Bruised and bleeding: Watching for von Willebrand disease

The simplest of assaults -- a nick while shaving or a too-close encounter with the bread knife -- starts a coagulation cascade, sending help to the endothelial wound. A few seconds of pressure or a piece of wet tissue on the gash and the cut seems fine. It's often an automatic response, rarely triggering any thought of the complicated clot-forming process.

But even when this process consistently fails to happen, a bleeding disorder often is not considered.

When Mary DeArmond was 3 years old, she fell and sliced her gum. The seemingly mild injury required a blood transfusion. At 12, a chair fell on her leg and triggered a joint bleed. Four years later, a wisdom tooth extraction required repeated sutures before healing. "Nothing was ever done and I did not realize it was odd," says DeArmond.

She got used to constant warnings from her parents to be careful on the playground. "When I was growing up, I had lots of cut knees and there were unbelievable amounts of blood," she says. She was finally diagnosed with von Willebrand disease at age 22.

First reported by Erik von Willebrand in 1926, von Willebrand disease is caused by a deficiency or abnormality of von Willebrand factor, a glue-like blood protein necessary for normal clotting. The Finnish physician studied abnormal bleeding patterns in a Scandinavian family, recognizing autosomal inheritance patterns and the increased threat to women. His index patient bled to death while menstruating.

Understanding has increased significantly over the years. "It is inherited equally by men and women," says Peter Kouides, MD, a hematologist who is the medical director and research director at Mary M. Gooley Hemophilia Center in Rochester, N.Y. "It's just that women are far more likely to have symptoms during menstruation and childbirth."

It's estimated that 2.6 million people -- as many as one in 100 -- are affected by vWD, the most common inherited bleeding disorder. But awareness remains low. The seemingly simple list of symptoms -- heavy or prolonged menstrual bleeding, easy bruising, frequent or prolonged nosebleeds, and prolonged bleeding following surgery, dental work, childbirth, or injury -- are often dismissed as normal. And it isn't until a crisis -- a boy hemorrhages following a tonsillectomy; a serious wound spontaneously bleeds days later; a woman hemorrhages postpartum -- that the patient is diagnosed.

"Mild defects may go undetected, and it isn't until the patient is challenged that it is recognized," says Andra James, MD, assistant professor of obstetrics and gynecology in the Division of Maternal and Fetal Health at Duke University School of Medicine in North Carolina. Dr. James recently served on the National Heart, Lung and Blood Institute vWD expert panel.

A 2004 study by the Centers for Disease Control and Prevention found, based on interviews with 75 women diagnosed with vWD, that the average time between symptom identification and actual diagnosis was 16 years. "The important thing is, in patients who have bleeding symptoms, pursue a diagnosis of an inherited bleeding disorder," says Barbara A. Konkle, MD, a hematologist and the regional director of the Penn Comprehensive Hemophilia and Thrombosis Program at the University of Pennsylvania Health System.

Sleuthing for a missing factor

A routine doctor visit finally set DeArmond on the right track. Noticing extensive bruising on her arms and legs, her physician began asking questions. "Once I convinced him it was not abuse, he sent me to a hematologist," she says. "I owe everything to that family physician. He was curious enough to ask."

DeArmond has type 3 vWD, the most serious form, which means her body does not produce any von Willebrand factor. Her father and her 13-year-old son Danny have type I, the most common and mild form, which produces a lowered amount of von Willebrand factor.

While patients with type 2 produce the blood protein, it does not work properly. Additionally, vWF protects factor VIII, also important in the clotting chain, from being destroyed in circulation. When vWF is low or absent, so is factor VIII.

But clinical evaluation of bleeding symptoms is a challenge, according to NHLBI experts. For starters, some of the symptoms are relatively common in healthy populations, making detection of the vWD's mildest form tricky. Also, the use of aspirin or other nonsteroidal anti-inflammatory drugs exacerbates bleeding tendency, making it difficult to decipher vWD from such other variables. To further complicate the issue, vWD, in rare cases, can be acquired as the result of other conditions like hypothyroidism, or from medication, especially among elderly patients.

In its acquired form, vWD can be addressed by treating the underlying cause, says Margaret V. Ragni, MD, MPH, professor of medicine in the division of hematology and oncology at the University of Pittsburgh. She also is director of the Hemophilia Center of Western Pennsylvania. "[But] for anyone with a bleeding history, refer to a hematologist for evaluation to be sure you are not missing something."

Because of the disease's diagnostic and management subtleties, the NHLBI responded to a fiscal year 2004 appropriations conference committee recommendation, urging the development of treatment guidelines for vWD. "We had been waiting for years for guidelines to come out," says Val Bias, CEO of the National Hemophilia Foundation in New York. "The NHF advocated with Congress to allocate the funds to research."

This February, the first U.S. clinical guidelines for the diagnosis and management of the disease were released. "We are pleased to see the institute affirm the importance of vWD and the need for professional guidance and education around this disorder," Dr. Konkle says. "We are hoping with the guidelines that physicians will think about it and say, 'this is what I can do.' "

Multifaceted approach needed for diagnosis

There is no simple, single laboratory test to screen for the presence of vWD. "Unfortunately, our testing is not perfect," Dr. Konkle says.

And lab work sent significant distances is often compromised because of changes in temperature and humidity. "There's a 50% to 80% chance that [results] will come back falsely," says Dr. Kouides. "Insist that the lab work goes to a local lab that does the levels on site."

Several studies are under way internationally to determine better methods of screening, testing, diagnosis and treatment, and to build on the information contained in the recent guidelines. At the University of Pittsburgh, for instance, Dr. Ragni is heading a clinical study of three questions surgeons can ask to screen for the disorder in addition to several drug trials and novel approaches to evaluation and diagnosis. "The new NHLBI booklet is the most comprehensive we have," she says. "But it does not have all the answers."

It wasn't until one of Cindy Lampertz's twin daughters hemorrhaged after a routine tonsillectomy that she and her children were diagnosed with type 1 vWD. "In hindsight, it all makes sense. I had many things that pointed to it," says Lampertz, a registered nurse from Brentwood, Tenn. "I also hemorrhaged with my tonsils. I always have bruises. I had a hysterectomy at 32 because of bleeding." But she also says that, despite her health care background, she still didn't realize she had a problem.

For many women, diagnosis follows pregnancy or comes after a son or daughter has a bleeding crisis. Heavy periods, a key element in the symptom constellation, are rarely the catalyst. In 2004, CDC researchers, in collaboration with the Rollins School of Public Health of Emory University in Atlanta, surveyed members of the Georgia Chapter of the American College of Obstetricians and Gynecologists to determine their perceptions of and experiences with bleeding disorders, particularly vWD.

According to the survey, menorrhagia is reported by approximately 10% of patients annually, or about 3 million women. Fifty percent of the cases are of unexplained gynecological origin, yet only 3% of responding physicians consider vWD. Most respondents believed that menorrhagia is within normal limits. "Gynecologists don't frequently think of bleeding disorders [in this situation]," says Dr. Konkle, who also chairs the National Hemophilia Foundation's Women with Bleeding Disorders Task Force.

It's estimated that from 5% to 20% of women with heavy menses have underlying vWD, according to the CDC. The American College of Obstetricians and Gynecologists recommends screening adolescents with severe menorrhagia, adult women with significant menorrhagia not explained by other causes, and women who are considering hysterectomies because of excessive menstrual bleeding.

Interestingly, during pregnancy, vWD almost always improves because vWF rises to protect women during childbirth. The gravest worries are postpartum. "Within 12 hours to a week, the levels will fall and there is a risk of delayed hemorrhage," says Dr. Kouides.

According to the NHLBI guidelines, women who have any type of vWD, a history of severe bleeding, or blood test results showing very low levels of von Willebrand factor or factor VIII, should be referred for prenatal care and delivery to a high-risk obstetric center that has a hemophilia treatment center.

Reproductive cycles present women with vWD with more frequent bleeding challenges, but anyone with the condition -- male or female -- worries about the next fall or bump. Daily missteps can equal serious outcomes. And what's serious for one might not be for another.

DeArmond's 13-year-old son has frequent nosebleeds. "This summer, he's had gushers," she said. "He wears a MedicAlert bracelet and has a letter he takes with him" to explain the medicine he needs in an emergency.

Similarly, Lampertz worries about her daughters, recalling a tense ski trip. "We were on vacation in the mountains, there was a blizzard and my daughter got a nosebleed. I couldn't stop it," she says. "Now we travel with her medicine and my rule is: If I can't stop it in two hours, we go to the hospital."

Overall, vWD offers physicians and patients a quandary. For physicians, it is difficult to diagnose and manage. For patients, it can present stark risks every day. And overall, at its earliest point, the condition is a puzzle that requires looking at the whole picture. The vague bleeding symptoms add up. "This is a condition we should think more about in primary care settings," says Dr. Kouides. His advice: Follow the guidelines and keep the antennae up.