Inhibitors

The Philippines: Unseen Forces of Support

Laurie Kelley November 10, 2024

My name is Angelo, and I am living with hemophilia in the Philippines. This condition has been a constant companion in my life, presenting unique challenges that not everyone fully understands. Hemophilia affects how my blood clots, making even minor injuries a potential crisis. This is my story of resilience, hope, and the invaluable support I’ve received from people who truly care.

Despite all the care and infusions, the aftermath of those hospitalizations left my veins delicate, making IV insertions a struggle. Even a 22G cannula, a larger-than-average needle, now poses challenges, often requiring multiple attempts to find a usable vein. I recall one hospital admission where a series of failed attempts to secure a line left me feeling exhausted and stressed. It was a wearisome experience, physically and mentally. Fortunately, my compassionate hematologist at the time understood my situation and allowed me to go home after a few successful transfusions, even though my hemoglobin levels were still below ideal. This was a small victory in a long and difficult battle.

Since my last hospitalization in 2017, I have managed my condition at home. I often choose to bear the pain of bleeds rather than face the struggles of another hospital admission. The thought of being poked and prodded again is daunting, so I’ve learned to cope with my condition as best as I can. My condition has also affected my mobility, I require crutches for support, relying heavily on my upper body to assist me in standing. Both of my feet, especially my right one, are significantly slanted and cannot lie flat on the floor, complicating my ability to move around. My knees, particularly my right knee, are severely restricted in movement, adding yet another layer of complexity to everyday life. Simple tasks like walking or even standing for long periods can become exhausting, and I often have to plan my day around my physical limitations.

Despite these struggles, I am deeply grateful for Hemophilia Advocates- Philippines (HAP), our hemophilia organization here, which has been a lifeline during emergencies. Their support has been crucial in moments when I needed help the most. Over the years, I have requested assistance for factor multiple times, with my most recent request made last October. Unfortunately, it was not granted due to low supplies that are only allocated for emergencies. While it was a challenge, I remained hopeful, knowing that support comes in many forms. In light of the situation, I turned to Ma’am Laurie Kelley, a compassionate individual known for her generosity. I shared my situation with her, and to my relief, she kindly offered to send me factor herself. Her willingness to help reminded me of the goodness that still exists in the world.

Living with hemophilia in the Philippines, where medical assistance for rare bleeding disorders is scarce and costly, has been a constant challenge. The healthcare system here is often strained, and access to specialized treatment can be limited. Although I am employed, the average salary here makes it incredibly difficult to afford the necessary treatments on my own. I sometimes worry about the future and how I will manage my condition without the support of others. Yet, through the relentless support of people like Rev. Fr. Kill, Ma’am Laurie, and HAP, I continue to find strength and hope. Their kindness has taught me that I am not alone in this fight.

This journey has taught me to appreciate every act of kindness and to stay resilient. I have learned that, while my condition presents many challenges, it has also brought extraordinary people into my life. For those of us with rare conditions, even small acts of understanding and support can make all the difference. It’s these connections that give me hope for a better tomorrow, where I can live my life with dignity, strength, and the support of those who care.

When Can an Inhibitor Be Diagnosed?

Laurie Kelley September 22, 2024

Inhibitors are relatively uncommon. If one develops, it’s usually detected when a child with hemophilia is young, usually in the first one to three years of life. The median time to development of an inhibitor is about nine to eleven exposure days— days on which the child received one or more infusions of factor VIII or factor IX. Parents may suspect that something is wrong, usually because a bleed will not resolve, or takes significantly longer to resolve, after an infusion of factor. Several situations might indicate that a child has an inhibitor:

Unresolved bleeds

All HTCs routinely monitor their patients for inhibitors, and many do so more frequently in the first months of treatment. But not every child with hemophilia is seen at an HTC, and older children may go only once a year for their annual comprehensive visit. You may learn that your child has an inhibitor the hard way: when factor no longer works well to stop bleeds. How do you know when factor isn’t working well? If you’re new to hemophilia, this may not be easy—you may not be sure how long it should take a bleed to stop after an infusion. You’re still getting used to identifying symptoms of different bleeds, learning about your child’s individual bleeding pattern, and determining whether a “normal” muscle or joint bleed takes one day or four days to resolve. With so much to learn, it may not immediately dawn on you that the infused factor isn’t working properly, and a bleed is taking much longer than it should to heal. It’s common for parents to think that they simply need to give their child more frequent infusions, or give a higher dose per infusion. Continued bleeding, even with repeated infusions of factor, is the primary way that parents discover their child has an inhibitor.

Increased bruising

Bruising in young children with severe hemophilia is common. But if your child uses factor frequently and you notice increased bruising, this may be a sign of an inhibitor. One mother commented that her doctor noticed increased, repeated bruising at her child’s infusion site, and suspected an inhibitor.

Routine clinic visit

Ideally, you’d like to learn that your child has an inhibitor before an emergency happens and before he gets a major bleed. A blood test at your child’s HTC comprehensive clinic visit can identify an inhibitor. It’s wise to have a child with hemophilia tested for inhibitors routinely: learning that he has an inhibitor in advance of surgery or a major bleed allows parents to have a plan in place and the correct treatment on hand.

Breakthrough bleeds while on prophylaxis

Prophylaxis is the scheduled infusion of factor to help prevent bleeding. Many children with hemophilia on prophylaxis receive factor two to three times a week, enough to keep the lowest level—called the trough level—of factor in the blood above 1%. Children on “prophy” usually will have enough circulating factor to prevent most spontaneous bleeds and abnormal bruising. When a child on prophy starts bruising or even bleeding more often than usual, an inhibitor may be inactivating some of the factor, thus lowering his factor level and increasing his risk of bleeding.

Bleeding after surgery

Because surgery often involves blood loss, it requires special precautions for children with hemophilia. A common first surgery is circumcision. In families with no history of hemophilia, elective circumcision is usually performed soon after birth, and prolonged bleeding that results from the surgery may indicate hemophilia. A blood test will confirm the diagnosis. Depending on the circumcision method, some babies with hemophilia have no bleeding problem with circumcision—even without an

infusion of factor. Others bleed profusely and need factor to control bleeding. Any kind of surgery on a child with hemophilia requires careful planning and monitoring of factor levels, and any child who continues to bleed following surgery, even with adequate factor, should be immediately tested for an inhibitor. Ideally, all children with hemophilia should be tested for an inhibitor before any surgery of any kind.

Allergic reaction following infusion

Inhibitor development in children with hemophilia B is rare—only 1% to 3% of people with hemophilia B get them. Unlike people with hemophilia A and inhibitors, about 45% of people with hemophilia B and inhibitors also develop allergic reactions at about the same time that they develop inhibitors. Allergic reactions may start out mild, and then increase in severity after repeated exposure to products containing factor IX, often to the point of a serious, life-threatening allergic reaction called anaphylaxis. Allergic reactions in hemophilia B patients are not in themselves an inhibitor, but are a sign that an inhibitor has developed.

Later in life

If an inhibitor is going to develop, it will usually do so within twenty exposure days, and almost always before the hundredth exposure day. And the patient will probably have severe hemophilia. Only about 1% to 2% of people with mild hemophilia develop inhibitors. Although most inhibitors occur early in life, in rare cases an inhibitor develops when a child is older, sometimes a teen or an adult. Unlike people with severe hemophilia, people with mild hemophilia who develop inhibitors tend to develop them later in life, usually after intensive exposure to factor during and after surgery or traumatic injury.

Regardless of how you discover your child’s inhibitor, the diagnosis can be both a relief—now you know what’s wrong—and a worry. What will happen next? Your HTC is the best place to turn to for treatments to help manage the inhibitor.

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

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.

Factor from Rabbits?

Laurie Kelley April 25, 2021

Paul Clement

Factor from rabbits you say? Yes! On April 1, 2020, The Food and Drug Administration (FDA) granted approval of a new recombinant factor VII (FVII) product—Sevenfact—to France-based LFB Biotechnologies Group.¹ In the US and Canada, Sevenfact is sold exclusively by HEMA Biologics, a Louisville, KY-based biopharmaceutical company.

Until now, all recombinant factor concentrates were produced by inserting a gene for a human clotting factor into mammal cells, which then gives the cells the ability to make human factor. These “transgenic” cells, such as BHK cells (baby hamster kidney); CHO cells (Chinese hamster ovary); or more recently, HEK-293 cells (human embryonic kidney), are then grown to great numbers in large stainless-steel tanks called bioreactors. As the cells grow in the liquid culture medium in the bioreactor, they secret factor into the liquid, some of which is periodically drawn off, purified, concentrated and eventually processed into clotting factor concentrate.

Enter Sevenfact.² The production of Sevenfact does not involve the use of cell lines and bioreactors, but instead involves rabbits. The rabbits are genetically engineered—given a copy of the human gene for FVII that is designed to be expressed in the mammary gland and secreted into the rabbit’s milk. During the separation and purification process of the FVII, the factor is activated, producing activated FVII, or FVIIa.

Why rabbits? Clotting factors are complex proteins. And although genetically engineering a cell by adding a gene for human factor may confer it with the ability to produce human factor, the factor is not fully functional until it is “finished” or modified by the addition of different compounds and folded into a specific shape. This modification process is largely dependent on the type of cell making the factor and most animal cells are not capable of properly finishing human factor proteins. Rabbits do the best job of making factor very close to how humans make factor. In other words, rabbits produce very “human like” factor, which may also have an added benefit of decreasing immunogenicity (the likelihood of producing inhibitors). Rabbits have several other advantages as well: they are small, reproduce rapidly and their milk has a high protein content, meaning they produce more factor than other animals when comparing the same volume of milk.

Producing factor in bioreactors is a rather inefficient process. Rabbits do this much more efficiently and at a much low cost—they do not require large, expensive, highly complex facilities to house bioreactors, and unlike conventional facilities that take years to plan and build, production can be rapidly scaled up. Rabbits can produce 200 milliliters of milk per day, or nearly 7 ounces, and they lactate for about three weeks. A single rabbit can produce about 1 to 1.5 liters of factor-rich milk per lactation period, for a yield of 10–15 liters of milk per year. And they do not have seasonal reproductive cycles that would limit milk production as do many other animals.

Sevenfact is very similar to another recombinant FVIIa product on the market called NovoSeven RT (Novo Nordisk). Sevenfact is a bypassing agent, meaning it’s indicated for the treatment and control of bleeding episodes occurring in adults and adolescents 12 years of age and older with hemophilia A or B with inhibitors (neutralizing antibodies to FVIII or FIX).

In addition to FVIIa, there is also another bypassing agent on the market for people with hemophilia A or B with inhibitors: FEIBA (Takeda), which is a plasma-derived activated prothrombin complex concentrate (aPCC). And in 2017 the FDA approved a novel antibody therapy called Hemlibra, which can be used for prophylaxis in people hemophilia A, with and without inhibitors (it’s not used to treat bleeds).³

Hemlibra has revolutionized the treatment of hemophilia A with inhibitors because it dramatically reduces the frequency of bleeds—but people may still have breakthrough bleeds, requiring the use of a bypassing agent. In clinical trials of Hemlibra, patients who used FEIBA at doses greater than 100 U/kg/24 hours sometimes developed unwanted blood clots, but no such adverse event was found in patients on Hemlibra treating bleeds with rFVIIa. Because of this concern, many patients on Hemlibra prophylaxis instead prefer a rFVIIa, such as SevenFact. LFB has conducted laboratory tests of Hemlibra and SevenFact, and is currently enrolling patients on Hemlibra in a clinical trial using SevenFact to treat breakthrough bleeds.⁴

For more information on Sevenfact, visit the HEMA Biologics website at: https://hemabio.com/

This is an original article with no corporate sponsor input or funding.

1. LFB Biotechnologies Group: Laboratoire Francais du Fractionnement et des Biotechnologies 2. Coagulation FVIIa [recombinant]-jncw or eptacog beta). 3. (emicizumab-kxwh [Hoffman‐La Roche]) 4. https://onlinelibrary.wiley.com/doi/full/10.1111/hae.14253