Q.Â How did the “extrinsic” and “intrinsic” coagulation pathways get their names?Â 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, andÂ “extrinsic” sounds like one that might happen in the lab, or outside the body. But that’s not at all what the names mean!Â 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).
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.
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.
You are an amazing teacher really. I’m a medical student in Greece and things that others explain in a 5-page essay, you make it happen only in one paragraph. Just amazing!
that is great thank you very much ,, ÙActually I took this lecture last week but I didn’t get it now I got it 🙂
Thanks a lot for the valuable explanation, it was actually impressive.
this is great . I use this blog about ip ep with students , med , college [they come to see what we do before eliding on their pathway , residents and , yes even fellows in heme . a great little page to start
Im a vascular surgeon in Ohio. im reviewing for my 10 year recertification boards. Nice job!
Thanks! So glad you found the post useful!
this is preethi.iam a student in kamineni mbbs student ,1st yr . ihave a doubt that hemophilia A is due to deficiency of 8th factor but extrinsic mechanism doesnot require 8th factor but even then hemophilia patients do not form clot by extrinsic way.WHY?
Great question! If you’re missing factor VIII, why don’t you just use the extrinsic pathway to make fibrin? The answer is because you need both pathways to make fibrin! In the lab, you can make fibrin using the extrinsic pathway (using the PT/INR) or the intrinsic pathway (using the PTT) – but in the body, you start out with the extrinsic pathway, then turn that pathway off and use the intrinsic pathway. Really! Here’s a post explaining more on exactly that question.
my sir questioned us what is the importance of 8th and 9th factor in extrinsic mechanism of blood coagulation? if any one will answer it he will give a guitar. he is so confident that no one will answer it so he told he will give his guitar .do u know what is the importance of 8th and 9th factorin extrinsic pathway
Hi Preethi –
Hmm, I think that might be a trick question. Either that, or there is some obscure connection that is not in most textbooks! The extrinsic pathway involves tissue factor and factor VII, along with the factors in the final common pathway (X, V, II and I). I’ve never heard of a way that VIII and IX are connected with the extrinsic pathway.
One way to approach it is to consider the PT/INR in patients who have hemophilia (and are missing either VIII or IX). In these patients, the PT/INR (which measures the extrinsic pathway) is normal. This would seem to be proof that VIII and IX are not connected to the extrinsic pathway.
Come back and let us know what he said!
Thank you Prof for this clarification.
-You mentioned that the intrinsic pathway has been called so because we do not need something from outside the blood. There is surface activator in the APTT reagent. Don’t you consider this activator as an extrinsic factor?
Hi,Nice thought provoking topic.!I love Pathbites from Dr.Kristine.
Thrombin activates factor 9,8,5. For thrombin to become active,it needs 10A,which is activated by factor 7A & TF. 8A also activates 9 to 9A.Confusing!! How to connect them.?
Continuation of activity of 8 and 9,requires thrombin,which requires 7A and TF.(through activation of 10).Does it mean without 7 and TF,there is no continuation of activity of factor 8 and 9? Is this indirect relationship between 7(EF)8 and 9(IF).
Additional link between EP and IP==Ability of TF and 7A to activate factor IX.
Not sure if this makes sense!
Good point, Hejji! I see what you’re saying – yes, you could say that the surface activator in the PTT reaction is extrinsic to the blood! But when the pathways were named, I guess they kind of ignored that point and focused more on the phospholipid and tissue factor. It’s not a perfectly descriptive way to name the pathways – but that’s the way it happened! Excellent point – and one that proves you understand a lot about the tests – good for you. 🙂
Hi Krishna –
Thanks! Yes – coag is complicated. I think the best way to remember the order of things is to simply draw out your own diagram (I put the extrinsic pathway on the right and the intrinsic pathway on the left), simplify it as much as you can (take out the contact factors, since they’re not important in vivo), and then memorize it. I have a way to do that that I go into detail about in my Clot or Bleed book. It is probably enough to just remember the intrinsic and extrinsic arms, which factors are in which arms, and the connection between the two (you start off the cascade along the extrinsic pathway, then you turn the extrinsic pathway off and start along the intrinsic pathway).
As soon as the extrinsic pathway is turned off,what stimulates the intrinsic pathway to form a clot?
Good question! The little bit of thrombin that has been formed by the extrinsic pathway is the the thing that kicks off the intrinsic pathway.
Can’t thank you enough
Your explanation and interpretation are simply fantastic.
Thanks a lot for your this far reaching effort.
Oh my dear you are a simply amazing teacher…!!!
Thanks! You are unique!