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

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.