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New Treatments for Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria is characterized by the presence of thromboses. Thrombocytopenia leading to hemorrhage, definitely there. Not dramatically common and then red cell hemolysis is constantly going on in these people with PNH paroxysmal nocturnal hemoglobinuria. Here’s the clinical features; young adults. This is an illness of male and female, slight preponderance in females, not dramatic. Anemia for the reasons that I’ve already mentioned, and this frequently leads to rather impressive iron deficiency. Hemoglobinuria, hemosiderinuria, abdominal pain is very very common.

This is the hallmark feature. Somebody gets up in the morning and passes this very rosy plus-colored urine. Looking at the peripheral blood smear one sees the rather impressive degree of hypochromia, some degree of fragmentation, plenty of platelets here - this is not really the DIC process but this looks very much like a terrible iron deficiency. And it is. There are three populations of red cells in individuals with this disorder, and that is a group here that’s very very sensitive to the presence of complement, less sensitive here and then there is another population.

These are brought about in three categories of type I red cells, where the survival is nearly normal; type II, and these are missing on the membrane, acetylcholinesterase decay-accelerating factor. There are components here of complement. Type III, more things are missing here on the red cell membrane, and this is what makes them very sensitive even to the normal activity of the complement system, bringing about red cell lysis. The red cell abnormalities, absence of acetylcholinesterase decay-accelerating factor, and these are things that avoid or prevent the complement system from doing in the red cell membrane.

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.

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.

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.

Resistance to activated protein C, which one finds on the list right here. Resistance to activated protein C among congenital inherited hyper-coagulable diseases. What’s this all about? What’s this due to? 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

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