Not a Member?
Email this page
Send the page ""
to a friend, relative, colleague or yourself.
Separate multiple email address with a comma
We do not record any personal information entered above.
Thank you. Your email has been sent.
Vitamin K Products
Fatal anaphylactoid reactions have occurred during and immediately after the intravenous administration (IV) and intramuscular administration (IM) of phytonadione; therefore, IV and IM routes of administration should be restricted to those situations where other routes are not feasible and the risk of serious hypersensitivity reactions or anaphylaxis is considered justified. Severe reactions, including shock and cardiac and/or respiratory arrest, have occurred primarily with IV administration, even when precautions have been taken to dilute phytonadione and to avoid rapid infusion. Similar reactions have occurred with IM administration. Some patients have experienced severe reactions when receiving phytonadione for the first time. Cutaneous reactions, including eczematous reactions, scleroderma-like patches, urticaria, and delayed-type hypersensitivity reactions, may also occur with parenteral phytonadione administration. Time of onset of such reactions has ranged from 1 day to a year after administration. If skin or serious hypersensitivity reactions occur, discontinue phytonadione and institute medical management.
Synthetic compound; chemically indistinguishable from naturally occurring vitamin KFor the treatment or prevention of hypoprothrombinemia due to vitamin K deficiency and oral anticoagulant-induced hypoprothrombinemiaAvoid IM and IV administration when possible due to risk of serious hypersensitivity and anaphylactoid reactions
AquaMEPHYTON/Phytonadione Intramuscular Inj Emulsion: 0.5mL, 1mg, 1mL, 10mgAquaMEPHYTON/Phytonadione Intravenous Inj Emulsion: 0.5mL, 1mg, 1mL, 10mgAquaMEPHYTON/Phytonadione Subcutaneous Inj Emulsion: 0.5mL, 1mg, 1mL, 10mgMephyton/Phytonadione Oral Tab: 5mg
120 mcg/day PO.
90 mcg/day PO.
75 mcg/day PO.
60 mcg/day PO.
55 mcg/day PO.
30 mcg/day PO.
2.5 mcg/day PO. The vitamin K intake for this age category is higher than the AI based solely on human milk because other foods become a more important part of the infants diet.
2 mcg/day PO. The AI is based on an average intake of milk of 0.78 L/day and an average phylloquinone concentration of 2.5 mg/L in human milk.
150 mcg IV vitamin K (as 10 mL of Adult MVI), added daily to the TPN. Alternatively, if using the 12-vitamin formulation that does not contain vitamin K, 0.5 to 1 mg/day IV or 5 to 10 mg IV once weekly as part of TPN.
200 mcg IV vitamin K (as 5 mL of Pediatric MVI), added daily to the TPN. Children weighing more than 40 kg should receive 10 mL of the Adult MVI which provides 150 mcg/dose.
80 mcg/kg IV vitamin K (as 2 mL/kg of Pediatric MVI), added to the daily TPN.
0.5 to 1 mg/day IM/subcutaneously or 5 to 10 mg IM/subcutaneously once weekly if using the 12-vitamin formulation that does not contain vitamin K.
Initially, 2 to 25 mg PO as single dose, repeated as necessary, depending on patient response and the severity of the deficiency. The dosage may be increased up to 50 mg, but this is not usually required.
2.5 to 5 mg PO, given 2 to 7 times/week may be required to prevent deficiency; up to 10 mg daily may be needed in children with cholestasis.
Initially, 2 to 25 mg IM/subcutaneously, repeated as necessary, depending on patient response and the severity of the deficiency. The dosage may be increased up to 50 mg, but this is not usually required.
Initially, 5 to 10 mg IM/subcutaneously, repeated as necessary, depending on patient response and the severity of the deficiency.
Doses of 1 to 3 mg IM/IV/subcutaneous have been administered in the setting of late Vitamin K deficiency bleeding (VKDB) in infants. Whole blood or component therapy may be indicated if bleeding is excessive; however, blood components do not correct the underlying disorder, and phytonadione therapy should be given concurrently. In some cases, vitamin K 1 mg was given for up to 3 days. However, most other cases have been successfully treated with 1 dose of vitamin K and studies have shown that a single dose of vitamin K in the setting of VKDB may be adequate to correct coagulation abnormalities. In most reported cases of VDKB, vitamin K was given IV. It is recommended that vitamin K be given IV, and not IM, until coagulation parameters normalize to minimize the risk of hematoma at the injection site.
1 mg IM/subcutaneous is the FDA-approved dosage. Higher doses may be necessary if the mother has been taking anticonvulsants or oral anticoagulants. Whole blood or component therapy may be indicated if bleeding is excessive; however, blood components do not correct the underlying disorder, and phytonadione therapy should be given concurrently. Doses of 1 to 3 mg IM/IV/subcutaneous have been administered in the setting of late Vitamin K deficiency bleeding (VKDB) in infants. In some cases, vitamin K 1 mg was given for up to 3 days. However, most other cases have been successfully treated with 1 dose of vitamin K and studies have shown that a single dose of vitamin K in the setting of VKDB may be adequate to correct coagulation abnormalities. Although the FDA-approved labeling recommends IM or subcutaneous administration, in most reported cases of VDKB, vitamin K was given IV. It is recommended that vitamin K be given IV, and not IM, until coagulation parameters normalize to minimize the risk of hematoma at the injection site.
1 mg IM as a single dose given immediately after birth is recommended by the American Academy of Pediatrics (AAP) and the FDA-approved labeling. Reserve the IV route for emergency use only. Larger or repeat doses may be required in infants whose mothers are taking anticonvulsants or oral anticoagulants.
0.2 to 0.5 mg IM as a single dose immediately after birth has been recommended. A single dose of 0.3 to 0.5 mg/kg IM for premature neonates weighing less than 1,000 g at birth and 1 mg IM for those weighing more than 1,000 g at birth is recommended by the American Academy of Pediatrics (AAP). The Canadian Pediatric Society recommends 0.5 mg IM as a single dose for premature neonates with birthweight of 1,500 g or less and 1 mg IM as a single dose for those with birthweight more than 1,500 g. Vitamin K plasma concentrations have been shown to be higher in premature neonates, particularly those younger than 32 weeks gestational age. Studies in premature neonates given a wide range of prophylactic vitamin K doses from 0.2 mg/kg to a full 1-mg dose have shown median vitamin K concentrations in the first week of life up to 1,000 times higher than the normal adult range of 0.15 to 1.55 ng/mL. A randomized, controlled study in 98 premature neonates (younger than 32 weeks gestation; range: 22.4 to 31.9 weeks; birthweight range: 454 to 1,950 g) found a significantly lower vitamin K1 serum concentration in neonates who received 0.2 mg IM compared to those who received 0.5 mg IM at 5 days postnatal age (median 59.3 ng/mL vs. 111.8 ng/mL; p = 0.45); however, there was no significant difference in undercarboxylated prothrombin (PIVKA-II) concentrations, a sensitive functional marker of deficiency in vitamin K, at 5 or 25 days postnatal age, indicating that the 0.2 mg dose maintained adequate vitamin K status. Vitamin K epoxide concentrations were significantly higher in infants who received 0.5 mg compared to those who received 0.2 mg, indicating possible overload of the immature liver. In another study, plasma vitamin K concentrations were not statistically significantly different on day 2 or day 10 of life in 7 premature neonates (mean gestational age 27.3 weeks; mean birthweight 1.08 kg) given 0.5 mg vitamin K compared to 20 premature neonates (mean gestational age 30 weeks; mean birthweight 1.48 kg) given 1 mg vitamin K. However, the plasma vitamin K concentrations were still very high in the premature neonates who received a lower prophylactic dose of 0.5 mg, suggesting that lower doses of vitamin K are necessary in this group.
Oral administration of vitamin K for prophylaxis of vitamin K deficiency bleeding (VKDB) is common in other countries; however, IM administration of vitamin K is standard practice in the US due to its superior efficacy for preventing late VKDB.
2 mg PO soon after birth, at 1 to 2 weeks of age, and at 4 weeks of age in breast-fed infants is recommended by the American Academy of Pediatrics (AAP) if IM vitamin K cannot be given ; however, the AAP recommends additional research to determine the optimal oral dosing regimen to ensure prevention of both early and late vitamin K deficiency bleeding. A single oral dose should not be used because the oral bioavailability is variable and does not result in adequate body stores of vitamin K. Although oral vitamin K has been shown to have similar efficacy compared to parenteral therapy in the prevention of early vitamin K deficiency bleeding, there is evidence that oral vitamin K is less effective for the prevention of late bleeding than intramuscular therapy, particularly in exclusively breast-fed infants who received a single oral dose. Repeated oral phytonadione doses given either weekly (1 mg) or daily (25 mcg) have been suggested to be as effective as intramuscular prophylaxis. Higher oral doses may be necessary in infants with bile disorders, such as biliary atresia and cholestasis, as higher rates of late vitamin K deficiency bleeding have been noted in these patients. Larger or repeat doses may be required in infants whose mothers are taking anticonvulsants or oral anticoagulants.
Maternal supplements of 5 mg/day PO of phylloquinone through the first 12 weeks of life increase plasma vitamin K concentrations (in breast milk and infant plasma) in exclusively breast-fed infants who receive one IM dose of vitamin K at birth. In exclusively breast-fed infants, a deficiency in vitamin K may be a concern because the intestinal flora of breast-fed infants produces less vitamin K and the content of vitamin K in human milk is lower than that of formula.
Due to the long half-life of superwarfarins (greater than or equal to 6 months), high doses (up to 200 mg/day PO) may be required for a period of years. In 1 case report, following stabilization with fresh frozen plasma, phytonadione 7 mg/kg/day PO divided every 6 hours was effective.
Lower or omit warfarin dose and monitor INR more frequently. Reinitiate therapy at a lower dose once a therapeutic INR is reached. If slightly above the therapeutic range, no dose reduction may be required.
Clinical practice guidelines recommend against the routine use of vitamin K. Omit the next 1 or 2 doses of warfarin, monitor the INR more frequently, and reinitiate therapy at a lower dose once a therapeutic INR is reached.
5 to 10 mg IV by slow infusion in addition to 4-factor prothrombin complex concentrate. Hold warfarin therapy.
Data are limited in pediatric patients. 30 mcg/kg/dose IV is recommended by guidelines for excessively prolonged INR (typically more than 8) with no bleeding. In the presence of significant bleeding, immediate reversal using fresh frozen plasma (FFP), prothrombin complex concentrates, or recombinant factor VIIa may be necessary. Vitamin K should NOT be given intramuscularly to pediatric patients on anticoagulants because of the risk of intramuscular hemorrhage.
2.5 to 5 mg PO with the expectation that the INR would be reduced substantially in 24 to 48 hours. Hold warfarin therapy. Monitor INR more frequently. If the INR is still elevated, additional vitamin K may be given. Reinitiate therapy at a lower dose once a therapeutic INR is reached.
15 mg PO once weekly has been associated with normal coagulation function and no hemorrhages. INR should be monitored during therapy; adjust dose according to INR and plasma concentrations.
†Indicates off-label use
Upper tolerable intake levels in healthy, non-vitamin deficient individuals of all ages are not determinable due to a lack of data.
Dependent on indication, but upper limits of single doses are 10 mg/day PO/IV/IM/subcutaneously.
Dependent on indication, but upper limits of single doses are 2 mg/day PO and 1 mg/day IV/IM/subcutaneously.
No dosage adjustment necessary. However if no response is seen, the underlying condition (e.g., coagulopathy) may not be related to vitamin K deficiency, but a reduced ability of the liver to produce vitamin K dependent proteins.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Oral absorption requires the presence of adequate bile salts. Patients with impaired production of bile should receive phytonadione by the parenteral route.The ACCP recommends oral administration over subcutaneous for treatment of supratherapeutic INR when no significant bleeding is present.The injectable formulation has been administered orally and is typically used when lower oral doses (e.g., 1 mg) are needed and no oral product is commercially available. The stability of injectable phytonadione solution (2 mg/mL) packaged in dropper containers has been evaluated. Phytonadione injection was packaged in 0.75 mL aliquots in amber glass dropper bottles with a glass dropper and rubber bulb and also in white polyethylene plastic squeeze dropper bottles with a dropper tip and detachable cap. Samples were stored for 30 days at room temperature exposed to light (8 hours each day) and in the refrigerator protected from light. Less than 10% loss in phytonadione occurred over 30 days in both containers stored in the refrigerator and in the amber glass bottles stored at room temperature; however, more than 10% loss of phytonadione was observed in about 40 hours in the samples stored in plastic bottles at room temperature.
Extemporaneous Preparation of 1 mg/mL Oral SuspensionTriturate six 5-mg tablets into a fine powder.Add 5 mL of purified water, USP and 5 mL of 1% methylcellulose to the powder and mix into a uniform paste.Transfer mixture to a graduate and add sufficient amount of sorbitol 70% to make a total volume of 30 mL.Storage: Store under refrigeration for up to 3 days. Shake well before administration.
Phytonadione can be administered intramuscularly (IM), subcutaneously, or intravenously (IV) by slow IV infusion. In general, the FDA-approved labeling recommends that the IM and IV routes be avoided; however, the IV route is the preferred route for rapid reversal of warfarin. IV and IM administration are associated with an increased risk of anaphylactoid reactions. Anaphylactoid reactions have occurred during the first infusion and in patients receiving IV phytonadione that has been diluted and injected by slow IV infusion. Similar reactions have been reported with IM administration. Therefore, restrict IV and IM administration to those situations where another route is not feasible and the increased risk involved is considered justified. The FDA-approved labeling recommends subcutaneous administration as the preferred parenteral route. However, subcutaneous administration often results in delayed and erratic absorption. Visually inspect parenteral products for particulate matter and discoloration prior to administration.Protect from light at all times.
DilutionPhytonadione injection must be diluted prior to IV administrationDilute the phytonadione injection with preservative-free 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection only; other diluents should not be used.Use diluted injections immediately and protect infusions from light at all times.Discard any unused portions of undiluted or diluted injection. Intermittent IV infusionInfuse slowly at a rate not exceeding 1 mg/minute.
If IM injection is necessary, inject deeply into a large muscle mass (e.g., anterolateral thigh or deltoid [children and adolescents only]). Inject very slowly, not exceeding 1 mg/minute. Aspirate prior to injection to avoid injection into a blood vessel.
Inject subcutaneously taking care not to inject intradermally.
Generic:- Avoid excessive heat (above 104 degrees F)- Store at room temperature (between 59 to 86 degrees F)AquaMEPHYTON:- Discard product if it contains particulate matter, is cloudy, or discolored- Discard unused portion. Do not store for later use.- Protect from light- Store at controlled room temperature (between 68 and 77 degrees F)- Store in carton until time of useMephyton:- Protect from light- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
The benefit of parenteral vitamin K administration to infants outweighs the previously reported possible risk of childhood cancer. The Vitamin K Ad Hoc Task Force of the American Academy of Pediatrics (AAP) reviewed the related data and concluded that there is no association between the intramuscular (IM) administration of vitamin K and childhood leukemia or other cancers. Oral vitamin K has been shown to have similar efficacy compared to parenteral therapy in the prevention of early neonatal vitamin K deficiency bleeding; however, there is evidence that oral vitamin K is less effective for the prevention of late bleeding than intramuscular therapy, particularly in exclusively breast-fed infants who receive a single oral dose. The optimal oral vitamin K regimen to maximize efficacy has yet to be determined.
There may be a decreased response to phytonadione in patients with hepatic disease. Failure to respond to vitamin K may indicate condition that is inherently unresponsive to vitamin K. Repeated large doses are not warranted if the initial response is unsatisfactory. Patients with biliary tract disease or obstructive jaundice require concurrent administration of bile salts to ensure oral absorption of vitamin K.
Patients receiving phytonadione for anticoagulant-induced hypoprothrombinemia are at risk for developing the previously treated hypercoagulable state. Although phytonadione is not a clotting agent, overzealous therapy with phytonadione may restore the previous hypercoagulable state resulting in thromboembolic disease. Dosages of vitamin K1 should be kept as low as possible, and the prothrombin time or INR checked at regular intervals.
Temporary resistance to anticoagulant therapy may result following treatment with phytonadione, especially if large doses are used. If relatively large doses of phytonadione have been used, it may be necessary when re-instituting anticoagulant therapy to use somewhat higher doses or to use an anticoagulant that acts by a different mechanism (i.e., heparin).
A clear association with phytonadione use during human pregnancy and adverse developmental outcomes has not been reported. Animal reproduction studies have not been conducted with phytonadione. There are maternal and fetal risks associated with vitamin K deficiency during pregnancy. Pregnant women with vitamin K deficiency hypoprothrombinemia may be at increased risk for bleeding diathesis during pregnancy and hemorrhagic events at delivery. Subclinical maternal vitamin K deficiency during pregnancy has been implicated in rare cases of fetal intracranial hemorrhage. If parenteral phytonadione use is required during pregnancy, consider a benzyl alcohol-free formulation. Some parenteral phytonadione formulations contain benzyl alcohol, which has been associated with gasping syndrome in newborns. Usually, supplementation of vitamin K during pregnancy is not required. The recommended Adequate Intake (AI) values for pregnant females are the same as non-pregnant females.
Phytonadione is present in breast milk. There are no data on the effects of phytonadione on the breast-fed child or on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for phytonadione and any potential adverse effects on the breast-fed child from phytonadione or the underlying maternal condition. If parenteral phytonadione use is required during breast-feeding, preservative-free formulations are recommended. Some parenteral phytonadione formulations contain benzyl alcohol. Previous American Academy of Pediatrics recommendations considered phytonadione as compatible with breast-feeding. The recommended Adequate Intake (AI) for lactating women is the same as non-lactating women. However, natural concentrations of vitamin K1 or K2 in breast milk will not provide adequate quantities of the vitamin to the infant. In newborns, vitamin K dependent clotting factors are 30% to 60% of adult concentrations, depending upon gestational age, and do not reach adult concentrations until about 6 weeks. The majority of newborns are not vitamin K deficient, however some are. Exclusive breast-feeding will not replete stores and may result in the development of vitamin K deficiency within 48 to 72 hours in at-risk newborns. Administration of phytonadione to the infant prevents further decline of vitamin K-dependent factors. The administration of phytonadione to the mother to increase breast milk concentrations may be possible. One study has reported that breast-fed infants whose mothers were supplemented with oral phytonadione 5 mg/day had higher plasma vitamin K1 concentrations due to higher vitamin K1 intake as compared to controls in whom no supplemental vitamin K was given. Prothrombin times were not significantly different between the 2 groups but the PIVKA-II (protein induced by vitamin K absence) concentration was significantly higher in the control group.
Parenteral phytonadione preparations contain benzyl alcohol as a preservative. Patients with a known benzyl alcohol hypersensitivity should not receive parenteral phytonadione. Use preservative-free phytonadione formulations in neonates, if available. A 'gasping syndrome' characterized by CNS depression, metabolic acidosis, and gasping respirations has been associated with benzyl alcohol dosages more than 99 mg/kg/day in neonates. However, the minimum amount of benzyl alcohol at which toxicity may occur is unknown and low-birth-weight and premature neonates may be more likely to develop toxicity. Normal therapeutic phytonadione doses would deliver benzyl alcohol at amounts lower than those reported with 'gasping syndrome'; however, the clinician should be aware of the toxic potential, especially if other drugs containing benzyl alcohol are administered. If further dilution of phytonadione is necessary, solutions for dilution should be preservative-free. In addition, certain parenteral phytonadione preparations contain polysorbate 80 and should be avoided in patients with a known polysorbate 80 hypersensitivity. Some literature suggests that low birth weight premature neonates exposed to polysorbate 80 at high doses or for prolonged periods of time may experience hepatotoxicity, hypotension, renal failure, ascites, and thrombocytopenia.
anaphylactic shock / Rapid / Incidence not knownserious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not knowncyanosis / Early / Incidence not knownrespiratory arrest / Rapid / Incidence not knowncardiac arrest / Early / Incidence not known
chest pain (unspecified) / Early / Incidence not knowndyspnea / Early / Incidence not knownsinus tachycardia / Rapid / Incidence not knownhypotension / Rapid / Incidence not knownerythema / Early / Incidence not knownhyperbilirubinemia / Delayed / Incidence not knownhemolysis / Early / Incidence not knownjaundice / Delayed / Incidence not known
weakness / Early / Incidence not knowndysgeusia / Early / Incidence not knownhyperhidrosis / Delayed / Incidence not knowndizziness / Early / Incidence not knownflushing / Rapid / Incidence not knownurticaria / Rapid / Incidence not knownvesicular rash / Delayed / Incidence not knowninjection site reaction / Rapid / Incidence not knownpruritus / Rapid / Incidence not knownrash / Early / Incidence not known
Castor Oil: (Moderate) Absorption of fat-soluble vitamins may be decreased with coadministration of castor oil. Cholestyramine: (Moderate) Cholestyramine can decrease the intestinal absorption of fat and fat-soluble vitamins. If used concurrently, administration of the two agents should be staggered for the longest time interval possible. Colesevelam: (Moderate) It is not known if colesevelam can reduce the absorption of oral vitamin supplements including fat soluble vitamins A, D, E, and K. To minimize potential interactions, administer vitamins at least 4 hours before colesevelam. Colestipol: (Moderate) Separate administration of fat-soluble vitamins by 1 hour before or 4 hours after a colestipol dose to limit effects on oral absorption. Because it sequesters bile acids, colestipol may interfere with normal fat absorption and thus may reduce absorption of fat-soluble vitamins. Food: (Minor) The food supplement olestra, if ingested in sufficient quantities, may decrease the oral absorption of vitamin K. Mineral Oil: (Moderate) Absorption of fat-soluble vitamins is reported to be decreased with prolonged oral administration of mineral oil. However, despite warnings in various texts, there is little direct evidence that the interaction is of practical/clinical importance with limited use as directed. It may be prudent for those taking dietary supplements of Vitamin A, D, E, or K to separate administration by 1 hour before or 4 hours after a mineral oil oral dosage to help limit absorption interactions. Theoretically, the effect on fat-soluble vitamin absorption may more likely occur with prolonged or chronic administration of mineral oil. Orlistat: (Moderate) Several drugs can interfere with the oral bioavailability of vitamin K including orlistat. In patients receiving orlistat routinely for a prolonged period of time (i.e., more than 2 weeks), vitamin K intake may need to be increased. Warfarin: (Major) Phytonadione antagonizes the actions of warfarin. Phytonadione catalyzes the hepatic synthesis of blood-clotting factors including active prothrombin (Factor II), Factor VII, Factor IX, and Factor X. Warfarin inhibits vitamin K-epoxide reductase depleting the reduced form of vitamin K (vitamin KH2), thus preventing the gamma-carboxylation of the vitamin K-dependent coagulant proteins resulting in the synthesis of inactive proteins. S-warfarin affects vitamin K to a greater extent than R-warfarin. The degree of effect on the vitamin K-dependent proteins is related to the dose of warfarin. Phytonadione, in doses proportional to warfarin-induced hypoprothrombinemia, can overcome this effect. Alterations in vitamin K intake influence the response to warfarin. Temporary resistance to warfarin or other prothrombin-depressing anticoagulants occurs after treatment with phytonadione; this may be long-lasting when large doses of phytonadione are used. If relatively large doses of phytonadione have been used, when reinstituting anticoagulant therapy it may be necessary to use somewhat higher doses or to use an anticoagulant that acts by a different mechanism (i.e., heparin).
Mechanism of Action: Phytonadione has identical activity to the natural K vitamins. Vitamin K functions as a co-factor for gamma-glutamylcarboxylase, which is involved in the post-translational carboxylation of glutamate residues into gamma-carboxyglutamate (Gla). Gamma-carboxyglutamate residues are found in specific proteins (Gla proteins) including the vitamin K-dependent clotting (Factors II, VII, IX, and X) and regulatory proteins (proteins C and S), proteins of bone metabolism (osteocalcin), and vascular proteins (matrix Gla protein [MGP], growth-arrest-specific gene 6 protein [Gas6]). The oxidation of vitamin K hydroquinone (KH2) into vitamin K 2,3, epoxide (KO) provides the energy to drive the carboxylation reaction to form Gla, which takes place late in the biosynthesis of specific proteins. Vitamin K must be reduced by vitamin K epoxide reductase from the quinone oxidation state to the hydroquinone form (KH2), which is the active cofactor for the vitamin-K dependent carboxylase. In addition, vitamin K epoxide reductase reduces KO formed during the carboxylation reaction back to KH2. Due to the limited amount of vitamin K intake and the 1:1 relationship between the conversion of KH2 into KO and the formation of Gla residues, vitamin K must be recycled. Vitamin K epoxide reductase works at low concentrations of vitamin K epoxide and vitamin K quinone and is important for the recycling of vitamin K. A second enzyme, DT-diapharase, reduces the quinone form of vitamin K but not the epoxide form; however, this enzyme requires high levels of vitamin K and does not appear to contribute to the recycling of vitamin K. This enzyme may play an important role when phytonadione is used to overcome warfarin-induced hypoprothrombinemia. During vitamin K deficiency, the carboxylation reaction cannot proceed, so Gla proteins are released in an undercarboxylated form. These descarboxy proteins or proteins induced by vitamin K absence (PIVKAs) have been shown to be inactive. Gla residues form calcium-binding groups in proteins, so the major difference between normal and descarboxy proteins is the binding of calcium and the adsorption of these proteins onto insoluble calcium salts.•Vitamin K-dependent proteins in blood coagulation: The role of vitamin K in blood coagulation is considered the classic activity of vitamin K. Gla residues in the coagulation factors (Factors II, VII, IX, and X) and proteins C and S function to facilitate the binding of these proteins to the negatively charged phospholipids on the surface of platelets. The Gla domains of these proteins are necessary for proper function of the coagulation proteins. The binding of calcium ions to the coagulation factors via Gla residues causes the factors to undergo structural changes leading to internalization of the Gla-calcium complex and exposure of the phospholipid-binding domain. Warfarin inhibits vitamin K epoxide reductase thus preventing the carboxylation reaction and results in Gla blood coagulation proteins to be released in an undercarboxylated form, and thus inactive form.•Vitamin K-dependent proteins in the bone: Although the exact function of Gla proteins in the bone (matrix Gla protein (MGP), osteocalcin, and protein S) has not been determined, all the known bone Gla proteins are produced by osteoblasts. Osteocalcin is only produced by osteoblasts and makes up about 20% of noncollagenous protein in bone. In mice, osteocalcin has been shown to be a negative regulator of bone growth; however, following ovariectomy, the decrease in bone mass is more pronounced in mice deficient in osteocalcin. Both epidemiologic and clinical studies have reported a decrease in hip fractures and increased bone mineral density in subjects receiving supplemental vitamin K. MGP appears to be critical for bone mineralization and growth; spontaneous and fatal calcification of arteries and cartilage has been observed in mice with MGP deficiency. In humans with Keutel syndrome, a DNA mutation leading to nonfunctional MGP has been discovered.•Vitamin K-dependent proteins in the vasculature: In arterial vessels, Gla proteins include protein S, MGP, and Gas6. Studies in MGP-deficient mice have shown that MGP is a strong inhibitor of soft-tissue calcification, including cartilage and vessel wall. The function of Gas6 has only been studied in vitro and may affect other tissues as well (e.g., spinal motor neurons, neurons of the basal root ganglia, and Schwann cells among others). Gas6 was shown to prevent the death of fibroblasts and smooth muscle cells from serum starvation and may act as a growth promoter.
Phytonadione is administered orally, intramuscularly, intravenously, and subcutaneously. Triglyceride-rich lipoproteins, in addition to LDL and HDL, are carriers of vitamin K; apolipoprotein E is also important for transport of vitamin K. Phytonadione concentrates in the liver temporarily. Skeletal muscle contains little vitamin K but significant concentrations are found in the heart and other tissues. In infants, the liver contains about one-fifth the amount of vitamin K1 as adults. Turnover of vitamin K in the liver is rapid and hepatic reserves are rapidly depleted periods of low intake of vitamin K. Circulating vitamin K levels after overnight fasting range from 200—800 pg/ml, but decrease rapidly with prolonged low-intake. Although it is considered a fat-soluble vitamin, the ability of the body to store vitamin K is much less than for other fat-soluble vitamins. It has been suggested that overall vitamin K status is not adequately assessed using plasma concentrations, and measuring Gla content of Gla-proteins may be more worthwhile. Circulating osteocalcin is more sensitive to poor vitamin K status than other Gla-proteins. A small amount of vitamin K crosses the placenta and is distributed into breast milk (see Contraindications). Almost no free, unmetabolized vitamin K appears in the bile or urine. High fecal concentrations are attributable to synthesis of the vitamin by intestinal bacteria.
All K vitamins are fat-soluble and are absorbed in the jejunum and ileum and require the presence of bile salts and pancreatic enzymes for absorption; dietary fat enhances absorption. Phylloquinone from cooked spinach was reported to be only 4% as bioavailable as the suspension product of phylloquinone (Konakion). The bioavailability of the spinach-derived phylloquinone increased 3-fold (to 13%) when butter was consumed with the spinach. Absorption of vitamin K from spinach is 1.5 times slower compared to the pharmaceutical preparation. Evidence of increased concentrations of blood-coagulation factors occurs within 6—12 hours of an oral dose of phytonadione.
Following parenteral administration of phytonadione, increased concentrations of blood-coagulation factors are evident within 1—2 hours, and hemorrhage is typically controlled within 3—8 hours.