form a clot (a gel like mass which is responsible for stopping the bleeding from the cut injury)
- It is to be kept in mind that this clot formed by platelets is a temporary clot. So in order to turn it into definitive and strong clot some protein fibers called fibrin fibers need to be added to the temporary clot which is made by platelets.
Now that we know that special fiberour protein material called fibrin is necessary for the formation of the final clot let us try to understand how this fibrin strand is formed.
A fibrin fiber or strand is formed from individual fibrin molecules when they attach with each other. Although these fibrin molecules are present in the blood but normally they don’t form a strand. This is because they are present in their inactive form in the blood (known as fibrinogen).
Fibrinogen need to be activated to form a fibrin molecule which would then form a fibrin strand. Interestingly the fibrinogen is also known to be the factor-I of the coagulation cascade which I will discuss in detail below.
Coagulation cascade is a sequence of interactions between 12 proteins (labelled in Roman numerals from 1-13) that is responsible for formation of fibrin from its inactive form fibrinogen at the location of tissue injury. The term Cascade literally means series of events.
Various participant proteins that take part in the coagulation cascade are known as ‘factors’. These factors are usually denoted by roman numerical.
I have mentioned the list of factors involved in coagulation cascade below.
Factors: - Name:
- I Fibrinogen
- II Prothrombin
- III Thromboplastin
- IV Ionic calcium
- V Liable factor
- VII Proconvertin
- VIII Antihemophilic factor
- IX Christmas factor
- X Stuart power factor
- XI Plasma thromboplastin antecedent
- XII Hageman factor
- XII Fibrin stabilizing factor
[Note that factor VI is not available in the cascade of reactions.]
Basically these factors (proteins) activate one another during the process of coagulation and at the end of the pathway help to form fibrin from fibrinogen. Let us see how this takes place.
Intrinsic and Extrinsic Pathways of coagulation:
There are two different pathways (intrinsic and extrinsic pathway) through which the fibrin formation takes place.
Let us look at the intrinsic pathway first.
- Intrinsic pathway is less important for initiating the coagulation than the extrinsic pathway. However the intrinsic pathway is very important for the amplification of the coagulation cascade.
- The first factor of the intrinsic pathway is the factor XII. When the factor XII comes in contact with negatively charged surfaces (most commonly these surfaces are the glass containers of pathology labs) then the factor gets converted into the active form. The active form is denoted by the letter ‘a’. So in this case the active form of factor XII is ‘XIIa’.
- Now factor XIIa causes the conversion of factor XI to factor XIa. Factor XIa then in turn converts the factor IX into factor IXa in the presence of calcium.
- Then again the factor IXa converts the factor X into Xa in the presence of calcium. But it does this with the help of factor VIIIa which is being created from factor VIII.
- Factor Xa can then convert prothrombin (factor II) to thrombin (factor IIa) in the presence of calcium with the help of factor Va which of course is formed from the factor V.
- Thrombin then converts the fibrinogen (factor I) to fibrin (factor Ia). Fibrin further needs to be stabilized to form a ‘fibrin mesh’ with the platelets at the site of injury. For this purpose factor XIII and calcium need to be present to stabilize it.
Now let us look at the extrinsic pathway.
- This pathway is much simpler than the intrinsic pathway. And it is the pathway that is responsible for initializing the coagulation cascade.
- It begins when a protein called ‘tissue factor’ is released from the damaged tissues. Factor VII is converted into its active form factor VIIa in the presence of calcium and thromboplastin (factor III). Then tissue factor and factor VIIa combine to convert factor X to Xa.
- From this point the pathway continues on as that of the intrinsic pathway until fibrin is produced.
- One last thing that we need to consider is the positive feedback thrombin has in the coagulation cascade.
- Thrombin has a role in accelerating the formation of factor XIa, factor VIIIa, and factor Va. In this way the cascade is amplified to produce the necessary amount of fibrin in a short amount of time.
Trick to memorize coagulation pathway easily:
- The first thing that makes this pathway confusing is the roman numerical that are used to denote the coagulation factors. For making it easy we will convert the roman numerical into normal numbers. So now factor IXa becomes 9a.
- The second thing we need to do is omit the activated factors. Remember that we are only omitting the inactive forms so that we can make the pathway easy to remember.
Doing so the whole pathway becomes like 12a→11a→9a→10a→2a→1a→stabilized fibrin
- Next we add details to the above numbers.
- Add factor 8a along with factor 9a, 5a along with 10a and 13a along with 1a, so that we get:
12a→11a→9a+8a→10a+5a→2a→1a+13a→ stabilized fibrin
- Next we add a dotted curved arrow to show the positive feedback that factor 2a has in activating factor 8a, 5a and 13a. [See picture]
- Now let’s merge the extrinsic pathway to our number diagram. For this purpose, just merge the7a that got activated in presence of factor 3 (thromboplastin) to 10a to our number diagram:
Thromboplastin →7a→ 10a
There this should help you remember the whole pathway very easily after 2 to 3 times of practice.
There is just one little thing left with our diagram.
We forgot to add the calcium which is needed to activate the various parts of pathway.
- Encircle the factors 9a, 10a, 2a, 7a and also the stabilized fibrin. This is where the calcium has its action.
This video explains the trick to memorize the pathway as mentioned above
Now that the fibrin is formed it can act along with platelets to form a fibrin mesh as a result of which the bleeding will be stopped.
But if this was all the rest of the story then when every time you had a little damage to your endothelium you would activate the coagulation cascade and the whole system would go out of control and you would become one large walking clot.
So the important question that remains behind is:
The interesting question
How do we know that once the coagulation cascade gets activated at the site of injury then it will stop by its own and not coagulate the whole circulating blood?
The answer to this question is explained by the presence of a negative feedback pathway in our body.
This negative feedback pathway is governed by the thrombin (factor II). It helps to create plasmin from plasminogen. This plasmin acts directly on the stabilized fibrin meshes and breaks them apart.
That is one helpful example but this on itself won’t be able to stop the production of other activated factors.
For this purpose the classic example of negative feedback is that thrombin produces anti-thrombin.
Anti-thrombin will decrease the amount of production of thrombin that is being produced from prothrombin and it is also going to stop the production of Xa from X.
What if this whole system of coagulation cascade did not work?
If that happened then the fibrin strands will not be produced and the platelet plug won’t be stabilized. So the blood will leak out of the damaged area. This is seen in certain peoples as a disease known as haemophilia.
Factor VIII deficiency causes haemophilia A.
Factor IX deficiency causes haemophilia B.
Factor XI deficiency causes haemophilia C.
Thanks for reading this article.
If you liked this article then please let others know about it by sharing it. And don't forget to comment how you felt reading this. Also do let me know if I have made any mistakes in this post. Your comments are welcome.