The History of the Discovery of Vitamin K

ABSTRACT

Vitamin K was discovered during the 1930s when a strange haemorrhagic disorder was observed in chickens fed a cholesterol‐free diet. A fat‐soluble agent, present in green leafy vegetables and hog liver, was able to restore haemostasis in the chickens. The chemical structure and the physiological role of vitamin K were uncovered resulting in the Nobel Prize being awarded to Henrik Dam and Edward Doisy in 1943. The discovery of vitamin K led to a breakthrough in our understanding of the human coagulation system, where vitamin K plays a pivotal role in activating prothrombin and other coagulation factors. The prevention of vitamin K–dependent bleeding in newborns by vitamin K prophylaxis was introduced in the 1940s and is today a strong recommendation by the World Health Organization. Vitamin K also became crucial to the management of diseases with high risk of vitamin K deficiency due to malabsorption of fat. Later a new type of drug was developed, vitamin K antagonists, counteracting the physiologic effects of vitamin K for the prevention of thrombotic events. Recent research has indicated that vitamin K may have important functions beyond coagulation in extra‐hepatic tissues by promoting healthy bone mineralization and preventing vascular calcification.

Plain Language Summary

Vitamin K was first discovered in the 1930s when scientists noticed bleeding problems in chickens lacking it. This breakthrough revealed its key role in blood clotting and led to life‐saving practices like giving newborns vitamin K to prevent bleeding. It also became essential for treating people with fat absorption issues and for developing drugs that reduce clotting risks. Today, research shows vitamin K may do more than help blood clot—it could support strong bones and protect blood vessels from harmful calcium buildup, making it important for overall health.

Abbreviations

DOACs

direct oral anticoagulants

GGCX

γ‐glutamate carboxylase

Gla

γ‐carboxy glutamic acid

MGP

matrix gla protein

NOACs

nonvitamin K antagonists

OC

osteocalcin

VKA

vitamin K antagonist

VKDP

vitamin K–dependent protein

VKOR

vitamin K epoxide reductase

WHO

World Health Organization

1. Introduction

The discovery of vitamin K starts in 1928 when the Danish biochemist Henrik Dam studied the effect of a cholesterol‐free diet in chickens (Figure 1). At this point in history, the vitamin research community was still in its infancy and the understanding of vitamins limited. It was the Polish chemist Casimir Funk that in 1912 first introduced the term ‘vitamine.’ He believed that the essential nutritional compounds were amines, thus the name. This was later refuted, leading to the shortening to ‘vitamin’ [1].

FIGURE 1.

Timeline of the most significant milestones in the discovery of vitamin K.

Funk described that diseases such as scurvy or beriberi could be prevented and cured by certain vitamins laying the foundation for the modern understanding of deficiency diseases [1]. Vitamins received great interest from the public and the research area moved quickly. Between 1928 and 1943, nine Nobel prizes were awarded for research in vitamins. It was during these years that vitamin K was discovered [2].

The aim of this narrative review is to describe the history of the discovery of vitamin K, the work that led to its discovery and identification of its molecular structure, its role in human physiology, as well as its implications for prevention and treatment of disease. This review also serves as a tribute to the researchers responsible for the discovery of vitamin K and its significant roles in human physiology and disease prevention. In addition, valuable lessons can often be drawn from the history of major scientific advances—lessons that can inform contemporary thought and research environments.

2. The Bleeding Chickens

The history of vitamin K starts with the Danish biochemist Henrik Dam. In 1928, he initiated a research project to investigate whether chickens could synthesize the sterol, cholesterol (Figure 1). It was known at the time that many animals were able to synthesize cholesterol, but evidence was not clear with regard to chickens. Dam designed the study by putting chickens on a sterol‐free diet. He found that the chickens could not survive on this diet. Many died after only 1 month and therefore he started giving them a small supplement of cholesterol with no improvement. The project led to a paper published in 1929 concluding that chickens could produce cholesterol. This suggested that the death of the chickens was not directly linked to a lack of cholesterol in the diet [3].

The chickens kept on the sterol‐free diet exhibited strange haemorrhaging under the skin, in muscles and internal organs, even with cholesterol supplement. The haemorrhages were also present in the chickens kept on a normal diet, but they were much smaller, up to 3 mm; the chickens on the sterol‐free diet had haemorrhages up to 40 mm. He found that the blood of chickens on the sterol‐free diet tended to coagulate slower compared to the control group [4].

It was this finding that later led to the discovery of vitamin K. However, the area of vitamins was still very new and unexplored. Dam focused on sterols, and in 1935, he finished his dissertation on sterols' biological importance. It did not have a conclusion on the haemorrhaging chickens [4].

Dam returned to the haemorrhaging chickens in 1933–1934. Other colleagues around the world argued that the bleeding had to be due to deficiency of vitamin C, which at that time had been recently discovered. However, Dam had already tested and refuted that hypothesis. Nonetheless, Dam and the medical doctor Fritz Schønheyder tested it again and found the same conclusion: Lack of vitamin C was not the cause of the bleeding. They examined numerous variations of diets for the chickens to determine the cause of the bleeding. They published their conclusion in Nature: ‘The cause of the disease must therefore be a deficiency in an antihemorrhagic factor different from vitamin C and occurring in cereals and seeds’ [5].

They continued studying this unidentified factor trying to narrow in where it could be found in the diet. Dam published their findings in Nature and Science in 1935 where he suggested the term ‘Vitamin K’ for the antihemorrhagic factor (Figure 1) [6]. They explained that the vitamin is fat‐soluble and is found in hog liver, hemp seeds, certain cereals, and vegetables. In the following years, several researchers confirmed the existence of vitamin K and worked to uncover its physiological functions, occurrence in nature, significance and chemical structure [7].

An important study was done by Dam, Schønheyder, and the medical doctor Erik Tage‐Hansen, in 1936. They clarified the role of vitamin K in blood coagulation (Figure 1) [8]. The understanding at that time of how coagulation worked can be seen in Figure 2. The figure explains that the bleeding must be because of lack of or low concentration of either: (1) prothrombin, (2) tissue factor (also called thrombokinase), (3) $\mathrm{C}{\mathrm{a}}^{2+}$ or (4) fibrinogen. They found that the lack of vitamin K in the diet leads to hypoprothrombinemia. Without prothrombin, fibrinogen cannot be activated into fibrin which forms the clot that stops the bleeding [9].

FIGURE 2.

The understanding of coagulation in 1936. It was believed that when a blood vessel was damaged, tissue factor would be exposed; this activated, with calcium ion, prothrombin into thrombin. Thrombin then activated fibrinogen into fibrin, thereby creating a stable blood clot. TF, tissue factor.

3. The Chemical Structure

In January of 1939 Dam and the organic chemist Paul Karrer succeeded in isolating the vitamin from alfalfa as a yellow oil [10]. However, later that year, Edward A. Doisy, a professor in biochemistry at St. Louis University School of Medicine, challenged the purity of the vitamin they had extracted. Doisy and his group also succeeded in isolating vitamin K as a yellow oil and determined the chemical structure of the vitamin (Figure 1). Doisy could conclude that the vitamin purified by Dam and Karrer was not entirely pure. Furthermore, the group was able to show that there are two types of vitamin K. They defined the vitamin that was a yellow oil: vitamin K₁ (phylloquinone), and they found the bacterial variant to be crystalline: vitamin K₂ (menaquinone).

Another scientist exploring vitamin K in the early stages was the biochemist Herman J. Almquist, who was one of the first to confirm Dam's findings. In 1936 Almquist worked with Evan Stokstad, his colleague from Berkeley. They found vitamin K in the faeces of chickens kept on a sterol‐free diet. This indicated that vitamin K could be synthesized in the colon. This knowledge combined with the fact that the chickens had a vitamin K deficiency gave an interesting insight into vitamin K [11]. The advantage of using chickens as an experimental model was that in chickens thrombocytes are not as important for blood coagulation as they are in mammals, and chickens rely much more on the formation of a fibrin clot. Furthermore, their large intestine is short compared to other species, which may cause lower absorption of vitamin K produced by intestinal bacteria [3].

Today, it is known that vitamin K is a fat‐soluble molecule and dependent on lipoproteins for absorption and transport to the liver and other organs. Lipoprotein particles are made of fat and protein are necessary for transporting the hydrophobic fat‐soluble components from the intestines through the hydrophilic fluids like blood, to the liver and other tissues [12]. Lipoproteins contain a central core of cholesterol [13]; this explains why chickens kept on a sterol‐free diet develop hypoprothrombinemia due to vitamin K deficiency. Cholesterol is a sterol; without it in the diet, lipoproteins could not be synthesized in adequate amounts, meaning that the vitamin K in the diet could not be absorbed and transported to the liver.

In western diets, vitamin K is obtained primarily as vitamin K₁, which is found in leafy green vegetables and vegetable oils like olive and rapeseed oil. Vitamin K₂ is mainly found in fermented foods, meats and dairy products [12]. Differences in food sources may influence the bioavailability of the two vitamin forms. Vitamin K₁ is tightly bound to chloroplast membranes in plant tissues, which limits its absorption and reduces its bioavailability. In contrast, vitamin K₂ is typically present in fat‐containing foods, which facilitates intestinal absorption [14].

Although both vitamin K₁ and K₂ share a common naphthoquinone ring structure, they differ in their sidechain, see Figure 3. Vitamin K₂ comprises a group of compounds known menaquinones (MK‐4 to MK‐13), which contain varying numbers of unsaturated isoprenoid units [2].

FIGURE 3.

The chemical structure of vitamin K₁ (phylloquinone) and K₂ (menaquinone‐n) that Edward Doisy discovered in 1939.

In particular, vitamin K₁ has a relatively short plasma half‐life, whereas several forms of vitamin K₂, especially the long‐chain menaquinones, remain in circulation for several days. As a result, vitamin K₁ is primarily taken up by the liver, where it supports the activation of coagulation factors, while long‐chain menaquinones are more readily distributed to extrahepatic tissues, including bone and vascular tissue [14]. Both forms are capable of activating VKDPs through carboxylation.

In Europe, the recommended daily intake of vitamin K is 1 μg phylloquinone/kg body weight [12]. This recommendation is assessed as adequate intake due to limited data on dietary intakes and effects on health outcomes beyond coagulation, as well as lack of generally accepted and validated biomarkers of vitamin K status [15].

The discovery of the chemical structure of the vitamin increased the understanding of the vitamin and paved the way for using it as a medical treatment. Because of the significance of discovering the chemical structure of vitamin K, it was decided in 1943 to award the Nobel Prize in ‘Physiology or Medicine’ jointly to Henrik Dam and Edward Doisy. By that time, vitamin K had been proven to be of great significance in coagulation and had proven to be a lifesaving treatment in patients with severe vitamin K deficiency. The prize was divided between them, Dam for the discovery and Doisy for the discovery of the chemical nature [2].

4. First Clinical Studies

The growing understanding of vitamin K and its function started speculations about the possibility of using vitamin K in medicine. While the exact biochemical function was not yet known, it was well established that vitamin K deficiency led to a slower blood coagulation. One group of patients that had shown this tendency was patients suffering from obstructive jaundice. This made it dangerous to perform surgical procedures on such patients because of the risk of excessive bleeding. This group of patients became the focus for the first clinical trials with vitamin K [16].

Several studies performed by multiple research groups around the years 1935–1937 found that removing bile flow to the intestines in dogs and rats caused bleeding tendency due to low prothrombin levels. It was known at the time that bile is an important factor for absorption of fat‐soluble substances, like vitamin K, and in 1936 the connection between vitamin K and prothrombin had been made. Some of the researchers administered vitamin K to these animals, either through a diet with a lot of vitamin K or by intravenous injections. This proved to eliminate the bleeding tendency [3]. These experiments gave insight into vitamin K's absorption and properties. It showed that bile is a necessary component for the absorption of vitamin K. This means that administering vitamin K orally requires coadministration of bile acids as well to secure absorption. Alternatively, an intravenous injection can be used with one of the more water‐soluble variants of vitamin K [3].

In the hope that this also could help humans with bile defects, Dam and the chemical engineer Johannes Glavind among others performed experiments to test this. In 1938, Dam and Glavind examined three patients with obstructive jaundice who had a slower tendency to coagulate. They gave them each a vitamin K injection and found that it prevented the bleeding [2].

Current research indicates that bile is essential for the absorption of vitamin K. It facilitates the incorporation of vitamin K into micelles, enabling enterocytes to absorb it and subsequently transfer it to the bloodstream through the lymphatic system, where it is bound to chylomicrons [17, 18].

Vitamin K–dependent bleeding in healthy adults is rarely seen. However, several medical conditions, other than obstructive jaundice, can lead to vitamin K deficiency and risk of vitamin K–dependent bleeding. Particularly, diseases with malabsorption of fat, for example, inflammatory bowel diseases (Morbus Crohn and colitis ulcerosa), celiac disease, and cystic fibrosis. Patients with chronic kidney disease are at high risk of vitamin K deficiency, although the reasons for this are not fully understood [19, 20, 21, 22].

5. Vitamin K–Dependent Bleeding in Newborn Infants

In the early 20th century, bleeding in newborns was relatively common and associated with high mortality. At that time, the intracranial bleedings were thought to be caused by trauma during birth, and could explain 25%–40% of case fatalities [23]. With the growing knowledge of vitamin K's role in coagulation, the medical doctor Kenneth Brinkhous and colleagues started to examine the cause of the bleeding and they could in 1937 announce that they had observed low prothrombin levels in the newborns that exhibited increased bleeding [24].

Dam, Erik Tage‐Hansen and the medical doctor Preben Plum also examined the phenomenon. They studied the prothrombin levels during the first period after birth and published their results in 1939. They and others found that it was during the first week of life that the prothrombin level was often critically low and that intravenous injection of vitamin K led to an increase in prothrombin [25]. This connection was more definitively proven by the medical doctor William Waddel, who treated 400 infants with vitamin K and compared them to a control group of 219 infants not receiving the vitamin. His study showed that 10.4% of the control group developed bleeding, whereas only 1% of the infants treated with vitamin K did [26]. In 1940, obstetricians carried out a study where they gave oral vitamin K prophylaxis to every other woman in labour admitted to obstetrical service at Johns Hopkins Hospital. In these two otherwise comparable series, the child mortality was 1.5% and 4.1% in the vitamin K and control group, respectively [27]. The study demonstrated a significant decrease in bleeding in a large group of infants and thereby established vitamin K supplementation in newborns as an important preventative measure for a potentially deadly disorder. Prophylactic injections of vitamin K in newborns became a standard preventive measure (Figure 1) [28].

Vitamin K deficiency is believed to be common in newborns due to limited placental transfer of vitamin K from mother to foetus and low vitamin K levels in breast milk [28, 29]. It has thus been proposed that establishing the bacterial flora in the intestine of the newborn is important due to production of vitamin K by intestinal bacteria [3].

Today, it is a strong recommendation by the World Health Organization (WHO) that all newborns receive 1 mg vitamin K by intramuscular injection shortly after birth [30]. Vitamin K prophylaxis in newborns has likely saved numerous newborn infants' lives and is a great public health success. Still, some countries in less affluent parts of the world do not provide vitamin K prophylaxis putting newborn infants at risk of vitamin K–dependent bleeding and death [28].

6. Cows and Clovers

In the early 1920s, an unusual phenomenon emerged in Canada and the United States, characterized by the sudden death of cattle due to extensive internal haemorrhaging. This prompted investigations that ultimately identified the diet as the probable cause. The affected cattle had consumed sweet clover, a commonly used forage, which had become contaminated with mould, rendering it toxic. The impaired coagulation was attributed to a reduced prothrombin level. At that time, the discovery of vitamin K and its role in prothrombin activation had not yet occurred [13].

In 1933, the biochemist Karl Link got interested in this problematic situation, when a farmer dropped 100 lbs of the spoiled hay and blood from the cows, off at his lab. Link and his student isolated and characterized this haemorrhagic agent. After 5 years, they succeeded in isolating what was later known as dicumarol [31].

In the following 20 years, the knowledge and understanding of vitamin K developed significantly. Especially important was the connection between vitamin K deficiency, low prothrombin levels, and severe bleeding. In 1939, Doisy and his group determined the chemical structure of vitamin K; Link recognized that it had a very similar structure to dicumarol, but the opposite effect. The low prothrombin levels caused by dicumarol could be counteracted by vitamin K [31].

Link and his group continued the studies on dicumarol; they found several analogues of dicoumarol that had similar antihemorrhagic effects. They synthesized and tested these and found one that was more potent than dicumarol, later named Warfarin. Link found it so toxic that he did not patent it, but one of Link's students, Mark Stahmann, saw its potential and patented it [31].

The connection between dicoumarol and vitamin K was important; it solved the problem of the cows, which could be cured by vitamin K injections. It also suggested a solution for patients suffering from thrombotic disorders. After testing the theory on animals, experiments were done in humans; it was implemented in clinical medicine in 1941 (Figure 1) [31].

From 1947, dicumarol was used as a highly effective rat poison, with a synthetic analogue showing up to a 100% mortality rate. Although it had been acknowledged in 1942 that it was a vitamin K antagonist (VKA) and that it was far more toxic to rats than humans, many doctors were hesitant to use the drug, which had been classified as a poison. However, it made its way into the medical field and analogues are still widely used today [32].

VKAs are a commonly used treatment of thrombotic disorders, such as myocardial infarction, stroke, or venous thrombosis. They are all acquired coagulation disorders, where the balance of pro‐ versus anticoagulation is tipped towards pro‐coagulation, causing fatal occlusions of vessels in the heart, brain or lungs [33].

The uncovering of the biochemical action and the metabolism of vitamin K has increased our understanding of how the functions of vitamin K, for example, how it is inhibited by warfarin.

Important progress was made in 1974 when a segment in prothrombin was identified as the amino acid γ‐carboxy glutamic acid (Gla). This led to the discovery that vitamin K's functions as a cofactor in a posttranslational modification where glutamate residues are carboxylated (Figure 1). Later, the same segment was identified in multiple of the coagulation proteins in the secondary haemostasis; these are factors VII, IX and X, prothrombin, and the anticoagulation proteins: protein C and S [15].

Eventually, the key enzyme of it all was purified, the γ‐glutamate carboxylase (GGCX). Later, the second key enzyme in vitamin K metabolism also purified, the vitamin K epoxide reductase (VKOR) [15]. The vitamin K metabolism is shown in Figure 4. When acting as a cofactor vitamin K gets oxidized (epoxide), and the VKOR reduces vitamin K to its active form again, ready for a new cycle. Warfarin is a VKA that inhibits the activity of VKOR thereby preventing vitamin K from assisting in the γ‐carboxylation of the coagulation proteins because they must undergo this modification to be active [34].

FIGURE 4.

Vitamin K metabolism. Vitamin K is a cofactor for γ‐glutamate carboxylase (GGCX) during the posttranslational modification of coagulation factors. During this process, vitamin K is oxidized (to an epoxide) and needs to be reduced by vitamin K epoxide reductase (VKOR) to become active again. Vitamin K antagonist (VKA) inhibits VKOR, thereby preventing a new cycle and resulting in inactive coagulation proteins.

More recently, an alternative for VKA has become available: the ‘nonvitamin K antagonist’ (NOACs), also referred to as ‘direct oral anticoagulants’ (DOACs). They inhibit either thrombin or factor X directly, whereas VKA inhibits activation of all vitamin K‐dependent proteins (VKDPs) [35].

7. Contemporary Understanding of the Role of Vitamin K in Coagulation and Beyond

The modern understanding of coagulation contains primary and secondary haemostasis, which together form a clot in the damaged vessel wall to stop bleeding, and fibrinolysis, which dissolves the clot. It requires delicate regulation with constant inhibition of coagulation by the intact vessel and a fast‐reacting system upon damage [33].

Primary haemostasis describes the initial step of coagulation; platelets circulating in the blood react to the suddenly exposed factors in the subendothelial tissue. These factors mediate the adhesion and activation of platelets. The activation causes a morphologic change in the platelets, release of granules, and relocating intracellular negatively charged phospholipids (PLs) to the external cell membrane; these are important for secondary haemostasis [33].

The primary haemostasis results in a platelet plug, formed by fibrinogen; it is fast reacting, but the clot is unstable, and this is where the secondary haemostasis catalyses the conversion of fibrinogen to fibrin.

Secondary haemostasis can be initiated through the extrinsic or intrinsic pathway, and they activate factor X in the common pathway [33]. Secondary haemostasis leads to the conversion of fibrinogen to a stable fibrin clot. The secondary haemostasis is a complex cascade of proteins activating others with cross‐reacting feedback mechanisms that amplify the stimulus. A simplified version of the cascade is shown in Figure 5. Initiation of the cascade happens with contact with factors and charges in the subendothelial tissue or the thrombocytes. An essential function of secondary haemostasis is the creation of complexes between coagulation proteins‐$\mathrm{C}{\mathrm{a}}^{2+}$‐phospholipids (on the surface of the thrombocytes), to activate some of the coagulation proteins. Most of the coagulation proteins are produced in the liver and require a posttranslational vitamin K–dependent γ‐carboxylation, which makes binding of $\mathrm{C}{\mathrm{a}}^{2+}$ possible; these are factor VII, IX, X and prothrombin. Protein C and protein S are also dependent on vitamin K but are both anticoagulation proteins that inactivate factor V and VIII, which are important amplifiers of the cascade [33].

FIGURE 5.

The secondary haemostasis. It is preceded by the primary haemostasis, which results in an instable platelet plug. Secondary haemostasis is initiated through the extrinsic and intrinsic pathways, both resulting in activated factor X, which starts the common pathway that leads to the creation of a stable fibrin clot. The extrinsic pathway is activated through the exposed tissue factor (TF) in the subendothelial tissue; the intrinsic is activated by contact between factor XII and the damaged vessel wall. The vitamin K–dependent proteins (VKDP) are marked in black, the non‐VKDP in brown. The VKDP is activated by making a complex with phospholipids on the platelets and Ca²⁺.

Over recent decades there has been increasing interest in the role of VKDPs beyond coagulation factors, for example, osteocalcin (OC) and matrix gla protein (MGP). OC is a VKDP present in bone tissues involved in bone formation. MGP is present in many extrahepatic tissues such as arterial endothelium and is a strong inhibitor of vascular calcification, which is part of the atherosclerotic processes and associated with high risk of cardiovascular diseases [15]. In the context of insufficient vitamin K supply, VKDPs manifest in elevated levels of their inactive undercarboxylated forms (ucOC and ucMGP) within the circulation. Consequently, these undercarboxylated forms serve as inverse biomarkers of functional vitamin K deficiency in research [12, 17]. It is crucial to consider the total levels of these VKDPs, for instance, by employing the ratio between ucOC and cOC. Nonetheless, these biomarkers have not yet been extensively adopted in clinical practice.

Various VKDPs, including MGP and OC [36], are expressed in vascular, skeletal, and other tissues. These proteins play a crucial role in calcium homeostasis, the inhibition of vascular calcification, and metabolic and inflammatory pathways, thereby providing a mechanistic foundation for their potential protective effects against chronic diseases. Observational studies consistently associate low vitamin K status, often indicated by elevated levels of undercarboxylated VKDPs, with an increased risk of cardiovascular disease and mortality. This association is potentially mediated by inadequate activation of MGP, leading to the progression of vascular calcification. Vitamin K–dependent carboxylation of OC plays a role in bone metabolism, with higher dietary vitamin K intake linked to modest reductions in fracture risk. However, randomized trials have shown inconsistent effects on bone mineral density [37, 38]. Patients with impaired kidney function face a significantly increased risk of vascular calcification and cardiovascular disease. It is well‐established that individuals with chronic or acute kidney disease exhibit low vitamin K status, prompting numerous attempts to reduce cardiovascular risk through vitamin K supplementation [39]. Currently, the evidence supporting this approach remains inconclusive. Recent data indicate potential roles in glucose metabolism, possibly through effects on inflammation and insulin sensitivity; however, interventional evidence remains inconclusive. Although epidemiological and mechanistic studies suggest a protective role of vitamin K in age‐related chronic diseases, randomized controlled trials have produced varied results [40, 41]. Consequently, the current evidence is insufficient to establish causality or determine optimal intake for extrahepatic health outcomes.

8. Conclusions

The discovery of vitamin K and its pivotal role in coagulation in the 1930s represents a breakthrough in our understanding of human physiology. The discovery was quickly implemented in both clinical and preventive medicine.

The prevention of vitamin K–dependent bleeding in newborns by vitamin K prophylaxis was introduced in the 1940s and is today a strong recommendation by the WHO. Vitamin K also became crucial to the management of diseases with high risk of vitamin K deficiency such as diseases with malabsorption of fat. Recent research has indicated that vitamin K may have important functions beyond coagulation in extra‐hepatic tissues by promoting healthy bone mineralization and preventing vascular calcification.

The history of the discovery of vitamin K is the story about the importance of curiosity and hard work in driving science forward. Of note is that the discovery of vitamin K started by Henrik Dam's unexpected observation of ‘the bleeding chickens’ in his investigation of animal physiology underlining that even major research discoveries may sometimes be accidental by nature.

Author Contributions

A.L. supervised and conceived the idea of the review. H.N.T. drafted the first version of the manuscript. A.L. provided expertise on vitamin K. L.Z. provided expertise on science history. All authors contributed to critical revision of the manuscript and have read and approved the final version of the manuscript. H.N.T. produced the illustrations.

Conflicts of Interest

A. Linneberg has received investigational products from Kappa Bioscience AS for an intervention trial (The InterVitaminK Trial; clinicaltrials.gov identifier NCT05259046) using vitamin K₂ supplements as the active intervention. The other authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.