Heparin and coumarins currently play an important role in the prevention and treatment of conditions and diseases in which blood clots can form in the veins and/or arteries (thromboembolism). With the development of NOACs (new oral anticoagulants), a new era appears to have arrived in 2015 for the prevention and treatment of thromboembolic complications. Time to look back at the discovery and development of the first generation of blood thinners.
Discovery of heparin
Heparin is one of the oldest medications that is still used daily. Heparin consists of a complex substance called glycosaminoglycan. The main function of this substance is to inhibit blood clotting by enhancing antithrombin III. Heparin was discovered in the early 1900s and it took many decades before it finally reached the patient from the laboratory.
William Henry Howell
There is a worldwide controversy regarding the discoverer of heparin. In 1916, medical student Jay McLean, under the supervision of physiologist William Henry Howell, conducted research into various substances that could control blood clotting. McLean saw that the livers of dogs contained certain fat-soluble substances that caused significant bleeding in laboratory animals. Ultimately, he shifted his research towards substances that would help blood clotting more quickly. This with the idea that this could be more useful for soldiers in the First World War.
Meanwhile, research into anticoagulants (drugs that inhibit blood clotting) continued in Howell’s laboratory. In 1918, another medical student named Emmett Holt, like Jay McLean, had discovered a fat-soluble substance that inhibited blood clotting. The term heparin was coined by Howell and was derived from the Greek word hepar which means liver.
production
At an annual conference in 1922, Howell presented these findings and shortly afterwards heparin was first produced by a local pharmaceutical company in Baltimore, USA. In 1931, Howell retired and stopped investigating heparin further.
Discovery of coumarin derivatives (warfarin, acenocoumarol, phenprocoumon)
Warfarin is the most commonly used anticoagulant in the world. In the Netherlands we do not use this drug, but we use acenocoumarol or phenprocoumon. However, these agents are comparable in effectiveness to warfarin.
White honey clover
The discovery of warfarin originated on the prairies of Canada and the northern United States in 1920. It was noticed that previously healthy cattle were dying from internal bleeding without an apparent cause. Livestock farming was one of the most important industries in that period, partly due to the economic depression (the great depression), so livestock farmers could not tolerate the extra losses. Since no microorganism was found that could explain the bleeding, the diet of the cattle was examined. It was noticed that the sheep and cows mainly ate the white sweet clover ( Melilotus alba, Melilotus officinalis ) and that bleeding occurred frequently when hay was damp. Ideal conditions for fungi such as Penicillium nigricans and Penicillium jensi . Few farmers could afford other feed, so they fed the moldy hay (with the white honey clover) to the cattle.
Breakthrough
About ten years later after the initial outbreak, there was a farmer, Ed Carlson, who also lost prize-winning cattle to internal bleeding. However, he did not believe the story of the white sweet clover, but he wanted a solution. He took a dead cow to local researcher Karl Link. However, he could only advise that the cows no longer eat moldy hay and that the cows be given blood transfusions. However, Karl Link continued to investigate moldy hay. The cause of the bleeding had been found, but the exact substance was still unknown. After six years of research (published in 1940), Karl found that the coumarin in the white sweet clover was converted by the fungus into the active dicoumarol.
Rat poison
In 1945, Link got the idea to use dicoumarol as a rat exterminator. He looked for the strongest and best available variant of dicoumarol; eventually he found it in warfarin. Initially it was mainly used as rat poison, but since it is very water soluble it was later also used on patients. In 1955, President Eisenhower was treated with warfarin after a myocardial infarction.
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