A basic introduction to coagulation

Blood has an incredible ability to regulate its own flow and consistency. It can be very very liquid; it can coagulate to become clotted and solid and then go back to being liquid again. It can be anywhere in between. A complex and tightly-regulated system of pro and anti-coagulant factors works to make your blood the right thickness at the right time and place. If this system breaks down and your blood clots when you want it to run or runs when you want it to clot, you could be in big trouble.

Two key mechanisms contribute to coagulation - platelets (also known as thrombocytes) and clotting factors.

 

How platelets work

Let's say you cut yourself chopping vegetables and start to bleed. The damage to the vascular endothelial cells (the ones lining your blood vessels) exposes bits of the cell architecture that are normally hidden. They're sticking out like bits of the internal frame of a house would if you swung a wrecking ball into it. One specific component that sticks out is called Tissue Factor.

Platelets are small cells circulating in blood that are involved in coagulation. When they come into contact with Tissue Factor, they bind to it and start sticking to each other. A substance called von Willebrand Factor is important in making this happen. Platelets also release granules which activate clotting factors locally. Quite rapidly, these stuck-together platelets plug the damage and (hopefully) you stop bleeding.

 

Platelet problems

Too much : Having too many platelets ("thrombocytosis") is uncommon but will make your blood more likely to clot at times and places it shouldn't. Similarly, having over-excitable platelets can do the same thing. In a condition called TTP, von Willebrand Factor forms giant multimers which make platelets go berserk.

Not enough : Too few platelets ("thrombocytopenia") may be present because they're not being produced by bone marrow or are being destroyed peripherally. Low platelet counts will prolong bleeding time and may cause spontaneous bleeding.

You could have a normal number of platelets which don't work properly. If you're lacking von Willebrand Factor because of a genetic disease, your platelets won't be able to stick to Tissue Factor and you'll have trouble clotting.

Drugs like aspirin screw up platelets by preventing them producing factors they normally use to link up with one another. This can be desirable - to reduce the chances of blood clots in your coronary arteries giving you a heart attack, for example.

Both : If for some reason, there's massive activation of clotting pathways, platelets and clotting factor get used up ("consumptive coagulopathy"). Initially, you form clots everywhere, hence the name of this very dangerous condition - Disseminated Intravascular Coagulation. Once you've spent all your clotting factors, you lose the ability to clot and start to bleed excessively.

 

How clotting factors work

Clotting factors are proteins that are normally present in the blood; there are lots of types and they're identified by roman numerals. When blood needs to clot - again, Tissue Factor is probably the most important instigator - the clotting factors interact in a complex cascade which ultimately converts fibrinogen to fibrin.

Fibrinogen is another protein normally present in blood and is soluble. When it's activated and cross-linked it becomes insoluble and is called fibrin. Fibrin forms long strands which stick to red blood cells and platelets and form a clot.

 

Clotting Factor problems

Clotting factors are commonly screwed up by drugs. The most famous of these is Warfarin, which interferes with the production of some important clotting factors. Warfarin is therefore used clinically when we want to stop clotting.

The family of diseases known as Haemophilias is caused by hereditary deficiencies in various clotting factors. People with these diseases bleed easily and excessively. As opposed to platelet problems which cause superficial bleeding or prolonged bleeding from cuts, haemophilia typically causes deep bleeding in tissues and into joints.

There are also conditions in which the factors which normally inhibit the coagulation cascade are absent or ineffective and you are more likely to form clots. These are mostly genetic and include Factor V Leiden and deficiencies in protein C, S or antithrombin III.

 

How does the body break down clots or stop them forming?

Of course, if there's a clotting system there must be an unclotting system. Some of the factors that inhibit clot formation have been mentioned above - protein C, S and antithrombin. Heparin works by activating the anticoagulant factor antithrombin III.

Once a clot has formed, it is broken down shortly after by the action of plasmin. This protein degrades fibrin clots and so lets blood flow freely again.The drugs known as "clot-busters" which can be used in the treatment of heart attacks and other conditions act by activating plasmin.

 


Sources/Further Reading

Guyton AC et al, Textbook of Medical Physiology, Saunders; 11th edition (2005)

Kumar V et al, Robbins & Cotran Pathologic Basis of Disease, Saunders; 7th edition (2004)

http://www.indstate.edu/thcme/mwking/blood-coagulation.html