Even though we live in New Zealand, we like to celebrate the American tradition of Thanksgiving. We have a big family meal and give thanks for the birth parents of our three adopted children (Angela got this idea from Mia Farrow). Afterwards, we get out our Christmas tree and lights to start the long process of decorating inside and outside the house.
I am interested in the history of medicine, so this year, I thought we could commemorate the scientists who brought us anticoagulants.
Karl Paul Link – discovered warfarin.
Warfarin was discovered following a chance encounter between two very different people, Karl Paul Link, an agricultural biochemist and Ed Carlson, a cattle farmer. The story starts in Wisconsin in the 1930s during the depression. Ed had a cattle farm in northern Wisconsin and was struggling like many other farmers. The situation was particularly bad in 1932 as the winter was very hard. To add to Ed’s woes, his cows started to die from a bleeding disorder known as Haemorrhagic disease of cattle. The vet knew that this was due to cattle eating spoilt sweet clover. Unfortunately, Ed had no access to alternative feed, and had no way of stopping the disease. At some point, he got so frustrated that he decided to go to the Agricultural Department in Madison, the state capital, to complain about his situation.
Blood and a dead cow
The story may be apocryphal, but it is believed that Ed loaded a dead cow and a milk churn of blood (that did not clot) onto his truck. He then drove 200miles in midwinter to Madison. When he arrived, the Agricultural department was closed. I guess he was extremely frustrated at this point and wanted to share his frustration with anybody who would listen. The Wisconsin Alumni Research Foundation was in a building nearby. This is where Karl Link worked and happened to be in his research lab that morning. Ed, finding nowhere else to go, burst into Karl’s lab and offloaded his frustrations. Surprisingly Karl’s research was related to chemicals in sweet clover, and he found Ed’s story fascinating. He realised that there could be a link between his own research and Ed’s dying cattle. As a result of this conversation, Karl changed the direction of his research to solve the problem of Haemorrhagic disease.
After six years of research, he extracted dicoumarol from sweet clover. This was the first oral anticoagulant used. Karl continued to work in the same area and developed several analogues of dicoumarol, including warfarin (named after Wisconsin, Alumni, Research Foundation). Initially, he thought warfarin was too dangerous to use in humans, and it was developed as rat poison. But later, it became clear it was safe as a therapeutic agent.
Jay McLean – discovered heparin
In 1916, at Johns Hopkins Medical School, Baltimore, USA, a second-year medical student, Jay McLean, was working under the physiologist William Henry Howell. Howell’s main interests were the substances controlling blood clotting. He believed that the release of a chemical called cephalin (so-called because it was first isolated from a dog’s brain) from platelets started the clotting process. Jay McLean had come to Baltimore the previous year and was given the job of examining the purity of cephalin.
He finished this work early and suggested to Howell that he could look at similar chemicals in other organs such as the liver. Jay carried out a similar extraction technique in the liver but found little cephalin activity; instead, he unexpectedly found a chemical that acted as an anticoagulant rather than an activator of coagulation. Initially, he was unsure of his findings but continued working alone without any funding. He repeated his studies and eventually plucked up the courage to present his work to Dr Howell, his supervisor. This is a quote from Jay’s own work,
“He was most sceptical. So I had [my assistant] bleed a cat. Then, into a small beaker full of its blood, I stirred all of a proven batch of heparphosphatides, and I placed this on Dr Howell’s laboratory table and asked him to tell me when it clotted. It never did clot.
He still did not believe that I had discovered a natural anticoagulant, but it was at this point that he became interested in my research problem,”
The substance Jay had discovered was heparin.
Thanksgiving for science
The work of these two great men has had a huge influence on medicine. Heparin has enabled bypass surgery and renal dialysis as well as the treatment of thrombosis. And warfarin was the only oral anticoagulant available in clinical practice for more than forty years; I suspect it has saved the lives of millions. It is easy to forget the contribution of these men. Thanksgiving is a good time to remember that they only achieved their goals through dogged perseverance often when the odds were against them. Any of us who have suffered a blood clot of any type should be grateful for their work.