Fall 2002 - Factor Nine News

The Coalition for Hemophilia B

Topics In Hemophilia

• The Factor IX Property - Dr. David Clark
• Trough Levels - Jill Lathrop
• Adirondack Spectacular Successful Event
• Factor IX Family Meeting November 1, 2002

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The Factor IX Property
Dr. David Clark

Factor IX has a peculiar property. When it is infused into the bloodstream about half of it immediately disappears. Therefore, patients use twice the amount of clotting factor that would normally be calculated as needed. This is one of many facts that are well known to hemophilia treaters, but which may not be as well known to patients and their families. In this issue we are going to describe some of these routine aspects of treatment. (Please do not double your Factor IX dosage. The missing Factor IX has already been taken into account in your current dosage.)

The amount of Factor IX needed to treat a bleeding episode varies depending on the particular event being treated. For early hemorrhages occurring in sites that pose a low risk, the Factor IX level might be raised to 15 - 20 % of normal, while for hemorrhages in particularly dangerous sites such as the brain, the level might be raised to 50 - 100% of normal. Note that the “normal” level is just an average over the whole population of people without hemophilia. People without hemophilia can actually have factor levels ranging from as low as 40% to as high as 200% of what is defined as “normal”.

The rule of thumb is that one unit of Factor IX infused per kilogram of body weight raises the level by one percentage point (One kilogram is 2.2 pounds; a 150- pound person weighs about 68 kilograms.) The amount needed is calculated in relation to body weight because larger people have a larger volume of blood and thus need more factor. However, these are just typical or average values. The actual amount of clotting factor needed can vary significantly from patient to patient. In fact, through experience a patient and his family usually become the best experts on what works for them.

The amount of Factor IX in a patient’s blood can be measured in several ways. The most common method used in the U.S. is a clotting assay. In this method the time that it takes a blood or plasma sample to clot is measured. That clotting time is then compared to the clotting time for a reference standard that has a known concentration of Factor IX to determine the amount of Factor IX in the sample being tested. The Factor IX concentration in a sample is often called its Factor IX potency. Because the clotting time is very sensitive to small changes in temperature and other conditions, the instruments used to perform clotting assays maintain these conditions at precise levels to ensure that the clotting times are reproducible from one test to the next.

The amount of Factor IX and of most other clotting factors is measured in units. A unit is the average amount in one milliliter of plasma from donors without hemophilia. (One thousand milliliters equals one liter, which is about the size of a quart.) However, because the concentration of Factor IX varies from person to person, a pool of plasma from a number of donors is used to establish the average value for a unit. Test laboratories may use a reference standard made from such a pool of donated plasma, or they may use a reference material obtained from an outside source.

Several national and international health organizations have developed reference standards. The amount of Factor IX in these standards is typically established by being tested by 25 laboratories around the world using various test methods. Each laboratory uses a local reference standard plasma pooled from at least 15 donors. The average of the values obtained by all these laboratories then becomes the potency of the standard. When a laboratory uses an international standard in their assays, their results can be expressedin International Units (IUs). Most factor IX concentrates have a potency expressed in IUs.

Factor IX has a half-life of about 24 hours. This means that half of the Factor IX in the bloodstream disappears every 24 hours. For instance, if a patient is infused with Factor IX to give a level of 50% of normal, 24 hours later his Factor IX level will have dropped to about 25% of normal, and 24 hours after that it will have dropped to about 12.5% of normal. Proteins and other molecules in the blood stream disappear by a normal process known as clearance. Proteins gradually wear out and are normally cleared and replaced at fairly constant rates. This continual production and clearance maintains a fresh supply of the protein in the body and keeps the level of the protein approximately constant. However, hemophilia patients do not replace their cleared Factor IX, so the level of factor injected into their bloodstream gradually decreases. In cases where factor infusions are given repeatedly over a period of time, for instance in patients undergoing prophylactic treatment or in patients being prepared for surgery, the Factor IX level in the bloodstream will rise and fall in a fairly regular fashion. The Factor IX level will reach a peak value immediately after infusion and then decline as the Factor IX is gradually cleared. The lowest level, known as the trough level, is reached just before infusion of the next dose. The goal is generally to keep the trough level above a certain point at which the patient has minimal bleeding problems, for instance above 1% or 5% of normal.

The amount of Factor IX that can be measured in the bloodstream after an infusion compared to the amount infused gives the recovery. As mentioned above, Factor IX has a recovery of about 50%, that is, only about half of the Factor IX infused can be found in the blood.

Recovery can also vary significantly from patient to patient over a range of 30 to 70% or more. It can also vary among Factor IX products. For instance, it is known that recombinant Factor IX, BeneFix, gives a slightly lower recovery in most patients, so slightly higher doses are normally used. Although historically recovery has been expressed as a percentage, today it is often expressed as the increase in units of Factor IX per deciliter of plasma divided by the units of Factor IX infused per kilogram of body weight or “U/dl / U/kg”. (A deciliter is one-tenth of a liter and is equal to 100 milliliters.) A recovery of 1.0 U/dl / U/kg is equivalent to a 50% recovery.

So where does the missing half of the infused Factor IX go? Researchers are still trying to answer this question. None of the other clotting factors exhibit this behavior. Although it is not completely understood, it appears that a significant amount of Factor IX binds to the surface of endothelial cells, the cells that line the inside of blood vessels. The bound Factor IX may represent a natural reservoir of extra clotting factor that can be released back into the bloodstream when needed.

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TROUGH, NADIR, ONE HOUR POST?
What does it mean for my child?
by Jill Lathrop

Both of my children have severe hemophilia B. As a result, they’ve had more than their share of blood tests done. It’s easy to get frustrated with all the lab work that is ordered, but we have learned how important the results are in calculating factor doses and evaluating our prophylaxis regime. When the boys need routine blood tests ordered by our pediatrician, they are done at a lab or clinic in our hometown. However, when we need specific information about how their bodies are responding to the factor we are infusing, the tests are done through the laboratory associated with our hemophilia treatment center. Factor levels, or assay studies, are very specific, sensitive tests that are not routinely run in clinic or hospital laboratories. In order to get results that are reliable and valid, it’s important to make sure the facility running the tests has extensive experience performing tests ordered by a hematologist.

Before our boys started on a regime of primary prophylaxis, we had never heard of a “one hour post” factor level or trough study. By the time we had settled in to our twice-weekly infusion routine, we felt like we were experts on the subject. We learned that trough studies are done to measure the amount of factor in their systems on their “lowest” day or just before their next infusion. Some medical professional may also refer to this as a nadir level. Knowing and understanding the results of the myriad factor assays is key in determining if an infusion regime is effective.

When Sam was started on BeneFIX for prophylaxis, there weren’t many other kids, if any, at our HTC who were using this product.

Our physician was adamant that we analyze the way his body uses factor and what his levels were not only right after he was infused, but also right before we infused him. When we would have a clinic visit, blood would be drawn before we infused his factor to see how much, if any, was left in his system from his last infusion which had been anywhere from 48 to 72 hours before our visit; these are trough or nadir levels. Blood was also drawn one hour after his infusion to see how much factor was circulating in his system at that time; these are called one-hour posts levels. Additional levels are sometimes drawn 24 hours after an infusion to further show how well a patient’s body is responding.

What we learned surprised us. We had been infusing enough factor to raise their levels to between 36 - 40% of correction twice a week. We expected that the one-hour post infusion levels would be right around that same percentage. Unfortunately, the levels were always much lower than that…in the mid-low twenties. By using this information, we established their half-life, or how quickly their bodies used up half of their factor. We thought that we may have to increase Sam’s dose to keep him at about 1% correction at all times. You can imagine our surprise when we received the results of their trough levels; those results indicated that Sam’s levels were staying between 3-7%; not less than 1% as we had surmised.

Had we only relied on the one-hour post infusion studies that were done, we probably would have significantly increased the amount of recombinant factor 9 that we had started out using. Instead, we were able to breath easy knowing that we were maintaining factor levels about 1%. Furthermore, our day-to-day lives showed us that we were doing the right thing. Our boys have stayed on primary prophylaxis infusing twice a week to a level of correction between 35-40% with no break-through bleed. We aren’t using more factor than we need either. For some, this may be vital as they near lifetime insurance caps. Our experience with the current recombinant product on the market has been positive. Because of thorough testing on the part of our HTC, especially in regards to the trough/nadirlevel studies, we know that we’re infusing the amounts that the boys need and at the same time not using moreproduct than we have to.

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Adirondack Spectacular Successful Event

The first annual Adirondack Spintacular, held on Saturday. September 21 was termed “spectacular” by all involved. This event, whose purpose was to raise hemophilia and organ donation awareness, attracted participants from NY, MA, FL, VA and other locales. Proceeds from this event benefited the Lawrence Madeiros Memorial Scholarship Fund, to be awarded to graduating seniors, living with a chronic disorder, continuing their educations at an accredited college or trade school.

Whether they laced up running shoes, filled bike tires with air, or just kicked back in a stroller, participants at the Spintacular were there to cycle, walk or run 6 miles along a scenic route in the Adirondack Mountains and along the Great Sacandaga Lake. Positudes, Inc. and the Center for Donation and Transplant, in Albany, NY were co-sponsors of the event. Following the Spintacular was a family style BBQ and silent auction, along with numerous children’s’ activities including a bounce house and a clown troupe performance.

Spintacular was created in memory of Lawrence Madeiros, to bring people together in a family type setting, to have fun, raise awareness and money for his memorial scholarship fund.

For more information about next years event, please contact Lisa or Carol at Positudes, visit their website at http://www.positudes.org, or call 1-866-POSITUDES (767-4883). ~

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Factor IX Family Meeting
November 1, 2002

PLEASE JOIN US FOROUR 3RD ANNUAL FACTOR IX FAMILY MEETING

Disney’s Coronado Springs Resort
Friday, November 1, 2002
8:15 AM - 9:30 AM
Coronado T Room

Our meetings have been quite successful. We bring families with Factor IX together to share ideas, support each other and discuss important issues. We hope to see you there.

If you have any questions, please call Kim at The Coalition for Hemophilia B, (212) 213-0547.

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Hemophilia B Online Support Group FYI

The hemophilia B email discussion group is online. This group was started by Jill Lathrop, a mother of two boys with hemophilia b.