How come the extrinsic and intrinsic pathways are named that way?

blue tube

Q. How did the “extrinsic” and “intrinsic” coagulation pathways get their names? It seems counter-intuitive.

A. Excellent question!! And one that a lot of students have asked in class. “Intrinsic” sounds like the important pathway that happens in the body, and “extrinsic” sounds like one that might happen in the lab, or outside the body. But that’s not at all what the names mean!

The two pathways were named that way because of the way blood clots in a test tube in the lab – not because of the way the pathways act in the body. Both pathways are totally necessary for coagulation to proceed in the body – let’s get that straight right off. But in the lab, you can do each pathway separately (the INR, or the PT, measures the extrinsic pathway, and the PTT measures the intrinsic pathway).

Extrinsic pathway

If you want to get the extrinsic pathway to run in a test tube, you have to add something extrinsic to the blood. Remember: the extrinsic pathway is kicked off by tissue factor combining with VIIa. Tissue factor is not normally present in the blood (it’s in little closed-up particles, or it’s in the subendothelium, or it’s in inflammatory cells…it’s a mysterious little substance). So if you want to get blood to clot in a test tube via the extrinsic pathway, you have to add tissue factor (which is extrinsic to the blood) to the test tube.

Intrinsic pathway

If you want to get the intrinsic pathway to run, you don’t have to add anything – everything that it needs is already in the blood. Remember: the intrinsic pathway is kicked off in the body by thrombin (and, less importantly, by other stuff, like bradykinin and high molecular weight kininogen). So everything you need for that pathway is already in the test tube; all the factors are intrinsic to the blood.

Of course, for both pathways, you have to replace the calcium and phospholipid surfaces you took out of the blood, because the coagulation factors need calcium and a phospholipid surface to work. For coagulation tests, you draw blood into a blue-topped test tube which contains a chelating substance that takes out the calcium in the blood (otherwise the blood would clot before you even got back to the lab). You also remove the platelets before running the tests (platelets provide a phospholipid surface for the coagulation factors to sit on in the body) – so you have to add back a phospholipid surface to the test tube to get the tests to run. But calcium and a phospholipid surface are normally present in the blood – so by adding them to your test tube, you’re not really adding anything new – you’re just replacing what you took out.

Ah, coagulation. Always a challenge! If you want to read a nice summary of coagulation (if I do say so myself), check out Clot or Bleed: A Painless Guide for People Who Hate Coag. It goes through both the intrinsic and extrinsic pathways, describes how they actually fit together in the body (which, strangely, is something nobody seems to talk about), and gives you a creative (if weird) way to remember which is which.

Phospholipids, tissue factor and the platelet plug

plug

Q. I have a question about forming the platelet plug. Where are the phospholipids that get exposed, and how does platelet aggregation affect that? If this is in the subendothelium why weren’t they exposed upon ripping or whatever caused the endothelial damage? Also, what is tissue factor?

A. The phospholipids you’re referring to are part of the platelet cell membrane. The platelet membrane contains many different kinds of phospholipids on its surface. This is important because many of the coagulation factors (for example, the factor Xa-Va complex) require a phospholipid surface to exert their effects. During platelet aggregation, some of the phospholipids undergo important changes, making them more available to the coagulation factors.

Here is how a platelet plug is formed:

1. The endothelium gets ripped up, which exposes subendothelial proteins (like collagen) to the blood.

2. The platelets see these subendothelial proteins, and they stick to them using von Willebrand factor (this step is called platelet adhesion).

3. As the platelets adhese, they flatten out and release their granules (which have a lot of functions, one of which is to attract other platelets).

4. Other platelets come to the adhesion site, and they stick down onto the platelets that are already there (this step is called aggregation).

5. Now the platelet plug is formed. One cool thing about the platelet plug – in addition to its function of plugging the hole in the vessel – is that the platelet membrane provides a phospholipid surface which is essential for many of the coagulation factors. In fact, when platelets aggregate, certain phospholipids in their membranes become even more available to be used by the coagulation factors.

Tissue factor is a separate thing. It is the substance that initiates the whole coagulation cascade in vivo. It’s present in different areas of the body (in the subendothelium, in some inflammatory cells, and perhaps even in little locked-up microparticles in the blood). It is not present in active form in the blood until it’s needed for coagulation. So when the endothelium is ripped up (or when inflammatory cells decide to release it, or when the little microparticles get a signal to open up), tissue factor is exposed to the blood, and it binds to factor VIIa, and the cascade proceeds along the extrinsic pathway.

A different kind of plug: the image of Claes Oldenberg’s giant three-way plug at the Tate was taken by jovike (http://www.flickr.com/photos/49503078599@N01/54082836/), under cc license.