Laurie Kelley

What’s in a Number?

Laurie Kelley February 6, 2022

Cazandra Campos-MacDonald

Numbers, numbers, numbers. Our society is flooded with numbers. From Social Security numbers to birthdays, PINs, passcodes and checking our weight, we can hardly get through a day without numbers. When you are living with a bleeding disorder, you monitor the assays of your factor, track the number of bleeds per month, check how many doses of product are on hand, and measure the circumference of a swollen knee. But when you live with an inhibitor, there’s another number that can become the focus of treatment: the Bethesda unit (BU).

The Bethesda inhibitor assay is a test that measures the titer (strength) of the inhibitor, described in Bethesda units. Inhibitor titers may range from less than 1 BU to thousands of BU. Knowing this number will help determine how bleeds are treated. If the inhibitor registers as low titer (less than or equal to 5 BU), bleeds may be treated with high doses of standard factor concentrate. If the inhibitor registers as high titer (greater than 5 BU), standard factor concentrates are ineffective and special factor concentrates called bypassing agents are used instead. Attempting to treat bleeds in the presence of inhibitors is less effective than treating bleeds without inhibitors—so the goal is to eradicate the inhibitor. If the inhibitor registers as less than 10 BU, this is when many providers will have patients begin immune tolerance therapy (ITT), also called immune tolerance induction (ITI), a treatment protocol designed to eliminate the inhibitor.¹ Knowing your BU is crucial in order to take the next step in working toward that goal.

It’s easy to put your faith completely in the numbers. Knowing your current BU is important, but know first that every individual is unique and there are several different ITT protocols. Each person does not react to ITT in the same way. One body may accept ITT easily, and his BU will come down in a short time. Others on the protocol may take years to get the same results. Numbers do not dictate that the treatment for one person will be the same as for another. For example, two brothers, both with severe hemophilia and inhibitors and with the same parents, can live very different lives with an inhibitor. My older son, Julian, was one year old when he was diagnosed with a low-titer inhibitor; it never rose above 5 BU. He immediately had a port inserted, and he started ITT for two and a half years. He tolerized, meaning his inhibitor dropped to zero, and he has never had an inhibitor resurface.

My younger son, Caeleb, was 11 months old when diagnosed with a high-titer inhibitor that registered over 2,200 BU. His titer dropped to 0 BU at one point after ITT, but now he is living with a low-titer inhibitor, and he receives factor daily to maintain his tolerance. My sons both reached 0 BU after ITT, but they had different outcomes.

The numbers can be promising and sometimes disappointing. But ultimately, the numbers are a key component to treatment.

Everyone who tracks his BU has an ultimate goal in mind: to lower the titer to zero. If your titer is 323 BU, your goal may first be 299 BU, then 250 BU.2 Another person may be hoping to get to double digits, and another to single digits. Of course, when you’re tracking your BU, you want to get to zero and stay there. When you reach 0 BU, you may think that the inhibitor is now a thing of the past—but not necessarily. Once 0 BU is attained, the next step is to monitor the half-life of the factor. To be successfully considered tolerized (this is also called complete tolerance), the following must be maintained:

• The inhibitor titer can no longer be measured.

• Factor recovery is greater than 66% of normal.

• The half-life of factor VIII is greater than six hours.³

But someone may live with 0 BU for many years without these three characteristics. This is called partial tolerance. For example, if your child has 0 BU and a three-hour half-life of factor in his body, he will probably continue with the same ITT therapy, which may be daily infusions. ITT is not always successful: an ITT attempt in which inhibitor titers fail to decrease at least 20% over three to six months, or remain over 5 BU after three to five years, is considered a failure. This example shows that not only is BU important, but monitoring the number of hours for the half-life is critical to treatment. So how does a family live with the numbers?

“Lab work disappointment” is a phrase Kari Atkinson’s family used when the numbers were not what they had expected for their son. “We had so much hope that the inhibitor would go away.” But now, says Kari, “we are not as concerned about the number because we can tell when [the BU is] up and down by how our son bleeds.” How an individual’s body reacts to treatment is the ultimate measure of success. If you’re living a full life with few bleeds and an active inhibitor, the important thing is that you are healthy, happy, and thriving. Eric Frey’s son, age seven, has lived with an inhibitor for over five years. “After time, we learned two things: First, we already knew what the results [BU] were going to show by the way our son was bleeding, bruising, and behaving. Second, the Bethesda number is far less important than how our son was bleeding, bruising, and behaving.”

Despite living full, healthy lives with an inhibitor, many families still worry about the numbers. “Making peace” with the inhibitor is something that most people don’t want to do. It can feel as if you’re giving in and accepting that the inhibitor will always be present. In order to live a life where hemophilia is not the center of everything, making peace is crucial. “We have had enough experience that we know if the inhibitor is under 7 BU, we are living pretty good,” says Kari. Her family is not focusing on 0 BU, but for now, they know that anything under 7 BU is acceptable. “It’s really hard to not focus on the numbers, especially when you have the active inhibitor and either you need to get below 10 BU to start ITT, or you are doing ITT and trying to get down to zero,” says Eric. “We understand how hard that is. Focus on health. Focus on wellness.”

Numbers are essential for people living with inhibitors. Keep track of bleeding episodes because this is a significant tool to see if your treatment is appropriate. Continue your regular blood draws according to your provider’s recommendations. Even if you’re not a slave to the BU, it’s vital to monitor the progress of your inhibitor. The key is to enjoy life. Savor every moment. When things aren’t going well, try to remember that life will get better. And when life is good, soak it in.

Cazandra Campos-MacDonald is a motivational speaker, educator, and patient advocate for families with bleeding disorders. She writes a blog chronicling the journey of her two sons with severe hemophilia and inhibitors, and has written articles and blog posts for other publications. Cazandra’s older brother, Ronaldo Julian Campos, died of complications from hemophilia as an infant. Cazandra lives with her family, Rev. Joe MacDonald, and sons Julian and Caeleb, in New Mexico.

1. ITT is a proven treatment toward eradicating inhibitors. Larger-than-normal doses of factor are given in the hope of overriding the inhibitor. ITT protocols can differ in frequency of infusing, depending on the physician’s and individual’s needs.

2. Once you achieve 10 BU, it doesn’t matter if the BU gets lower, because all infused factor is inactivated in minutes. Even so, families living with an inhibitor will find emotional relief when the numbers get closer to zero.

3. D. M. DiMichele, W. K. Hoots, S. W. Pipe, G. E. Rivard, and E. Santagostino, “International Workshop on Immune Tolerance Induction: Consensus Recommendations,” Haemophilia 13(2007): 1–22.

This article first appeared in the Parent Empowerment Newsletter, May 2017

Cell Therapy Hits a Stumbling Block

Laurie Kelley January 29, 2022

by Paul Clement

Despite the heightened anticipation of the development of a successful gene or cell therapy for hemophilia, sometimes things hit stumbling blocks.

Sigilon Therapeutics has paused development of its hemophilia A cell therapy candidate, SIG-001, after one of three patients enrolled in their Phase 1/2 clinical trial developed inhibitors and the implanted cells were found to be dead.

What exactly is SIG-001? It’s a modified form of cell therapy in which live human cells—not derived from the patient—are genetically engineered to express factor VIII and implanted into a patient.

Normally, foreign cells implanted in a person would be rapidly killed by the person’s immune system. In SIG-001, the genetically engineered cells are encased in tiny spheres of a proprietary synthetic biomaterial, which not only protects them from attack by the immune system, but also allows nutrients and waste to flow through the spheres, allowing the cells inside the spheres to survive. The synthetic spheres also allow factor VIII to flow out, making them little factor VIII “factories.”

How is this different than say, gene therapy? Sigilon’s cell therapy technology—and other similar cell therapies such as Sernova’s “cell pouch”—could have several advantages over gene therapy:

(1) most people with hemophilia would not qualify for gene therapy—it’s not for children, and they tend to be unsuitable for liver or kidney disease patients, those with inhibitors, or those with pre-existing antibodies to the viral vector used in the gene therapy (vectors are modified viruses used to deliver genes, such as the factor VIII gene, to cells).

(2) Gene therapies cannot be re-dosed if their efficacy starts to wane because, once dosed, the patient develops antibodies to the vector, which would rapidly destroy another dose, unless the patient was put on a regimen of immunosuppressive drugs. However, because SIG-001 protects the engineered cells from the immune system, patients could be re-treated if necessary–or have some spheres removed if the dose is too high. (The spheres are administered by injecting them into the patient’s abdomen through a large syringe.)

And (3), the most important potential advantage is cost. Gene therapies are hugely expensive (estimated to cost between $2-$2.5 million) and no satisfactory payment model has so far been worked out. SIG-001 would be off-the-shelf and easily scalable, making it more cost-effective.

So, what happened to SIG-001? In July 2021, the FDA put a clinical hold on the SIG-001 study after a patient developed inhibitors. Inhibitors in hemophilia A patients are common—as many as one-third of people with hemophilia A develop inhibitors, and they usually develop within the first few dozen infusions of factor. However, participants in the SIG-001 clinical trial were pre-screened to be at low risk of inhibitors. In order to qualify for participation in the clinical trial, prospective participants were required to have had at least 150 exposure days to factor, making the risk of developing inhibitors very low. So, a patient developing inhibitors in the clinical trial was concerning.

In November 2021, the inhibitor patient underwent a laparoscopic procedure to retrieve the implanted spheres, which were found to be fibrosed (covered with scar tissue) and the cells within them dead. For SIG-001, its proprietary synthetic biomaterial, specifically designed to prevent fibrosis which occurs when our body detects a foreign object, had failed.

In December 2021, Sigilon decided to pause SIG-001 development in a “strategic reprioritization” in which they laid off approximately 38% of their workforce and refocused their efforts for now on developing a cell therapy for a rare lysosomal disease.

Sigilon has an excellent concept, but unfortunately, its product met an unexpected stumbling block. With each stumbling block though, we also learn, and get one step closer to a successful “cure” for hemophilia.

Paul Clement is a science writer for the hemophilia community who enjoyed a long career as a high school science teacher. He is especially adept at translating complex topics into easy-to-understand language. He is the chief science writer and editor for LA Kelley Communications’ publications, including the Parent Empowerment Newsletter from 1998-2021 and PEN’s Insurance Pulse magazine from 2009-2020. He is co-author of the books Managing Your Child’s Inhibitor and A Guide to Living with von Willebrand Disease. He holds a bachelor’s degree in biology and a master’s degree in science education from California State Polytechnic University. Paul lives in southern California with his wife Linda. They have two adult children, Erika and Brett, who has severe hemophilia A.

The First Reported Case of an Inhibitor in Hemophilia

Laurie Kelley January 23, 2022

by Richard Atwood

By 1940, leading hematologists considered the presence of an inhibitor in circulating blood to be a theoretical possibility. But there were no known cases of hemophilia with an inhibitor, or a “circulating anticoagulant,” as it was commonly identified.

University of Rochester School of Medicine and Dentistry in Rochester, New York

Then in a 1942 medical journal article, Dr. John S. Lawrence and Dr. John B. Johnson at the University of Rochester School of Medicine and Dentistry in Rochester, New York reported a case of hemophilia with a circulating anticoagulant in his blood. W. Purcell, a 44-year-old unmarried patient with hemophilia was, identified as patient No. 27899.

There was a history of hemophilia in the extended Purcell family: in addition to Purcell, a maternal uncle had died from bleeding following an incision and Purcell’s brother had a typical picture of hemophilia.

Purcell was born in 1897. When he was 3, he had a bleeding episode lasting 22 days from a cut in the lip. At the age of 6, he had blood in his urine, and up to age 15, he oozed blood from his gums. Purcell also suffered from sporadic pain and swelling in the elbows and knees with subsequent stiffening or ankylosis of the joints. He had several tooth extractions with subsequent bleeding. His first hospital admission was on September 19, 1929 for bleeding following extraction of a tooth. He had 18 subsequent hospital admissions for bleeding from his teeth (twice), hematuria (9 times), gastro-intestinal bleeding (4 times), hemoptysis (once), and hemorrhages into his joints (7 times). Purcell received many transfusions as treatment.

Purcell’s coagulation time varied from 12 hours to 70 minutes. A standardized technic resulted in coagulation times of less than 2 hours. Strangely, repeated coagulation times in minutes taken from 1939 to 1941 were not markedly reduced after transfusions with normal blood or fresh plasma, and were reduced less than would be expected in patients with typical hemophilia. The circulating anticoagulant in the Purcell’s blood could not be identified. This led physicians to advise checking the coagulation time shortly after the administration of fresh normal blood to every patient with hemophilia to rule out the presence of a circulating anticoagulant.

Follow-up on Purcell was provided later in a 1947 medical journal article by Charles G. Craddock, Jr., MD and John S. Lawrence MD from the University of Rochester School of Medicine and Dentistry in Rochester, New York. Over the 5 year span since the previous report, the 50-year-old unmarried male had many recurrent episodes of bleeding in his joints, genito-urinary tract, and gastrointestinal tract. He was treated with transfusions of fresh blood or plasma, which had little effect. A test taken in 1945 for the presence of a circulating anticoagulant was negative.

Purcell was hospitalized from December 1945 until March 1946 because of a severe continuous rectal hemorrhage. During these 3 months, he received 30 transfusions of 500 cc. each of whole fresh blood. The patient did not improve and the coagulation time consistently varied from 60 to 120 minutes. No tests for a circulating anticoagulant were performed. The last transfusion was given on February 9, 1946 and the patient slowly improved once the bleeding ceased. A test on September 9, 1946 for the presence of a circulating anticoagulant was negative.

Purcell was readmitted on April 15, 1947 because of rectal bleeding of 3 to 4 hours duration. He was pale and suffered repeated attacks of precordial pain. He received 6 transfusions of fresh whole blood with no improvement by either clinical or laboratory findings. The transfusions with whole blood were stopped. Purcell then received 500 cc. of washed red cells and showed some signs of symptomatic improvement. Another transfusion of whole blood given inadvertently caused an immediate recurrence of symptoms. The patient then received another 500 cc. units of washed red cells and showed steady symptomatic improvement. Though the clotting time remained prolonged, and the circulating anticoagulant persisted, Purcell gradually improved.

His physicians believed that Purcell was deficient in or lacked antihemophilic globulin in his blood. With laboratory testing, his circulating anticoagulant was shown to be associated with the gamma globulin fraction of plasma. The physicians hypothesized that the action of the anticoagulant against antihemophilic globulin was essentially that of an antibody-antigen reaction, or “isoimmunization,” as a result of repeated transfusions or injections of antihemophilic globulin, either in the form of whole blood, plasma, or Fraction I of Cohn (commercially available from Cutter or Squib).

They concluded that certain hemophiliacs deficient in a globulin fraction may be capable of developing antibodies against the antihemophilic globulin when it is given repeatedly. Purcell is truly the first person with hemophilia known to have an inhibitor!

References:

Craddock CG and JS Lawrence. 1947 Hemophilia: A report of the mechanism of the development and action of an anticoagulant in two cases. Blood 2:505-18.

Lawrence JS and JB Johnson. 1942 The presence of a circulating anti-coagulant in a male member of a hemophiliac family. Trans Am Clin Clim Assoc 57:223-31.

Out of Silence: Leadership

Laurie Kelley January 16, 2022

My last two blogs focused on leadership, and two beloved leaders who have passed, much too soon, from this life. I have spent this week with another amazing leader, very much still with us: Eduardo Strauch, a survivor of the 1972 plane crash in the Andes, of “Alive” fame.

You may know the incredible story, dubbed “The Miracle of the Andes.” On October 13, 1972, Uruguayan Air Force Flight 571 crashed at 11,710 ft in the inhospitable Andes, while bringing 19 young members of a rugby team, and their families and friends, to neighboring Chile. Thus began perhaps one of the greatest survival stories known. Amazingly, 33 of the 45 on board survived the initial crash, some with injuries that would later claim their lives. And 72 days later, 14 were rescued after two more of the survivors walked out of the Andes for 10 days to find help.

It was a miracle anyone survived. Due to pilot error, the plane descended too early in dense cloud cover, and struck a mountaintop. The right wing snapped off, flipped and severed the tail, then the left wing sheared off. What remained of the fuselage tobogganed down a steep slope and smashed into a mound on a glacier, traveling top speed. Stunned, many in agony from wounds and shock, wearing only street clothes, the survivors sprang into action, displaying heroic teamwork.

Approaching the Valley of Tears and Crash Site

What happens to us personally, when we are hit with an unexpected tragedy, say, like giving birth to a beautiful child, only to learn he has a life-long, life-threatening bleeding disorder? We can collapse and give up; we can grieve endlessly; we can become dependent on others for help; or we can take action to improve our lives and those of our loved ones. The Andes boys took immediate action, even though many of them were wounded. They helped one another, they organized whatever they had, they started planning. They survived.

Horseback through rivers and high cliffs

I journeyed this past week to the crash site, high in the Andes, accessible only by hiking or horseback, to pay my profound respect to those who perished. They are buried in a mass grave on a ridge near the crash site. There is also a makeshift memorial, with an iron cross, upon which people leave personal mementos. This story has touched millions of lives throughout the last 50 years, and only a few get to come here, to the “Valley of Tears,” to see the place where so much agony, sorrow, terror, solitude, struggle and leadership took place.

A Transformational Leader Remembered

Laurie Kelley January 9, 2022

We lost a few of people in our bleeding disorder community over the holidays, including young people with hemophilia. But in two weeks we lost two outstanding leaders in their fields. One was Val D. Bias, who I wrote about last week. The other was Dr. Tahir Shamsi of Pakistan. Both were my friends.

Tahir was a special sort of friend to me. We inhabited very different worlds: I am a woman, Christian, nonmedical, American. He is a man, Muslim, nationally-recognized physician and researcher, Pakistani. We were united not only by hemophilia, but by our burning desire to alleviate suffering.

We met on a boat in Rotterdam, in 1998. I was just beginning my work overseas, funded at that time by Bayer Corporation. Bayer had sponsored this cruise around the harbor, on a Tuesday evening during the World Federation Congress. As I walked about the ship, I saw him and he saw me. He is friendly, but intense. Efficient, wastes no time. Who was I and what was I doing there?

I explained about my program to identify patient leaders in developing countries, and teach them about leadership, not just management; about advocacy, not just meetings. About vision, mission, goal setting.

He invited me on the spot to come to Pakistan.

That startled me. Me? Mother of three young children, in Pakistan? Pakistan at the time was pretty isolated from the world. Almost no one went there unless they were diplomats. It seemed so… so foreign. And yet I was intrigued. I love challenges and love risks. How would the Pakistanis accept me? What could I possible do for them?

He assured me all would be well. I could stay with him and his wife, and family. He would arrange my visits while there.

A year later, I went. It’s a story for another time (maybe another book) but I fell in love with Pakistan. Never have I been so welcome in a country and made to feel at home. And that seems odd, given our “differences.” I learned the differences are mostly superficial. We have so much more in common than different. I returned three more times and would have gone in this past year, were it not for Covid.

Tahir and I maintained contact throughout the years; I watched his family grow from two young children to five. I played with his children at their house, rode camels and ponies on the Arabian sea with them, took selfies, went to the mall, and had a ball. And Tahir and I met patients throughout Pakistan, worked with the new hemophilia society to help it grow, and we supported his surgeries with donated factor. We traveled to Nepal together, met up in Paris at a conference, and always had ideas brewing.

In fact, it was in Nepal, after our huge conference we gave for medical personnel, that Tahir shared his vision for a new institute in Pakistan. Somehow, we ended up sitting on the floor of a coffee shop, with him sketching out (on a napkin!) an idea for a new blood institute that would handle all sorts of cases, disorders, diseases of the blood, and be a research and training facility.

1999 Laurie and Tahir on Arabian Sea
First Visit to Pakistan

It all came to pass. The National Institute for Blood Diseases was created and Tahir founded Pakistan’s first bone marrow transplant program. The president of Pakistan recognized him for his incredible achievements. And the president offered his condolences in a tweet shortly after Tahir’s passing.

He got up to go to work in December, as usual. We had just messaged one another about how I would come over as soon as it was safe to travel, and stay at his new home, which accommodated all his growing family. He messaged, “You are always welcome.” Combination work and social visit. The kids are mostly grown, though the youngest is still just 15. I imagine he kissed them good-bye, as he adored his family, and had his driver take him to the office. We would have had interns to meet with, surgeries and patient visits planned. I do know he felt ill suddenly, and asked to be driven to the hospital. He suffered a massive brain hemorrhage, of all things. He never recovered and died, age 60, with so many depending on him, with so many achievements, but I know with so many more things he wanted to accomplish.

I don’t ever recall him saying he had a vacation in the 23 years that I knew him.

His death shocked me. You can never believe so wonderful a healer could be so ill. I could and would just pick up my phone whenever, and could message this famous and highly regarded physician, and chat with him like you would a regular person and friend.

But no more. Never again. He was gone, in a flash, a heartbeat, as if he sped away to attend to a medical emergency and never returned. He was always helping others.

The grief over his passing was palpable and deep. The NIBD team wrote on Facebook: “He was a national asset, a mentor to the juniors, a patron for many noble causes and a fatherly figure to all. Our loss cannot be described in words as the void he leaves behind is unfillable. He was director of the stem cell program, paragon of health research, an outstanding individual with excellent mentorship abilities, and an incredible human being. May Allah grant him the highest place in Jannah. Ameen.”

I will return to Pakistan, but it will never be the same without my friend, this incredible pioneer of medicine. He was a transformational leader, of the rarest type.