“Coagulation” may not always be as beautiful as resin turning into amber or water droplets turning into snowflakes, but sometimes it can come at an inopportune time, such as when blood clots in the blood vessels. Therefore, we need drugs to fight against it, namely anticoagulants. Warfarin is an important member of the anticoagulants. It doesn’t have an illustrious pedigree, but its efficacy is outstanding and enduring. It is both convenient and cumbersome to take, and while the dosage must be taken with care, as if dancing on a tightrope. There are many interesting stories about it. The “Rat Race” from the Pasture In 1921, a strange phenomenon spread across many pastures in Canada and the northern United States. Cattle and sheep suddenly became so vulnerable that their blood could not clot properly after bleeding wounds, and operations that would not normally seem life-threatening, such as castration or dehorning, caused them to bleed to death. Strangely enough, the living conditions and the feed the animals ate were no different than in previous years, leaving the ranchers puzzled. In order to find out the culprit of the strange events, Canadian veterinary pathologist Frank Schofield (Frank Schofield) investigated. He found that in that year, the weather was so unusually warm that the farm’s stored forage (a leguminous plant commonly known as wild alfalfa) became moldy and rotted, so he speculated that the moldy forage was causing a blood clotting disorder in the livestock. Scofield fed fresh and moldy forage to rabbits, and the rabbits that ate the moldy forage suffered abnormal bleeding, while the rabbits that ate the fresh forage were unharmed, thus confirming his own conjecture. In 1940, chemist Karl Paul Link finally isolated a substance with anticoagulant properties from these moldy forages and determined its structure. This is a bicoumarin-like substance, consisting of two molecules of coumarin-like substances combined. Coumarins are very common in plants and are responsible for the sweet aroma of the herb (which is why it is called “Sweet Clover”, as the plant actually tastes bitter). The single coumarin molecule by itself does not cause blood clotting disorders, but when two molecules combine to form a bicoumarin structure, a reaction that occurs when the grass goes moldy, this effect occurs. In the years since, several substances with similar molecular structures have been discovered. Unsurprisingly, they all had an anticoagulant effect. In the first few years after the discovery of this substance, people did not think of using it as a drug, but made it into rat poison. This was probably due to the fact that the tragic deaths of cattle and sheep in the pastures left the impression that “bicoumarin = poison”. In order to make the rat poison more powerful, Link modified the structure of bicoumarin, and in 1948 obtained a more potent anticoagulant substance, and named it warfarin. At this point, the protagonist of this article officially debuted. Warfarin has been used as rat poison for several years since then. Rats are wary by nature, and once they realize that their kind has eaten something and then immediately died, other rats won’t touch the food, which makes it a challenge to make the rat poison effective in the long run. However, it is said that rats do not die immediately after eating warfarin, making it difficult for their forgetful brethren to directly link warfarin to the death of their brethren, and so the rat poison remained effective for a longer period of time. As a result, warfarin was a popular rat poison for a long time and is still used today. Rat poison has always been associated with suicide, and warfarin was no exception: in 1951, a disillusioned U.S. soldier attempted suicide by ingesting warfarin rat poison. Fortunately or unfortunately for him, the man was rushed to the hospital and made a full recovery after being treated with Vitamin K. (Vitamin K counteracts the effects of warfarin, as will be mentioned below). This accident led to the realization that this rat poison was accidentally quite safe to use on humans. It is also true that many patients need anticoagulant substances to prevent blood clots from forming. Thus, research began to develop warfarin into an anticoagulant drug, and in 1954, warfarin was officially approved for use in humans. In 1954, warfarin was officially approved for use in humans, opening a new chapter in the history of anticoagulant drugs. Oral anticoagulation, unique Coagulation is a very complex process, the process of memorization has been deeply troubled many students of physiology (including me = = =). The process consists of a series of interlocking reactions, often visualized as a “coagulation waterfall”. The key to clotting is the activation of the enzyme thrombin, which then allows the formation of a fibrin clot. The activation of thrombin requires the cooperation of several coagulation factors. Of the many clotting factors, a significant number require the involvement of vitamin K for their formation and activation. Vitamin K is constantly recycled in the body with the help of vitamin K epoxide reductase, and warfarin can impede this cycle by preempting vitamin K epoxide reductase. As a result, the vitamin K-dependent coagulation factors are deprived of their “backing”, and their amount and activity are greatly reduced, making the blood less likely to clot. The clinical position of warfarin is quite important and even irreplaceable. Many patients are prone to abnormal clotting, or thrombosis, in their blood vessels due to disease. Not only can the clot block the blood vessel in place and interfere with the blood supply, but it can also dislodge and then embolize elsewhere along the bloodstream – either of which can be dangerous, especially if it occurs in a very important organ such as the heart, brain, or lungs. That’s when anticoagulant drugs are needed to help prevent blood clots. Before warfarin came on the market, the anticoagulant drug used in clinical practice was heparin (an anticoagulant substance originally present in the body and still in use today), which can only be injected, making it very inconvenient for patients who need to use it for a long period of time. The advent of warfarin solved this problem, and taking a few tablets was obviously much more acceptable than getting injections every day. Moreover, no new oral anticoagulants have appeared in the decades since warfarin came on the market, which has made it enduring. Although some new oral anticoagulants that are more convenient to use have appeared in recent years, such as rivaroxaban and dabigatran, which may gradually take the place of warfarin in the future. However, for the time being, warfarin is inexpensive and has a lot of experience in clinical use, and will remain the mainstream for a number of years to come. Balance on the wire There is no doubt that warfarin is a very effective drug, and just a few milligrams are enough to prevent the formation of blood clots. But it can also pose some problems. Warfarin has a narrow therapeutic window; a smaller dose won’t have the desired effect, while a larger dose increases the risk of bleeding. Bleeding is the most common side effect of warfarin, and it’s also a dangerous one that can be just as life-threatening as blood clots. This makes warfarin treatment like walking a tightrope, where the balance must be carefully maintained to reach the treatment goal safely. Even more troubling, the conditions of this balance are not set in stone. Warfarin’s effectiveness can be swayed by many factors. A gravity-sensing game called Wire Heroes is probably the most apt illustration of this influence. In the game, the player controls a tightrope-walking clown toward the end of the line at the other end of the wire. Balancing on a tightrope is not easy, but what’s worse is that there are many interruptions along the way, such as a bird resting on a balance pole or a sudden gust of wind, which must be adjusted in order to establish a new equilibrium. For starters, vitamin K intake is an issue. Vitamin K can diminish or even completely counteract the effects of warfarin, and some foods are rich in vitamin K, such as spinach (90 grams of cooked spinach contains 444.2 micrograms of vitamin K, which is 555 percent of the average person’s daily requirement) and kale (67 grams of raw kale contains 547.4 micrograms of vitamin K, which is 684 percent of the daily requirement). Such foods, if eaten in excess, will naturally prevent warfarin from working. In addition to this, the effectiveness of warfarin is affected by many medications. Many drugs are metabolized in the body by the liver into inactive metabolites and then excreted from the body, and this is also the case with warfarin. Drug metabolizing enzymes are not a “one-to-one service” and many drugs share the same enzymes as warfarin. When they coexist with warfarin in the body, they will compete with warfarin for the metabolizing enzyme, resulting in slower metabolism of warfarin and higher drug concentrations. There are also drugs that can increase the synthesis and activity of metabolizing enzymes, which in turn can reduce the concentration and efficacy of warfarin. The number of these drugs that can affect the effectiveness of warfarin is quite staggering and includes some herbs (e.g. ginseng can reduce the effects of warfarin). In addition to this, genetic differences between people should not be underestimated. In recent years, the phenomenon of genetic differences causing differences in drug efficacy has become better known, and a new discipline, pharmacogenetics, has developed as a result. The genes that can affect the efficacy of warfarin are mainly the genes coding for its target enzymes and the genes of drug metabolizing enzymes, which have multiple alleles with different levels of activity. People carrying different alleles have considerable differences in their sensitivity to warfarin, and require different dosages. With so many different factors to consider, it can be a headache for doctors and pharmacists. Fortunately, there is a “no change” solution – monitor the efficacy and then adjust the dose. The efficacy of warfarin is directly reflected by the coagulation function, which is relatively simple to measure with a blood draw. All that is needed is to start treatment with a smaller dose and then monitor the clotting function frequently, adjusting it according to the results so that the results eventually stabilize. However, even after the results have stabilized, regular monitoring is still required. Such monitoring is indeed a bit cumbersome and discounts the convenience of warfarin as an oral medication. But having it escorted is what allows warfarin to dance on the tightrope and become a long-lasting anticoagulant.