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New Treatments for Trousseau Abnormality

Trousseau abnormality is a recurrent, migratory arterial and/or venous thrombosis associated with the presence of neoplastic tissue. That is the Trousseau abnormality. The neoplasm; most of the time it’s very very small. It’s occult, frequently metastatic and histologic types, the mucin-secreting type, is the most common. In several series up as high as 80-some percent of these people may have non-bacterial thrombotic endocarditis. I’ll show you a picture of that, and of course hemorrhage is a very common feature of this problem. By using vein diagrams one can see the overlap and interrelationship between thrombosis, non-bacterial endocarditis.

It’s interesting here, it’s involving the mitral valve, the aortic valve, the tricuspid and so on with these vegetations. If it’s ever seen on the right side, it’s always seen on the left side of the heart. Never the right side alone. Maybe left side alone but never the right side without simultaneously seeing these lesions on the right side. These are the different tissues that are most commonly found in the Trousseau abnormality, and again common things are lung neoplasms, stomach and so on down the list. This just shows here an example of an individual with these, under the valve surface, these thrombotic endocarditic-type lesions. Here they are as a close-up, underneath the valve on the under surface on the left side of the heart.

What’s the etiology of this? Well, it was a tremendous search and we see that down here - this is the stomach - when one histologically resectioned this, this clearly was a gastric neoplasm. There is even some metastatic lesion up here at the chiasm in the brain. So the amount of tissue that’s there may be very minimal, yet it has some potent ability to secrete a variety of things and induce this problem here of DIC in the Trousseau abnormality. And these are the laboratory features, much like those that I mentioned in the

Again, the tip-off with a prolongation of the activated partial, the prothrombin time, the number of activated coagulation. Initially hyper-fibrinogen falling to hypo-afibrinogenemia initially with neoplasms, very common to have elevated platelet count. Once this problem triggers it becomes thrombocytopenia and again these others fall into place. One can find these abnormalities in various reported series, from 30 all the way up to 92% of the patients with Trousseau abnormality. What’s happening here is that from the neoplastic cell something is released into the circulation that sensitizes a big network of cells. Most commonly this is the monocyte, which is very rich in tissue thromboplastin. That’s released from that cell and then bingo, down into the coagulation and the plasminogen plasmin system to trigger off the DIC process. This just shows the survival in patients with this abnormality. It’s really not very good. Here’s the number of

The real treatment of course is to eliminate the neoplastic process, and that will solve everything, if this can be done. The use of antiplatelet agents, cyclooxygenase inhibitors, phospho-diesterase inhibitors, not met with any great success. Warfarin anticoagulation is fairly useless and if you find somebody who is anticoagulated with warfarin, whatever the reason may be and you find that they experience a thrombotic episode while on adequate or therapeutic range warfarin

Heparin is the absolute best agent. If needed, one can employ thrombolytic agents to open up a big blood vessel, particularly if you’ve found the neoplasm, you can remove it. Yes these agents can be helpful in that situation, but the real agent that is the most helpful is heparin. Here shown is an individual who had this problem, was on heparin anticoagulation. We see here that at time zero the heparin was stopped and we see the plasma fibrinogen. Here we see pretty good numbers at five hours, eight hours, twelve hours later. By 30 hours later we see that the plasma fibrinogen is dramatically reduced in concentration. The degradation product titer obviously is very high and these other abnormalities follow suit. Here when one restarts heparin in this situation, one sees that by six, eighteen, twenty four hours later one now has again got some reasonable numbers in the circulation. Again, heparin inhibiting this process where there is a bunch of tissue thromboplastin in the circulation triggering this. This is of course an attempt to

The treatment with heparin, clearly the optimal way is intravenous continuous infusion. The use of these other techniques are not too great. Intermittent and subcutaneous type routes, you are puncturing, making more holes, more bleeding. The objective here is to normalize these

When the diagnosis is established one of the most important things to do is develop a very good relationship with the patient and the family because the outcome - unless you can remove the neoplasm - is usually a difficult thing. This is Professor Trousseau and he recognized one time early in January of a given year that he had phlebitis on his upper extremities. He called his chief resident and said, "I know I have a fatal situation on my hands." This was in January and by May he was dead. There is often another individual that one sees, particularly when thinking about French individuals, who also has his hand here inside his jacket, and who’s this? Napoleon. Napoleon maybe had that same difficulty. He might have been one of the originals with the Trousseau abnormality.

Thrombotic thrombocytopenic purpura, also the hemolytic uremic syndrome, sometimes considered to be the same entity. More recently probably two different entities. Not absolutely certain, very closely related, recognizable-type of illnesses. The classical characteristics of the TTP, HUS or the TTP entity is the presence of thrombocytopenia, striking hemolytic anemia and neurologic abnormalities; anything from a headache to profound coma, and fever almost 100% of the time, and renal disease. Now the renal disease may be anything from microscopic hematuria all the way to azotemia, uremia and anuria. So the entire spectrum of anything here in

The epidemiology and the medical science, virtually everyone here has been called to duty to try to find out what is the trigger of this problem, because this was uniformly fatal. There wasn’t a single - well, there was one survivor in the literature when actually we started to employ our present protocol of plasmapheresis and exchange, which I will show you here in a moment - there was only one survivor as reported in the world’s literature up to that time. And this was by a fellow in California who employed some type of extra-corporeal hemodialysis. And it’s recognized here that there is a considerable familial occurrence; siblings, husband and wife have been reported, or people living in the same domicile, not necessarily related. There is also a

The frequency here is not particularly common. Certainly there is probably more than 3 or 4,000 patients reported in the world’s literature today. Distribution-wise, age; it’s more common in infancy through 80 years and the peak frequency is in the third decade. Without question there is about an 8 to 9 to 10:1 female preponderance. The reason for this I have no good explanation or clue. This is from some of our early studies here. You can see the high frequency is in the third decade. Some people, because of the relative infrequency of this

If there is any problem of making this diagnosis, biopsy of gingiva is the number one site we go for, and this shows intra-lumenal vascular occlusion, hyalin thrombosis, fibrin, platelets and so on. Specific staining techniques with IgM, IgG, complement and so on has not uniformly shown this to be an immune-mediated process. This just shows here laboratory data and people when they are admitted with this problem, and you see here, with respect to the hematocrit value, this is impressively low. Again the white count here is essentially normal. The platelet count is very very low, and the reticulocyte count is usually fairly impressive. LDH, because of red cell destruction, is usually very very high, and so on. The real tip-off here is when you look at the

With respect to the etiology; again, virtually every branch of medical science has been called to duty here. Is this a toxin, an infectious agent? When I was in school up in this place called Boston, one night right next to the _ somebody found an infectious agent and said, "Oh, this is it. This is the cause of TTP." Well it was a microtata bioti organism and that wasn’t yesterday that I was in medical school; quite a few years ago. Not a single report since that time. So the etiology here remains to be identified. There are a number of features of this entity associated with various chemotherapeutic agents and some people think that this really isn’t TTP. Well, I don’t want to get into a real argument with such individuals but if there is a recognizable cause, no it’s

Here’s things that are there that are found in the circulating plasma and here are things that belong there but are actually missing. I’m sorry about this. This doesn’t project particularly well, but this is the last 108 patients that we have treated and you can see we initially always start out with corticosteroids and try to give everybody a trial on corticosteroids if we can, if we have time. This is 100 mg intravenously of methylprednisolone every 12 hours. And the reason for doing that is that there are some people who do respond, do improve, and we do not have to go on to plasmapheresis and exchange. Unhappily they are in the minority, but there are some that exist and they certainly merit the opportunity since no one can identify who they are at the time they present. If they fail they move over here to plasmapheresis and exchange. The

Relapse is unhappily a very common type problem and it’s most common within the first month. After that we very seldom if ever see any relapses. What is it that initiates the relapses? Again, I see this working at the bedside, removing the plasma with plasmapheresis and exchange, saving the plasma, looking in the plasma to find out a clue. Again, too stupid to know what it is but this is a very common problem in TTP. Here are these laboratory data when these patients are

The survival, female, male and here’s the survival since we’ve been employing our protocol. This is taking into consideration everybody that we’ve looked at since the 1970’s and I have not had a demise since 1984. Here is the Kaplan-Meyer curve and when I took this over … had this done by someone who had the software in the Oncology Department, they said, "Wow, what illness is this? You’re not from Oncology." And I said, "No, I’m not." So with TTP again the optimal treatment here is initially corticosteroids. Some respond to that, and if not one moves on to plasma therapy of some sort and exchange, plasma exchange is clearly the optimal way to go. Antiplatelet agents, splenectomy and these other things that are done are simply not realistic. This is one very important thing here; do not infuse these people with platelets because they.

Now this survival here; what’s this due to? A dramatic turnaround in survival going from not a single survivor reported when we started, now to a 95, 96 and so on percent. Certainly it’s due to better general medical care. Earlier diagnosis and definitely the use of plasma in some form or other, and the optimal way is plasmapheresis and exchange, not simply infusion of

Paroxysmal nocturnal hemoglobinuria is characterized by the presence of thromboses and these are extensive but almost uniquely limited to the intraabdominal venous network. Thrombocytopenia leading to hemorrhage, definitely there. Not dramatically common and then red cell hemolysis is constantly going on in these people with PNH. 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 - and what the reason for that is, I wish I had a clue - and it is without question an acquired problem. This is the overall survival in a sizable number of people that we and

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, a third population that has essentially a

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. But unhappily they are missing and they are missing because of a link that doesn’t allow attachment of those proteins onto the

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

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