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A. Hemostasis:

1.

In a previous page (link) we discussed the general principles of hemostasis: stopping the blood for bleeding through a hole in a blood vessel. Link: D.4. Thrombocytes and Hemostasis

2.

This hemostasis consisted, as you may remember, of three steps:

  1. Vasoconstriction (by the muscular wall)
  2. Plug formation (by the platelets)
  3. Formation of fibrin (by the process of coagulation).
3.
This final stage, coagulation, is so important (and, unfortunately for you, so complex) that I have dedicated a special page to this process: Coagulation!
4.
The purpose of coagulation is to make the plug strong and tight, so that the bleeding stops.
B. Coagulation:
1.
In the blood circulation, there are several compounds that are working to promote coagulation (= pro-coagulants) and other compounds that inhibit coagulation (= anti-coagulants).
2.

In the circulation, there is a delicate balance between pro- and anti-coagulants. Too much pro-coagulation and you induce intravascular clotting, to little and you may have bleeding that does not stop.

3.
To much coagulants -> intra-vascular clotting -> in brain or heart vessels -> infarcts -> dead tissue -> dead person!?
4.

Not enough coagulants -> risk of bleeding -> in the brain or the heart -> causes cell and tissue death -> dead person!?

5.
Either way, the outcome of a disturbance in the coagulation system is dramatic. Therefore, there must be a (delicate) balance between pro- and anti-coagulants.
C. Blood Coagulation System:
1.

The coagulation system consists of two branches coming together in a final common pathway:

  1. Intrinsic pathway (inside the blood)
  2. Extrinsic pathway (outside the blood; i.e. in tissues)
  3. Common pathway

2.

All three pathways consist of many different components (= coagulation factors) that are present and dissolved in plasma.

3.
What you see happening during coagulation is a complicated (but well-regulated) chain reaction of these compounds.
4.

The ultimate goal of this coagulation chain-reaction is to produce fibrin; a non-dissolved compound that fixates the platelet plug that was formed during the hemostatic process.

D. Intrinsic Pathway:
1.

Let’s start with the intrinsic pathway. “Intrinsic” means that this chain reaction starts and develops within the blood.

2.

Inside the blood, several compounds (called “factors”) are present and dissolved in the plasma. These are factors XII, XI, IX, VII and X. (remember the Roman numerals?)

3.

If a serious disturbance, or a trauma, occurs inside the blood, or exposure to something from outside the endothelium such as collagen, then factor XII will be activated. This is shown as XIIa (a = activated).

4.

Once XIIa is present, it will, in turn, activate factor XI. Then, XIa will activate factor IX. Meanwhile, due to the trauma, factor VIII has also been activated. This will, together with IXa also activate factor X into Xa.

5.
This Xa, the product of this intrinsic pathway will now activate the Prothrombin-activator; the beginning of the Common Coagulation Pathway.
Remember the Roman numerals?
; I = 1; V = 5; VII = 7; X = 10; XI = 11, XII = 12
E. Extrinsic Pathway:
1.
The extrinsic pathway is shorter but probably even more important because it reacts to any trauma in the tissue (outside the blood).
2.
So, a tissue trauma activates a tissue factor (there are many compounds in the tissue that can act as a “tissue factor”).
3.
This tissue factor activates factor VII (which is in the blood that streams through this traumatized tissue).
4.
Both the Tissue factor and factor VIIa activate factor X. This in turn, activates the Prothrombin-activator, also the entry point to the common pathway.
5.
Note that both in the intrinsic and in the extrinsic pathways, calcium-ions are required for the activation process.
F. Final Common Pathway:
1.
When the intrinsic or the extrinsic pathway (or both) have activated the Prothrombin-activator, then we come to the final common pathway.
2.
This pathway is very short: the prothrombin-activator activates Prothrombin which becomes Thrombin.
3.

This thrombin, in turn, activates the available, dissolved, fibrinogen into the insoluble Fibrin. Coagulation! Finally.

G. Some important notes:
1.
As I said before, calcium ion (Ca2+) is very important in enabling these reactions.
2.

This is usually no problem at all in the body (without calcium ions, many things would immediately stop!), so that’s not the issue.

3.
But this makes it possible to store blood, as a fluid, in a container outside the body!
4.

For example, in the case of a vena puncture, when you draw the blood outside the body into syringe, you don’t want the blood to coagulate.

5.

In that situation, you can avoid coagulation by adding EDTA to the blood. This EDTA removes all the Ca2+ from the plasma and stops the coagulation process.

6.

Another important point; many coagulation factors are produced by the liver. Therefore, if there is a liver problem (for example liver cirrhosis), you may also develop a coagulation problem.

7.
In addition, many factors also require vitamin K.
8.

In fact, the presence of these coagulation factors is so important that we have given a special name for blood in which the blood factors have been inactivated (by EDTA for example). This plasma without coagulation factors is called: serum.

9.

Finally, this chain reaction is one of the few examples in the body of a positive feedback reaction in the body! Link: A.1.2. Physiological Concepts

10.

It is really a cascade that is waiting to happen in the blood and where the blood, hopefully at the right spot, coagulates quickly (1-2 min) to stop the bleeding!

H. Clotting Factors and their Synonyms:
1.

As you can imagine, looking at the complex coagulation chain reactions, it has taken a long time and the work of many investigators to unravel all its components and describe this chain of reactions.

2.

Therefore, many of these factors have been given different names, sometimes dependent on the country of the investigators, sometimes because of certain diseases involved in these reactions.

  1.  

Here is a list of some important synonyms in the coagulation system:

4.
Note the synonyms of factors VIII and IX; anti-hemophilic factor A and B.

5.
 Apparently, these factors are absent in people suffering from these two diseases!

Slides D.5. Coagulation System
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