By KAREN BARROW

Published: January 30, 2012

Hemophilia, which affects 20,000 Americans, is a genetic disorder in which the body lacks a clotting factor needed for blood to coagulate. Depending on severity, it can lead to life-threatening, seemingly unprovoked bleeding episodes — or it can go undetected for years, until a serious injury or a routine medical procedure suddenly touches off uncontrolled bleeding.

Hemophilia is more common in boys and men. But some girls and women have the disorder, and it can cause complications during menstruation and childbirth.Hemophilia (actually a group of disorders, marked by different missing blood factors) has no cure. But treatment has improved substantially in recent years. Today many bleeding episodes are prevented by prophylactic injections of the missing factor; until this treatment was developed, patients had to rely on transfusions after a bleeding episode, leaving them vulnerable to infectious diseases and chronic joint damage.

At nytimes.com/health, five people living with hemophilia talk about how the condition affects their lives. Here are three.

Danielle Schwager, 24

Cleveland

We had a family history of hemophilia, as my mother’s father was a hemophiliac. So my mom knew that if she had boys, hemophilia would be an issue. Well, she had twin girls and thought, “If anything, they are carriers, just like me.”

When we were growing up, I was always bruised. But it wasn’t until I had my teeth pulled at the age of 11, and I bled for 10 days afterward, that I was diagnosed with hemophilia B.

I injured my shoulder my sophomore year of college, and now that’s a joint that I’m going to have to be very careful with the rest of my life. It’s a matter of being more aware of the activities that I do. It doesn’t mean I don’t do those activities; I just need to be a little more cautious than the average person.

Val Bias, 53

Manhattan

The hemophilia community has a unique relationship with the nation’s blood supply. Early on, the products used to control our bleeding disorder were plasma-based. So we have been exposed to over the years to hepatitis B in the ’70s, H.I.V. in the ’80s and hepatitis C in the ’90s.

We like to call it the “alphabet soup,” and I have it all. I have H.I.V. I have hepatitis C. I was infected by hepatitis B as a child and cleared it. And all the complications of living with H.I.V. and hepatitis C, I suffer from.

Today’s blood supply is much safer, and maybe safer than it’s ever been in the history of mankind.

When you belong to a disease group that is as small as hemophilia, it’s best that you provide some example that you exist, and that you’re living a full life.

Kimberly Martin, 43

Houston

I’m from Texas, and I guess that I thought — as every mom might from down here in the South — that my sons are going to play football and be strong, virile young men. And it really scared me. I didn’t know if my son Scott would live. I didn’t know what his life would be like. My first thought was that it sure wouldn’t be normal, and the idyllic life that I thought that I would have was shattered.

My job as his mother is to teach him how to take care of himself. And his being able to be confident and have enough courage to face this head-on at such a young age — I know that we’re moving in the right direction.

A version of this quote appeared in print on January 31, 2012, on page D6 of the New York edition with the headline: Changed, but Not Defined, by Hemophilia.

ArticleTo the Editor:
Patients with hemophilia A (a deficiency of factor VIII [FVIII]) have spontaneous bleeding because of abnormal thrombin generation, which results in the formation of weak, unstable clots.1 The formation of these weak clots is also the result of delayed and reduced activation of coagulation factor XIII (FXIII).2 The standard treatment is based on FVIII substitution to control and prevent bleeding, but this process is expensive and time-consuming. We hypothesized that supraphysiologic levels of FXIII would normalize clot stability at low levels of FVIII.

Clot stability was recorded by means of the changes in plasma turbidity after the simultaneous addition of tissue factor (dilution, 1:40,000) and tissue plasminogen activator (0.75 nM). FVIII-deficient, platelet-poor plasma, spiked with increasing concentrations of recombinant FVIII plus plasma-derived FXIII or buffer, was compared with normal control plasma. The primary end point was the area under the curve (AUC) for turbidity.

The addition of FVIII improved the AUC (Mann–Whitney test, P<0.005), but the maximum concentration (1 IU per milliliter, 100% of normal levels) failed to normalize clot stability (Figure 1AFigure 1
Clot Stability and Thrombin Generation with Increasing Concentrations of Factors VIII and XIII.). Normal clot stability was achieved at very low concentrations of FVIII in the presence of supraphysiologic levels of FXIII (10 μg per milliliter equals a 50% increase in plasma levels, which should be achievable through intravenous infusion of 25 IU per kilogram of body weight) (Figure 1A).

Calibrated automated thrombin generation (at 1 pM of tissue factor) was measured after the addition of recombinant FVIII, with and without plasma-derived FXIII (pdFXIII). The speed and quantity of thrombin generation was not altered by the addition of pdFXIII (Mann–Whitney test, P>0.1 for all comparisons) (Figure 1B and 1C).

We have shown that clot stability in patients with hemophilia A can be normalized with the addition of pdFXIII, even at very low levels of FVIII. Data suggest that pdFXIII may correct the imbalance between fibrin formation and FXIII activation in the blood of persons with hemophilia.2 The Km of thrombin-dependent FXIII activation is higher3 than the plasma concentration of FXIII. Hence, the rate of FXIII activation by thrombin should increase if the plasma concentration of FXIII is increased.

These observations suggest that FXIII therapy may be useful as an adjunct in factor-sparing and cost-effective regimens. Because FXIII has a half-life of 9 days,4 dosing would be infrequent, improving convenience and limiting expense. Since FXIII fully corrects plasma clot stability at low concentrations of FVIII, it could be useful in the treatment of bleeding events or in supporting hemostasis during surgery in patients with nonsevere hemophilia. Finally, adjunct FXIII may prove helpful when used in combination with new long-acting FVIII concentrates as a bridging therapy, when FVIII levels are low between doses.

Catherine J. Rea, M.B., B.Chir.
King’s College London, London, United Kingdom

Jonathan H. Foley, Ph.D.
University of Vermont, Burlington, VT

Benny Sørensen, M.D., Ph.D.
St. Thomas’ Hospital, London, United Kingdom

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

4 References
1
Blomback B, Carlsson K, Fatah K, Hessel B, Procyk R. Fibrin in human plasma: gel architectures governed by rate and nature of fibrinogen activation. Thromb Res 1994;75:521-538
CrossRef | Web of Science | Medline
.2
Brummel-Ziedins KE, Branda RF, Butenas S, Mann KG. Discordant fibrin formation in hemophilia. J Thromb Haemost 2009;7:825-832
CrossRef | Web of Science | Medline
.3
Naski MC, Lorand L, Shafer JA. Characterization of the kinetic pathway for fibrin promotion of alpha-thrombin-catalyzed activation of plasma factor XIII. Biochemistry 1991;30:934-941
CrossRef | Web of Science | Medline
.4
Visich JE, Zuckerman LA, Butine MD, et al. Safety and pharmacokinetics of recombinant factor XIII in healthy volunteers: a randomized, placebo-controlled, double-blind, multi-dose study. Thromb Haemost 2005;94:802-807
Web of Science | Medline
.

Symptoms improved significantly in adults with the bleeding disorder haemophilia B following a single treatment with gene therapy developed by researchers at St. Jude Children’s Research Hospital in Memphis, US and demonstrated to be safe in a clinical trial conducted by UCL.

The findings of the six-person study mark the first proof that gene therapy can reduce disabling, painful bleeding episodes in patients with the inherited blood disorder. Results of the Phase I study appear online ahead of print today in the New England Journal of Medicine. The research is also scheduled to be presented on 11 December at the 53rd annual meeting of the American Society of Hematology in San Diego, US.

Four study participants stopped receiving protein injections to prevent bleeding episodes after undergoing the therapy and have not suffered spontaneous bleeding. Several have also participated in marathons and other activities that would have been difficult prior to gene therapy. The study participants were all treated at the Royal Free Hospital in London under the care of Professor Edward Tuddenham, a pioneer in the field of blood coagulation and a study co-author.

“This is a potentially life-changing treatment for patients with this disease and an important milestone for the field of gene therapy. It could have ramifications for the treatment of haemophilia A, other protein and liver disorders and chronic diseases such as cystic fibrosis,” said first author Dr Amit Nathwani, UCL Cancer Institute, Royal Free Hospital, University College Hospital (UCH) and NHS Blood and Transplant (NHSBT).

Haemophilia B is caused by an inherited mistake in the gene for making a protein called Factor IX, which is essential for normal blood clotting. The gene is carried on the X chromosome. As a result, haemophilia B is almost exclusively a disease of men. About 1 in 30,000 individuals inherit the mutation.

Previous efforts to ease haemophilia B symptoms by introducing a correct copy of the gene have been unsuccessful.

This is a potentially life-changing treatment for patients with this disease and an important milestone for the field of gene therapy

Dr Amit Nathwani

The current study used adeno-associated virus (AAV) 8 to deliver the Factor IX gene along with additional genetic material into the patient’s liver. AAV8 was picked because the incidence of natural infection with AAV8 is low. It belongs to a family of viruses that target liver cells, but do not cause disease in humans or integrate into human DNA. Participants in this study received no immune suppressing drugs prior to gene therapy. This approach was jointly pioneered by St. Jude and UCL, initially in the laboratory of study co-author Professor Arthur Nienhuis a member of the St. Jude Department of Hematology.

For this study, each patient received a one-time infusion of the vector into a vein in the arm. Two patients each were treated with escalating doses of the vector. Following treatment, Factor IX levels rose in all six patients from less than 1% of normal levels prior to the gene therapy to between 2 and 12%.

Factor IX levels increased the most in the two study volunteers who received the highest dose of the experimental vector, researchers said. After treatment, levels of the protein ranged from 3 to 12% in those men. Even modest increases that raise Factor IX production to more than 1% of normal levels has the potential to dramatically affect a patient’s quality of life and reduce bleeding episodes, said the study’s senior author Dr Andrew Davidoff, chair of the St. Jude Department of Surgery.

“The first patient has been followed for the longest time, and his levels have remained at 2% for more than 18 months. These results are highly encouraging and support continued research. More patients are scheduled to be enrolled in future trials scheduled to begin later this year,” Davidoff said.

One of the participants who received the highest dose of the vector underwent successful, short-term steroid treatment after his liver enzymes rose slightly after the vector infusion. The rise signalled mild liver damage. The volunteer remained otherwise healthy, his Factor IX levels remain above pre-infusion levels and his liver enzymes have returned to normal. Liver enzymes also rose slightly, but remained in the normal range, for the other participant who received the highest dose of the vector. The participant also received a short course of steroids.

Researchers believe an immune response targeting the vector triggered the elevated enzyme levels. A similar response was reported in earlier gene therapy trials conducted by other investigators using a different vector.

The vector used in this study was produced at the Good Manufacturing Practices (GMP) facility on the St. Jude campus. The GMP operates under government-approved manufacturing guidelines and produces highly specialized medicines, vaccines and other products that pharmaceutical companies are reluctant to pursue. The vector can also now be produced in a similar facility at UCL.

The research was funded in part by The Katharine Dormandy Trust, Medical Research Council, Wellcome Trust, NHS Blood and Transplant and the UCLH/UCL National Institute for Health Research Biomedical Research Centre, all in the UK. In the US, the research was funded by the National Institutes of Health, the Assisi Foundation of Memphis and ALSAC.

Baxter Healthcare Corporation has sent a notice of a labeling error affecting the expiration date of the Sterile Water for Injection that is packaged as a diluent with RECOMBINATE [Antihemophilic Factor (Recombinant)]. The Sterile Water for Injection label indicates that the shelf life is longer than what was actually approved by the FDA.

Please continue to use the RECOMBINATE product as labeled on the kit. There is no impact to the safety or efficacy of Recombinate if the Sterile Water for Injection diluent is used before the expiration date of the RECOMBINATE.

The following are the NDC and Lot numbers of the Sterile Water for Injection vials:

NDC Number
Lot Number
Size
Expiration Date

0944284210
TRA11802AC
10 mL
01-23-2014

0944284410
TRA11810AC
10 mL
03-22-2014

0944284410
TRA11803AC
10 mL
01-25-2014

0944284410
TRA11803AD
10 mL
01-25-2014

0944284410
TRA11810AA
10 mL
03-22-2014

0944284510
TRA11805AA
10 mL
02-01-2014

0944284510
TRA11805AB
10 mL
02-01-2014

0944284510
TRA11805AC
10 mL
02-01-2014

0944284510
TRA11819AA
10 mL
06-20-2014

0944284310
TRA11808AC
10 mL
02-23-2014

0944284310
TRA11816AA
10 mL
05-18-2014

0944284310
TRB11820AA
10 mL
07-14-2014

0944284310
TRA11806AC
10 mL
02-07-2014

If you have any questions, please call Stericycle, Inc. at 1-888-UPDATE-U.

PHYSICIANS: Please distribute this information to all providers in your area who treat patients with hemophilia.

CHAPTERS: Please distribute this information to your membership.

Please sign up for the Patient Notification System (PNS) to be notified directly about the latest recall or withdrawal of recombinant and plasma products. The system is confidential and time sensitive. It is administered by an independent third-party organization and is free of charge. To enroll in the PNS, please go online at http://www.patientnotificationsystem.org/ or else call (888) UPDATE-U.

By Elizabeth Thompson Beckley | 06.24.2010
Originally Published January 2007 | Updated June 2010

Hopping a plane can be stressful nowadays, as you deal with long check-in lines, baggage fees and enhanced security. But for people with hemophilia and other bleeding disorders, the biggest concern is often how to transport their factor products and supplies safely to their destination. Here’s what you need to know about traveling with medication.

After the discovery of a 2006 London terrorist plot involving liquid explosives, airlines limited the amount of liquids, aerosols and gels travelers can carry on board airplanes. This regulation particularly affects passengers who need to keep medical supplies with them. This includes clotting factor products, needles, syringes and other supplies required for treatment of bleeding disorders. Being prepared with complete information about your medications, and packing them properly, will go a long way toward smoothing the security screening process.

Medical Exceptions
The Transportation Security Administration (TSA) has implemented the 3-1-1 rule. This means each traveler is allowed to carry travel-sized toiletries—each in three-ounce or smaller containers—that fit in one quart-sized, clear plastic, zip-top bag through security checkpoints. After passing through security screening, passengers may purchase and carry on drinks and other items in the secure boarding area.

Exceptions to the ban include appropriately labeled prescription medicines, baby formula and breast milk (if traveling with a baby or toddler), up to five ounces of diabetes glucose treatment (including juice), and up to four ounces of essential nonprescription medications. The TSA requires that prescribed medications have a professionally made label identifying what they contain. The label must match the name on the passenger’s ticket, according to TSA spokeswoman Amy Kudwa.

“Several variables would affect what people with a bleeding disorder might take on a flight,” says Paul Clement, a high school science teacher in Southern California who has a son with severe hemophilia A. Clement is an active member of the bleeding disorders community and contributes to the Parent Empowerment Newsletter published by LA Kelley Communications, Inc.

What to Pack in Your Carry-On
When deciding what to pack in a carry-on bag, you should consider:
The type and severity of the bleeding disorder
The climate in the departure and arrival cities
The type of bleeds the person with the bleeding disorder typically experiences
The length of time you will be away from home
Your destination (Will you be in a developed or developing country? Is there is a hemophilia treatment center [HTC] nearby?)
Your accommodations (hotel, motel, youth hostel, cabin or campsite)
It can be helpful to also anticipate flight delays or missed flights and to pack accordingly. According to Clement, most people with severe hemophilia A or B should carry:

Factor concentrate (a lyophilized powder in a small bottle) in original box packaging
Diluent (sterile water to reconstitute the powdered factor). For most factor products, the diluent volume varies from 2.5 ml to 10 ml (10 ml is one-third of a fluid ounce)
A reconstitution device or transfer needle and filter needle, plus a butterfly needle (for infusion of factor), for each dose of factor
Syringes
Alcohol swipes
Sharps container
People who have children with ports will also need to pack disinfectants to be used prior to infusions and sterile saline and/or heparin for flushing the port after an infusion. Some use EMLA cream on children prior to infusions.

Travelers with inhibitors and those with HIV, hepatitis C or other conditions will need to pack additional medications and supplies. Medications may be easier to carry onboard than items such as gel ice packs to treat minor internal bleeds or refreezable cooling devices to store medications at appropriate temperatures.

Keeping Factor Products Safe
Most factor products can be stored at temperatures up to 77–86 degrees Fahrenheit for approximately three months, so gel or ice packs may not be necessary. Each product has different requirements, however, so check the product manufacturer’s Web site under “Prescribing Information.” Once you remove factor from the refrigerator, do not refrigerate it again later. Gel packs can be slipped into checked baggage prior to checking it. Factor and diluent can be refrigerated before packing and then packed into a small, insulated travel kit specially designed for factor transport (ice may not be necessary).

Factor products should never be packed in checked luggage, because wide temperature fluctuations may affect the potency of the factor, rough handling may break the glass containers and your luggage could be delayed or lost. A homecare company or specialty pharmacy may be able to deliver the product to your destination, but your HTC probably won’t mail it to you. If you’re thinking of mailing it to yourself, check with the Postal Service about restrictions.

Negotiating Questionable Items
“It’s very difficult to anticipate all eventualities when we make the prohibited item list,” Kudwa says. “We try to make common-sense decisions for passengers who have medical conditions.”

The conversation about questionable items “will be had at a checkpoint with a security officer,” she continues. “Supporting information and documentation would help in that process.”

The National Hemophilia Foundation (NHF) advises that when traveling with clotting factor, passengers should bring a prescription from their doctor that includes contact information, and a travel letter from the doctor or HTC with a brief description of their condition and the need for the medication.

“Always make sure all your products are together in a separate carry-on bag so they can go through all of your materials at once,” suggests Neil Frick, NHF vice president for research and medical information. “It just makes it simpler for them to go through the letter to see what you actually need to treat yourself.” If traveling overseas, especially a developing country, it is advisable to have your travel letter translated into the local language. Don’t assume customs agents in all countries read English. Consider carrying a flash drive with the contact information and maps of HTCs or hospitals in the countries you will be visiting, along with digital copies of your travel letter, prescriptions, health insurance information and any other pertinent medical records. Saving the files in rich text format (RTF) allows them to be opened by a wide range of word processing programs.

You can request that TSA officers visually inspect your medication and supplies instead of putting them through the X-ray. Frick also recommends that you talk to your HTC about what you should do when traveling. “There may be specific treatment issues, in terms of inhibitors or adjusting prophylactic schedules to different time zones, or in case there is an emergency,” he says. “Also, you always want to have your medical alert bracelet or ID with you.”

After you’ve worked out your travel plans with your HTC, make sure treatment is available at your final destination. Be sure to bring enough product for the time you’re going to be gone, Frick says. Remember to bring your insurance card. Before you leave, make sure your insurance covers you in the state or country where you’ll be traveling. If traveling overseas, check that your insurance covers medical evacuation in case of an emergency.

TSA security officers may not recognize that a passenger has a bleeding disorder or other “invisible” medical condition. According to the TSA Web site, “you can, but are not required, to tell the security officer if you have a medical condition or special situation which requires extra care, sensitivity or special treatment.” For example, in case you had a joint bleed or recent surgery, if you undergo a personal search, inform the officer that you are in pain and explain the areas that will require greater care. The officer should avoid touching the wand on sensitive areas and use light pressure when inspecting them.

“The best advice to travelers with medical conditions is to be prepared,” Kudwa says. “TSA and the airlines do an excellent job of keeping their Web sites up to date. There are toll-free customer contact numbers for TSA and just about every airline.”

Frick also recommends checking with your airline two days before your trip for its specific regulations.

Tips on Preparing for Security Screening
Sample Travel Letter

Notify your airline or travel agent in advance if you need assistance at the airport. TSA can only help with the screening process; your airline will help you through the airport facility and the screening line.
The limit of one carry-on and one personal item (purse, briefcase or computer case) does not apply to medical supplies, equipment, mobility aids or assistive devices.
Pack your medications in a separate pouch or bag to simplify the inspection process. Don’t fill medication containers too full, and make sure that all your medications are clearly identified. If you have medications you don’t want exposed to X-rays, don’t pack them in your checked baggage. Instead, send larger quantities of medications to your destination by mail.
If you have medical documentation about your medical condition or disability, present it to the security officer. TSA does not require this documentation, and it will not exempt you from the security screening process.
Make sure to have an ID tag on all carry-on items, equipment, mobility aids and devices.
For concerns about potential civil rights violations, you can contact TSA’s Office of Civil Rights: 877.336.4872.
Source: TSA

Learn More
For Transportation Security Administration updates on security measures specific to travelers with disabilities and medical conditions, visit tsa.gov or call 866.289.9673.
For air travel recommendations specific to the bleeding disorders community, check NHF’s Web site: hemophilia.org.
Visit the World Federation of Hemophilia Global Treatment Center Directory, which also has tips and sample letters for travelers, at wfh.org. Click on “Resources,” then “Passport.”