XIIbHere’s a great coag question from a Path Student reader:

Q. I am wondering why Factor VII deficiency causes significant bleeding problems but Factor XII deficiency does not. One source I found stated that this is because the extrinsic pathway is the primary pathway in vivo and that the intrinsic pathway is of lesser importance. However, the more I thought about it, I then wondered why Hemophilia A and Hemophilia B are so severe since they are involved in the intrinsic pathway. Why doesn’t the extrinsic pathway just “pick up the slack” allow the patient to remain asymptomatic as it seems to with Factor XII deficiency?

A. It turns out that factor XII is pretty important in vitro, but not in vivo. In the test tube, XII is activated by contact factors (like HMWK), and then XIIa catalyzes the conversion of XI to XIa. In the body, though, the main thing that converts XI to XIa is thrombin (not XIIa). I don’t even include XII in my drawing of the cascade for my students, since it’s of no clinical consequence. The intrinsic side is complicated enough!

With regard to the extrinsic and intrinsic pathways: both are critical for fibrin formation in vivo. I wouldn’t say that either one is of lesser importance – they just do different things.

In vivo, the cascade starts on the extrinsic side with TF showing up and binding to VIIa. The TF-VIIa complex converts X to Xa, and things proceed from there. The weird thing is that as soon as a little Xa is made, it actually goes and turns off the extrinsic pathway! It inhibits it using something called tissue factor pathway inhibitor (TFPI).

By this point, you already have a little thrombin around – and that thrombin goes and kicks off the intrinsic pathway. Thrombin converts XI to XIa, which converts IX to IXa, which – together with VIIIa – converts X to Xa.

Bottom line: the cascade starts with the extrinsic pathway, but that pathway gets shut off very quickly. Thrombin activates the intrinsic pathway, which proceeds to convert fibrinogen to fibrin until you need to turn it off.