Two paths

Janarthan sent in a great question on one of our posts about the two coagulation paths: the intrinsic and extrinsic pathways. He writes:

Great explanation. 🙂
As a corollary, does this mean INR/PT test for Extrinsic Pathway (EP), Intrinsic pathway (IP) and Final common pathway (FCP)…and PTT test for IP and FCP?
hmm, so this mean a defect in intrinsic pathway, is going to cause INR and PTT to be prolonged?

These are great questions – and if you had them, I am sure others had the same questions too. So let’s talk about them here where others might benefit!

If the intrinsic and extrinsic arms are interdependent, then does the INR test really test for both arms?
Regarding the first part of your question (“Does this mean INR/PT test for Extrinsic Pathway (EP), Intrinsic pathway (IP) and Final common pathway (FCP)…and PTT test for IP and FCP?”): The short answer is no. The INR/PT tests only the extrinsic pathway (and the final common pathway). You’re right about the PTT, though: it tests only the intrinsic pathway (and final common pathway).

This is because although the intrinsic and extrinsic pathways are dependent on each other (and must both work well) in the body, they are not dependent on each other in the lab. The INR and PTT measure only the time it takes for the first fibrin strands to form – then the test ends at that point. These tests don’t really care about the interdependence of the pathways in real life; they just want to know how long it takes to get to fibrin formation by one of the two arms.

The PT/INR measures the time it takes to form fibrin after adding a tissue-factor-like substance (called thromboplastin) to the test tube. Once you do that, the cascade is going to progress down the extrinsic arm (ignoring the intrinsic arm, which couldn’t care any less about tissue factor), and make some fibrin, which the machine will measure. As soon as some fibrin is made, that is the end of the test. Yeah, we could let it go on, and the intrinsic pathway could get activated by the thrombin that was generated during our little test, and even more fibrin would be made…but by that time, we’d have quit measuring time and nobody would really care. Sad but true.

Same for the PTT. In the PTT, all you do is add “partial thromboplastin” to the tube of blood. Partial thromboplastin is just the phospholipid portion of the thromboplastin molecule (without the tissue factor portion), which is why they call it “partial thromboplastin” – simple but extremely confusing until someone explains it to you. So basically you’re adding a phospholipid surface, and also some sort of initiator (silica, for example, activates factor XII, which can kick off the intrinsic pathway in the test tube. It doesn’t do a heck of a lot in the body – thrombin is the main activator of the intrinsic pathway in vivo  – but we’re talking about test tubes so let’s stay on topic…). Coagulation then proceeds down the intrinsic pathway with no input from the extrinsic pathway (which doesn’t give a crap about silica or factor XII). As soon as you form a little fibrin, the test is ended, and you have your result.

Will a defect in the intrinsic pathway cause both the INR and PTT to be prolonged?
The second part of your question (“hmm, so this mean a defect in intrinsic pathway, is going to cause INR and PTT to be prolonged?”) gets at the same concept from a slightly different angle. If a patient had a defect in the intrinsic pathway (let’s say they had an inadequate amount of factor VIII), that would affect the PTT for sure.

That same defect in the intrinsic pathway would not  affect the INR though! Because to get the INR to run (in the LAB, remember), you don’t need factor VIII. All you need to do is add a tissue-factor-like substance to complex with factor VII, and fibrin formation will occur following the extrinsic pathway.

Good planning, test-creator-people!
This is all good news. Because if you think someone has a coagulation problem, it would be nice to figure out which part of the pathway was messed up so you could go about looking for a diagnosis and treatment. And that’s exactly what these tests will do: if a test is abnormal, it points you to a particular part of the pathway so you can narrow down your diagnosis.

Of course, there are times when both the intrinsic and extrinsic arms will be messed up. In severe liver failure, for example, the liver isn’t up to the task of making coagulation factors. Factors on both sides of the cascade will be missing (or decreased), which means that both the INR/PT and PTT will be prolonged.