When Emily Bartko, 4, of Las Vegas, was an infant, bruising came easily. All it took was the pressure from a car seatbelt or her parents’ hands as they picked her up to leave telltale marks. When Emily learned to crawl, her knees and palms were constantly black and blue. Once she started walking, those bruises shifted to her feet.
Emily has factor I deficiency, also known as fibrinogen deficiency, a rare bleeding disorder that affects an estimated one or two people in a million. Like 85% of people with this disorder, afibrinogenemia, her umbilical cord would not stop bleeding at birth. That was the first symptom. It led to others: bruising, a severe bleed in her knee and the flulike fatigue that goes along with chronic pain and discomfort.
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“She would be on the sidelines, wanting to do things but not having the energy,” says Emily’s mother, Alison. Emily wanted to be like her big sister, Abigail, 6, but that was a challenge. At the time, Emily couldn’t go down a three-foot plastic slide in the backyard without fear of a blackened backside from bruising.
Limited Treatment Options
When Emily was diagnosed, the only available treatment was cryoprecipitate, a frozen product that is derived from plasma and is rich in coagulation factors. Her parents are pharmacists and were concerned about the dangers of transmission of disease-causing viruses. Because cryoprecipitate doesn’t undergo the same viral inactivation processes as modern factor concentrates, it carries a risk of infection. And because cryoprecipitate is not concentrated, infusions take much longer—hours, in some cases—and require much larger doses.
Things changed for the Bartkos, though, when they petitioned for and received “compassionate use” approval from the US Food and Drug Administration (FDA) to treat Emily with a factor I concentrate. At the time, it was available in other countries but was not approved for use in the US. Emily received her first infusion when she was 2 years old.
“The change in her after the first infusion was phenomenal,” Alison says. “She must have been so uncomfortable and in so much pain before, because within the first 24 hours of the infusion, she was like a different child, running and playing.”
With biweekly treatments, Emily started to keep up more with her big sister. Without the swelling in her feet, she was able to wear tap or ballet shoes for dance classes. She even got her ears pierced on her third birthday.
The Bartkos had overcome a problem people with rare bleeding disorders often face—the lack of up-to-date treatment. Factor concentrate products for such small numbers of patients typically take years to develop and market in the US. In this case, though, factor I concentrates were already available in Europe and Japan. Seeing how much it helped her daughter, Alison appeared before an FDA advisory board to advocate for product approval in the US. With the board’s recommendation, factor I product was approved in January 2009, under the name RiaSTAP.
“This type of patient needs a fair shot to be treated the way other patients are, with access to factor products,” Alison says.
One Name, Three Bleeding Disorders
Factor I, or fibrinogen, is a protein that helps form the “glue” as part of the clotting process. It also plays a role in breaking down clots. Factor I deficiency actually refers to three different fibrinogen deficiencies that affect both men and women, says Suchitra Acharya, MD, associate professor of pediatrics in the Division of Pediatric Hematology and Oncology at Schneider Children’s Hospital in New Hyde Park, New York.
Patients with afibrinogenemia, like Emily, lack fibrinogen or have minute quantities of it. Afibrinogenemia usually is discovered at birth with umbilical cord bleeding. Bleeds can also occur in the skin, gastrointestinal tract, genitourinary tract and, less frequently, the central nervous system. Women with afibrinogenemia often experience heavy bleeding during menstruation (menorrhagia) and difficulty conceiving or carrying a pregnancy to term because fibrinogen plays a role in the implantation of the embryo. Afibrinogenemia is an autosomal recessive disorder, meaning that both parents must carry it to pass it on to a child.
Like afibrinogenemia, hypofibrinogenemia is considered a quantitative disorder because people with it have low levels of the protein. They may have symptoms in infancy, too, but many don’t discover the disorder until after a trauma or during a surgery later in life. Hypofibrinogenemia can be either autosomal recessive or autosomal dominant, in which case only one parent is a carrier.
The third type, dysfibrinogenemia, is considered a qualitative disorder. Patients have a normal level of fibrinogen in the blood, but it does not function properly. The disorder is predominantly autosomal dominant.
“This molecule is so interesting because you can have problems associated with bleeding and you can have the opposite: problems associated with clotting,” Acharya says.
She and colleagues published an overview paper, “Rare Inherited Disorders of Fibrinogen,” in a special 2008 issue of the journal Haemophilia, a “resource room” about bleeding disorders available on the National Hemophilia Foundation’s website. This paper and others represent a push for researchers to better understand rare bleeding disorders to improve treatment. (Also see “The Resource Room” sidebar, HemAware May/June 2009.)
In the paper, Acharya discussed the state of research into fibrinogen disorders. Interestingly, she notes, with afibrinogenemia and hypofibrinogenemia, there isn’t a strong correlation between genetic mutations and specific symptoms. With dysfibrinogenemia, however, specific mutations have been associated with bleeding symptoms, clotting symptoms and both. Why these discrepancies occur is one of many mysteries researchers are working to understand.
The prevalence of these disorders is another mystery. Rare bleeding disorders registries in Italy, Iran, the United Kingdom (UK) and the US have tracked numbers in those countries, but concrete worldwide estimates are tough to gather. The numbers in Iran, for example, are much higher than in the Western world, most likely because of the role consanguinity, or common ancestry, plays in inherited disorders. In Iran, the numbers for fibrinogen deficiencies are closer to those for hemophilia than to the much smaller numbers for fibrinogen deficiencies in the UK and US.
Acharya says that an International Rare Bleeding Disorder Registry, a collaborative effort from European countries, the US and other countries willing to participate, is in the works. It will provide doctors and researchers a more complete picture of fibrinogen deficiency. “Hopefully at some point, when we merge these international registry data,” she says, “we may be able to estimate the true prevalence of these disorders.” (See “Rare Registries” sidebar, HemAware May/June 2009.)
Unexplained Bleeding and Bruising
Sue Fletcher of Chapel Hill, North Carolina, has a combination of hypofibrinogenemia and dysfibrinogenemia. “I don’t have enough of the protein,” she says. “And what I have doesn’t work properly. So I bleed, and I clot.”
Since being diagnosed in 2008, Fletcher, now 54, has become active in the bleeding disorders community and educated about her own condition. But she spent most of her life in the dark about her disorder.
Like Emily, Fletcher experienced bleeding and bruising as child. After a procedure on her arm as a teen, she had such severe swelling and bruising that her doctors were befuddled. At the same time she had heavy, irregular periods.
Fletcher had such difficult childbirths with excessive bleeding that she was bedridden for long periods. And through it all, she didn’t know she had a bleeding disorder. Neither did her doctors.
“They just say, ‘hey this happens to some women during childbirth,’” Fletcher says. “Now, I wish I had pushed harder for answers.”
In 2006, after being diagnosed with breast cancer, Fletcher had a double mastectomy. But her troubles didn’t end there. “Those darn wounds would not heal,” Fletcher says. “They did multiple surgeries. Now, looking back, it’s just exasperating. I had some kind of wound in my chest for 11 months.”
Finally, in 2008, Fletcher’s new hematologist, Alice Ma, MD, associate professor of medicine at the University of North Carolina, Chapel Hill, diagnosed her with hypodysfibrinogenemia. She offered Fletcher a little bit of relief and self-realization. I could go back all the way to my swollen knee when I was a kid, and it all made sense,” Fletcher says.
Motivated to Help
Fletcher’s diagnosis also means that now, if she has to have surgery, she can be treated with cryoprecipitate and avoid so many of the frustrations in her past. However, because of the “dys” part of her disorder, she is not able to take the current factor concentrate.
RiaSTAP is not licensed for treating dysfibrinogenemia because of the increased risk of thrombosis, or blood clots. While it can be used to treat dysfibrinogenemia off-label, it must be done with caution and the physician should look closely for problems such as excessive clotting. The treatment has also caused blood clots, though to a lesser extent, in people with other forms of fibrinogen deficiency. Acharya believes the benefits of the improved treatment seem to outweigh those issues. The goal now, she says, is to figure out the best way to balance the thrombotic risk, possibly by complementing infusions with anticoagulants.
“These people need these products, but if we know they can cause thrombosis, we need to do something more to help patients,” Acharya says.
Helping other people with rare bleeding disorders that are often overlooked can motivate people within the bleeding disorders community. It’s what drove Alison to travel across the country to let decision-makers in the FDA see firsthand what treatment had done for her daughter, Emily. And it’s what drives Fletcher to be an advocate, in the hopes that future patients won’t have to go through what she went through.“I know things could have been different,” Fletcher says. “That’s why I want to be involved in the community.”