Phytomenadion
Vitamin K1 as antidote and for coagulation disorders
Phytomenadione is the pharmaceutical form of vitamin K1, the plant derived vitamin involved in the γ carboxylation of coagulation factors II, VII, IX and X as well as the anticoagulants protein C and S. In Germany, Konakion MM (mixed micelle formulation) is available both as oral drops and as a solution for injection for intravenous, intramuscular and subcutaneous administration. In newborns, Konakion is routinely given as prophylaxis to prevent so called vitamin K deficiency bleeding.
Phytomenadione is the standard antidote for overdose with vitamin K antagonists such as warfarin or phenprocoumon. In the case of bleeding or relevant INR elevation, the substance restores coagulation factor synthesis within hours. Outside this indication, phytomenadione is used for nutritional vitamin K deficiency, for malabsorption, for cholestasis and for certain paediatric indications.
Mechanism of Action
Vitamin K is a cofactor of γ glutamyl carboxylase, an enzyme that post translationally carboxylates the glutamate rich N terminal domains of coagulation factors II, VII, IX and X. Through this modification the factors bind calcium and anchor to phospholipid membranes, a prerequisite for activation of the coagulation cascade. At the same time, vitamin K activates the anticoagulant proteins C and S.
Coumarins such as warfarin and phenprocoumon inhibit vitamin K epoxide reductase (VKORC1), the enzyme that recycles vitamin K into its reduced active form. The result is a functional vitamin K deficiency despite normal intake. Supplying exogenous vitamin K bypasses this blockade. Synthesis of new, correctly carboxylated coagulation factors begins within a few hours; full normalisation of the INR takes 12 to 24 hours after oral phytomenadione and 4 to 8 hours after intravenous administration.
In severe acutely life threatening bleeding under vitamin K antagonists, phytomenadione alone is not sufficient because its action is delayed. In such cases, prothrombin complex concentrate (PCC) is additionally administered, which immediately substitutes the missing factors II, VII, IX and X. Fresh frozen plasma is a less effective alternative.
Indications
- Bleeding and INR derailment under vitamin K antagonists (warfarin, phenprocoumon, acenocoumarol)
- Vitamin K deficiency in malabsorption, cholestasis, chronic diarrhoea, long term antibiotic therapy
- Vitamin K deficiency bleeding of the newborn (VKDB) as standard prophylaxis
- Accidental coumarin ingestion (for example in children, through rodenticides containing super long acting coumarins)
- Vitamin K deficiency states during parenteral nutrition without adequate vitamin K substitution
- Coagulation disorders in liver cirrhosis as adjunctive therapy
DOACs (direct oral anticoagulants such as apixaban, rivaroxaban, edoxaban, dabigatran) are not antagonised by vitamin K. Specific antidotes exist for DOACs: idarucizumab for dabigatran and andexanet alfa for factor Xa inhibitors.
Dosage and Administration
INR elevation without bleeding: for INR 4.5 to 10, 1 to 2.5 mg orally; for INR above 10, 2.5 to 5 mg orally. Recheck INR after 6 to 12 hours. Mild to moderate bleeding under VKA: 5 to 10 mg orally or slowly intravenously. Severe life threatening bleeding: 10 mg intravenously plus PCC (25 to 50 IU per kg according to INR and weight), hourly INR checks.
Newborn prophylaxis: 2 mg orally on the first day of life, on day 4 to 6, and during the 4th to 6th week of life (three dose scheme). Alternatively 1 mg intramuscularly once at birth, especially in cases of elevated risk (preterm infants, complications). Oral administration is suitable only for healthy term neonates; in failure to thrive or cholestasis the intramuscular form is preferred.
Coumarin intoxication with super long acting rodenticides (brodifacoum, difenacoum): high dose 50 to 100 mg per day orally for weeks to months, depending on clinical course and INR. These accidental poisonings pose a particular challenge because the half lives of the rodenticides extend over several weeks.
Renal impairment: no dose adjustment required. Hepatic impairment: in severe impairment synthetic capacity for coagulation factors is reduced; vitamin K alone is often not enough, PCC or FFP may be needed.
Side Effects
Uncommon and rare: taste disturbances, local irritation at the injection site, rash, itching, flushing, dizziness.
Rare to very rare: anaphylactoid reactions particularly after rapid intravenous administration, venous thromboembolism with overdose, haemolytic anaemia in newborns with G6PD deficiency, kernicterus in preterm infants after high doses.
Important: intravenous bolus must be given slowly (over at least 30 seconds to 1 minute) to avoid anaphylactoid reactions. The mixed micelle formulation of Konakion MM reduces this risk compared with older Cremophor based preparations, which were withdrawn from the market because of such reactions.
Interactions
- Vitamin K antagonists (warfarin, phenprocoumon): phytomenadione antagonises the effect, which is the desired therapeutic action in bleeding but unwanted with dietary intake of vitamin K rich food
- Broad spectrum antibiotics: can reduce vitamin K producing gut flora and aggravate endogenous deficiency
- Cholestyramine, colestipol, orlistat: reduce absorption of vitamin K
- High dose salicylates: can increase vitamin K requirements
- Mineral oil, cod liver oil, fat soluble vitamins: compete for absorption
Special Notes
Diet and VKA therapy: patients on warfarin or phenprocoumon should maintain a vitamin K intake from food that is as constant as possible. Green leafy vegetables (spinach, kale, broccoli, rocket) are rich in vitamin K; once the INR is set it remains stable under a consistent diet. Strong fluctuations destabilise the INR.
Newborn prophylaxis: since the introduction of vitamin K prophylaxis in the 1960s, the incidence of vitamin K deficiency bleeding has dropped dramatically. The late form of this bleeding can involve intracranial haemorrhage and cause irreversible damage. Prophylaxis is the medical standard and is recommended by all paediatric professional societies.
Pregnancy: phytomenadione can be used in pregnancy, in maternal vitamin K deficiency also in the third trimester to prevent neonatal bleeding. Breastfeeding: passes into breast milk in small amounts; breastfeeding during therapy is possible and desirable. Breastfed infants have a higher VKDB risk than bottle fed infants, which is why prophylaxis is especially important.
Monitoring: INR in VKA patients every 6 to 12 hours after antidote administration until normalisation. No laboratory monitoring is needed for newborn prophylaxis. With prolonged high dose therapy after rodenticide exposure, monitor INR closely together with liver values and blood count.
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Frequently Asked Questions
Why do newborns receive vitamin K?
Newborns have low vitamin K stores because placental transfer is limited and the gut flora that produces vitamin K still has to develop. Without substitution there is a risk of vitamin K deficiency bleeding, which in its late form can involve intracranial haemorrhage. Prophylaxis is the worldwide medical standard.
When is vitamin K given as an antidote?
In INR derailment or bleeding under warfarin or phenprocoumon. The dose depends on the INR value and the extent of bleeding. In life threatening bleeding, prothrombin complex concentrate is additionally administered because vitamin K alone takes hours to act. DOACs are not antagonised by vitamin K.
Can I eat green vegetables while on warfarin?
Yes, a constant amount of green vegetables is even beneficial because the INR is calibrated to this baseline. Strong fluctuations (one week no vitamin K, then large quantities of spinach) destabilise the value. Complete avoidance of vitamin K is not necessary and not recommended.
What happens in rodenticide poisoning with vitamin K?
Super long acting coumarins like brodifacoum have half lives of weeks and cause prolonged coagulation disorders. Therapy with phytomenadione in high doses over months is standard, with INR checks guiding the dose. Accidental ingestion occurs regularly in children, and prompt toxicological evaluation is important.
Sources
- EMA, European Medicines Agency
- AWMF, S3 Guidelines on Anticoagulation and Newborn Prophylaxis
- Gelbe Liste, Phytomenadione active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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