Research

Blood Ties

Tracing thrombophilia’s genetic connections can help some people thwart the potentially deadly disease.

By Sonya Collins

It began three months before her wedding day in 2012, when Rebekah Bradford Plath had just started hormonal birth control.

“I immediately had swelling in my legs,” says Plath. Her gynecologist said her body was just adjusting to the hormonal contraception and dismissed her symptoms. But it wasn’t just her legs that were bothering her. Her fitness seemed to be deteriorating.

Plath is a speed skater; she competed in the 2010 Winter Olympics. But two years later, during an intense summer training session at the Utah Olympic Oval ice rink in Salt Lake City, her calves were swollen and tender. It even hurt to wear jeans or to pull on the spandex tights that she wore to train. “It was the summer of the skirt,” Plath recalls.

She was also having chest pain and difficulty breathing. Plath decided she needed some conditioning, so she started playing ultimate Frisbee. At a game, she ran into one of the other players and felt as if she had broken a rib.

A sports doctor gave Plath a cortisone shot for the rib pain. But the chest pain and difficulty breathing persisted. A month later she was so out of breath that she had to crawl rather than walk. “I didn’t know what to do. I just curled up on the floor, clutching my wedding photo, and waited for my husband to come home from work,” she recalls. After six months of the mysterious and worsening symptoms, Plath’s husband insisted they go to the ER.

In the ER, doctors quickly discovered that the swelling in Plath’s legs and the pain in her chest were caused by blood clots. She had deep vein thrombosis (DVT) — blood clots in her legs — and pulmonary embolisms (PE) — clots that travel to the lungs and block arteries there. A chest scan showed she’d had a partial infarct. The supposed rib break during ultimate Frisbee was actually a blood clot in her lung, blocking blood flow, causing tissue to die from a lack of oxygen.

Other doctors might have dismissed Plath’s telltale signs of DVT and PE because they are the last things a doctor would expect to find in an Olympic athlete. But a genetic test, conducted during the ER visit, revealed that it didn’t matter whether she was an athlete or not. She had hereditary thrombophilia, a genetic predisposition to developing blood clots.

While most blood clots arise in connection with surgery, cancer, bed rest, pregnancy, or other circumstantial risk factors, several different genetic mutations can make a person more prone to blood clots. This usually means the person will be more likely than others to have a blood clot when provoked by other risk factors. But for some people, genetic thrombophilia can cause a blood clot to develop seemingly out of nowhere. In some cases, genetic testing might be appropriate to confirm the presence of this condition and to help guide health-related decisions.


What is thrombophilia?

Think of thrombophilia as the opposite of hemophilia. Rather than a tendency to bleed without clotting, thrombophilia is a tendency of the blood to clot unnecessarily. Blood clots that typically start in the arms or legs can travel to the heart or lungs, causing organ damage or even death. On rare occasions, these clots can make their way to the brain, resulting in stroke.

Most types of thrombophilia are acquired from some triggering circumstance that changes the way your blood clots; for example, prolonged bed rest or taking some types of hormonal contraception, as Plath did. But some forms of thrombophilia are genetically inherited, which means a person inherits one or more genetic variants from a parent that can increase the risk of blood clots.

“Does carrying a genetic mutation for thrombophilia mean you definitely will get a blood clot? Absolutely not,” says Amy Sturm, a licensed genetic counselor and associate professor in the Cardiovascular Genetic and Genomic Medicine Program at Ohio State University. “Many people who have [inherited] thrombophilia will never go on to have an issue. It might be the combination of genes plus environment that determines whether they ultimately have a blood clot. ”

That is to say that genetics alone don’t usually cause blood clots. Plath, for example, might never have developed clots if she hadn’t used hormonal contraception.


The genetics of thrombophilia

Certain proteins circulating in the blood ensure that blood coagulates only when necessary. In addition to other genetic factors, changes in five genes responsible for making these proteins could cause thrombophilia.

The most common of these gene alterations is factor V (five) Leiden, named for the Dutch city in which researchers discovered it. Factor V is a protein that helps clot the blood. After factor V has done its job, two other proteins — C and S — break factor V down and clear it from the blood to prevent too much clotting. In people, like Plath, who have the Leiden mutation, factor V has an abnormal shape and proteins C and S are unable to break it down properly.

“Factor V Leiden carries about a fivefold increased risk for developing a venous blood clot,” says Kenneth Bauer, a hematologist and a professor of medicine at Harvard Medical School. But, he adds, that translates to a relatively low lifetime risk of developing a clot.

According to the National Institutes of Health, about 10 percent of people who have the gene mutation will have an abnormal blood clot. About 5 percent of Caucasians have factor V Leiden, while 1 to 2 percent of African-Americans, Hispanic Americans, and American Indians do. (Asians rarely have it.)

Many people who have [inherited] thrombophilia will never go on to have an issue. It might be the combination of genes plus environment that determines whether they ultimately have a blood clot.

A gene mutation that causes overproduction of another clotting protein — prothrombin — can also cause thrombophilia. About 2 to 4 percent of Caucasian people have the mutation known as prothrombin G20210A; less than 1 percent of African-Americans do. It’s extremely rare in other groups. A genetic deficiency in antithrombin — a protein that prevents clotting — leads to thrombophilia in fewer than half of 1 percent of Americans. Genetic deficiencies in protein C or S, which make the body unable to clear factor V properly, occur in up to one in 200 and one in 700 people respectively.

Although thrombophilia-related gene mutations are not all that rare, whether they lead to blood clots depends on several other factors. A person can inherit one copy of any one of these gene variants from one parent or, in rare cases, one copy from each parent. Some people may also inherit a copy of more than one of the different thrombophilia gene variants from a parent. People with two copies of the same variant or multiple thrombophilia-causing variants may have more severe cases of the condition through which blood clots could occur unprovoked. For others, the genetic mutation will only increase the risk for blood clots in the presence of other risk factors.

“Venous thrombosis is multifactorial. When you put many risk factors together — aging, birth control pills, long-haul travel, genetics — that is when risk increases,” says Bauer.


Testing guidelines

After Plath learned she had factor V Leiden, her mother was tested as well. They wanted to know whether her mother’s or father’s side of the family carried the variant. It turned out that Plath’s mother was a carrier; she recalled that her own father had blood clots in his 60s.

Genetic testing for thrombophilia isn’t necessarily recommended for any and all relatives of someone who has the condition. Like most genetic tests, thrombophilia screening comes with pros and cons. Identifying the condition can aid in medical decision-making, but it can also cause anxiety or guilt, in the case of parents who pass it on to their children. People who test positive may also undergo unnecessary treatment or precautions.

But family members of someone with thrombophilia who test negative for the condition may have a false sense of reassurance. They still have an elevated risk of clotting through, some researchers presume, other shared gene variants not included in the test.

In many cases, identifying genetically inherited thrombophilia wouldn’t change anything about the way people live their life or manage their health. “The whole question is how testing would influence [medical care],” says Bauer.

If a person has had a blood clot with no apparent cause or if a family member has genetic thrombophilia, he or she might choose to be tested if the test result would influence a medical decision. Consider a woman whose mother has genetic thrombophilia and who wants to take birth control pills, or who is going to have surgery, or who plans to become pregnant. In each of these cases, thrombophilia could change the course of action or require special precautions.

In cases where test results wouldn’t change anything, screening is probably unnecessary. A recent review of clinical practice from the University of Michigan came to the same conclusion: Given the expense and the low yield, inherited thrombophilia testing should be approached with caution (and genetic counseling, of course).


Prevention

Testing positive for thrombophilia could also be just the impetus a person needs to stop smoking, to lose weight, or to get more exercise. Smoking, obesity, and inactivity all raise risk for clots. Of course, Plath didn’t have any of these risk factors. But screening did change her life.

She stopped using hormonal contraception. Whenever she travels long distances by plane or car, she takes blood thinners and wears compression socks. When she becomes pregnant, as she plans to do one day, she will need to use blood thinners throughout her pregnancy.

But before she starts a family, Plath has her sights set on the 2018 Winter Games. Pulmonary embolism and recovery stripped Plath of her hard-won strength and endurance.

“When my team was going out for a two-hour bike ride, I went out for a 10-minute walk,” she says. “You learn to cry silently, because when you cry, you irritate your lungs.”

But Plath built up from those 10-minute walks, and 13 months after her pulmonary embolism, she was in fighting shape again. Recovery was expected to take two years, but Plath didn’t want to miss out on the 2014 games in Sochi, Russia. In order to even compete for a spot, speed skaters must make a World Cup team, which Plath did. “I am able to say that as a survivor [of pulmonary embolism], I was able to become a world-class athlete again,” she says. “That was a major victory.” Against all odds, Plath then vied for a spot on the Sochi team. She missed qualifying by one-tenth of a second.

Since then, Plath has been working full-time as an executive assistant for an air ambulance company and training several hours a day before and after work. She says she feels stronger now than she did before her pulmonary embolism. “I want to show other people that there is life after blood clots.”

Plath returned to full-time Olympic training in the fall. “I know what I’ve been capable of in the past, and I wouldn’t move forward if I didn’t think that I could get up there again.”