Q. I understand that hemophilia is caused by factor VIII or IX deficiency and both factors work in the intrinsic pathway. But in patients who are missing factors VIII or IX, isn’t there still the extrinsic pathway that can activate factor X to convert fibrinogen to fibrin? Please help.

A. Great question!

You are absolutely correct: the extrinsic pathway does, in fact, convert factor X to Xa, which then converts prothrombin to thrombin, which leads to fibrin formation. So why can’t you just use that side of the pathway?!

It turns out that you actually need both the intrinsic and extrinsic pathways in your body. In a test tube, you can form fibrin along either pathway. But in the body, the pathways are intertwined in such a way that if you’re missing something on either the extrinsic or intrinsic side, you won’t be able to clot properly.

In our bodies, the thing that kicks off the clotting cascade is tissue factor “exposure.” Tissue factor is not floating around in the blood normally – or at least, it isn’t normally “visible” to the blood (it might be in little membrane fragments, but it’s not active until it’s needed). When you need to form a clot, tissue factor appears, and together with factor VIIa (which happens to be just floating around in the blood) it converts factor X to Xa (which then converts prothrombin to thrombin, which converts fibrinogen to fibrin). So: clotting initially begins along the extrinsic pathway.

The weird thing, though, is that as soon as we make a little Xa, that Xa (along with the aptly-named tissue factor pathway inhibitor) turns off the extrinsic pathway! A little thrombin is formed, though, before the pathway gets turned off – and that thrombin kicks off the intrinsic pathway (the other side of the cascade, with factors VIII and IX). Fibrin formation then proceeds along this pathway until it’s no longer needed.

The bottom line is: you need both the intrinsic and extrinsic pathways to form fibrin in vivo. If you don’t have factors VIII or IX, you can’t utilize the intrinsic pathway – and you’ll have a very hard time forming fibrin!


14 Responses to Why do you need the intrinsic pathway when you have the extrinsic pathway?

  1. Anna says:

    Thank you so much! I’m currently studying for an exam & was wondering this exact thing. Very clearly explained. Cheers :).

  2. Mantas says:

    Best explanation on coagulation ever.

  3. Alex Tran says:

    Thank you so much for this explanation Dr. Krafts! You should come visit San Diego again, and speak at UCSD as a guest lecturer on the topic of hemophilia for the Molecular Basis of Human Disease course. You will be LOVED.

  4. Kristine says:

    Aw thanks Alex!! That is sounding nice about now…we are under a foot-deep blanket of snow and it will be getting old soon…it would be fun to talk about coag out there!

  5. Dr. Rajan says:

    wonderful answer

  6. Shay Fabbro says:

    Love the simplicity of this answer! I am going to use this to help my students understand the basics of the coagulation pathways in their anatomy classes. Many thanks! 🙂

  7. Matthew Benger says:

    Many thanks for this incredibly succinct explanation.

    Robin – Med student UCL

  8. ravi s says:

    Thank you

  9. Dr Khandke says:

    Best explained

  10. Hejji says:

    clearly explained. Thanks

  11. hagar mohamed says:

    thanks 4 this answer ,i understood coagulation well now

  12. Sashi says:

    Great answer, thank you.

    Just for clarification. Thrombin converts factor XI to XIa and VIII to VIIIa in the intrinsic pathway (also V to Va, fibrinogen to fibrin, and XIII to XIIIa). Factor IX is in the cascade of the intrinsic pathway, but not converted or kicked off by thrombin, whereas factor VIII is converted/kicked off by thrombin; the wording in the answer may be interpreted that way.

  13. Kristine says:

    Hi Sashi –
    Yes – that is all correct!

  14. Umna says:

    Thank you so much for this comprehensive explanation.

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