Information For The Recently Diagnosed

Factor V Leiden, Activated Protein C Resistance and Protein C Deficiency
By Michael Wosnick

As everyone on this list probably knows, the clotting "cascade" as they call it is very complex with multiple steps. It is not an A to B kind of thing, but rather and A to B to C to D to ....

You can think of this pathway as a road through a series of points, with your ultimate destination being a blood clot at the end of the pathway. But, at each step you can think of having a traffic cop that tells you to speed up (towards clotting) or to slow down (towards not clotting). There are multiple traffic cops and multiple control points. Messing up any of these control points can lead to excess clotting (car is going too fast) or not enough clotting (car is going too slow).

Factor V itself is a clotting factor, whose normal role is to help blood to clot when an appropriate trigger is present. However, like all steps in the complex clotting cascade, Factor V is subject to regulation to keep it under control so that clots don't form too easily or too quickly. If you think of normal Factor V as a car on a road, then left to its own devices, it will drive towards the formation of a blood clot.

Normally, however, Factor V is not just left to its own devices, but is in fact quite controlled by one of several "traffic cops". The main traffic cop is called Activated Protein C (APC). Another helper traffic cop working with APC is Protein S. Normally, APC interacts with Protein S, and together they make a combo whose job it is to slow down the Factor V so that it does not lead to excessive clotting. To be precise, APC combines with Protein S and functions to inactivate some of the normal Factor V by clipping it into a couple of pieces, rendering the car immobile. Ergo, no clot forms.

What happens when you have Factor V Leiden is that there is a single point mutation (mistake) in the Factor V gene that just so happens to be RIGHT EXACTLY at one of the points where the APC normally clips it. This tiny change means that APC can't clip it so effectively, and so the APC/Protein S traffic cop role doesn't work so well as usual. More of the Factor V gets to its destination, since less of it is clipped and inactivated along the way. The end result is that you have a tendency to OVER-clot.

This is why FVL, which can lead to excess coagulation, is also known as APC resistance. Normal Factor V is clipped and inactivated by APC (cop shoots out all the tires and stops the car). Factor V Leiden is NOT as easily clipped, and is therefore "resistant" to this regulation step (cop cannot shoot out two of the tires and so the car keeps moving).

This also explains why the inheritance of FVL is a Dominant trait. Assuming you are heterozygous, you have one normal FV gene and one FVL gene. Each of these genes control the production of half of your circulating Factor V. So, let's say that half of your circulating Factor V is normal and can be clipped by APC (slowed down by the traffic cop), but the other half is the FVL variety and is not so easily clipped by the same traffic cop. More of the Factor V than usual gets through to the end of the road (clot). That is why even having one bad copy of the gene leads to a potential problem. Just because one gene is good, does not allow the bad gene's effects to be totally masked.

You can readily see from this why having 2 bad copies (homozygous) of the gene is a bigger problem. In that case ALL if the Factor V is resistant to APC clipping, not just half of it, and so there is no traffic cop at all. This is why individuals who are homozygous are at much higher risk.

However, you can also see from this that APC resistance caused by having the FVL gene is only ONE route to over clotting. For example, you could have a normal set of Factor V genes but have too little Protein S (Protein S deficiency). In that case, there is not enough Protein S to combine with the APC so the net result is that the traffic cop is not so effective and you get less clipping of Factor V and more clotting activity. Conversely, if you have a normal Factor V gene but an abnormal or deficient Protein C, it too can lead to the same end result - too much activity of Factor V and a tendency to over-clot.

That is why the APC resistance assay, which is a coagulation test, while fairly sensitive, is therefore NOT 100% specific for FVL, since it could be positive due to any perturbation in the activity of APC, of which FVL is the leading cause, but not the only cause. There is also the possibility that the APC Resistance assay will be indeterminate if you have a border line level.

The more foolproof test is a DNA test for the FVL gene mutation itself. It is non-ambiguous, but will only tell you if you are carrying one or two FVL genes. It will not tell you about any other mutations.

The DNA test looks specifically for the tell-tale G1691A mutation which shows that in the Factor V gene at position 1691 an "A" occurs where a "G" is supposed to be. This changes an amino acid in the Factor V protein from a residue called Arginine to one called Glutamine. This small change happens to be right at the site where APC normally cleaves Factor V, and this small change therefore is the cause of the APC resistance that the other test measures.

The DNA test is therefore by far the more precise, but is narrower in scope. Therefore, while most people use the terms "APC-Resistance" and "FVL" interchangeably, in fact they are not precisely the same thing.

All FVL will be characterized by APC resistance, but not all APC resistance will be caused by FVL.

To further complicate matters, some people have both FVL AND a Protein C deficiency. Since the tendency to hypercoagulate can be attained either by having less Activated Protein C in the first place (normal cars but not enough traffic cops) or by having a mutant Factor V protein that is less susceptible to being cleaved (normal traffic cops but cars with steel tires that can't be shot out), it can easily be seen that if you have BOTH an APC deficiency and an FVL mutation, you are unfortunately worse off than if you had either one by itself.

<< Back to Information For The Recently Diagnosed