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New Treatments for Activated Protein C Resistance

Resistance to activated protein C is a congenital inherited hypercoagulable disease. The problem here is that normally protein C with a co-factor of protein S controls the activity, if you will, down the coagulation pathway starting with number 11, then 12, 9, 8 and so on as the cascade moves down. This system here normally protein C co-factor S inactivates number 5 and number 8 coagulation factor proteins. They are kind of keeping a balance here to prevent ongoing conversion of soluble fibrinogen to insoluble fibrin.

We see here that here is factor V and normally this undergoes degradation. But in resistance to activated protein C there is at position 506 in the factor V molecule, arginine moiety is replaced by glutamine, and this is what identifies this. The factor V gene also has an abnormality in it at position 1691. The factor V at 506, the factor V molecule, this arginine is replaced by a glutamine, it’s resistant now to the normal degradation of activated protein C, and the factor V gene here at 1691 a glutamine is replaced by an arginine.

This problem is variously reported in different articles and publications to be at a frequency rate in some places of 30, 40, 50, 60% of the populations that are studied. However you and I all know that thrombosis is not in any way shape or form found in that frequency. So one must be somewhat concerned about this and the absolute direct connection that it may have. This may not always really be the answer for this situation, but of the things that you can look for today, it’s certainly going to be high on the list for an etiologic or diagnostic test that can be done. So don’t forget about this population of resistance to activated protein C. The presence of the factor V Leyden molecule, which does not undergo normal degradation as it should, by protein C with a co-factor of protein S.

Alkaline phosphatase classically reduced to near zero again because it is missing, because the link isn’t there to hold it on. No cytogenetic abnormalities have been identified. Thrombocytopenia is very common. The survival here is pretty good. The function is normal and the real problem here is that these cells are very very sensitive to antigen antibody-type reaction and some individuals use PNH cells to detect, with other techniques, undetectable antigen antibody-type of interaction. They are very very sensitive.

And here’s the ball-game here. What’s missing is this phosphatidylinositol link in the PNH patient. Here’s the normal individual and it’s this phosphatidylinositol glycosyltransferase that’s missing here and fails to put this on and we see in the PNH there is some trans-membrane protein here but the majority of this is missing. This is what makes these cells very very sensitive. Here’s the glycolipid anchored abnormalities. These things are all missing because of the absence of that trans-membrane link, decay-accelerating factor, membrane inhibitor-releasing factor and so on down the line. This is the one to really look for today, employing flow cytometry which makes the diagnosis. Here in the past, the diagnostic test they used a sucrose hemolysis with peripheral blood. It’s still a very good and reliable, fairly simple type of test to do. But if flow cytometry is available to you, ask them to look for CD59 and in this illness it’s gone. It’s not there. That will promptly make the diagnosis. Otherwise sucrose hemolysis is very very good, and again absence of alkaline phosphatase.