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!

30 Responses to Intrinsic vs. extrinsic pathways

  1. ogechi says:

    Perfect answer to the question. You broke it down to the basics. Thanks Dr Krafts

  2. nsaho maro says:

    love it more

  3. ehsam says:

    Hi, thanks alot for such a nice text! Extrinsic and intrinsic pathways are flash and fire actually!

  4. Janarthan Rama Murti says:

    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?

  5. Jack Simmons says:

    Finally, someone has started an explanation for the difference between extrinsic and intrinsic pathways; for me at least. I have been struggling with understanding the differences between the two for a looonnnng time.

    I kept getting hung up on the term intrinsic, meaning from within an organ or system. But, if truly intrinsic, this pathway would always be on and we would always be having thrombotic activity, not good and not reality.

    One arm is actually tied to the other. The intrinsic does not get started until the extrinsic is on and, apparently in the process of being turned off. And while the extrinsic path is triggered by a true extrinsic factor (tissue factor) the intrinsic path uses nothing external to the blood system.

    Now it is starting to make sense.

  6. Kristine says:

    Yes! Perfect explanation 🙂 I know – it seems so confusing until someone explains it to you – then it’s so simple. Glad it helped!

  7. Kristine says:

    Hi Janarthan- the INR/PT tests the intrinsic pathway and final common pathway (but not the extrinsic pathway) – and the PTT tests just the extrinsic and final common pathway (not the intrinsic pathway). In the lab, we can bypass one or the other pathway (IP or EP), depending on which reagents we add to the test tube. In the body, it’s all tied together, though. Regarding your last question – a defect in the intrinsic pathway will cause the INR/PT to be prolonged (but will not affect the PTT).

  8. Kristine says:

    Good analogy, Ehsam.

  9. madelyn says:

    thank you!!!!! You made this seem so simple! =)

  10. Joyce says:

    Kristine, this is regarding your comment to Janarthan on 8/3/15 @1:10PM. You seem to have the intrinsic/extrinsic pathways reversed as to which is tested for by the PT/INR and the PTT. The PT/INR monitors the extrinsic and common pathways, while the PTT monitors intrinsic and common pathways. Confirm?

  11. Kristine says:

    Thanks, Joyce – yes – you are absolutely correct: the PTT tests the intrinsic pathway and the PT tests the extrinsic pathway. Looking back I see in my comment I wrote it the other way around! Thanks for catching that 🙂

  12. nouf says:

    hello Kristine 🙂 you are an amazing explainer..the way you explained it in such easy and understandable terms is higly appreciable..i have subscribed to love bites a few days ago and i am so glad i did and i regret that i didnt know about this before..i have been struggling with this since the past 1 week but finally i understood now 🙂 ..all thanks to you..i just have one doubt Kristine that the names of the tests of the intrinsic and extrinsic pathway , PT and PTT ,so does these names have anything realted to prothrombin or partial thromboplastin because i cant relate to how does partial thromboplastin effect intrinsic pathway ,though i can somewhat relate with prothrombin that prothrombin activates thrombin in intrinsic and so the name of the test..plz do let me know if i am right about the extrinsic one and my doubt regarding the name of PTT of intrinsic pathway…

  13. nouf says:

    prothrombin activates thrombin in extrinsic i mean not intrinsic ..sorry for that

  14. nouf says:

    and i was referring to pathology student ..i am extremely sorry for the wrong name

  15. Kristine says:

    Thank you!! Here’s a post that answers the question of why the PT and PTT are named the way they are. It has to do with the reagents (thromboplastin and a thromboplastin derivative) that are added in the PT and PTT. Here’s an excerpt:

    Coagulation questions seem to come up all the time! Here’s a good one from one of our readers.
    Q. In both the PT and PTT we add thromboplastin, right? So how come the PT measures the extrinsic pathway and the PTT measures the intrinsic pathway?

    A. This is a great question because it really gets at the underlying concepts of the PT (INR) and PTT. When I was a medical student, I never really thought about why the INR only measured the extrinsic pathway and the PTT measured only the intrinsic pathway. I just memorized the substance added to the test tube in each test, and the pathway the test measured. Later on, though, I realized I didn’t have a clue as to why the tests measured the pathways they did.

    Before we get into the reasoning behind the tests, a quick correction is in order. We don’t add thromboplastin in both the INR and PTT. In the INR, you add thromboplastin, and in the PTT you add phospholipids (not thromboplastin). It turns out thromboplastin is a substance that contains both phospholipids AND a tissue-factor-like substance. That’s why they call the assay the “partial thromboplastin time” – because you only need to add part of the thromboplastin reagent (the phospholipid part) to get this test to run.

  16. nouf says:

    Thank You so much made everything so easy to understand :):)..i highly appreciate your efforts 🙂

  17. Ana Palmeiro says:

    I loved reading this, you make it sound so fun! Keep it up!

  18. Genevieve Blais says:

    Beautiful Explanation 🙂 Thanks

  19. Mahesh says:

    Thank You so much Dr.Kristine
    Really awesome.

  20. Wills says:

    thanks for the enlightenmenment i was really lost abt that

  21. Vive RUGIRA says:

    very clear explanations Dr Kristine. Thank you very much. wish every Lecturer did it like you did, why always make it hard in class!

  22. Chikaodiri says:

    Wow so simplistic.
    Thank you Dr. Kristine.

  23. Kristine says:

    So glad you liked it! Thank you!

  24. David says:

    Dude awesome post!! Thanks a lot

  25. Bhagyashri says:

    Awesome seriously!!!! Brilliant!!

  26. Zahra says:

    Thanks a million. Perfect explanation.

  27. lewin says:

    thank you!!

  28. Daniel Amevor says:

    thanks a lot Dr

  29. Arwa says:

    You are an amazing, unbelievable teacher thank you very much ^^

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