Blame it on the Girl Scout cookie. That’s what Josh Beck, 27, of Franklin, Wisconsin, was eating when he was 14 years old and started hemorrhaging from the back of his throat. A week earlier he had undergone a routine tonsillectomy and adenoidectomy—his first surgery. “Everybody told me, ‘It’s a piece of cake, they do this type of surgery every day,’” he recalls. But his experience was far from a cakewalk. “During the 45-minute drive to the ER, I filled up half of a small garbage can with blood. I thought I was going to die,” Beck says.
Once at the hospital, the staff tried several different ways to stop the bleeding. Finally, the doctor soaked a cotton ball with an anticoagulant and placed it in the back of Beck’s throat, where his adenoids had been. Within 15 minutes the bleeding stopped. “Nobody was talking about a bleeding disorder at that point,” says Beck. “They thought I had choked on the Girl Scout cookie and it had caused the clots to become dislodged.”
The next day, Beck went through a battery of tests. The ear, nose and throat doctor who had performed the surgery told Beck he had von Willebrand disease (VWD). It wasn’t until the following year when Beck went to Children’s Hospital of Wisconsin in Milwaukee for further testing that his real diagnosis was revealed—factor XI deficiency (FXI), also known as hemophilia C.
“I had absolutely no idea I had any type of bleeding disorder until I was in 8th grade,” says Beck, who now teaches English at Cudahy High School. Most people with factor XI deficiency have such mild symptoms or (none at all) that, like Beck, they often go undiagnosed or are misdiagnosed. Typically, symptoms do not appear until after surgery, trauma or, in women, the onset of menstruation.
FXI deficiency is considered a rare bleeding disorder. Estimates of its prevalence range from 1 in 100,000 to 1 in 1 million. Among Ashkenazi Jews, however, the disorder affects approximately 8% of the population.
Having a rare bleeding disorder such as FXI deficiency can be a challenge. So few patients have it in the US that many providers and even some hematologists have little or no exposure to it. Beck is the only FXI patient his hematologist sees. He ends up sharing resources on his disorder with people who need to know—his doctors, school staff, family and friends. “Whether it was my mom when I was younger, or me once I was older, we’ve all had to educate others,” Beck says.
Factor XI’s Function
Factor XI is a clotting protein that participates in clot formation and indirectly prevents its breakdown. In patients with hemophilia A (factor VIII deficiency) or hemophilia B (factor IX deficiency), the severity of bleeding is directly related to the level of the factor in the blood. Unlike factor VIII and IX deficiencies, the level of factor XI in the blood doesn’t necessarily correlate with its bleeding severity in the patient. “What is characteristic of factor XI deficiency is that you can have a severe factor XI deficiency with a level of less than 1% and be asymptomatic,” says Ann Hurlet-Jensen, MD, associate professor, pediatric hematology-oncology, Mount Sinai School of Medicine in New York. “On the other hand, you can have a level in the 30% to 40% range and have bleeding.”
A Quirky Mutation
Since FXI is not linked to the X chromosome, men and women have an equal chance of inheriting it from their carrier parents. “Factor XI deficiency is considered autosomal recessive, which means that unlike factor VIII or IX deficiency, you have to inherit it from both your parents,” says Constance Gibb, MS, genetic counselor, pediatric hematology and oncology at the Weill Cornell Medical Center in New York. Gibb acknowledges a few published reports citing instances of autosomal dominance, where only one mutation causes the severe form of the disorder, but says those incidences are few.
Due to the quirky nature of the genetic mutation, symptoms can vary within a family. “There is variable expressivity and reduced penetrance,” says Gibb. “One family member with the same mutation as another family member may have different bleeding symptoms or no symptoms at all. There is no predicting.” Prasad Mathew, MD, director of the Ted R. Montoya Hemophilia Center at the University of New Mexico in Albuquerque, sees a teenager at the hemophilia treatment center (HTC) who has severe FXI deficiency. “She’s just started her menstrual cycle and it’s a little heavy for her. Her father, who also has severe FXI deficiency, rarely has a bleed, but the daughter has frequent nose bleeds.”
Gibb meets with individuals and families to discuss the disorder and recommend tests. “Once they think about it and talk about it, the patients do not ask for prenatal diagnosis,” Gibb says. But several have requested genetic testing to determine the specific mutation—typically type II or type III for Ashkenazi Jews—and a panel of other mutations for non-Jewish populations. “While there is variability, it is usually not life-threatening,” she says.
Diagnosing the Disease
“When we see a patient with a history of bleeding, we recommend a workup that includes the platelet count, the PT [prothrombin time] and aPTT [activated partial thromboplastin time, also called partial thromboplastin time, PTT]—the global coagulation tests. We usually also do a von Willebrand workup,” says Hurlet-Jensen. If the aPTT comes back abnormal, Hurlet-Jensen says, the next step is to assay factors VIII and IX, the two factor proteins that are reduced in hemophilia A and B, respectively. If those results come back normal, then a FXI assay is done, which confirms the diagnosis. Taking a family history is also important to determine if any patterns exist.
FXI levels that are 20–60 U/dL (units per deciliter) are considered mild or partial deficiencies, while levels less than 15–20 U/dL are considered severe. “It’s good to know what the levels are,” says Mathew. “If they are low, patients need to be supported during surgical procedures.”
The majority of factor XI deficiency patients do not experience spontaneous bleeds or joints bleeds. Instead, their symptoms result from injury or surgery in areas of the body that have high fibrinolytic activity, where the body tries to break down fibrin, the main component of clots. Such areas include the mucous membranes of the mouth, nose, throat and genital system. People may experience their first bleed after a dental procedure, such as wisdom teeth extraction; surgery, including tonsil and adenoid removal, circumcision or hysterectomy; or, for women, when they first start menstruating.
Nosebleeds are a common symptom for some FXI patients. “Typically every spring I have bad nosebleeds,” says Beck. “In the spring of 2001, I was in the ER six times.” Cauterizing, or sealing the exposed blood vessels in the nose, can stop recurrent nosebleeds in some patients. “My ENT considered it,” says Beck. “But there isn’t one spot—the bleeding comes from everywhere.”
Another confounding factor for FXI patients is that bleeding doesn’t always occur right away. After surgery, for instance, it can take hours or days for bleeding to begin. Some patients don’t bleed after trauma, while others bleed only after certain surgical procedures. Many patients, for example, have no bleeding after orthopedic surgery.
For severe bleeding, which can occur in people labeled “mild,” other factors can be at work. “I’ve had patients with a FXI level of 40%, but if they’re bleeding a lot they might have something else, like a platelet function disorder or even von Willebrand disease,” says Hurlet-Jensen. Low FVIII and von Willebrand factor levels can produce a higher risk for bleeding in some patients with FXI.
Menorrhagia—heavy, prolonged menstrual periods that often produce cramping and pain—can be a diagnostic symptom of a bleeding disorder, including FXI deficiency, in women. But it’s easy to miss. Many women chalk up their heavy menstrual bleeding to a family tendency, without realizing that it’s an indicator of an underlying disorder. “FXI could be diagnosed when you workup a woman who has some menorrhagia or who has some increased bleeding after pregnancy,” says Hurlet-Jensen. “Usually I do a von Willebrand workup and PT/PTT. If those are normal, sometimes I look at the platelet function.”
A 1999 study published in the American Journal of Hematology (AJH) reported that 59% of women with FXI deficiency, compared with 10% of the general population, experienced menorrhagia. Of those, 65% to 75% bled through protection, experienced “flooding” at night and passed blood clots.
It is vital that girls with factor XI deficiency who are beginning to menstruate recognize symptoms. “I will inform the parents to be very careful when a girl has the first menstrual period to watch for increased bleeding,” says Hurlet-Jensen. Heavy menstrual bleeding in young girls is often due to hormone imbalances. “You have to be very careful not to blame it on the FXI deficiency, because it could be another diagnosis, like VWD,” Hurlet-Jensen says. “They have to be followed by a good gynecologist to be sure it’s nothing else.”
Pregnancy, labor and delivery can also be challenging for women with FXI deficiency. The 1999 AJH study revealed that FXI levels are inconsistent during pregnancy. The authors recommend that FXI levels be obtained during the initial visit and monitored during the woman’s third trimester. Further, the study reported that postpartum hemorrhage in FXI patients was 16%, compared with 5% in the general population. For all of these reasons it is important for women who suspect they might have a FXI deficiency to be tested and diagnosed before pregnancy.
Invasive gynecological procedures, such as D & C (dilatation and curettage), endometrial ablation for menorrhagia or hysterectomy, might not be necessary in FXI patients. “Our view is not to go to radical surgery in women, especially of childbearing age, unless it’s an absolute emergency,” say Hurlet-Jensen. Her center prefers to treat the coagulation problem first.
A mainstay of the orthodox Jewish faith is circumcision, which is performed eight days after birth. For families of Ashkenazi origin who suspect their son might have FXI deficiency, there are concerns about bleeding. “It’s rare to have bleeding,” assures Hurlet-Jensen. “It is not necessary to treat prior to the procedure.” What is necessary, though, is education of the family and the rabbi about potential complications, she says.
Treating patients with FXI deficiency is not straightforward. The best product for each patient depends on the severity of the disorder, bleeding history and, if surgery is recommended, the site of the procedure. The variability of bleeding within the same patient also complicates the issue. Further, the treatments themselves are not yet optimal. Depending on the product, the side effects can range from allergic reactions to inhibitor development or thrombosis.
Since most people with factor XI deficiency do not have spontaneous bleeds, home infusion of clotting factor is usually unnecessary. “FXI bleeding happens so infrequently that it doesn’t make sense to teach the parents to infuse any type of product,” says Hurlet-Jensen.
Still, some patients in the US would like to have another option: FXI concentrate. “They have treatments for hemophilia C in Great Britain and Europe, but not in the US,” says Beck. “That’s frustrating.” FXI concentrate was available for a limited period in the US in the late 1980s and early 1990s, but was withdrawn because of safety concerns. However, a FXI concentrate made by a French company could lead to clinical trials in the US in the future. (See sidebar, “Concentrate Conundrum.”)
Several readily available products in the US can help curtail bleeding from injury, surgery or menorrhagia in FXI patients. “The treatment for major bleeds or to prevent bleeding after surgery or during trauma is to use a plasma product, like fresh frozen plasma (FFP),” says Mathew. Treatment is given before and after major surgical and dental procedures, but there are drawbacks: A large volume is needed, which could overwhelm the circulatory system, and it contains only a small amount of FXI. In addition, it exposes the patient to potential infectious agents and may cause an allergic reaction in some people.
To prevent the risk of contracting hepatitis from plasma products or other sources, the National Hemophilia Foundation’s (NHF) Medical and Scientific Advisory Council’s (MASAC) Recommendation #128 states that all patients with bleeding disorders should be vaccinated against hepatitis A and B.
“An alternative that I use before surgery is a bypass agent—activated factor VII,” says Hurlet-Jensen. “It’s a genetically engineered recombinant product, but you have to be very careful not to give too much because it can cause thrombosis.” The recombinant FVIIa, or rFVIIa, triggers a burst of thrombin on the surface of the activated platelet, bypassing the need for FXI. A 2008 study published in Haemophilia reported on the use of rFVIIA in 14 patients with mild or severe factor XI deficiency. The patients evaluated had undergone such procedures as molar extraction, total hip replacement, elbow surgery or vasectomy. “Hemostasis was classified as effective at all times points in all patients,” the authors wrote. Although this data is promising, rFVIIa has not been approved by the FDA for this use.
Fibrin glue is a topical agent that stops bleeding and helps clot formation in the mouth after tooth extraction and as an adjunct with FFP in circumcision and hernia repair. It is made from human plasma that has been treated to protect against viruses.
Antifibrinolytic agents help hold clots in place by inhibiting plasmin, the enzyme that dissolves clots. They are useful for preventing and curtailing bleeding in dental extractions, nosebleeds, surgery and injury. The most familiar products in the US are aminocaproic acid (Amicar) and tranexamic acid (Cyklokapron). “Amicar can be very helpful in everybody with a factor deficiency and recurrent nosebleeds, including FXI deficiency,” Hurlet-Jensen says. But it doesn’t stop the bleed immediately. “You have to take it regularly for at least three days,” she says.
HTCs Help Make Plans
Most people with factor XI deficiency visit their HTC annually for a comprehensive visit. “At each clinic visit we review the diagnosis, factor level, clinical symptoms, treatment and when the patient should seek medical care or advice,” says Jennifer Donkin, RN, PNP, Children’s Hospital of Los Angeles. “The benefit of coming to an HTC is our knowledge and expertise in the comprehensive care of patients and their families.”
Since patients may have a wide range of severity of bleeding, says Donkin, they are encouraged to contact the HTC prior to any procedure. The team will create a treatment plan based on the patient’s history, bleeding severity and type of procedure to be performed. The HTC then shares the treatment plan with the other healthcare providers involved in the patient’s care, including oral surgeons and ENTs.
Education Goes Both Ways
With FXI deficiency, it’s not just the providers who do the educating. Patients also step into the role of information specialists. “Educating people has been a challenge,” says Beck. So far, he has educated his internist, ENT, oral surgeon and several ER nurses about FXI deficiency. “My biggest frustration is the lack of knowledge that most medical professionals have about it,” says Beck. “Whether it’s dentists or doctors or people in the ER, they look at you like you’re crazy.”
But Beck isn’t one to complain for long. He has created a Web log, or blog, to further educate people on FXI deficiency and, hopefully, meet others with his disorder. After all that he’s been through, Beck remains upbeat. “If anything, having factor XI deficiency has made me more curious.”
Access Beck’s blog.