THE FOLLOWING ARTICLE APPEARED IN THE

DECEMBER 1999 ISSUE

THE POISON SLEUTHS

DEATH BY BRODIFACOUM

-Dr. Anil Aggrawal

"Good morning doctor. Oh, my God, what are you doing today? You have the dead body of a young girl today. What happened to her? Please tell me.”

“Good morning Tarun. The name of this young girl is Rama and she was found dead in the morning in her house. She is about 24 years old, and was in deep love with a boy Suresh who studies with her in college. They were both chemistry students. The police have come to know that their relations had recently soured, as Suresh wanted to marry someone else...”

“Oh, so Rama committed suicide by ingesting some poison?”

“Let me complete. Suresh had come to Rama’s house yesterday and had left after some time. But nobody really knows why he came there. He had stopped coming to Rama’s house about six months back. The police are totally clueless about the cause of her death. It is quite possible that Rama committed suicide after Suresh came to her house to severe all relations with her. It is also possible that Suresh poisoned her to get her out of his way. A rare possibility - although very real- is that Rama may have died a natural death. My job is to find out how she actually died.”

“How are you going to do that doctor?”

“By examining the body thoroughly. Do you see these multiple colored spots all over the body. These are the areas where bleeding has occurred underneath her skin. These areas are technically known as hemorrhages. Look at her shin. There are so many hemorrhages here. Other parts of her body are also showing similar appearances.”

“Yeah, I do see these spots. What are these? I never concentrated on these.”

“Tarun merely these spots have told me which poison has been given to her.”

“Really? That is very clever of you. Which poison has been given to her. Please tell me.”

“Tarun, most probably she has been given Brodifacoum, and she has died because of that.”

“What? Brodifacoum?? Never heard of that poison. What type of poison is that? And where is it available?"

“Tarun, before going further, let me introduce a red herring, and first tell you a bit about anticoagulant drugs, so you could follow my discussion better. Let me tell you that in medical terminology, anything that prevents the blood to clot, or at least makes it take more time to coagulate is known as an anticoagulant.”

“Okay doctor, as you say. Tell me about anticoagulant drugs?”

“We all know that blood has a remarkable property. As long as it circulates in the blood vessels within the body, it does not coagulate. But the moment there is some injury and a blood vessel is cut, the blood coagulates. This prevents further oozing of the blood, because the clotted blood forms a kind of “plug” over the broken blood vessel. Thus the mechanism of blood clotting is actually a safety feature, and one would normally not want to disturb this. But in several cases, doctors want to reduce the clotting power of their patients’ blood.”

“Really? Why?”

“I will tell you shortly. Let me first tell you how this clot ultimately forms in a normal man. When a blood vessel is broken, a kind of chain reaction sets in which leads to the formation of a chemical known as Thromboplastin. Thromboplastin converts a chemical prothrombin into thrombin, and thrombin converts a chemical fibrinogen into fibrin. This fibrin is actually a thread like material which forms the clot. Both prothrombin and Fibrinogen are already present in the blood, but in the absence of Thromboplastin, a clot can not be formed. Thromboplastin is released only when a blood vessel is broken, and this starts a kind of chain reaction, which ends up in the formation of the clot.”

“Oh, I see. This is very interesting indeed.”

“As you can see, nature has developed this remarkable mechanism, whereby blood will not clot when the blood vessels are intact. But in certain conditions, blood acquires an increased tendency to clot, and forms clots even within intact blood vessels. This is dangerous, as these blood clots can get detached from where they are formed, and then they start flowing freely in the blood. Ultimately they get deposited in the vessels going to lungs, where they can cause severe problems. These impacted clots can cause death too. Such clots have an increased tendency to form after surgical operations. Mostly they form within the calf veins. They get detached from there, start travelling upwards and ultimately get lodged in the arteries going to lungs. This phenomenon is called Pulmonary embolism. This is a dangerous condition and can cause immediate death. So naturally doctors want to reduce the blood’s tendency to form clots after surgical operations. Blood also clots readily after artificial valves are placed in the heart. There are a number of other conditions where the doctors are interested in reducing the blood’s tendency to clot. For doing this, they give their patients anticoagulants.”

“Oh, I see. But how is all this related to Rama’s death?”

“You will shortly see that Tarun. Anticoagulants can either be injected or given by mouth. Administration by mouth is technically known as oral route. The story of oral anticoagulants is an interesting one. In the early 1920s, a strange cattle disease broke out in North Dakota and Alberta. Cattle were dying of bleeding which was quite unexplained. Normally if a cattle gets a minor cut or abrasion, the blood would immediately clot preventing further bleeding, but the blood of these cattle had apparently lost its power of clotting. The result was that the cattle would die even from minor scratches and abrasions. In 1922, F.W. Schofield, a veterinarian in Alberta, showed that this was because these cattle were eating hay prepared from spoiled sweet clover. So apparently there was something in spoiled sweet clover, which was destroying the blood’s capacity to clot. In 1931, another veterinarian L.M. Roderick of North Dakota found that whatever was present in spoiled sweet clover was doing so, by reducing the activity of prothrombin. But nobody till that time could isolate this substance.”

“Oh, the story is getting curiouser.”

“On 28th June 1939, a scientist H.A. Campbell, who was working in an experimental station run by the University of Wisconsin College of Agriculture, finally isolated crystals of this potent anticoagulant. Two members of his group, Mark Strahmann and Charles Huebner, spent the next nine months chemically identifying this substance, and on 1st April 1940, they confirmed that it was a compound known as 4-hydroxycoumarin. I may tell you Tarun, that it is one of the very few scientific discoveries that have been made on April Fool’s day!”

“Oh, that is interesting. What next?”

“Doctors could easily see how this new drug could benefit their patients recuperating from surgery. In 1942, the Abbott and Lilly companies marketed the new anticoagulant under the trade name dicoumarol. Since then hundreds of coumarins - drugs which have a chemical structure similar to 4-hydroxycoumarin - have been shown to be of clinical use. The best known of these Coumarins was patented by the Wisconsin Alumni Research Foundation in 1947. Quite appropriately it was named Warfarin. I am sure you know why it was called Warfarin.”

“I can make a guess. Come on, let me see. The initial letters of Wisconsin Alumni Research Foundation are WARF. Add to this “arin” from the last letters of “Coumarin” and you get Warfarin. Right?”

“Yes, you are right Tarun. Later on all oral anticoagulants which had a structure similar to Warfarin, came to be known as warfarins. Quite surprisingly, Warfarin was used not so much for treating patients as for killing rats. In other words, it was used as a rodenticide.”

“Doctor how could this drug be used as a rodenticide?”

“Tarun, Warfarin is colorless, tasteless and odorless. So if you mix it in rat bait, rats would easily consume it. One dose may not affect them, but if they continue eating this bait over a period of days or weeks, very soon their blood would lose the capacity to clot. In such a situation rats develop many fatal bleedings within their bodies. I may tell that in all organisms, including man, minor internal bleeding can start occasionally on its own, but normally we are not aware of it because the blood immediately clots there and plugs the leak. But if the blood has lost the capacity to clot, it can not plug the leaks and the rat would very quickly die of internal bleeding. On average, it takes approximately 3 days of Warfarin administration to reach a steady-state anticoagulant effect. But a rat would not die of it in 3 days. To obtain 100% lethality in a common house mouse, more than 21 days of Warfarin laced bait is usually required. Gradually rodents developed resistance to Warfarins, and to counter this, the scientists developed new compounds known as “Superwarfarins”. These are also structurally related to coumarins. Two most common Superwarfarins are difenacoum and brodifenacoum.”

“Brodifenacoum! So slowly we are coming back to how Rama died.”

“You are right Tarun. Superwarfarins are about 100 times more potent than Warfarin on a mole for mole basis. In addition they have a longer duration of action than the traditional warfarins. While warfarins kill a house mouse in 21 days, Superwarfarins can kill them in a single day. These Superwarfarins are also odorless and tasteless and so can easily be administered not only to a rat, but also to an unsuspecting human being.”

“Doctor, I am seeing what you are trying to get at. Suresh came yesterday evening and mixed Brodifacoum, an easily available rat poison in Rama’s food. She ate the food later and died.”

“You are right Tarun. This is exactly what has happened. Look at her lungs. They also show hemorrhages, that I would expect in such a poisoning. I also sent a policeman to go to Suresh’s house and look for Some rat bait. He brought back a packet of rat bait, and I found it contained Brodifacoum. He had bought it only yesterday, and it was half empty. We have searched Suresh’s house, and have found no balls of rat bait there, which could have explained half empty packet of Brodifacoum. I have found Brodifacoum in Rama’s organs also. I have no doubt in my mind that Suresh has killed Rama by giving her Brodifacoum. Come on, let us tell the police who the culprit is.”

"That was very clever of you doctor. Without your clever deduction everybody would have thought Rama died of some mysterious natural disease. This was a most interesting discussion doctor. Tell me what are you going to tell me the next time?"

"Tarun, next time, I would tell you about a very interesting poison - Succinylcholine."