Why Doesn’t FVIII Deficiency Prolong PT?

A question from Lucas Tarquino at the University of Medicine and Dentistry of New Jersey:

Hello,
I am a medical student studying for USMLE step 2 and have a question about factor VIII deficiency.  Since factors IX and X are in both the intrinsic (partial thromboplastin time, PTT) and extrinsic (prothrombin time, PT) pathways, why does deficiency of factor VIII, which is a cofactor in the conversion of factor IX to IXa and therefore also affects factor X, only prolong the PTT but not PT?  I would appreciate your help in understanding this.  Thank you, Lucas Tarquino.

Hello, Mr. (soon to be Dr.) Tarquino, thank you for your question. You are correct that theactivated factor VIII/activated factor IX (VIIIa/IXa) complex activates factor X, which is part of the common pathway. From a strictly mechanistic analysis of the coagulation pathway, it would seem factor VIII or IX deficiency would prolong both the PT and the PTT.

In the coagulation mechanism, extrinsic pathway activated factor VII (VIIa) activates IX but also directly, albeit weakly, activates factor X. The reason the PT is insensitive to factor VIII or IX deficiency is that the PT reagent; which consists of synthetic tissue factor, phospholipid, and ionic calcium; avidly triggers the activation of factor VII, and through this alternate pathway, factor X, without the need for VIIIa or IXa. If you dilute the PT reagent to about 1:200, you can actually demonstrate a dose-response to factor VIII and factor IX activity. Such a large dilution, however, markedly prolongs clotting and renders the PT useless for monitoring oral vitamin K antagonist antithrombotic (warfarin, coumadin) therapy, its primary duty.

As an aside, the PT reagent was originally a biological extract of mammalian brain or lung tissue called “tissue thromboplastin,” and although most PT reagents are now synthetic, the name thromboplastin has stuck. The original formulation was specifically designed to be insensitive to VIII or IX deficiency and to be most responsive to coumadin therapy. Geo