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Vitamin K-deficient hemorrhagic syndrome in newborns and children in the first months of life

Summary

The article is devoted to hemorrhagic disease of the newborn (HRD). Data on the biological role of vitamin K and its metabolism in newborns are presented. The frequency of development, causes and clinical symptoms of the early, classical and late forms of the disease are presented. Based on a review of domestic and foreign publications, the issues of laboratory diagnosis, prevention and treatment of HRD are considered. Given the risk of developing life-threatening bleeding, emphasis was placed on the need for maximum coverage of newborns with prophylactic administration of vitamin K in accordance with the Clinical guidelines for the diagnosis and treatment of hemorrhagic disease of the newborn, developed by the Association of Neonatologists (2015). A clinical case of the development of a late form of HRD in a child who was exclusively breastfed and did not receive vitamin K for prevention after birth is described.

Keywords: hemorrhagic disease of the newborn, vitamin K Deficiency hemorrhagic syndrome, newborns, vitamin K

Neonatology: news, opinions, education. 2015. No. 3. S. 74-82.

Hemorrhagic disease of the newborn (HrDN) (ICD-10 code - P53), or vitamin K-deficient hemorrhagic syndrome, is a disease manifested by increased bleeding in newborns and children in the first months of life due to insufficient blood coagulation factors (II, VII, IX, X), whose activity depends on vitamin K.

The term "hemorrhagic disease of the newborn" was coined in 1894 (Townsend, 1894) to refer to bleeding in newborns not associated with traumatic exposure or hemophilia. More recently, vitamin K deficiency has been shown to be the cause of many of these bleedings, leading to the more accurate term being "vitamin K deficiency bleeding" (VKDB) [1].

The biological role of vitamin K and its metabolism in newborns

The biological role of vitamin K is to activate gamma-carboxylation of glutamic acid residues in prothrombin (factor II), proconvertin (factor VII), antihemophilic globulin B (factor IX) and Stuart-Prower factor (factor X), as well as in antiproteases plasma C and S, which play an important role in the anticoagulant system.

With a lack of vitamin K in the liver, there is a synthesis of inactive decarboxylated forms of K-dependent factors that are unable to bind calcium ions and fully participate in blood coagulation (PIVKA - protein induced by vitamin K absence or antagonism) [2-4]. In studies, the determination of the level of PIVKA-II, a decarboxylated form of prothrombin, is usually used.

In 1929, the Danish biochemist H. Dam isolated a fat-soluble vitamin, which in 1935 was named vitamin K, but to date, the pathways of vitamin K metabolism have not been fully understood.

The main source of supply for the body is vitamin K of plant origin, which is called vitamin K1, or phylloquinone. It comes from food - green vegetables, vegetable oils, dairy products. Another form of vitamin K, vitamin K2, or menaquinone, is of bacterial origin. Vitamin K2 is mainly synthesized by the intestinal microflora. The role of vitamin K2 has been studied very little. Its largest amount is located inside bacterial membranes and, possibly, is poorly absorbed. It is believed that vitamin K2 is of little importance to the body. It is known that the deposition of vitamin K occurs in the form of menaquinone-4 (MK-4) in the pancreas, salivary glands, and brain. Currently, research is underway to study the metabolic pathways of various forms of vitamin K. One of the ways to convert vitamins K1 and K2 into a deposited form is their metabolization in the intestine into an intermediate substance - menadione (vitamin K3). Then, from the menadione circulating in the blood, the deposited form of menaquinone-4 is synthesized in the extrahepatic tissues [4-7].

All newborns are relatively deficient in vitamin K. The transfer of vitamin K1 across the placenta is extremely limited. The maternal-fetal gradient for vitamin K1 is 30:1, as a result of which the concentration of vitamin K in the blood of the fetus and its reserves at the time of birth are extremely small. Cord blood vitamin K1 levels range from very low (<2 mg/mL) to undetectable. Vitamin K2 in the liver of newborns is practically not detected or occurs in extremely low quantities. This form of vitamin begins to accumulate gradually during the first months of life. It may be that breastfeeding infants accumulate vitamin K2 more slowly because of their predominant gut microflora ( Bifidumbacterium , Lactobacillus ) does not synthesize vitamin K2.

Bacteria that produce vitamin K2 - Bacteroides fragilis , E. coli , are more common in children receiving artificial milk formulas [1, 4, 8].

At the same time, in 10-52% of newborns in the umbilical cord blood, an increased level of PIVKA-II is determined, indicating a deficiency of vitamin K, and by the 3-5th day of life, a high level of PIVKA-II is found in 50-60% of children, who are breastfed and have not received prophylactic administration of vitamin K [4, 9, 10]. Thus, for newborns, the only source of vitamin K is its exogenous intake: with human milk, artificial nutritional formula, or in the form of a drug.

It is known that HrDN develops more often in breastfed children, since the content of vitamin K1 in breast milk is much lower than in artificial milk formulas, usually <10 µg/l [4]. While artificial milk formulas for full-term babies contain about 50 µg/l of vitamin K, and mixtures for premature babies contain up to 60-100 µg/l.

Classification of hemorrhagic disease of the newborn

There are 3 forms of HRD depending on the age of symptom onset: early , classical and late .

Bleeding in all forms of the disease is based on vitamin K deficiency. However, the risk factors and causes of symptoms differ in different forms.

Early HRD

Not well studied. Occurs rarely. Manifests during the first 24 hours of a child's life.

As a rule, the cause of the development of the early form of HRD is the maternal use during pregnancy of drugs that disrupt the metabolism of vitamin K, such as indirect anticoagulants (warfarin, phenindione), anticonvulsants (barbiturates, carbamazepine, phenytoin), anti-TB drugs (isoniazid, rifampicin ).

The incidence of this form in children whose mothers received these drugs during pregnancy without vitamin K supplements reaches 6-12% [1, 11]. In general, the frequency of the early form of HRD, according to a 6-year follow-up in Switzerland from 2005 to 2011, was 0.22 per 100,000 [12].

In the early form, bleeding of any localization, including in the brain, is possible. Bleeding associated with birth trauma is typical [9, 13]. It is believed that this form of the disease usually cannot be prevented by the prophylactic administration of vitamin K after childbirth [1, 14].

Classical form of HRD

Manifested by bleeding on the 2-7th day of life.

In addition to the above reasons for vitamin K deficiency in the fetus and newborn, there are 2 more important reasons for the development of this form: 1) lack of prophylactic use of vitamin K immediately after birth and 2) insufficient milk supply.

Gastrointestinal bleeding, skin hemorrhage, bleeding from injection/invasion sites, umbilical cord, and nose are common. Intracranial hemorrhages are less typical [2, 9, 15].

The estimated incidence of classical HRD without vitamin K prophylaxis is 0.25-1.5%. Prophylactic administration of vitamin K immediately after the birth of a child makes it possible to practically eliminate this form of HRD [1, 12].

Late form of HRD

It is diagnosed in cases of development of bleeding symptoms in the period from the 8th day to the 6th month of life, although, as a rule, the manifestation occurs at the age of 2-12 weeks [1, 2, 9, 14, 16].

There are 3 main groups of children who are at risk of developing a late form of HRD.

The first group consists of children with vitamin K deficiency: exclusively breastfed and not receiving vitamin K prophylaxis after birth [12, 14, 17].

Group 2 includes children with malabsorption of vitamin K in the gastrointestinal tract. This condition is observed in cholestatic and intestinal diseases accompanied by malabsorption (diarrhea for more than 1 week, cystic fibrosis, short bowel syndrome, celiac disease) [1, 18, 19].

Group 3 includes children receiving long-term parenteral nutrition with inadequate vitamin K supply. or death [1, 11, 20-22].

In some children, some time before a cerebral hemorrhage (from a day to a week), small "warning" hemorrhages are observed [16, 17, 23, 24].

Without the prophylactic use of vitamin K immediately after the birth of a child, the frequency of the late form of HRD is in the range of 5-20 per 100,000 newborns. Intramuscular prophylactic administration of vitamin K can significantly reduce the frequency of the late form, virtually eliminating the possibility of its development in children without cholestasis and malabsorption [1, 12, 25, 26]. under conditions of triple oral prophylactic administration of a water-soluble form of vitamin

K (2 mg on the 1st, 4th day and 4 weeks) showed that the frequency of the late form is 0.87 per 100 thousand, while all cases of late bleeding appeared in children who are breastfed and with cholestatic disease. The development of the classical form is not registered [12].

Laboratory signs of HRD

Laboratory signs of HRD are primarily changes in prothrombin tests: prolongation of prothrombin time (PT), decrease in prothrombin index (PTI), increase in international normalized ratio (INR). A significant change in prothrombin tests is characteristic - 4 times or more. In more severe cases, prolongation of the activated partial thromboplastin time (APTT) is added [11, 23, 27, 28].

Fibrinogen levels, platelets, thrombin time, as a rule, does not change. However, with massive bleeding and critical conditions, these indicators can also become pathological, which is more often observed in the late form of HRD.

Diagnosis is confirmed by normalization of prothrombin tests and cessation of bleeding after administration of vitamin K [15, 17, 20, 27]. According to Russian authors, complex treatment of the late form of HRD (administration of menadione and fresh frozen plasma) leads to normalization of prothrombin tests within 6-8 to 18-24 hours [17, 24].

When evaluating a coagulogram, it must be taken into account that the normative values ​​of hemostasis in newborns and children in the first months of life differ from the reference values ​​in adults and are subject to significant changes immediately after birth. And premature babies have their own peculiarities of hemostasis depending on gestational age, characterized by a significant range of values. Newborns and premature babies are characterized by a hypocoagulable orientation of the plasma-coagulation link of hemostasis against the background of an increase in intravascular blood coagulation and fibrinolysis activity [an increase in the level of fibrin degradation products (FDP) and D-dimers] [28-34].

The absolute values ​​of hemostasis parameters depend on the reagent and analyzer, therefore it is recommended that each laboratory determine its own reference values ​​for newborns and premature infants in accordance with the methodology used [34, 35].

Determination of vitamin K is not of diagnostic value due to its low concentration in newborns [11].

The level of PIVKA-II can help in the diagnosis of latent vitamin K deficiency, however, it is not classified as the main diagnostic marker of HrDN in practice and is mainly used in scientific papers [4, 9].

Treatment of HrDN

Based on the principles of hemorrhage control and elimination of vitamin K deficiency.

Any child with suspected HrDN should be given vitamin K immediately, without waiting for laboratory confirmation. In the Russian Federation, the vitamin K preparation is menadione sodium bisulfite (Vikasol) - a water-soluble synthetic analogue of vitamin K3. It must be taken into account that its action begins after 8-24 hours.

In case of ongoing and life-threatening bleeding, fresh frozen plasma is indicated, 36]. Instead of plasma, it is possible to use a concentrated preparation of the prothrombin complex [2, 9, 37]. Its administration should be monitored due to the risk of thromboembolic complications [38].

HrDN prevention

HrDN prevention is a priority for neonatal and pediatric services.

To increase the concentration of vitamin K in the body of a pregnant woman and in breast milk, a woman is recommended a diet using foods rich in vitamin K1, as well as taking multivitamin complexes [4, 13, 15].

Pregnant women who take drugs that interfere with vitamin K metabolism during pregnancy are recommended to take additional vitamin K: in the III trimester at a dose of 5 mg/day or 2 weeks before delivery at a dose of 20 mg/day [1, 14]. However, all these measures are not considered sufficient for the full prevention of all forms of HRD.

Taking into account the physiology of the coagulation system and vitamin K metabolism in newborns, in developed countries, prophylactic administration of a vitamin K preparation to all newborns is accepted, while from 1960s only vitamin K1 preparations are used. Studies conducted so far have shown that menadione has an oxidizing effect on fetal hemoglobin, leading to hemolysis, the formation of methemoglobin and Heinz bodies in erythrocytes, which is associated with impaired glutathione metabolism against the background of insufficient antioxidant protection in newborns and, especially, in premature babies. The toxic effect of menadione has been identified when using high doses (more than 10 mg) [4, 15, 39, 40].

Prophylactic use of vitamin K1 preparations has been shown to be effective in numerous studies. It is believed that a single parenteral administration of vitamin K1 after the birth of a child is sufficient to prevent the classic and late forms of HRD in children who do not have symptoms of cholestasis and malabsorption. In some countries, enteral supplementation of vitamin K1 is used for the same purpose, but in these cases it is necessary to take several doses of vitamin K1 orally according to certain schemes. In the presence of cholestasis syndrome or malabsorption, the child will need additional administration of vitamin K [1, 11, 16, 20, 27, 41, 42].

Taking into account the lack of vitamin K1 currently registered in the Russian Federation, for the prevention of vitamin K-deficient hemorrhagic syndrome in our country, intramuscular administration of a 1% solution of menadione sodium bisulfite is used, which is administered in the first hours after birth. During surgical interventions in newborns with possible severe parenchymal bleeding, as well as in children with cholestasis or malabsorption syndrome, additional administration of vitamin K is necessary (see figure).

The efficacy of menadione can be considered proven for the prevention of the classic form of HRD in full-term infants, since many studies have yielded identical results: the administration of menadione intramuscularly (including at a dose of 1 mg) led to a significant increase in PTI, a decrease in APTT, PT , the level of PIVKA-II, a decrease in the frequency of bleeding, while toxic effects were not registered [27, 29, 43, 44].

The high frequency of intracranial hemorrhages in late form of hemorrhagic disease in children who are exclusively breastfed makes the prevention of this form particularly relevant. Numerous foreign studies have shown the effectiveness of a single parenteral administration of vitamin K1 immediately after the birth of a child to prevent this form of the disease. There are practically no studies on the effectiveness of menadione for the prevention of the late form of HRD in the modern literature, which is to some extent explained by what happened in 1960s in many countries by replacing it with a vitamin K1 preparation. Nevertheless, there are few publications in the domestic literature that indicate that the cases of the late form of HRD developed in exclusively breastfed children who did not receive prophylactic administration of menadione in the maternity hospital.

One of the publications presents an analysis of 9 cases of late hemorrhagic disease accompanied by intracranial hemorrhages. The disease developed in children aged 1 month to 2 months 20 days, who were breastfed and did not have a serious somatic pathology. The disease ended unfavorably in 7 (78%) patients: death occurred in 6 children, disability - in 1. The authors try to draw attention to the fact that none of the patients received prophylactic administration of vitamin K in the maternity hospital [17].

Another review presents an analysis of 34 cases of late HRD with intracranial hemorrhage.

The disease manifested from the 3rd to the 8th week. All children were breastfed and did not receive vitamin K prophylaxis [24].

Clinical case of late form of HRD

Boy D . was born from the 3rd pregnancy (1st - frozen, 2nd - delivery on time, the child is healthy), proceeding without features, from 2 births at 39week with body weight 2820 g, height 50 cm. Apgar score was 9/10 points. Attached to the breast in the delivery room. Vaccinated with BCG and hepatitis B vaccine at the maternity hospital. Vitamin K was not administered prophylactically. He was discharged from the maternity hospital in a satisfactory condition with a bilirubin level of 200 µmol/l. Was breastfed. During the first month, he gained 500 g in weight.

At the 2-3rd week of life, there was a slight umbilical bleeding, he did not receive treatment. At the age of 27 days, there was a slight bloody discharge from the nose and a hemorrhagic crust in the nose. The next day, at the age of 28 days, the mother noticed a small hematoma in the child on the back under the shoulder blade, about 1.5 cm in size. In the morning at 29On the 1st day of life, a single vomiting was noted, the child did not suckle well, was restless, tucked up his legs. The doctor on duty at the polyclinic diagnosed intestinal colic.

By evening the child became lethargic, pale, vomiting was observed. On the morning of the 30th day of life, due to the progressive deterioration of his condition, he was hospitalized with a diagnosis of prolonged jaundice, intestinal colic, hydrocephalic syndrome.

Upon admission to the hospital. The condition is extremely difficult. Body temperature 38 °C. The child practically did not react to examination. There was a decortication posture, pronounced hyperesthesia, an irritated monotonous cry, bulging of the large fontanel, anisocoria on the right, the skin was of a pale icteric color, on the back there was a hematoma 1.8-2.0 cm in diameter, the subcutaneous fat layer was thinned, tachycardia was noted. On other bodies - without visible deviations.

Examination data

In the clinical blood test: Hb 99 g/l, erythrocytes 2.71×1012/l, platelets 165×109/l. In a biochemical blood test: total protein 57 g/l, total bilirubin 227 µmol/l, direct 16.1 µmol/l, glucose 5.1 mmol/l, ALT 12 U/l, AST 13.4 U/l.

Coagulogram. Conclusion: hypocoagulation associated with a deficiency of K-dependent coagulation factors (see table).

Based on the anamnesis, clinical picture and additional examination, the diagnosis of HRD (vitamin K-deficient bleeding), late form was established.

Intraventricular hemorrhage III degree. Posthemorrhagic anemia.

The main diagnosis was treated: vikasol 1 mg/kg 1 r/day for 3 days, dicynone, two transfusions of fresh frozen plasma, transfusion of erythrocyte mass.

During treatment 1 day after admission, the coagulogram parameters returned to normal (see table)

1 month later, due to the development of occlusive tetraventricular hydrocephalus, the child was transferred to a neurosurgical hospital, where he underwent ventriculoperitoneal shunting.0003

Conclusion

HrDN is a serious disease that can lead to death or disability, especially if it develops in a late form. It should be taken into account that the formation of severe intracranial hemorrhages in the late form of HRD can be prevented by timely prophylaxis.

The accumulated experience convinces of the need for prophylactic administration of vitamin K preparations to all newborns in the first hours after birth and to maintain vigilance for the late form of HRD.

In this regard, in 2015, the Association of Neonatologists developed clinical guidelines for the diagnosis and treatment of HRD. A scheme for the prevention of HRD has also been proposed [36]. Unfortunately, in the Russian Federation, 100% routine HRD prevention is difficult to implement, since hemolytic disease in a newborn is an official contraindication for prescribing the only vitamin K drug registered in our country, menadione; its appointment in this group of children is possible only if there are serious arguments (see figure).

Prevention of the late form of HRD should include the administration of vitamin K in the maternity hospital and maintaining vigilance for this disease in children of the first six months of life from high-risk groups: those who are breastfed, those with cholestasis syndrome and malabsorption syndrome. In this regard, the appearance of hemorrhages in children during the first months of life requires immediate differential diagnosis and the exclusion of vitamin K-deficient bleeding.

These warning hemorrhages include:

✧ epistaxis;

✧ bleeding from the umbilical wound;

✧ petechiae and ecchymosis of the skin or mucous membranes;

✧ intermuscular hematomas or bleeding from invasive intervention sites (injections, vaccinations, blood sampling sites, circumcisions, operations).

If HRD is suspected, menadione should be given immediately to avoid life-threatening bleeding.

After the registration of vitamin K1 in Russia, clinical guidelines for the prevention and treatment of vitamin K-deficiency bleeding in children will be revised and the use of vitamin K1 preparations will be recommended.

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Vitamin K2, essential for newborns and valuable for children and the elderly

Vitamin K2 plays an important role in the health of newborns and is valuable for both children and the elderly, where, among other things, it has a cardioprotective effect. In addition to the known benefits of regulating blood clotting and bone health, as well as various other benefits.

In a recent scientific review published on Children (Kozioł-Kozakowska A, Maresz, 2022) summarizes the extensive scientific literature on a vitamin that the human body cannot synthesize and therefore must be consumed in the diet. (1)

Vitamin K2 sources

Vitamin K (Naphthoquinone) is fat soluble and is divided into two types according to origin.

- K1 (phylloquinone), plant origin and mainly found in green leafy vegetables such as spinach, broccoli, lettuce, Brussels sprouts.

- K2 (menaquinone) MK-7, of bacterial origin and present in large quantities in "natto", a Japanese dish based on fermented soybeans (cover). Its MK-4 form is also found in rarely eaten animal organs (liver, brain, kidneys, pancreas).

Other Sources Meat (especially chicken, bacon, and ham), egg yolks, and full-fat dairy products such as hard cheeses are important sources of vitamin K2.

Vitamin K in algae and microalgae

Algae and microalgae in turn, they are valuable sources of vitamin K:

- nori seaweed ( porphyry sp. or washbasin contains approx. 60 g/m2) dried vitamin K,

- wakame seaweed ( Undaria pinnate ) and hijiki ( Sargassum fusiform ), dried, containing respectively 1293 mcg/100 g and 175 mcg/100 g of vitamin K1,

- microalgae and cyanobacteria are also valuable sources of vitamin K (2,3).

Fig. 1 - Vitamin K in algae and microalgae (Simes et al., 2020. See notes 2,3).

Vitamin K2 and activation of essential proteins

Scientific research now it is clear that vitamin K2 activates proteins that perform important biological functions:

- mineralization of bones and teeth, including for anti-caries function,

- cardiovascular health,

- brain development,

- joint health,

- body weight control.

Studies scientific evidence from the review under consideration suggest the use of vitamin K2 already in some pathological conditions of childhood and adolescence, such as: - inflammatory bowel disease and liver disease,

- severe disability often associated with malnutrition, malabsorption, microbiota changes and liver dysfunction.

Koziol-Kozakovska A., Maresh K. Effects of vitamin K2 (menachionones) on children's health and disease: a review of the literature. Children. 2022

Vitamin K2, Essential Dietary Supplement

In addition to the cases mentioned In terms of disease, the significant decline in intakes of vitamin K, and vitamin K2 in particular, is due to the impoverishment of Western dietary patterns over the past 50 years. With severe health consequences.

To aggravate the situation Therapy used in pediatric practice based on antibiotics and glucocorticoids for a long time contributes to: skeleton causing osteoporosis.

Risk of deficiency in newborns

Vitamin K deficiency this is common in newborns. This is due to poor synthesis of the vitamin due to the fact that the intestines are still poorly colonized by bacteria, reduced passage of vitamin K through the placental barrier and low accumulation in breast milk (with the exception of newborns in eastern countries). Japan).

Such a deficiency of in newborns can cause bleeding, even fatal. A safe form of prophylaxis is a single intramuscular injection of vitamin K at birth, according to the recommendations of the renowned pediatric hospital Bambino Gesu in Rome, which explains: This administration is recommended for all newborns (not just those at increased risk of bleeding). '. (4)

Vitamin K, role in adulthood and the elderly

The proteins that are dependent on vitamin K ( vitamin K-dependent proteins , VKDP)—widely distributed in tissues, even outside the liver—are best known for their protective role in bones and the cardiovascular system. In addition to being involved in cell differentiation and proliferation, inflammation and signal transduction.

Deficiency Thus, vitamin K has been associated with various chronic diseases such as cardiovascular disease (CVD), chronic kidney disease, osteoarthritis, rheumatoid arthritis, osteoporosis, cancer, dementia, certain skin diseases, functional impairment and disability. Pathologies are largely associated with pathological calcification and inflammation, where the role of VKDP and vitamin K is highlighted.

study Rotterdam Avenue - conducted in 4,807 people without a history of myocardial infarction and followed for 7 years - low levels of vitamin K2 (and not also K1) were associated with a significant risk of coronary heart disease ( Coronary heart disease CHD ), all-cause mortality, and severe aortic calcification. (5)

Room Prospect-EPIC cohort of 16,057 women without CVD, since follow-up median 8.1 years - an inverse relationship was found between vitamin K2 (particularly MK-7, MK-8 and MK-9) and the risk of coronary artery disease with an 85-100% reduction in coronary events for every 10 mcg increase in vitamin K2 intake. (6)

K2, safe and effective

In the form of MK-7 , vitamin K2 has a documented history of safe and effective use in children and adults. The only possible contraindication is the use of anticoagulant drugs such as coumarins, which can interfere with vitamin K production.

Expert Panel The Scientific Committee on Diet, Nutrition and Allergies (NDA) of EFSA, in its opinion dated 22.5.17, confirmed the dietary reference values ​​established by the Scientific Committee on Foods in 1993.

Daily amounts of adequate vitamin K intake are indicated at:

- 10 mcg for children aged 7 to 11 months;

- 12 micrograms for children aged 1 to 3 years;

- 20 micrograms for children aged 4 to 6 years;

- 30 micrograms for children aged 7 to 10 years;

- 45 micrograms for children 11 to 14 years of age;

- 65 micrograms for adolescents 15-17 years of age e

- 70 micrograms for adults, including pregnant and lactating women. (7)

Martha Strinati and Dario Dongo

Nippon.com cover image, https://www.nippon. com/hk/japan-glances/jg00116/

Attention

(1) Kozel-Kozakovska A., Maresh K. Effects of vitamin K2 (menachionones) on children's health and disease: a review of the literature. Children. 2022; 9 (1): 78. https://doi.org/10.3390/children

78

(2) Dina S. Simes, Carla S.B. Viegas, Nuna Araujo, Katarina Marreiros (2020). Vitamin K as a dietary supplement affecting human health: current evidence on age-related diseases . Nutrients. Jan 2020; 12 (1): 138. doi: 10.3390 / nu12010138

(3) Vitamin K1 synthesis has been found in several species of macroalgae and microalgae, such as porphyra sp , ( Rhodophyta

(4) Bambino Gesu Children's Hospital. Vitamin K . https://www.ospedalebambinogesu.it/vitamina-k-89768/

(5) Geleiinse JM, Vermeer C., Grobbeehlight DE, Schurgers LJ, Knapen MHJ, Van Der Meer IM, Hofman A., Witteman JCM (2004 ). Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: a study in Rotterdam . J. Nutr. 2004, 134: 3100-3105. doi: 10.1093 / v / 134.11.3100

(6) Gast GC, de Roos NM, Sluijs I., Botsnary ML, Beulens JW, Geleinse JM, Witteman JC, Grobbee DE, Peeters PH, van der Schouw YT (2009). High consumption of menaquinone reduces the incidence of coronary heart disease. Int. Metab. Cardiovas. Dis. 2009, 19:504-510. doi: 10.1016 / j.numecd.2008.10.004

(7) Recommended dietary values: EFSA publishes opinion on vitamin K. 22.5.17 https://www.efsa.europa.eu/it/press/news/ 170522-1

Martha Strinati

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Professional journalist since January 1995, working for newspapers (Il Messaggero, Paese Sera, La Stampa) and periodicals (NumeroUno, Il Salvagente). An author of journalistic food reviews, she published the book Reading Labels to Know What We're Eating.

Dario Dongo

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Dario Dongo, lawyer and journalist, PhD in international food law, founder of WIISE (FARE - GIFT - Food Times) and Égalité.

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