By Krista Conger
Illustration by Jonathon Rosen
Not many second-graders manage to clear the school with a single show-and-tell project. But 8-year-old Holbrook Kohrt had a knockout demonstration. Literally.
Kohrt, a hemophiliac, was showing his class how he had learned to give himself lifesaving injections of a blood-clotting factor that his body was unable to make naturally. Engrossed in the performance of what was for him a routine occurrence, he was startled by the reaction of others in the room.
“Halfway through, my teacher passed out, as did many of the other students,” he says. Because his rural Pennsylvania school was both remote and minimally staffed, the entire school was dismissed for the afternoon.
Kohrt, now an assistant professor of medicine at Stanford with an MD and a PhD to his name, is keenly aware of the importance of healthy blood — mostly because he doesn’t have any. He tells the show-and-tell story in a wry tone, acknowledging the inherent comedy in the scene. But it’s a rare light-hearted moment in a childhood that was, by any measure, harrowing. As a child in the early ’80s, he, like other hemophiliacs, was forced to rely on transfusions from apparently healthy donors to prevent bleeding to death from even minor injuries. But these treatments carried a significant risk of lethal infection.
“From when I was about 10 until I was about 15 or 16, I was very aware that my risk of contracting HIV and other pathogens increased with each transfusion,” recalls Kohrt. “I was also very aware, though, that without the transfusion, I would die. I watched some of my best friends become infected in this way, and saw them go through the process of dying from AIDS and the stigma the disease carried at that time. The whole experience was very shaping.”
All told, about 80 percent of people with severe hemophilia during the early 1980s were infected with HIV, according to the National Hemophilia Foundation. Many of these people died as a result. In 1998, the federal government set up a system of restitution through the Ricky Ray Hemophilia Relief Fund Act for those affected by the slow or inadequate screening of the nation’s blood supply.
Kohrt’s story is a scrapbook of how treatments for a blood disease have gone from being nearly universally fatal to treatable with routine, safe injections of a recombinant form of the clotting factor. Recent advances in gene therapy, including an ongoing clinical trial at Stanford and elsewhere, have researchers cautiously optimistic that it may one day be possible to provide a permanent cure for patients like Kohrt.
It’s also what’s led Kohrt to a career in hematology and oncology, and a rare dual understanding of what it’s like to be both a bedridden patient and a bedside caregiver. Kohrt has parlayed his experience into a burgeoning career as a physician-scientist with an intensely personal mission: to help patients with life-threatening conditions in any way he can.
“Other families in our small town might have meat or groceries delivered to their homes; We had blood-delivery trucks pulling up...”
“Holbrook has the unique ability to see clinical problems from the patient’s perspective as well as a clinician’s,” says Ronald Levy, MD, director of Stanford’s lymphoma program with whom Kohrt has worked to design new clinical trials for patients with that blood cancer. “He’s acutely aware that he himself has been the beneficiary of this type of clinical research, and he’s eager to bring similar advances to other patients who are suffering.”
Hemophilia is firmly anchored in the annals of human history — a fact for which we can thank the British royal family. Queen Victoria passed the mutation that causes the blood disorder, which is carried on the X chromosome, to at least three of her eight children. Those children went on to intermarry with the royal and notable families of Europe and spread the disorder to many descendants, including Victoria’s great-grandson Alexei Nikolaevich Romanov.
Hemophilia is a recessive trait, meaning that female carriers of just one defective copy are asymptomatic carriers of the disorder. These women have a 50 percent chance of passing the mutated gene to their children; boys like Kohrt who receive this copy will display symptoms because they have only one X chromosome. There are two main types of hemophilia, categorized by the gene that’s disrupted, and the disorder can occur in varying degrees of severity. Kohrt has a severe form of what’s known as hemophilia A; his gene for a clotting protein known as Factor 8 is completely non-functional.
But Kohrt’s parents, Alan Kohrt, a pediatrician, and MaryLou Kidd, a nurse, knew nothing of Brook’s (as they call him) genetic destiny when he was born in 1977. Kohrt’s mutated Factor 8 gene had occurred spontaneously; they had no family history of hemophilia. So they were alarmed when their newborn son began to develop large, unexplained bruises all over his body and bled profusely after his circumcision.
“We experienced the same kind of shock and denial when he was diagnosed that all parents feel: This can’t be happening to our child,” recalls Alan Kohrt, MD, who now chairs the department of pediatrics at the University of Tennessee College of Medicine in Chattanooga and is the senior medical director of the Children’s Hospital at Erlanger. At the time, the family was living in a remote area of Paupack Township in Pennsylvania, where Alan Kohrt was working as part of his enrollment in the National Health Service Corps.
“The most difficult thing to accept was that Brook didn’t just have hemophilia, he had severe hemophilia,” says the elder Kohrt. “This changed everything for our family, from planning where to go to vacation to learning how to deal with him as an infant crying in the night. Was he hungry, or was there something more serious, like a bleed, happening? And things became even more challenging when Brook became a toddler and started crawling and falling.”
Until relatively recently, most people with severe hemophilia died young — sometimes as infants. The best treatment was preventive, and patients sought to avoid any injury or trauma that could cause life-threatening internal or cerebral bleeds. Many sufferers experience spontaneous bleeding into the joints that can cause debilitating pain, swelling and lasting damage. Kohrt wore a helmet to protect himself from injury until he was about 7 years old, and frequently used a splint after a joint bleed. He quickly became a spokesperson for the condition.
“Brook was always a trouper,” says Alan Kohrt. “He’d explain to the other kindergartners about his helmet and his condition. After he was born, his mother went to work for the local branch of the Red Cross and in middle school Brook was often featured in ads explaining the benefit of donating blood.” At the time, blood, or blood components, from healthy people was the only source of the clotting factors missing in hemophilia patients.
In 1840, physicians at St. George’s Hospital Medical School performed the first successful whole-blood transfusion on a person with hemophilia. Whole, healthy blood contains minute amounts of the clotting factors made by the liver of the unaffected donor. This type of transfusion can be slow, dangerous and painful, however, even if the blood types of the donor and recipient are carefully matched. In the late 1950s, physicians began to use fresh, frozen blood plasma — the pale yellow liquid that remains behind after blood cells are removed by centrifugation — which eliminated many of the unpleasant side effects in the recipient. But neither whole blood nor plasma contains a concentration of clotting factors sufficient to completely prevent bleeding, and physicians had to transfuse large volumes for any effect.
Photo by Erin Kunkel
In 1977, however, there were other options for Kohrt and his family: a powder called cryoprecipitate, which is collected from the plasma of between one and four blood donors, or purified clotting factor isolated in large quantities from the pooled plasma of hundreds or thousands of donors.
Cryoprecipitate was discovered accidentally in 1964 when Stanford researcher Judith Pool, PhD, tested the composition of the residue left behind in a bag of thawed plasma. It had a high concentration of Factor 8, and it allowed physicians to treat patients with much smaller volumes. In the late 1960s, physicians and researchers had learned to isolate from large batches of plasma purified clotting factors, which were even more convenient to use.
These advances freed for the first time patients and their family members to administer appropriate treatment at home.
“Before this, or if a parent didn’t know how to transfuse their child, the family would have to go into the hospital or clinic as often as every other day,” says Kohrt. “But when I was about 6 years old, my parents taught me how to give myself infusions. Other families in our small town might have meat or groceries delivered to their homes; we had blood-delivery trucks pulling up filled with giant coolers of cryoprecipitate.”
His parents’ choice of cryoprecipitate over the purified factors was deliberate.
“We were doing everything we could to make sure that the product Brook received was the safest possible choice,” says Alan Kohrt. “We stayed with cryoprecipitate for as long as possible, in part because that comes from one donor, or a limited number of donors. And we treated him only when he had a bleed, instead of giving it on a regular basis.”
His parents would keep the cryoprecipitate as a powder in the freezer until Kohrt experienced a bleed. As an infant, Kohrt’s parents injected him with about 10 to 30 milliliters of the cryoprecipitate-containing solution — a process that could take as long as an hour. As he grew, the volume of the injection grew to around 100 milliliters and Kohrt began treating himself. Eventually Kohrt, who by then was experiencing chronic joint pain and problems, had to accept regular, prophylactic therapy to head off bleeds before they occurred.
“Basically the treatment involved taking in a lot of unpurified blood product,” says Kohrt. He relied on cryoprecipitate, which contained multiple blood components other than the Factor 8 clotting factor, and as a result eventually triggered severe allergies. But when he switched to the purified, concentrated form of the clotting factor, the risk of infection was much higher because it was purified from the blood of many more people.
Although the cryoprecipitate and purified clotting factor were lifesaving for Kohrt and others with hemophilia, both carried an unavoidable risk of exposure to blood-borne diseases. By the early 1980s it was clear that hemophilia patients across the nation were contracting hepatitis C and HIV from the pooled plasma, and Kohrt and his parents knew they were playing a deadly game of roulette.
“There was always that apprehension,” says Alan Kohrt. “We never knew if that day’s treatment was going to be contaminated. But we tried to give him as normal a childhood as possible. I don’t know how much of how we all handled it was denial, and how much was us simply praying he didn’t get it.”
The uncertainty lasted until the mid-1980s, when physicians began to heat the plasma to kill viral contaminants. In March of 1985, however, blood banks across the country implemented new screening techniques that vastly improved the safety of the nation’s blood supply. [To learn about Stanford’s pioneering role, see page 18.] In 1984 researchers cloned the gene for Factor 8, and in 1992, the Food and Drug Administration approved the use of what’s called a recombinant form of Factor 8. This recombinant form is made by specially engineered hamster cells under laboratory conditions, and eliminates any exposure to the blood of other people.
“I feel like my experiences have prepared me to provide some level of empathy for my patients who are newly diagnosed with cancer.”
These changes didn’t come soon enough for many of Kohrt’s friends, however. As an adolescent, he attended a yearly, weeklong summer camp outside of Philadelphia for children with hemophilia. The camp had hundreds of attendees, and Kohrt made many close friends by teaching his peers how to perform their own transfusions, practicing on oranges and other thick-skinned fruits. As the years passed, however, attendance dwindled.
“About 80 percent of these kids got HIV,” says Kohrt. “As a result, there are about 50 percent fewer hemophiliacs alive today than there would have been without HIV. That was a horrible time. It was incredibly difficult at a young age to see all those people who were not as lucky as I was.”
Kohrt switched to the recombinant form of Factor 8 as soon as possible, but he didn’t escape those early years of uncertainty unscathed. When he was 13 he contracted a severe case of hepatitis C and was hospitalized for six weeks with nearly full liver failure. His immune response rallied and eradicated the virus — an outcome that happens in only about 20 percent of patients with active hepatitis C.
Kohrt’s experiences as a patient with hepatitis sparked an interest into how clinicians might jumpstart a patient’s immune system to fight other diseases such as cancer and fueled his entrance into medical school, then research. Today Kohrt, together with lymphoma program director Levy, is focused on several ongoing clinical trials for patients with lymphoma. In 1997 the FDA approved the use of an antibody called rituximab developed in Levy’s lab for these patients. Now Levy, a professor of medicine, and Kohrt are designing ways to help the antibody work even better.
“Essentially, we’re working on developing a second antibody that, in combination with rituximab, can help the immune system respond more vigorously to the cancer,” says Levy. “In animals the results are very synergistic and quite remarkable. We hope that it will do as well in people.”
Not one to do things halfway, Kohrt crafted his own PhD program focused on clinical trial design, and the treatment is now being tested in several small groups of patients.
“I feel like my experiences have prepared me to provide some level of empathy for my patients who are newly diagnosed with cancer,” says Kohrt. “I can really feel how scared they can be because I remember what it was like to be in that situation. What I’m doing now, all of it, is fueled by my personal background with hemophilia. I want to give the benefit of this type of translational research to other people. That is the fuel to my fire and my inspiration. Without recombinant Factor 8, I would likely not be here today.”
“Learning how you can help other people is the best gift you can receive in life,” says Alan Kohrt. “That’s the one thing that’s going to give you the most back. Brook has been able to focus on this idea and say, ‘This is what I want to do.’ He’s always been that kind of person, and I think he was truly meant to do the work that he is doing.”
It’s not known exactly why Kohrt remained uninfected. Research conducted by the Centers for Disease Control on him and others who escaped HIV didn’t turn up any molecular cause, like an underlying resistance to the virus, for his good fortune.“Essentially I just got really, really lucky,” says Kohrt. “What it really underscores for me is that, in some parts of your life, things are under your control, and in others they are not. Initially there is a very high level of fear when you realize that the outcome is out of your hands. You have to choose whether you’re going to perseverate on that and feel that fear every day, or if you’re going to hope and move forward.”
Think about the last time you bled from an injury: While you were cursing and looking for a Band-Aid, the very blood oozing from your wound was also forming a clot to keep you safe. That is, unless you had hemophilia. In that case, a faulty gene for one of the 12 main clotting proteins means your blood would have kept running.
For decades, scientists have pursued the dream of gene therapy for hemophilia, seeking to replace the relevant faulty gene to get a long-term fix. The research appears to be starting to pay off.
Stanford’s Mark Kay, MD, PhD, has long been on the front lines of the hemophilia gene-therapy effort. His lab conducted some of the first experiments, starting in the early ’90s, on gene therapy for hemophilia B, which is caused by a faulty Factor 9. Though not the most common type of hemophilia (that would be hemophilia A, caused by a defective Factor 8), they chose it partly because the Factor 9 gene is smaller and easier to work with.
In experiments in mice and dogs with hemophilia, he and his colleagues showed that a human virus called adeno-associated virus could be used to insert copies of Factor 9 gene into the animals’ cells and reduce or eliminate bleeding. Subsequent tests on humans proved encouraging at first, yet disappointing when the patients mounted an immune response against the viral proteins. Though the death of a patient in a different gene therapy trial, at the University of Pennsylvania, was a severe blow to the entire field, some gene therapy trials continued.
Recently Kay, a professor of pediatrics and of genetics, worked with a team of international collaborators to conduct a trial on six patients in the United Kingdom with hemophilia B using a different version of the virus. The new virus, which was isolated from monkeys, is thought to be less likely to cause an immune reaction in humans.
“It looks promising,” says Kay, who conceived of the new vector, conducted early studies and helped design the trial. “Since then, a number of other patients have been treated and, although some do develop a transient immune response, it’s been well-controlled with short courses of oral steroids.”
Four of the six patients began to produce enough clotting factor after the gene therapy that they no longer needed additional treatment with injected Factor 9. (The other two were able to reduce the amount of external Factor 9 they used.) The results of the trial were published in the New England Journal of Medicine in December 2011. Kay and collaborators are now recruiting patients for the next phase of the trial, in which they increase the dose of the virus. Kay’s lab is also continuing to experiment with ways to make the virus more tolerable to the immune system.