Inhibitors

What’s in a Number?

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

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.

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

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?

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

Inhibitors 101

Paul Clement

Paul Clement

For many parents of children newly diagnosed with hemophilia, the word “inhibitors” soon becomes part of their vocabulary. And although they may not know at first what an inhibitor is, they may have learned to associate the word with something fearful. But for people with hemophilia A and inhibitors, things aren’t as bad as they once were.

What exactly is an inhibitor? Who gets them? What happens when you get an inhibitor? How do you treat bleeds if you have an inhibitor? Do inhibitors go away on their own, or can you grow out of them or eliminate them?

What Is an Inhibitor?

Inhibitors are specialized proteins called antibodies. They’re a part of the immune system that protects us from bacteria, viruses, and foreign proteins—in other words, anything that the body identifies as not belonging, and as being potentially harmful. But sometimes the immune system makes mistakes: it may even attack the body itself, as in autoimmune diseases including rheumatoid arthritis or multiple sclerosis. With hemophilia, the immune system also makes a mistake: it misidentifies a helpful agent—infused clotting factor—as something harmful, and then mounts an immune response against the factor to neutralize it and mark it for removal from the body.

Inhibitors are very efficient. When an inhibitor is present in hemophilia, some or all of the infused factor is neutralized within minutes. This prevents the factor from participating in the clotting process to stop bleeding. And it means that people with inhibitors can’t use standard clotting factor concentrates to control bleeds.

Unfortunately, the alternative therapies we have for treating bleeds with inhibitors aren’t as effective as standard factor at controlling bleeds. As a result, people with inhibitors tend to bleed longer, develop target joints (joints that bleed frequently), and suffer from joint damage more often than people without inhibitors. Fortunately, for people with hemophilia A and inhibitors, treatment has improved dramatically over the past three years.

Diagnosing Inhibitors

How do you know if you have an inhibitor? There are usually no outward signs. Inhibitors are sometimes diagnosed during routine hemophilia treatment center (HTC) clinic visits; and sometimes inhibitors are suspected after you notice that factor infusions fail to adequately control bleeding. Your HTC should test for inhibitors at least annually and always before any surgery, and you should request a test whenever you feel that bleeds aren’t being controlled effectively with your usual dose of factor.1

 When an inhibitor is suspected, a diagnostic test called a mixing study (activated partial thromboplastin time, or aPTT) is performed: the patient’s blood plasma is mixed with normal plasma to see if this corrects the clotting time. In someone with hemophilia without an inhibitor, a mixing study results in a normal clotting time; but if an inhibitor is present, then the clotting time is abnormally prolonged. If this happens, then another test, the Bethesda inhibitor assay, is done to determine how much of the inhibitor-causing antibody is present.2 The Bethesda assay is a quantitative assay, meaning that it measures the amount of inhibitor and the results are expressed in numbers.

Note: Testing for inhibitors is a bit tricky. It’s best to have a Bethesda assay done at an HTC, because the lab techs there have more experience performing the tests, and the results are more likely to be accurate when compared to tests done at other hospitals.

Strength of the Inhibitor

To develop a strategy for treating bleeds, your doctor will need to know the strength, or concentration, of the inhibitor. The inhibitor strength is reported as a “titer” and is expressed in Bethesda Units (BU).3 Inhibitor titers can be as low as 1 BU or higher than 10,000 BU.

An inhibitor titer less than or equal to 5 BU (≤5 BU) is considered a low-titer inhibitor. An inhibitor greater than 5 BU (>5 BU) is considered a high-titer inhibitor. If you have a low-titer inhibitor, you can still use standard factor to treat bleeds, although in higher doses to accommodate for some of the factor being neutralized by the inhibitor. If you have a high-titer inhibitor, standard factor concentrates are not effective because all the factor is quickly neutralized after an infusion.

In addition to the inhibitor titer, inhibitors are categorized by how the immune system responds to infused factor. For some people, the inhibitor titer stays more or less stable and doesn’t rise after the patient is exposed to factor. If your child has an inhibitor titer ≤5 BU, and it remains at or below 5 BU for several days after an infusion, he is a low responder.

For others, when factor is infused, the immune system quickly ramps up inhibitor production in an effort to neutralize the infused factor. This results in an increase of the inhibitor titer within four to seven days of exposure to factor, peaking within one to three weeks. This ramping up of inhibitors after factor exposure is an anamnestic response (meaning a memory or recall response). If, after exposure to factor, the inhibitor titer rises above 5 BU over a few days, then your child is classified as a high responder. High-responding inhibitors are more challenging to treat than low-responding inhibitors because normal factor concentrates are useless with high-titer, high-responding inhibitors. Treating bleeds with these inhibitors requires special factor concentrates called bypassing agents, such as FEIBA or NovoSeven.

 But there’s one case where standard factor can be used to treat bleeds in high responders. In high responders, the immune system often produces fewer and fewer antibodies over time if it isn’t exposed to factor. If someone hasn’t been exposed to factor for several months, then the inhibitor titer may have decreased to a level low enough that normal factor concentrates may be used to treat bleeds successfully for a few days—that is, before the anamnestic response kicks in and the inhibitor titer increases again, making the factor ineffective.

1. You can get free inhibitor testing at federally funded HTCs by participating in the Centers for Disease Control and Prevention’s (CDC) Community Counts Registry for Bleeding Disorders Surveillance program.  2. There are several different types of inhibitor assays; the Bethesda assay is the most widely used.  3. A Bethesda Unit (BU) is the amount of an inhibitor that will neutralize 50% of factor VIII in normal plasma after 120 minutes’ incubation at 37°C.

When Hemophilia Throws a Curve Ball


This past week I was reminded first how blessed I am to have a son with “only” hemophilia, and second, how important it is to remember our community members who are in the hospital or confined at home. I visited Rich P., a 23-year-old with hemophilia and inhibitors, who is as compassionate as he is passionate, and who is as proactive as he is intelligent and thoughtful. He is a leader with the NHF Youth Commmittee, on at least two patient advisory boards, a full-time college student, and has volunteered on two trips this year to help the poor in Jamiaca and in New Orleans.

Sadly, Rich has been hospitalized for over two weeks, for complications related to his inhibitor. Rich called me the day he was hospitalized, and would be an inpatient for another two weeks. For a guy as active as Rich, being immobilized in the hospital is nothing short of mental torture. When I visited he was surrounded by balloons, cards and stuffed animals and eventually his wonderful friends. As blessed as he is with charisma and a loving family, he was suffering terribly. Yet he still had the kindness to ask about my family and work! Some devoted friends in the hemophilia community have been visiting him, advocating for him, and keeping his spirits high. I was proud to see how our community cares for its own. And I was completely impressed and touched when the VP of a factor manufacturer traveled hours to spend an afternoon with Rich.

Thankfully, many of us will never know that kind of suffering, thanks to advanced treatment. But once in a great while, hemophilia throws us a curve ball. Do you know of someone who is bed-ridden, in the hospital or in pain due to hemophilia? Don’t forget them. Send a card, flowers, make a call. You won’t believe the difference it will make in their spirits. The attention you show really helps relieve pain, anxiety and loneliness. Bless all of you who care for the sick, suffering and lonely in our community.

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