DESCRIPTION

Vitamin K is an antidote for anticoagulants that deplete vitamin K₁.

FORMS AND USES

• Phytonadione is a synthetic derivative identical to naturally occurring vitamin K₁.
• Phytonadione is used in the treatment of vitamin K deficiency.
• It is also used for coagulopathy induced by anticoagulants that deplete vitamin K-dependent clotting factors.
• Pharmaceutical formulations include:
  • Oral preparation (Mephyton) 5 mg tablets
  • Intramuscular preparation (Konakion) 1 mg or 10 mg/ampule, not to be administered intravenously
  • Intravenous preparation (AquaMephyton) 2 mg/ml in 0.5-ml vial; 10 mg/ml in 1-ml, 2.5-ml, or 5-ml vials

MECHANISM OF ACTION

• Vitamin K₁ is an essential cofactor for the production of coagulation factors II (prothrombin), VII, IX, and X.
• During normal coagulation factor synthesis, vitamin K₁ is converted into an inactive metabolite, vitamin K1 2,3-epoxide; the epoxide can be converted back into the active form by a microsomal epoxide reductase.
• The warfarin types of oral anticoagulants interfere with the epoxide reductase and inhibit the reactivation of biologically inactive vitamin K₁ 2,3-epoxide to biologically active vitamin K₁, thereby creating a coagulopathy.
• Following treatment with vitamin K₁, the time to reversal of anticoagulant effects depends on several factors:
  • Individual variability in hepatic synthesis of factors II, VII, IX, and X.
  • Potency of the anticoagulant agent
  • Severity of anticoagulation
  • Route of administration
    • Oral treatment may take 24 to 48 hours to increase levels of coagulation factors.
    • Intravenous treatment may take 2 to 8 hours to increase levels of coagulation factors.

DRUG AND DISEASE INTERACTIONS

Some compounds inhibit the reactivation of vitamin K₁ 2,3-epoxide.

• Warfarin and super-warfarins (brodifacoum, difenacoum, bromadiolone, chlorophacinone, diphacinone, flocoumafen, pindone, valone, coumateralyl)
• Moxalactam
• Cefamandole
• Salicylate

PREGNANCY AND LACTATION

• US FDA Pregnancy Category C. The drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.
• Newborns are at risk for vitamin K deficiency and hemorrhage because vitamin K crosses the placenta poorly and breast milk contains little vitamin K.
• It has been suggested that hyperbilirubinemia with the potential for kernicterus may occur with near-term maternal administration.
• In the treatment of poison-induced coagulopathy, vitamin K₁ should be used in pregnant women as it is in other adults.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• MECHANISM OF ACTION
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

• Coagulopathy induced by long-acting products such as rodent poisons (brodifacoum and others)
  • Marked prolongation of prothrombin time (PT) or international normalized ratio (INR) without bleeding: patients with an INR over 2 should receive therapy; oral route may be used.
  • Severe prolongation of PT or INR and frank bleeding: vitamin K may be administered intravenously; fresh frozen plasma (FFP) should also be administered to reverse coagulopathy until response to vitamin K₁ develops.
• Coagulopathy produced by pharmaceutical product [warfarin (Coumadin)]
  • Due to relatively short duration of action (days), vitamin K₁ therapy is often not used. Instead, patients with a prolonged PT or INR, but without frank bleeding, should have warfarin doses withheld until PT or INR improves.
  • Patients with life-threatening bleeding should be completely reversed by treatment with FFP and vitamin K₁.
• Vitamin K deficiency
  • Vitamin K₁ is prophylactically administered to all newborns
  • Patients receiving total parenteral nutrition should receive supplementation.

CONTRAINDICATIONS

• Known hypersensitivity to vitamin K precludes its use.
• Patients with a known ingestion of an anticoagulant and a normal INR should not receive therapy before INR becomes elevated.
• Many patients will not develop coagulopathy; administration of vitamin K₁ prior to development of coagulopathy will make interpretation of PT/INR difficult.

ADVERSE EFFECTS

• Administration of large doses orally may cause mild gastrointestinal distress.
• Anaphylactoid and anaphylactic reactions may occur and are most common following a rapid intravenous administration of undiluted solution.
• Dermatologic lesions overlying the intramuscular injection site are rare but have been reported; lesions may develop 1 to 2 weeks following the injection and commonly consist of erythematous plaques.
• Patients with severe hepatic insufficiency may have a paradoxical decrease in prothrombin concentration following large doses of phytonadione.
• Patients who require anticoagulation may be refractory to oral anticoagulation following large doses of phytonadione.
• Hemolytic anemia and thrombocytopenia have been reported but are rare.
• Intramuscular administration in excessively anticoagulated patients may result in hematomas; oral or subcutaneous administration is preferred.

Section Outline:

• CONTRAINDICATIONS
• ADVERSE EFFECTS

COAGULOPATHY INDUCED BY LONG-ACTING PRODUCT

Marked Prolongation of PT or INR without Bleeding

• Initial adult dose is 25 to 100 mg/day orally as a single or divided dose, depending on severity of PT/INR prolongation. Pediatric dose is 0.6 mg/kg or more, as a single or divided dose depending on severity of coagulopathy.
• INR and PT should be repeated daily and dose increased as needed to normalize INR or PT; dosage may reach more than 200 mg/day.
• Vitamin K₁ therapy may be needed for weeks or months; once the appropriate dose to normalize INR has been achieved, PT/INR should be monitored weekly.
• After 1 month of therapy the dose can be halved and the INR repeated in 3 to 5 days. If PT or INR increases, return to previous dose for 2 to 4 weeks. This process should be repeated until the patient no longer requires therapy.

Severe Prolongation of PT or INR and Bleeding

• Vitamin K₁ should be administered intravenously in a critical care setting.
  • Phytonadione 25 to 50 mg should be diluted with dextrose 5% in water or 0.9% sodium chloride and infused slowly at a rate not to exceed 1 mg/minute.
  • The dose should be repeated two to four times daily, depending on response of PT/INR to therapy.
  • Parenteral vitamin K₁ in doses as high as 400 mg has been used.
  • The clinician should be prepared to treat anaphylactoid reactions.
• After the coagulation abnormality is controlled, the patient should be switched to oral preparation.
• The dose should be titrated and gradually reduced as described above for PT prolongation without bleeding.
• Deaths from anaphylactoid reactions have occurred following intravenous administration; therefore patients without bleeding should be treated with oral or subcutaneous administration.
• Intravenous administration of vitamin K₁ should be performed in a critical care setting.

COAGULOPATHY PRODUCED BY PHARMACEUTICAL PRODUCT [WARFARIN (COUMADIN)]

• Patients with life-threatening bleeding should be completely reversed with FFP.
• Patients who require anticoagulation and are reversed to a normal PT or INR may require heparin therapy to prevent thrombosis.
• Adult. Small doses (1 to 5 mg/dose) of vitamin K1 should be administered intravenously to titrate patient to a normal PT or INR.
• Intravenous administration of vitamin K₁ should be performed in a critical care setting.
• Patients with a prolonged PT or INR, but without frank bleeding, should have warfarin doses withheld but usually do not require vitamin K₁ or blood component treatment.

VITAMIN K DEFICIENCY

• Newborns should receive 0.5 to 1.0 mg intramuscularly.
• Patients on total parenteral nutrition typically receive 2.5 mg/day intravenously.

Section Outline:

• COAGULOPATHY INDUCED BY LONG-ACTING PRODUCT
  • Marked Prolongation of PT or INR without Bleeding
  • Severe Prolongation of PT or INR and Bleeding
  • COAGULOPATHY PRODUCED BY PHARMACEUTICAL PRODUCT [WARFARIN (COUMADIN)]
• VITAMIN K DEFICIENCY

• FFP should be used in addition to vitamin K₁ for immediate reversal of life-threatening hemorrhage.
• Rapid intravenous infusion can result in an anaphylactoid reaction and has caused death.
• The health-care provider should avoid pretreatment of long-acting anticoagulants (before PT/INR becomes prolonged) with empiric vitamin K, because it obscures the meaning of the INR to assess toxicity and may result in unneeded therapy.
• Vitamin K₁ will not reverse the anticoagulant effects of heparin.
• Vitamin K₁ does not correct hypoprothrombinemia resulting from hepatic insufficiency.
• Other forms of vitamin K (vitamin K₂, K₃, K₄) should not be used as therapy.

Poisoning by agents primarily affecting blood constituents: anticoagulants.

See Also: SECTION IV, Brodifacoum, Coumadin, and Warfarin chapters.

RECOMMENDED READING

Hirsch J, Dalen JE, Deykin D, et al. Oral anticoagulants: Mechanism of action, clinical effectiveness and optimum therapeutic range. Chest 1992;102[suppl]:312-326.

Author: Edwin K. Kuffner

Reviewer: Katherine M. Hurlbut