Skye Peltier’s life changed on a playground when she was 5 years old. After going down a slide, she lingered too long at the bottom. Another child came whizzing down and knocked her forward. Instinctively, Peltier put her hands out to cushion her landing. Instead of avoiding injury, she broke her right arm.
This typical childhood mishap led to a diagnosis of a condition that’s anything but typical. The break in her arm healed, but she still had pain in her elbow. On top of that, she had the seemingly unrelated symptom of blood in her urine. A hematologist put the pieces together and diagnosed Peltier with severe factor VII deficiency (FVII), a rare bleeding disorder formerly known as proconvertin deficiency.
Congenital FVII deficiency was first recognized in 1951, and it is the most common among rare bleeding disorders. An article about factor VII deficiency in a special edition of the journal Haemophilia in November 2008 estimates the incidence at one in 500,000 people. But because of difficulties documenting those with rare bleeding disorders—including mild cases that may never be diagnosed—the exact number of people with the disorder is uncertain.
“It is difficult to know the true incidence,” says Amy Shapiro, MD, medical director of the Indiana Hemophilia & Thrombosis Center in Indianapolis. “It is a similar issue to knowing how many people with mild hemophilia there are.”
Factor VII deficiency is an autosomal recessive disorder, meaning that both parents must carry an abnormal gene for a child to inherit it. Despite its rarity, diagnosis is relatively straightforward. It is based on two tests, prothrombin time (PT) and partial thromboplastin time (PTT). A combination of high PT levels and normal PTT levels point to FVII deficiency, in which case doctors will follow up with FVII-specific tests.
Men and women have an equal chance of inheriting the deficiency, although women tend to show symptoms more often because of such complications as menorrhagia, or heavy menstrual bleeding. That’s one symptom that hit hard for Peltier, now 37, although it isn’t the only one. Once, she poked herself in the mouth with a fork and bled for days. Over the years, she has had surgery to correct bleeds in her elbow and knee. Like many women with FVII deficiency, she has suffered anemia because of her menorrhagia. And at age 30, she underwent endometrial ablation, a procedure that destroys the lining of the uterus and stops menstrual periods. This meant giving up the option of having children, but the improvement in her quality of life made this hard choice the right one for her.
“That’s a lot of things to go through just because your blood doesn’t clot,” Peltier says. She doesn’t wallow in self-pity, though, and quickly adds, “Other people have to deal with worse things.”
Information sharing
Factor VII deficiency ranges from mild to severe and symptoms vary. Peltier was first diagnosed as a result of a joint bleed during childhood, but many severe cases show up during infancy.
Michael Guerrera, MD, director of the Coagulopathy and Bleeding Disorders Program at Children’s National Medical Center in Washington, DC, saw his first severe case of factor VII deficiency in 2005 when a newborn boy started having nosebleeds in the first two weeks of life. The baby faced further issues when he had a central nervous system (CNS) bleed, or bleeding in the brain. Those bleeds can cause devastating effects, including seizures and brain damage.
According to data from the Haemophilia study, conditions such as CNS bleeds and gastrointestinal bleeds are the most frequent symptoms in the first six months of life, and often the triggers for diagnosis. Although they are the most frequent symptoms, they’re still rare enough to come as a surprise to a doctor who hasn’t seen them before. “That first case, because I was new to factor VII deficiency, was kind of shocking,” Guerrera says. “We hadn’t seen a case in our institution in 10 or 15 years.”
Guerrera began treating an infant girl with a CNS bleed and similar symptoms in 2008. He says this case wasn’t as surprising, despite the fact that any one doctor having two such cases is a statistical rarity. Both cases were life-threatening, and he treated the patients with frequent doses of recombinant factor VIIa.
Both infants responded well to this treatment. Bleeding is under control, with no subsequent episodes. But now Guerrera faces uncertainty about the proper time to remove the children from replacement therapy. There isn’t enough literature yet to standardize treatment for FVII deficiency to that degree.
Such uncertainties are common when dealing with FVII deficiency. For example, the Haemophilia study—based on data drawn from the International Registry on Congenital Factor FVII Deficiency (IRF7)—indicates that there isn’t a clear correlation between FVII levels in the blood and bleeding symptoms. People with less than 1% clotting levels in their blood may present no symptoms, while those with more than 5% still may have severe bleeds. And US studies have noted that African-Americans with the deficiency are often asymptomatic, for unknown reasons.
“We don’t fully understand why some people bleed and some don’t,” says Peltier, a physician’s assistant at the Children’s Hospital Hemophilia Center in Minneapolis. “I have no factor VII, so you would think I would have more problems. But I’ve never had a problem with nosebleeds, for example.”
Similarly, a higher frequency of symptoms for women correlates to menorrhagia, but the study authors point out that women also have more minor bleeds, with no clear explanation. Researchers continue to seek answers to these questions, just as practicing hematologists continue to seek best clinical practices.
Guerrera’s approach to research and treatment is both common and appropriate. “You do an extensive review of the literature, come up with a plan and ask experts in the field what they think,” he says. “We do that all the time in medicine.”
Toward Better Treatment
The Haemophilia article summarizes and weighs the treatment options available for factor VII deficiency. Coming to consensus on the best treatment is crucial because, according to the study authors, people with FVII deficiency have a good prognosis and a long life expectancy when they receive treatment.
Fresh frozen plasma and prothrombin complex concentrates were used in the past, but both present a higher risk of potential complications than the presently accepted therapy, recombinant factor VIIa. Only one recombinant factor VIIa, NovoSeven, is available at this time. Pipe, Shapiro and Guerrera all consider it the preferred treatment option, although a standard treatment schedule has yet to be defined—one more reason the IRF7 Study Group proposes future clinical trials.
Although NovoSeven was originally approved by the FDA to treat inhibitors in people with hemophilia A and B, it received approval for treating FVII deficiency in 2005.
Doctors were using NovoSeven for FVII deficiency even before 2005, though. Peltier has kept it handy for the past seven years or so, and it helped control bleeding during knee surgery. Even if she only uses it twice a year, knowing that she has a safety net expands her freedom.
“I’ve taken it with me to South Africa, Israel and other places,” Peltier says. “I haven’t always had to use it, but knowing it’s there makes a difference. If it weren’t for inhibitor patients, it wouldn’t even be available. It’s a windfall for me.”
Peltier’s use of NovoSeven for infrequent bleeding episodes and surgical purposes exemplifies one typical use. Guerrera’s infant patients illustrate another. Although prophylaxis is not a common treatment for factor VII deficiency, it is used in infants with severe deficiency. But there is room for improvement. For example, Guerrera notes that the large vial size of NovoSeven, ideally suited for its original purpose of treating inhibitors, leads to excessive waste—up to 85% of a very expensive vial—when treating an infant.
Although there is more work to be done, Peltier appreciates the fact that she can now live a relatively healthy life. And she’s doing her part to give back to the bleeding disorders community through her profession.
“I feel like I can use my personal experience in understanding patients and where they’re coming from,” she says. “I’ve found the spot where I’m supposed to be.”
Researchers, clinicians and advocates will continue to work so that others with factor VII deficiency can find a similar peace of mind.
Rare Registries
When seeking to understand rare bleeding disorders—those affecting relatively small numbers of people scattered throughout the world—the first goal is simple.
“We have to get our hands around how many patients there are and what problems they experience,” says Amy Shapiro, MD, medical director of the Indiana Hemophilia & Thrombosis Center in Indianapolis. Shapiro takes part in the National Hemophilia Foundation’s Medical and Scientific Advisory Council’s (MASAC’s) efforts to centralize and enhance resources for rare bleeding disorders.
As part of those efforts, Shapiro and Donna DiMichele, MD, co-chair the Rare Bleeding and Clotting Disorder Universal Data Collection Working Group. They work with the Centers for Disease Control and Prevention to develop data-gathering tools. A 10-year study called the Universal Data Collection (UDC) project has focused on creating a database of information about people with hemophilia A and B, and von Willebrand disease. Now, a UDC rare disorder working group is modifying that system to include information about people who have rare bleeding disorders.
A similar international effort, led by Flora Peyvandi, MD, associate professor of internal medicine at the University of Milan and the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, is well under way. The Rare Bleeding Disorders Database project has collected information on more than 400 people from around the world since 1996. The goals are to better identify people with rare bleeding disorders, to define the symptoms and presentations of those disorders, to create a network of the clinicians who care for them so they can better share expertise, and to work together to create clinical trials using shared resources.
The UDC project shares the same long-term goals, and Shapiro says everyone involved hopes to harmonize the US-based system and the international database in the future for an even more effective network of data-sharing.
The Resource Room
The National Hemophilia Foundation’s (NHF’s) Medical and Scientific Advisory Council (MASAC) wants to make the search for answers easier for doctors such as Michael Guerrera, MD, director of the Coagulopathy and Bleeding Disorders Program at Children’s National Medical Center in Washington, DC. MASAC is committed to ensuring that resources are accessible to both clinicians and consumers. The November 2008 special edition of Haemophilia, which contains articles about many rare bleeding disorders, is one manifestation of these efforts.
“We needed one-stop shopping to find information about these disorders: their clinical presentation, the scope of problems that patients experience, the pathophysiology and the scope of present research,” says Amy Shapiro, MD, medical director of the Indiana Hemophilia & Thrombosis Center in Indianapolis. She is the MASAC member who led this initiative.
Shapiro’s work with plasminogen deficiency, an extremely rare disorder, got her thinking. She realized that the people she treated needed advocates who could not only make their plight visible, but also push for improved access to treatment options, virtually nonexistent for many of the rarest disorders. She also realized that doctors would benefit from a centralized research database (see sidebar, “Rare Registries”).
In 2004, MASAC passed Recommendation #174, underscoring these issues and emphasizing the need to identify ways to move forward. The next year, an informal MASAC task force assisted the US Food and Drug Administration (FDA) with a workshop to address many relevant issues, including pharmaceutical and patient-care perspectives. The overall goal, Shapiro says, was and is to identify avenues to overcome issues such as the cost of research and development, the difficulty in data collection for rare disorders, and the relative lack of financial incentive for pharmaceutical companies.
“The FDA is presently far more sensitive to these issues,” Shapiro says. “It is willing to work with companies to determine what is a reasonable study to provide the data the FDA requires.”
The Haemophilia special edition also flourished because of MASAC’s work. It’s a veritable resource room for clinicians and people with rare disorders. Experts spread across the world representing varied disorders present the most current and useful information available on FVII deficiency and other disorders.
Shapiro notes that the publisher of Haemophilia, Wiley-Blackwell, permitted both NHF and the World Federation of Hemophilia to publish the special edition online. Such open sharing is unusual, but everyone involved recognized the importance of making these resources accessible to as many people as possible.
“It’s just as likely that a clinician in a small town in India will encounter a rare bleeding disorder as for me to encounter one,” says Steven Pipe, MD, MASAC member and associate professor of pediatrics at the University of Michigan in Ann Arbor. “Having these resources available to clinicians everywhere is really important.”
Both Pipe and Shapiro submitted data about people with FVII deficiency to the IRF7 registry, the source of data for the group’s study, as did doctors around the world. The group collected the data and presented a current understanding of the genetics, diagnosis and treatment of FVII deficiency, but ambitions aim even higher. The next step, as laid out in the Haemophilia article, is to coordinate an international study that focuses on treatment options.
“This is the norm when you’re talking about rare bleeding disorders,” Pipe says. “It takes not just multi-institution collaboration, but even multinational cooperation to really make some inroads in research investigation.”