One of the most confusing things about coagulation (until someone explains it to you) is the idea of the intrinsic and extrinsic arms of the coagulation cascade, and the way they interact during coagulation in the body.
How come you have two arms, anyway? Can you just use one or the other? How does the body decide which one to use?
It turns out that both the intrinsic and extrinsic arms are necessary in vivo. We know this because people that have a problem with one arm have problems making fibrin (the other arm can’t just compensate!).
This is because in real life, in vivo, coagulation starts along the extrinsic arm (with tissue factor binding to VIIa). It progresses down the final common pathway (making some Xa, some thrombin, and finally a little fibrin). Then – for some reason – the extrinsic arm gets turned off. Yes, turned off! This actually happens as soon as you make a little Xa; Xa interacts with tissue factor pathway inhibitor (TFPI) and turns off the extrinsic arm. By that point, though, there’s enough thrombin around to kick off coagulation along the intrinsic arm (the one with XI, IX and VIII) – and from there on out, the intrinsic arm supplies the rest of the fibrin.
So to summarize: coagulation starts with the extrinsic arm. As soon as you make a little Xa, the extrinsic arm is turned off. The small amount of thrombin that has been generated during the action of the extrinsic system goes up and turns on the intrinsic arm, which finishes out the job of making the rest of the fibrin. Weird, but true.
Someone sent in a very good question about lab testing in light of this weird turning-off phenomenon.
Q. If the extrinsic pathway is almost immediately turned off, then why is the prothrombin time (PT) normal? Because the prothrombin time is for the extrinsic pathway, and if extrinsic pathway is turned off, then why does a person have a normal prothrombin time?
A. Love this question. The answer has to do with the fact that coagulation tests are done in vitro (in test tubes in the laboratory), and the whole point of the tests is to measure how long it takes for the blood to form fibrin. The PT (or INR, same thing) – measures how long it takes to form fibrin using the extrinsic system, and the partial thromboplastin time (PTT) measures how long it takes to make fibrin using the intrinsic system.
To do a PT, you add something that acts like tissue factor to the blood in the test tube, and you measure how long it takes to make fibrin. This mimics what happens in the body: the blood gets “exposed” to tissue factor, and it progresses along the extrinsic pathway to make fibrin.
The fact that the extrinsic pathway gets turned off shortly after it starts really doesn’t come into play when you’re performing the lab test. That’s because the PT simply measures how long it takes to get from tissue factor exposure to fibrin formation. The extrinsic pathway gets turned off after that (and the intrinsic pathway takes over), but at that point it doesn’t matter! Fibrin has been formed, and the test is done.
So yes: people with a normal coagulation system have a normal PT despite the fact that the extrinsic pathway only plays an initial role in coagulation. This is because the PT simply measures the time from tissue factor exposure to fibrin formation – and what happens after that is of no importance to the test!