Cows, rats and you: How a dairy farmer's scourge led to a widely used medicine, and why everyone is trying to get rid of it

BY DAVID STEINKRAUS
Journal Times

Wednesday, April 23, 2008 4:25 AM CDT

On a snowy February day in 1933, a farmer from northern Wisconsin walked into a laboratory building in Madison carrying a mystery in a bucket.

The farmer’s name was Ed Carlson. He was from Deer Park, and he had come to Madison desperately looking for the state laboratory of hygiene because his cows were ill, said David Nelson, a professor of biochemistry at the University of Wisconsin-Madison. “And it was Saturday so the hygiene lab was closed, and he walked across the street to biochemistry and by chance bumped into Link.” That was Karl Paul Link, a biochemistry professor in the university’s College of Agriculture. “And he stood there with a bucket of blood in his hands, and he said, ‘You’ve got to help me. My cattle are dying. Their blood won’t clot.’ ”

It was a common disease on dairy farms at that time, Nelson said, and of course it was devastating for farmers whose cattle contracted it because there was no cure. “They would cut themselves on barbed wire and bleed to death.”

Link decided to devote his whole laboratory to the problem. Eventually, Nelson said, he traced the cause to the sweet clover used as cattle feed. When it was stored too long or stored in the wrong way it spoiled, and one of the compounds produced prevented blood from clotting. It took time, but Link eventually found that this stuff interfered with vitamin K — also discovered about that time — which was necessary to form several compounds in the chain of reactions that leads to formation of a clot.

When he had the solution, Link patented his discovery. He constructed a name out of the last letters of the chemical’s family name, coumarin, and the first letters of the Wisconsin Alumni Research Foundation, and came up with warfarin.

And warfarin is still with us. Link was known to embellish his stories, Nelson said. Yet it is clear that his discovery was a major advance for both medicine and public health. And despite continuing attempts to displace warfarin, it remains a commonly used drug today and, unless it is displaced, may become even more commonly used in the years ahead as the number of older people increases.

Broad action

You may know warfarin as warfarin or perhaps as Coumadin, the brand name, but it’s the same basic drug. It can prevent clots from forming in your legs, lungs, heart and elsewhere, and if those clots don’t form they can’t break loose and shut down a lung or migrate to your brain and cause a stroke. Of course, if your dose is too high, you can also bleed internally, or have a bleeding stroke in the brain.

Warfarin works not just at one or two points in the chemical sequence that leads to a clot but several. And that’s important, said Dr. David Moliterno, chief of cardiology at the University of Kentucky. “What needs to be appreciated is — you know whatever you believe with regard to evolution — blood clotting is incredibly important for the survival of any animal, and so it’s not surprising that we have a complex and redundant system.

And so oftentimes if you pick out one spot in a multipoint pathway, the body has a way to work around that.”

Warfarin also lasts for a while. The body’s own anticoagulant, heparin, doesn’t. Even the synthetic versions, used in hospitals and the subject of news stories when Chinese manufacturers shipped contaminated doses, is effective for only 60 to 90 minutes in healthy people.

The problem with warfarin is that its effectiveness is determined by many factors. People on it have to avoid foods with vitamin K in them, such as dark green leafy vegetables, and there are any number of drugs which react with warfarin. Warfarin is broken down in the liver by one of a large family of enzymes known as cytochromes, also used to break down many other substances. Because of that, warfarin may be incompletely broken down if there isn’t enough cytochrome left, or if it takes up a lot of cytochrome, other medications may not be broken down, meaning their concentrations stay too high and may cause side effects.

The latest wrinkle, which caused a recent revision of the warfarin label, was the discovery of a genetic variation. It changes the shape of an enzyme that processes vitamin K (which you’ll remember is involved in producing all those clotting factors), and that means people who have the variations process warfarin more slowly, meaning their blood stays thinner for a longer time.

Warfarin already was causing plenty of problems. “And as much as we see in a small community hospital, it has to be a major problem nationwide,” said Dr. Stephen Welka, a cardiologist at Memorial Hospital of Burlington. An article published in a medical journal last year said that warfarin and insulin combined caused about one of every seven emergency room visits for drug problems.

“We are fortunate here because we have a dedicated Coumadin clinic,” Welka said. And that’s another problem with warfarin — the amount of time it requires. Patients must visit a physician’s office every three to four weeks at least so their clotting time can be checked, and the range of proper warfarin dosing is very narrow. Those patients take up staff time. At Memorial Hospital, Welka said, there are two nurses who spend their entire workweeks reviewing clotting time reports and advising patients about changes.

Clinical trials

And if this small community hospital is a typical example of managing warfarin, it’s also involved in finding a solution. Welka got the hospital involved in an international clinical trial of a drug called rivaroxaban, a potential replacement for warfarin. It is hoped the drug will be a simpler compound to use with none of the constant checking and drug interactions of warfarin.

This particular trial will involve 15,000 people from across the world for several years of tests and follow-up tests, and it’s intended to compare rivaroxaban to warfarin in the prevention of clots resulting from atrial fibrillation, which is a flutter of one of the heart’s secondary pumping chambers. Fibrillation can lead to clots which increase the risk of stroke. It occurs in middle-aged people because of other problems such as hypertension or obesity. “But to a certain degree, if you live long enough it’s inevitable that you develop A-fib,” Welka said. It occurs in about 40 percent of people older than 75. “So maybe it’s because we’re living longer that the prevalence is becoming (greater).”

In other words, as the large number of baby boomers age, they will be at increased risk and are likely to be prescribed warfarin if there is no replacement. There was one for a while. Exanta looked good. “It was an awesome anticoagulant. It was just hurting people,” Welka said. After it had been in use for a time it damaged patients’ livers, and the maker pulled it from the U.S. market a couple of years ago.

Aside from being able to bring what would otherwise be big city medical trials to a community hospital, Welka likes being part of the rivaroxaban trial because so many drugs have been commonly tested on young, healthy Caucasian male college students. Problems show up later when drugs are used by older people, less healthy people, women and those of other races.

“Research trials are terribly biased because you’re picking the low-hanging fruit,” Welka said. “Well the criticism’s been, ‘You’re not applying it to the general population.’ Well here we’re applying it to the general population ... there’s not enough women studied, not enough blacks, Hispanics, in at least cardiovascular research.”

It’s just money

And if rivaroxaban doesn’t work out as Exanta didn’t, there are candidates waiting in the wings. A medical journal article published in February noted the promising number of anticoagulants active in tick saliva — a very logical place to find them when you think about what ticks need to do. Ticks aren’t the only potential sources of new anticoagulants, and having more isn’t the point. The point, Moliterno said, is developing them.

It is often said that aspirin wouldn’t pass government muster these days because of the risk of gastrointestinal bleeding, said Dr. Gurvaneet Randhawa, a senior advisor on personalized medicine and genomics at the federal Agency for Healthcare Research and Quality.

For a few million dollars, researchers can screen substances such as tick saliva for anticoagulants, Moliterno said. “We’ve had aspirin for more than 100 years, and aspirin is one of the most effective, cheapest cardiovascular drugs in medicine, and here it’s coming from the bark of a willow tree.” The real cost comes in developing the drugs and doing the clinical trials to prove their safety in humans. And in this post-Vioxx-lawsuit era of drug discovery, he said, pharmaceutical manufacturers are less willing to invest in drugs that may bite them in court later.

The other factor opposing any replacement for warfarin, Moliterno said, is the sheer volume of knowledge built up by doctors over decades of use. Problematic though warfarin is, he said, doctors understand it very well and thus know how to use it. A new drug is a new unknown with side-effects that also may be unknown.

“No drug is going to be completely safe,” Randhawa said. “The only question is how long and what would it take to uncover those side effects, and how serious are they.”

There’s no question that warfarin will eventually be displaced by a newer drug that is easier to handle, Moliterno said.

“But we all appreciate it’s probably going to take, literally, triple digit millions to find that drug and get it FDA approved.”

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