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New Treatments for Hemophilia

Hemophilia affects 15-20 of every 100,000 males born in the United States. There are probably about 17,000 patients with hemophilia in the United States. So itís a fairly rare disease. Why are we wasting your time talking about it, if itís not very common? Itís a very expensive disease to treat and weíd like to be able to prevent the first slide; that is, these are people in whom we think they are eminently treatable.

About 85% of patients that we are going to talk about have hemophilia A, so only about 15% of patients that you would see with hemophilia have Christmas disease, or factor IX deficiency, or hemophilia B. Roughly 50-60% have severe disease and about 40-50% have a mild to moderate form of hemophilia. So about even for mild/moderate versus severe. So that means that somewhere around probably 9,000 patients in this country have severe hemophilia at any one time. As I suggested, the most significant issue are the hemarthroses.

In general, the treatment of hemophilia for moderate and severe patients is either a plasma-derived concentrate, and weíll talk about that in some detail, or now available for both VIII and IX deficiency, recombinant factor VIII or factor IX concentrates. The benefits of gene cloning. These concentrates of either VIII or IX are extremely effective and if I donít leave you clearly with this message, there really is no doubt about their efficacy and currently in this day and age, they are extremely safe.

Well, letís get down to it. What are we talking about? Patients with hemophilia have severe disease if they have less than 1% of the measurable factor, either factor VIII for hemophilia A or factor IX for hemophilia B. They tend to have spontaneous joint bleeds and thatís the major limiting factor of their life. Moderate patients are somewhere between 1-4%, will have spontaneous bleeds but not commonly, and mild patients between 5 -25% rarely bleed.

You can often see these children in the emergency room. Parents being accused of child abuse before the diagnosis is made. They will frequently present in infancy with either tongue-bleeding, frenulum-bleeding often, and tongue and oral pharynx.

The molecular genetics, briefly; both the factor VIII and the factor IX gene are in the distal end of the X chromosome, occupy about 1/10% of the total genetic information on the X chromosome. The XQ28 defect is the defect in hemophilia. The gene was cloned in about 1985 by three or four laboratories all about the same time, pretty much, and a variety of defects have been described. Until the muscular dystrophy gene was cloned this was the largest gene.

Now the cloning of the gene has made prenatal diagnosis quite possible for both factor VIII and factor IX deficiency. Here Iím showing you fetoscopy. But we donít like to wait that long, because you really have to wait 18-20 weeks to do fetoscopy and as early as 10 weeks with chorionic villus sampling we can do very good prenatal diagnosis by gene techniques, either by indirect or direct. By either pedigree analysis, with or without a combination of either indirect mutation analysis looking for cleavage sites, abnormal cleavage products by restriction fragment length polymorphism analysis, one can do a leal tracing in the family.

So letís finish up with treatment. This is a young boy getting factor concentrate from his mother at home, and thatís really what we do. I have patients now - as long as they are over about three-years-of-age - just about all my patients are on home therapy and at this age, almost all of them are on some sort of a prophylactic regimen. If money were no object, in my judgment - and thatís the big caveat - in my judgment all our patients with hemophilia would be on prophylaxis before age two and with recombinant material.

Thatís a complex scientific term that I use frequently along with schmutz, which is the stuff you get off the side of a test tube. But this is the data from Inga Marie Nielsen - and I donít want to say her data is bad, itís not bad data, itís wonderful data - it shows that if you start children at a very young age and look at them up to 15 years later and look at their joint scores, and the higher the joint scores the more disability, if they are on prophylaxis - the black bar is by exam and the white bar is by x-ray - you can see that they have very little joint disease.

That study is randomized between primary prophylaxis started between 0-2 years of age, generally 1-2 when bleeding first starts, so no more than one or two bleeds allowed. Patients are randomized to receive either this regimen or a very aggressive demand regimen in which the first sign of a bleed the child is treated three times in 24 hour intervals, generally, very aggressively. And we are doing exhaustive cost/benefit analysis data. But this is the result of retrospective analysis by Peter Smith when he was on sabbatical with our group at the CDC and published a few years ago in The Journal of Pediatrics showing that episodic treatment, demand therapy, you would expect would occur much more often than bleeds on patients.

Now the treatment of hemophilia has an interesting history. I wonít go over in detail, but certainly in the 1960ís with the development of corral precipitate by Judith Graham Poole at Stanford was a landmark. Those who donít understand history are doomed to repeat it so the problem was that there was no free lunch. Even though we made very high affinity purified materials with monoclonal antibodies, even the monoclonal antibody purified concentrates had a problem. This is a birdcage, actually a canary cage. Yes. Youíre right. Heís gone completely nuts. Why is he showing me a slide of a bird in a birdcage? Well, because miners used to take this cage into the mines down way low, and as soon as toxic gas came up that they couldnít smell - carbon monoxide - the canary dropped dead and theyíd run like hell before the mine exploded. Well, people with hemophilia are the canaries in the mine shaft for the American blood supply. One vial of factor concentrate contains the therapeutic.

Now, a variety of viruses affected the blood supply. HIV, which you know is an RNA virus. Itís lipid-envelope coated and therefore fortunately it turned out to be very sensitive to high temperature heating and a new process called "solvent-detergent", using a solvent and a lipophilic detergent you can essentially remove the envelope to a whole variety of viruses.

Ill just finish by quickly going over some other complications of plasma-derived factor concentrates. One of which is immunosuppression - and Iíll come back to that - allergic reactions that you can see with any blood product, hemolysis is rare, primary pulmonary hypertension almost never occurs anymore since the aggregates have been removed from the concentrates, thrombosis however does occur with so-called prothrombin complex concentrates. The more recent concentrates do not contain activated clotting factor, so this no longer seems to occur with the more highly purified factor VIII concentrates. We did a study some years ago, published in the Lancet in í93, in which we looked at patients with HIV disease.