Chapter 07: Treating Hemorrhage in Pediatric Leukemia Patients

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Chapter 07: Treating Hemorrhage in Pediatric Leukemia Patients

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Description

In this chapter, Dr. Freireich talks about treating hemorrhaging in pediatric leukemia patients.

Identifier

FreireicEJ_01_20010723_C07

Publication Date

7-23-2001

Publisher

The University of Texas MD Anderson Cancer Center

City

Houston, Texas

Topics Covered

The Researcher; Overview; Definitions, Explanations, Translations; Discovery, Creativity and Innovation; Discovery and Success; Professional Practice; The Professional at Work; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; Technology and R&D; Patients, Treatment, Survivors

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

Disciplines

History of Science, Technology, and Medicine | Oncology | Oral History

Transcript

Emil J Freireich, MD

While this was going on, Dr. Zubrod made rounds one day. He was a bureaucrat administrator. He had to run the whole thing, and he used to come on rounds about once a month. He came on rounds on leukemia service with Tom Frei. We walked into a boy's room. He was 5 years old, and he was a lovely child. His name was Scotty Dinsmore, and he had lovely parents who were totally devoted. The father was a minister, and his wife was a homemaker. This child was lying in bed in a coma, and he was bleeding extensively because he had no platelets.

When you're in coma, you have a type of breathing which is called Cheyne-Stokes. The breathing is intermittent because the respiratory center is suppressed. There are periods where you don't breathe, and then you get CO2 stimulation to the brain, and then you breathe rapidly. So this child was breathing rapidly when we entered the room.

We walked into this room, and the parents are there. They're wearing surgical gowns, and they're covered with blood. Blood is on the ceiling; it's all over the room. It looked like a slaughterhouse. When we walked in, we realized we couldn't stay there very long or we'd get covered with blood, so we walked back out in the hall. Zubrod said, "You know, Freireich, you ought to do something about this bleeding." "Yes, sir." Here we go again.

Lesley Brunet, MA

So you did.

Emil J Freireich, MD

That's a really terrific story, because to get platelet transfusion going, if you think my first controversy was controversial and that chemotherapy was controversial, this was controversial. It was controversial for several reasons. Controversy is always because the established gestalt is not superficial. It's not a bias. It's based on real experiences. There are geniuses who work hard to create the body of certain knowledge that we think we have. If the body of certain knowledge is challenged by someone, it's obvious that the challenge is wrong, and to get it over that hump is very difficult.

At the time, I consulted a lot of people. We had a guy working at one of the basic science labs. His name was Koloman Laki. He was a Hungarian immigrant, and he had figured out how fibrinogen polymerizes. The biochemistry of fibrinogen polymerizing is the thrombin which an enzyme clips a little peptide off the large fibrinogen molecule, and that makes the fibrinogen molecule polymerize. It's just like they now chemically make plastics. The first plastic was fibrinogen. Dr. Laki had isolated this peptide and worked out the chemistry of how it went together, so he was already famous. He's one of the people I consulted. This was around 1956, and at that time, 90 percent of the children died of hemorrhage. That was the cause of death. Of course, leukemia caused the bone marrow failure, but they died of hemorrhage. The question was why are they bleeding all over the place?

I read all the literature, and it turned out that one of the world's authorities on hemorrhagic diathesis was in the NIH. His name was George Brecher, and his colleague was a guy named Eugene Cronkite. They had done some absolutely brilliant experiments, before they came to the NIH, on the bleeding associated with radiation injury. They had done all these experiments in dogs and rats and monkeys. And then there was Frank Gardner. Frank Gardner was assistant professor at Harvard when I was in Boston, and he had done some brilliant experiments on platelet transfusion in the dog. He'd worked out phenotypes. A lot was known about this. The geniuses were right there around me. I'm young and stupid, and I don't know up from down, so I read the literature, and I said, "Well, that's interesting. What am I going to do? Zubrod says I have to cure hemorrhage." I had a little lab, so I said, "We'll do some experiments." I started collecting blood from these children, and I had a neighbor who worked in the Heart Institute. His name was Ed Korn. He's now the scientific director of the Heart Institute. I said, "You know, you guys are working on all these fats, and what I've read in the literature is that the clotting process begins with the blood platelets, and the platelets have lipoprotein. It seems to me that if we could isolate this lipoprotein—it could be made chemically—we could cure bleeding." He said, "No problem. We've just invented the ultracentrifuge." The ultracentrifuge was high centrifugal force, and it was developed primarily to separate lipids. You put solutions that had a given specific gravity in the tube, and then you put it in the very high centrifugal force. Everything that's heavier than this goes to the bottom, and everything light stays on the top.I said, "Okay." I read the literature about lipoproteins. I went to his lab, we got platelets from the blood bank, we broke them up with a Sonicator, we stuck them in this thing, and we cut this. I made a thing which was called platelet factor 3. This had been described by other scientists. Walter Seegers, one of the famous coagulationists, had described platelet factor 3. We knew it was there, but we didn't know how to get it. We got platelet factor 3, and I wanted to give it to children with leukemia, not to animals, so we got approval from our Institutional Review Board.

Lesley Brunet, MA

So you still have your IRB even that early?

Emil J Freireich, MD

It was even worse then.

Lesley Brunet, MA

It was worse then?

Emil J Freireich, MD

Sure, because no one had ever experimented on people. We had an external advisory committee that watched everything we did like hawks. They were terrified that we would experiment on patients, because here was this hospital in the middle of nowhere with no professors, a bunch of young guys, and sick patients.

Lesley Brunet, MA

They were terrified that you would experiment on patients?

Emil J Freireich, MD

Yes.

Lesley Brunet, MA

Isn't the point to experiment?

Emil J Freireich, MD

We needed supervision. We were young and innocent, young and foolish yet. If you say it fast, it comes out right. We were heavily supervised. I got approval to do this thing. We got it sterilized, we got some children, and we ran this stuff in. And by golly, bleeding stopped immediately. We got it in a bag, I added it to these children's serum, and they all clotted.

We wanted to publish this. The problem was that as soon as we stopped shooting the stuff in, the bleeding started again. So we said, "Now I understand clotting. The problem is that these children don't have any platelets, so they don't have platelet factor 3. If I give them platelet factor 3, it corrects it. So there is no anticoagulant. There is no mystical factor." It was believed that the disease caused an interruption with the fibrinogen-thrombin reaction. The biochemistry is complicated.

I had done it in vivo, so it's obvious to me that what the platelet did was deliver platelet factor 3 to the bleeding site, and the platelets survived for 7 to 10 days. My stuff only survived for 10 minutes, because it got cleared by the R.E. system. So the platelet is a delivery system for platelet factor 3. I can cure the bleeding if I can make their platelet factor 3 level elevated. Now, that's the controversy.

Chapter 07: Treating Hemorrhage in Pediatric Leukemia Patients

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