Chapter 01: A New Idea and A Controversy: Transfusing Platelets in Leukemia Patients

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Chapter 01: A New Idea and A Controversy: Transfusing Platelets in Leukemia Patients

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Dr. Freireich begins this chapter by explaining the origin of his first name, "J". Next, he describes how he worked with pediatric patients in the fifties, noting that he would see blood sprays on the walls of childrens' hospital rooms from their hemorrhages. This led to his decision to treat the patients with massive doses of platelets. Dr. Freireich gives detailed accounts of the patients' physiology, the technical challenges to overcome when giving patients blood from donors (as opposed to a bank blood), as well as the clinical trails he ran to determine the treatment's efficacy. Dr. Freireich explains in very dramatic terms, how treating leukemia patients was influenced by confrontations between those who advocated for laboratory over clinical research, as well as by intra-institutional political conflicts. What results is a full and realistic portrait of how scientific and clinical paradigms shift in complex social/political contexts

Publication Date

10-5-2011

Publisher

The Historical Resources Center, The Research Medical Library, The University of Texas MD Anderson Cancer Center

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; Personal Background; Overview; Definitions, Explanations, Translations; On Research and Researchers; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; The Researcher; Professional Practice; The Professional at Work; Collaborations; Devices, Drugs, Procedures; Faith, Values, Beliefs; Portraits; Patients; Discovery and Success

Disciplines

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

Transcript

Emil J Freireich, MD:

Well, when I grew up I was addressed by my family as “brother” because I had a sister. So there was “brother” and “sister.” In school, my name was Emil, but when I received my induction notice at the age of seventeen to go into the military, they required a birth certificate. As you know, I grew up in a very modest part of town, and we finally discovered that the city of Chicago did have a birth certificate. Lo and behold, the birth certificate said Freireich, Emil J, so I consulted my mother, and she said that when I was born she’d only been in this country about five or six years. She was young and didn’t speak much English, and the nurse said, “What do you want to name him?” So she said, “I want to name him after his grandfather whose name was Emil.” They were Hungarian, but they spoke German. They were located in that slit that was betweenAustria,Hungary, andGermany. She named me Freireich, Emil J. It was supposed to be junior, but the birth certificate had no “R,” just “J.” So I became Emil J Freireich, because it didn’t stand for junior, it didn’t stand for anything. It was just J. That’s how it happened.

Tacey Ann Rosolowski, PhD:

Does that have any significance for you?

Emil J Freireich, MD:

Yes, because Americans don’t like this name Emil. It’s kind of European. As you pointed out, many people—Americans—call it “ee-mil.” The French call it “a-mil.” But it’s very European. And when I married my wife—my ever-loving wife—she didn’t like the name at all, so she began calling me J, so everybody calls me J. Some people call me J Emil Freireich.

Tacey Ann Rosolowski, PhD:

It just shows the power of that initial with no period after it.

Emil J Freireich, MD:

When I write papers, as you know, the period always appears. Typesetters can’t avoid it.

Tacey Ann Rosolowski, PhD:

I did notice that, yes. They add things. Well, if you don’t mind, I’d like to talk about some of the areas in which you’ve made contributions, specifically starting with the work on the continuous-flow blood separator. I know that you developed that with George Judson when you were at NCI from 1955 to1965, but the one topic that really wasn’t covered in too much detail in the 2001 interviews was how the blood-flow separator was developed technically once you got to MD Anderson. I’m wondering if you could tell me that story, and then about the trials that you began to run.

Emil J Freireich, MD:

Did she give you the reprints I gave her?

Tacey Ann Rosolowski, PhD:

Yes.

Emil J Freireich, MD:

That’s a nice story.

Tacey Ann Rosolowski, PhD:

Yes, I did read it.

Emil J Freireich, MD:

But of course it’s very published, so it’s very slim. I can give you a little more color. When we started treating children with leukemia and patients of all kinds, we recognized that whatever you did to kill a tumor inhibited the normal bone marrow, which is a rapidly growing organ, and the gastrointestinal tract. The gastrointestinal tract you can handle by replacing fluid, but the blood was a problem. We went to work on the platelets because the leading cause of death in patients treated when they had leukemia or otherwise was hemorrhage. The hemorrhage story is also told. It’s very colorful because it had already been proven unequivocally that thrombocytopenia was not responsible for the bleeding. The science of that was volumes deep.

But we decided to do a simple, clinical thing. See, I’m a great advocate of bedside to bench and back. People think that if you discover everything in the laboratory, it will immediately apply. You’ll call up some doctor, and he’ll do whatever—give him a drug or something. But in fact everything that advances our knowledge about humans and human disease begins with clinicians observing patients, and then you can go to the library, so we decided to do that. We noticed that thrombocytopenia was present whenever they were bleeding, low platelets, so we did a retrospective study where we just looked at the charts and wrote down how often the nurses and the doctors noticed that the patients were bleeding, and we wrote down the platelet counts on those days, which we did on a regular basis, and we wrote what’s a citation classic. It’s a paper that shows that there is a direct relationship between the degree of thrombocytopenia and the occurrence of hemorrhage.

So then, now it’s time to go to the laboratory. I went to the lab and I said, “Well, it’s obvious we have to replace the platelets.” So I took platelets out of my blood, and I got blood out of all these children bleeding to death. I put my platelets in, and all the in vitro tests of coagulation were normalized. I said, obviously there’s something missing here. We’ve got to do an in vivo experiment. We have to give them platelets. Now there’s a challenge. This may be more detail than you care about.

Tacey Ann Rosolowski, PhD:

No, detail is good.

Emil J Freireich, MD:

It’s all in the paper. The first thing we did was recognize that the way blood was collected in the blood bank, once it’s stored three or four days, the platelets are mostly dead; they disintegrate because there’s acid and citrate. It’s refrigerated, and that lends to clumping of the platelets and so on, so we realized we needed fresh blood. When I had done it, I had fresh blood, but fresh blood is not something blood banks do. Blood banks operate on the basis that the blood is stored until needed and use the oldest ones first. If you use the fresh blood, you’ll never have any blood in the bank. So we said, how do we get fresh blood? That was a challenge. It so happened that there was another young doctor working in the blood bank. His name was Alan Kliman. He was like most of us. We were serving our military time in 1955. I said, “Kliman, I want to get some fresh blood.” He said, “Oh, yeah, we’ll do it.” So we got some donors. He bled them in the blood bank and delivered the blood to me, and we treated these children—home run.

But it was already established that it does not work, so how can you say that it does work? No matter what I did, it was just me talking. There was only one way. My mentor was Dr. Gordon Zubrod, who came out of the malaria program. The malaria program learned one thing during the war. As you know, more soldiers died of malaria than of war injury.

Tacey Ann Rosolowski, PhD:

I didn’t know that.

Emil J Freireich, MD:

That was true during the war in the Pacific with the Japanese. They mounted the atomic bomb project, and they got the best brains in the country into a room and said, “You’ve got to figure out what to do about malaria.” Out of that project came all the anti-malarials we use today—chloroquine and so on. Dr. [Gordon] Zubrod was in that program, conscripted, of course, and what they learned is that in order to detect anything, you have to eliminate the most powerful force in the human mind, which is bias. People conclude what they know about the world from experience that they had. Once that’s true, everything fits into that because we’re innately biased. We learn on the basis of what we’ve known.

The experiments which showed that platelets don’t do anything were all conducted in animals. They were experiments where you remove the platelets by centrifuging and putting in platelet-poor blood, and these animals never bled, so it was obvious platelets weren’t it. Moreover, in the animals that were radiated who bled, they found that there was an anticoagulant in the blood. It turned out this anticoagulant is a fibrinolytic enzyme, but that will come later.

So anyway, we had to eliminate bias, so we did the first prospected randomized trial and transfusion in the world’s history. What we did is we had children who were bleeding, and the blood bank agreed to give us one unit of fresh blood or one unit of bank blood more than seven days old in a random fashion, double blind, and then it was my job to assess whether it had any effect on the hemorrhage. These were children who had one m2 body surface, about fifty or sixty pounds. They were all under ten. The small size helps enormously, of course, because their blood volume is smaller, so we conducted this study in a setting where the opposition both had certain data. We knew it would work, and they knew it would not work, so this was very tense. We had all the safeguards built in—you can’t talk, we can’t know, you can’t do.

After we had done ten or twenty children, Dr. [Emil “Tom”] Frei, my colleague for life, decided let’s break the code. So in a situation like this, we had a very tense meeting. We had gathered in a room with the statistician who was in charge of analyzing the data with the opposition—Dr. [George] Brecher who ran laboratory medicine—world famous hematologist who had done all this work on platelets during the war. He invented the platelet counting method. He was very famous, very accomplished, brilliant man, European—Dr. [Paul] Schmidt, who ran the blood bank, and myself and my fellows, Larry Gaydos and my boss, Dr. Frei, in the room, with the statistician. Patient one, bleeding or no bleeding? Stopped bleeding—fresh. We did it one at a time. By the time we got through, it was 100% successful. Every patient that got fresh blood improved, every patient who got bank blood did not, and the measurements we made were objective and quantitative. We measured hemoglobin in the urine. We measured hemoglobin in the bleeding nose. We measured hemoglobin in the stool. We did bleeding times on the patients by stabbing and seeing how long it took to stop bleeding, so the data was not only the platelet counts, but we had objective data. Problem solved.

Don’t forget bias. After the glow wore off, I got a call from Dr. [G. Burroughs] Mider, who was our scientific director, a very rough guy—pathologist. “Freireich, Brecher, and Schmidt tell me you’re causing trouble.” “No, sir.” “Well, what’s all this about blood? You have to have fresh blood, and you did this phony study, and it all came out wrong. If you don’t stop making trouble, you’re fired.”

Well, I was young and easily intimidated, so I talked to Dr. Zubrod and Dr. Frei. Dr. Zubrod said, “Let’s have a grand rounds.” On the top floor of the clinical center there was a very luxurious meeting room, like the Hickey Auditorium. We had an NIHY grand rounds on the subject of bleeding and platelets. The forces of evil—Schmidt and Brecher—presented the data that proved that platelets had nothing to do with it, unequivocally, and it was the gestalt; that was what everybody believed, and then we presented our little ten patients thing. Brecher got up and said, “Conclusion, it’s a bunch of foolishness.”

I have to tell you one other part. With the conversation with Dr. Mider, the claim that was made was that when the children needed transfusion, their parents would go down and donate fresh blood. I would interview the parents so I knew which ones got fresh blood, because if it was bank blood, no one went down to donate, so I was not only intimidated by being a troublemaker, but I was dishonest. I was cheating.

Tacey Ann Rosolowski, PhD:

It wasn’t really blind, so they claimed.

Emil J Freireich, MD:

Cheating. So we had this grand rounds, and they presented and we presented, and, to his credit, with all the prestigious people from the clinical center in the room, Dr. Zubrod stood up and said, “Dr. Schmidt, if the doctors in my department order fresh blood, it will be your obligation to provide it.” Amazing that it took the courage of this man to do that even though his boss, Dr. Mider, was on the side of the blood bank.

After that, it was a simple matter to confirm the—well, first of all, we had to publish it. It got accepted in the New England Journal. Dr. Brecher refused to put his name on the paper. He was sure we were cheating, but Dr. Schmidt did—the blood bank director. From that point on, what we did is we systematically transfused platelets when the platelets were low.

We developed a very simple procedure for using plastic bags. The way we collected blood in 1955 was with glass bottles, rubber tubing, and steel needles. All of those surfaces take the platelets out of the blood and destroy them. During the war they had discovered the plastic blood bags, and the reason it was discovered was not because of platelets. It was discovered because it was a way to transmit plasma for battle wounds. The bottles were always breaking, so the plastic bags were very useful for transporting, but we found that plastic is non-wettable and therefore platelets don’t stick to the plastic surfaces. We adopted a collection technique where the steel needles were coated with silicone, therefore not wettable, plastic tubing, and plastic bags, so the platelets were not stuck to the surfaces but in the blood, so we collected platelets much more efficiently.

We also devised a little thing which is in the first paper. I have a slide of it. It’s a beautiful thing. We just took two bags, connected them to each other so that you can, in a closed way, collect a unit of blood, take out the platelets or plasma, put the red cells back in, collect another unit and run it to the second bag, and it was all closed so it was sterile and safe.

Tacey Ann Rosolowski, PhD:

I was looking at that, and I have to say, I kind of tried to map out the process for myself. Was the idea that you gave one unit of blood that was rich in platelets to the patient, and then you returned the other unit, which was rich in red blood cells, to the donor?

Emil J Freireich, MD:

Correct.

Tacey Ann Rosolowski, PhD:

Okay, so I understood it.

Emil J Freireich, MD:

Actually, we took platelet-rich plasma, so we only separated supernate and precipitate. The platelets are centrifugally light so they stay in the liquid part. The red cells are heavy, and the white cells are heavy. So we collected supernate and precipitate. Precipitate when back to the patient; supernate went to the side bag. Second unit, same thing, side bag, so we had two units of platelet-rich plasma for transfusion.

Now, during the one unit of blood transfusion, we worked out the quantities. We knew that you needed one unit of blood which contained approximately 1011— if you’re familiar with that kind of numerals—platelets per square meter of body surface area of the child. And that transfusion would result in the increment of 5000 per mL, so we had the quantities all worked out. We knew that two units would give you roughly ten or twelve, so we knew how to treat hemorrhage. We knew where the hemorrhage began because we had this relationship—so. So we systematically began to replace platelets.

We had no trouble getting volunteer donors because all these children had parents and friends. By the time we had done that for a year or two, one of our fellows, Dr. [Jules] Hirsch, eventually came here and did a retrospective study and showed that bleeding is the cause of complications and death. It was essentially ninety-five percent reduced. So the cycle was completed.

Tacey Ann Rosolowski, PhD:

Can I ask you just a quick question. I wanted to go back just to that moment when Dr. Zubrod stood up. I think it’s hard for people who aren’t scientists to understand exactly how dramatic those moments are and how much rides on them.

Emil J Freireich, MD:

Dramatic—everybody stopped breathing.

Tacey Ann Rosolowski, PhD:

What could the consequences have been if he hadn’t done that? What might the consequences have been for him if his boss had taken a different attitude?

Emil J Freireich, MD:

Well, I don’t think that was the problem. What’s going on in the scientific community is credulity. Since the evidence was so conclusive, that to change the paradigm required people to overcome their internal bias, which is very difficult. It’s like convincing Obama that his plan is no good. Once you’ve got it in your computer, it’s very hard to change direction. It’s kind of like a gyroscope. So it was the intellectual courage. People couldn’t believe that in the face of the existing paradigm anyone would be willing to question it based on a very small study, so that’s what impressed people. It’s kind of like the king has no clothes. I mean, if someone is willing to say, well, you all think he looks gorgeous, but he doesn’t have any clothes on. It’s part of the human nature.

So that was a very courageous thing for Dr. Zubrod, and he did it because he was—both he and Dr. Frei were men of enormous objectivity. They were both devout Catholics, so they had faith in the truth, as opposed to convention, as opposed to the fundamentalist-type convention, so they were people of that kind of character. For me, none of those were issues. For the people digging the ditches, you don’t care about the anatomy and the physiology and the biochemistry, you’ve just got to get the job done. That was me in the trenches just doing the work. The kids were dying, and we had to do it. You heard the Scotty Dinsmore episode?

Tacey Ann Rosolowski, PhD:

I did.

Emil J Freireich, MD:

That was the one that impressed me the most because we not only stopped his bleeding, but we were able to count the platelets after we stopped the transfusion and watch when the bleeding recurred in relationship to the platelet count. We redid in a patient what we had done retrospectively from the chart review, so we knew what the truth was, but the truth—it’s difficult to see the truth. That’s why progress is made by people who have that ability to see through the existing paradigms. So that’s the platelet story.

Tacey Ann Rosolowski, PhD:

What do you think gave you the ability to see through existing paradigms?

Emil J Freireich, MD:

Well, because I was the guy with the shovel. There’s a difference when you’re in the library. Brecher was working with animals in a laboratory. When I came to the cancer institute, Dr. Holland had just left. He left four or five bleeding kids on the ward, dying, and since I was a hematologist and Zubrod gave me the job of curing leukemia, all the other guys that were there said, Freireich, you take care of those people. So we didn’t have staff, we didn’t have trained nurses, we didn’t have equipment, we didn’t have help. This was digging ditches. The kids were dying. I was there all day long and all night with the parents, holding their hands and bleeding to death and the ward is full of blood—blood on the ceiling, blood on the curtains, blood all over your jacket. It was like at an abattoir. It was—it’s the digging ditches thing. You had to do something.

Tacey Ann Rosolowski, PhD:

I think it’s really hard for people to imagine that, because now the image of a hospital is so staffed and clean.

Emil J Freireich, MD:

Yeah, sure—sure. That’s actually what happened. Zubrod came on rounds one day, and after we sat down and talked about it—how much methotrexate and we were doing chemotherapy studies—he said, “Freireich, this ward looks like an abattoir. It’s full of blood everywhere. Why don’t you do something about the bleeding?” I said, “Yes, sir.” So you can’t have prejudice when you’re dealing with—when you’re drowning. You have to breathe.

Chapter 01: A New Idea and A Controversy: Transfusing Platelets in Leukemia Patients

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