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New Treatments for Von Willebrandís Disease 

The function of von Willebrand factor is really twofold. The one we hear about most and probably is usually the one most impaired in this disease is the primary hemostatic problem.

That has to do with the bridging function that von Willebrand factor plays in bridging between platelets and wounded vessels with subendothelial structures. So this is a bridging function that occurs between platelets and subendothelium. And at high shear rates it also binds or bridges between platelets and platelets. It has a second important function and that is to protect factor VIII. It forms a non-covalent bond with factor VIII in the circulation, which protects factor VIII.

What about the clinical presentation? Iím sure most of you are aware that this is generally an autosomal dominant disease. It may be as frequent in the population - if you measure asymptomatic subjects - it may be as high a prevalence as 1%. However probably only 10% of those so described or found will be symptomatic. Usually patients will present with mucosal bleeding. It can be gastrointestinal, which is the most serious of the bleeding, but usually it is epistaxis, bleeding after dental procedures, in women of child-bearing age it may be excessive

I want to emphasize the variability and the difficulty in the diagnosis of von Willebrand disease. The symptoms that weíve just described are fairly common. Bruising, epistaxis, some gum bleeding, that often may occur in patients. Perhaps theyíve taken some non-steroidal antiinflammatories or some aspirin and they will complain of those very symptoms, but they donít necessarily have von Willebrand disease. The problem can be even further compounded because there is variability. This was taken from Charlie Avogardís study in the 80ís indicating that even the laboratory testing can vary quite a bit. Here we see bleeding time varying in a patient who has von Willebrand disease as well as the factor VIII. The factor VIII antigen

Physiologic variables can certainly confound not only a ristocetin cofactor but the antigen as well and factor VIII as well. Conditions that are considered physiologic, such as pregnancy, or pathologic problems which include the chronic inflammatory conditions or acute illnesses and of course stress that occurs with invasive procedures will all raise the von Willebrand factor level. So one does not want to make a diagnosis during these times if it can be helped. The other physiologic regulation that we understand now is that of blood groups. The blood groups

Iíd like to turn now a little bit to the classification, and not to belabor it, but two points about it; one is that it is important because it will help you select the right treatment for the patient. The second reason for going through some of the classification is that it has helped us to understand how von Willebrand factor works, especially some of these subtypes that weíll talk about. It is interesting that the classic or type I von Willebrand disease is the most common. Perhaps 70-75% of patients have this type. We know how to diagnose it generally, with decreased ristocetin induced platelet aggregation, decreased antigen and decreased ristocetin cofactor. And if one

Skipping down to the type III, or the severe patients, these patients are either unlucky enough to have received two alleles, two genes, one from each parent, that are abnormal and the same abnormality which would lead to a true recessive problem. Some are doubly heterozygous because we know that there are different defects that occur in some patients who have severe disease. In this illness usually there is really no measurable von Willebrand factor activity. That is, the ristocetin cofactor and the antigen are extremely low, less than 2% or not measurable, and

I want to spend a little bit of time on these variants, especially type IIA and type IIB, which are the most common. Iíll point out on this slide that there is going to be a very helpful test to distinguish these two, and that is the ristocetin induced aggregation in type IIB. But we will come to that in a moment. Hereís a multimer gel with a normal pattern in lane two, and a platelet normal in lane five. Here in lane three is a type IIA pattern that we see on electrophoresis of the patientís plasma. Iíll point out that there is a little bit of an increased density in these lower molecular weight multimers compared to the normal, and that may be part of the problem in this patient. In fact, a number of years ago Dr. Grolnick in the lab actually added some inhibitors

Actually a second cause has been discovered for the very same type of phenotype. Beside increased sensitivity to proteolysis it appears that there is abnormal intracellular transport and decreased secretion of the larger multimers in some of these patients. Very interestingly, the region where these defects occur in the gene appear to be in whatís called the region A2 which contains a site that normally is a site for proteolysis even in a normal von Willebrand factor

Letís turn to type IIB von Willebrand disease. The fourth lane here actually shows a patient who has type IIB and as you can see they are missing the high molecular weight multimers also. But itís less of a decrease than in the type IIA, and in general thatís the case, that one will see a little bit better preservation of these middle weight multimers in type IIB. Now to understand this we have to go back and think about what we learned about the molecule, and that is that von Willebrand factor is going to bind here to a platelet membrane, shown here as bi-layer, that has its receptor, the primary receptor for von Willebrand factor glycoprotein 1B present. Now

We can find this more easily in the laboratory by simply doing platelet aggregation studies. In this case we see here in the left hand side, a normal platelet aggregation. This is a ristocetin induced platelet aggregation that I said weíd come back to. And you can see that the quantities of ristocetin here at .8 and .9 mg/ml does not or barely causes any platelet agglutination. However, once you get above 1 or 1.1 usually you see this agglutination quite clearly. In a patient with type IIB we see here that actually very low concentrations - .3, .4, .5 mg/ml - will allow this platelet agglutination to take place. So this will tell us that there is an abnormal von Willebrand factor that requires very little stimulation to bind the platelet. Thatís a very useful test, therefore this

The region of the monomer for von Willebrand factor thatís been shown to be defective contains most of the mutations, is the so-called A1 region and that is the region that was identified as the glycoprotein 1B binding site, and thatís how this was found. Again, this diagram from Sadler showing this A1 region with a number of mutations present.

Now there is another way, as you might expect, that you can get to this same phenotype and thatís if you have a hyperreactive receptor for normal von Willebrand factor. That occurs in so-called or pseudo or platelet-type von Willebrand disease, and itís really not von Willebrand disease at all. Itís really a platelet disease, however it results in a loss of some of the larger multimers of von Willebrand factor so it has borne that name as well as the platelet name. In this case, as I mentioned, it is an abnormal glycoprotein 1B that will bind the larger multimers of

In this disease also, if you take platelet-rich plasma with these abnormal platelets and add high concentrations - say from a concentrate of von Willebrand factor - you will see that the platelets will aggregate. So this phenotype can represent either type IIB von Willebrand disease or platelet type von Willebrand disease, and we would see in our lab tests decreased large forms of von Willebrand factor. In those electrophoresis studies we would see that the activity will be

There are two other subtypes, and I will just very briefly talk about them because they are not very frequent, but the so-called IIM, for multimer, von Willebrand disease is very much like the IIA except that the multimers are all present. The defect within the monomer is not something that will decrease the multimer formation. So we can see that actually, or make the molecule more susceptible to degradation. So in this case we simply see that there are

The type IIN, the last of the two variants, is a very interesting disease because it often will present as mild hemophilia A. The basic problem is that there is decreased binding of factor VIII by the abnormal von Willebrand factor. Generally it does not present with any platelet problems but it will present with bleeding symptoms, soft tissue, perhaps joint bleeding, similar to hemophilia A. Usually itís not so severe that there has been very much spontaneous hemorrhage, but with invasion these patients will have bleeding. Itís usually, of course in order to

So to summarize here, weíve got about 70-75% of patients who have classic von Willebrand disease. They just have a concomitant decrease in all of the von Willebrand factor function; its antigen and also a decrease in factor VIII because of the decreased binding, because of the decrease in numbers. The variants weíve just discussed and we have more information about

The treatment will vary according to the type of von Willebrandís disease, particularly if you have a variant. So these classifications are important once youíve made a diagnosis, a basic diagnosis of von Willebrand disease, usually using the ristocetin cofactor and the

So what about treatment? Look at the middle panel here talking about DDAVP first because that is really the main treatment that we ought to be focusing on. The 70% of patients who have type I von Willebrand disease usually will have made some von Willebrand factor and it will be in the circulation and it will also be in the storage sites where it is made; in endothelial cells primarily and some in platelets. When you administer DDAVP it will release those storage sites of their von Willebrand factor and increase the levels, usually two to fivefold. It will do so very quickly with intravenous infusion of about 15 minutes. Peak levels may occur around 45 minutes to an hour and the effect lasts briefly, but usually over a four to six hour period and often it is sufficient to undergo invasive procedures. So this is the mainstay of treatment for von Willebrand disease. If a patient has very severe von Willebrand disease and is not making any von

Just to show you what DDAVP does or desmopressin; in normals you can see that there is a release of the higher molecular weight multimers and you can tell even by the increased density that there is more of the von Willebrand factor present in the circulation. In a patient with type I, in this case quite severe disease but not yet a type III, after DDAVP there was a very nice response and a release of von Willebrand factor that lasted, as shown here, for at least two

Back to our case. This was a patient who had thrombocytopenia during her pregnancy. As I mentioned, the patient went into spontaneous labor. Her platelet count was around 40,000 or so at the time and unfortunately had a very difficult vaginal delivery that yielded a stillborn and had bleeding sufficient following that delivery to require 65 units of blood products. She was studied later, many years later, during a second pregnancy and we found that at the time she began her second pregnancy she actually had a normal platelet count. Her factor VIII and von Willebrand factor studies however were low. The factor VIII was normal but low normal and her von

As her pregnancy progressed, her platelet count dropped and we saw during the third trimester she dropped as low as she had before, although her other values had increased as one would expect. Not to that extent but from their baseline they made a fairly good rise. Interestingly enough, in her VWF multimers there was still a decrease in her highest molecular weight multimers but there were more of them present. So that as she released more of this von Willebrand factor, her abnormal von Willebrand factor, she did maintain in the circulation more of the high molecular weight multimers but also more of them must have bound to platelets and