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Reversal of the Anticoagulant Effects of Warfarin by Vitamin K1

1998; Elsevier BV; Volume: 114; Issue: 6 Linguagem: Inglês

10.1378/chest.114.6.1505

1931-3543

Jack Hirsh,

Atrial Fibrillation Management and Outcomes

Vitamin K is a cofactor for the posttranslational carboxylation of glutamate residues to λ-carboxyglutamates on the N-terminal regions of vitamin K dependent proteins.1Whitlon DS Sadowski JA Suttie JW Mechanisms of coumarin action: significance of vitamin K epoxide reductase inhibition.Biochemistry. 1978; 17: 1371-1377Crossref PubMed Scopus (306) Google Scholar, 2Fasco MJ Hildebrandt EF Suttie JW Evidence that warfarin anticoagulant action involves two distinct reductase activities.J Biol Chem. 1982; 257: 11210-11212PubMed Google Scholar, 3Choonara IA Malia RG Haynes BP et al.The relationship between inhibition of vitamin K 1,2,3-epoxide reductase and reduction of clotting factor activity with warfarin.Br J Clin Pharmacol. 1988; 25: 1-7Crossref PubMed Scopus (78) Google Scholar, 4Trivedi LS Rhee M Galivan JH et al.Normal and warfarin-resistant rat hepatocyte metabolism of vitamin K 2,3-epoxide: evidence for multiple pathways of hydroxyvitamin K formation.Arch Biochem Biophys. 1988; 264: 67-73Crossref PubMed Scopus (24) Google Scholar, 5Stenflo J Fernlund P Egan W et al.Vitamin K dependent modifications of glutamic acid residues in prothrombin.Proc Natl Acad Sci USA. 1974; 71: 2730-2733Crossref PubMed Scopus (614) Google Scholar, 6Nelsestuen GL Zytkovicz TH Howard JB The mode of action of vitamin K.Identification of gamma-carboxyglutamic acid as a component of prothrombin. J Biol Chem. 1974; 249: 6347-6350Google Scholar The process of λ-carboxylation is necessary for the biologic activity of vitamin K-dependent clotting factors, because it is required for calcium dependent complexing of the clotting proteins to their cofactors on phospholipid surfaces. During the carboxylation reaction the reduced form of vitamin K (vitamin KH2) is oxidized to vitamin K epoxide, which is recycled to vitamin K by vitamin K epoxide reductase, which in turn is reduced to vitamin KH2 by vitamin K reductase (Fig 1).Warfarin exerts its anticoagulant effect by inhibiting vitamin K epoxide reductase1Whitlon DS Sadowski JA Suttie JW Mechanisms of coumarin action: significance of vitamin K epoxide reductase inhibition.Biochemistry. 1978; 17: 1371-1377Crossref PubMed Scopus (306) Google Scholar, 2Fasco MJ Hildebrandt EF Suttie JW Evidence that warfarin anticoagulant action involves two distinct reductase activities.J Biol Chem. 1982; 257: 11210-11212PubMed Google Scholar, 3Choonara IA Malia RG Haynes BP et al.The relationship between inhibition of vitamin K 1,2,3-epoxide reductase and reduction of clotting factor activity with warfarin.Br J Clin Pharmacol. 1988; 25: 1-7Crossref PubMed Scopus (78) Google Scholar and to a lesser extent vitamin K reductase.2Fasco MJ Hildebrandt EF Suttie JW Evidence that warfarin anticoagulant action involves two distinct reductase activities.J Biol Chem. 1982; 257: 11210-11212PubMed Google Scholar This process leads to the depletion of vitamin KH2 and as a result, limits the λ-carboxylation of the vitamin K-dependent coagulant proteins (prothrombin, factor VII, factor IX, and factor X) and the regulatory anticoagulant proteins (protein C and protein S).The anticoagulant effect of warfarin can be overcome by vitamin K1 (both dietary and medicinal) because this oxidized form of the vitamin can be reduced through a warfarin resistant vitamin K reductase enzyme system (Fig 1).Dietary vitamin K17O'Reilly R Rytand D "Resistance" to warfarin due to unrecognized vitamin K supplementation.N Engl J Med. 1980; 303: 160-161PubMed Google Scholar,8Suttie JW Mummah-Schendel LL Shah DV et al.Vitamin K deficiency from dietary vitamin K restriction in humans.Am J Clin Nutr. 1988; 47: 475-480Crossref PubMed Scopus (109) Google Scholar is obtained predominantly from phylloquinone in plant material.8Suttie JW Mummah-Schendel LL Shah DV et al.Vitamin K deficiency from dietary vitamin K restriction in humans.Am J Clin Nutr. 1988; 47: 475-480Crossref PubMed Scopus (109) Google Scholar Increased intake of dietary vitamin K sufficient to reduce the anticoagulant response to warfarin7O'Reilly R Rytand D "Resistance" to warfarin due to unrecognized vitamin K supplementation.N Engl J Med. 1980; 303: 160-161PubMed Google Scholar occurs in patients on weight reduction diets (rich in green vegetables) and those treated with intravenous nutritional fluid supplements rich in vitamin K.Therapeutic Vitamin to Reduce the International Normalized Ratio in Anticoagulated PatientsThere is a strong relationship between the level of the international normalized ratio (INR) and the risk of bleeding. The risk of bleeding rises sharply when the INR exceeds 5.0, but the risk of bleeding is likely to be increased in high-risk patients (such as those having surgery) even when the INR is 1.5 to 2.0. If a patient has an elevated INR and is not bleeding or does not require surgery, then it is reasonable to reduce the INR to a safer level of <5.0 within 24 h. If the patient has serious bleeding the INR should be reduced to 1.0 as soon as possible. If the patient requires elective or urgent surgery it is reasonable to reduce the INR to 1.0 to 1.5 at the time of surgery.Three approaches can be used to reduce the INR. The first, and least rapid, is to discontinue treatment, the second is to use vitamin K1, and the third and most rapid, is to transfuse the patient with fresh plasma or prothrombin concentrate. The choice of these approaches is based largely on clinical judgment since randomized trials using clinical end points have not been performed.Discontinuation of Warfarin TherapyWhite and colleagues9White RH McCurdy SA von Marensdorff H et al.Home prothrombin time monitoring after initiation of warfarin therapy.A randomized, prospective study. Ann Intern Med. 1989; 111: 730-737Crossref PubMed Scopus (183) Google Scholar reported that it takes about 4 days for the INR to return to the normal range when warfarin is stopped in patients whose INR is between 2.0 and 3.0.Use of Vitamin K1Vitamin K1 is available as an injectable solution, an oral solution, or as a tablet. It is able to reduce an elevated INR in anticoagulated patients within 24 h. Vitamin K1 may be indicated to lower the INR in anticoagulated patients in three different clinical circumstances. These are in patients: (1) with an elevated INR who are not bleeding, but are considered at increased risk, when it would be reasonable to reduce the INR to less than 5.0 within 24 h; (2) who require surgery, in which case it is reasonable to reduce the INR to 1.0 to 1.5 at the time of surgery; and (3) in those with serious bleeding, who should have their INR reduced to 1.0 as soon as possible.Ideally, vitamin should be administered in a dosage that rapidly reduces the INR into a safe range without: (1) exposing the patient to an unnecessary risk of thrombosis; (2) rendering the patient resistant to warfarin when it is restarted; and (3) exposing the patient to a risk of an anaphylactoid reaction.The optimal dosage and the optimal route of administration of vitamin K have never been evaluated using a rigorous study design. Consequently, recommendations vary from doses ranging from less than 1 mg to up to 10 mg and all three routes of administration; intravenous, subcutaneous, and oral have been advocated.High doses of vitamin K1 (≥10 mg) are effective but can lead to warfarin resistance for days after they are discontinued. The intravenous route is likely to give the most predictable response, but can be complicated by anaphylactoid reactions, and there is no definitive evidence that this rare, but serious complication can be avoided by using low doses intravenously.The risk of over-correction and warfarin resistance can be reduced by using low doses of vitamin K1 and the risk of anaphylactoid reactions avoided by using the oral route of administration. A number of recent studies have confirmed older reports that both low doses of vitamin K1 and the oral route are effective.The effectiveness of low-dose oral vitamin K1 was demonstrated in a randomized trial by Pengo and colleagues10Pengo V Banzato A Garelli E et al.Reversal of excessive effect of regular anticoagulation: low oral dose of phytonadion (vitamin K1) compared with warfarin discontinuation.Blood Coagul Fibrinolysis. 1993; 4: 739-741Crossref PubMed Scopus (80) Google Scholar in 1993 who showed that 2.5 mg oral vitamin K1 was more effective than withholding warfarin for correcting the INR to 9.0, since it failed to lower the INR to 5.0 and who were not bleeding. Oral vitamin K1 was administered as a scored 5 mg tablet. Patients who required reversal of their INR prior to minor surgery or a dental procedure took vitamin K1 36 h before the procedure and continued their daily dose of warfarin: the aim was to reduce their INR to between 1.5 and 2.0. Patients whose INR was >5.0 held their dose of warfarin and received a dose of vitamin K1 that was predicted (from the formula) to lower their INR into the targeted therapeutic range. There was a strong correlation between the actual and predicted change in the INR. The mean dose of oral vitamin for the first (preoperative) group was 5 mg and for the over-anticoagulated group it was 10 mg.Taken together, the results of these studies indicate that oral vitamin K1 is effective for reducing the INR in patients treated with warfarin. A dose of 1.0 to 2.5 mg is effective when the initial INR is between 5.0 and 9.0, but a larger oral dose (eg, 5 mg) is required when the INR is >9.0. A formula for vitamin K1 dosage has been developed to aid in dosage selection, but as pointed out by the authors, the validity of their formulas should be confirmed by other laboratories using thromboplastins with different International Sensitivity Index values.Since oral vitamin K1 is effective for lowering the INR, it is the route of choice unless very rapid reversal of the INR is considered to be critical, in which case vitamin K1 can be administered by slow intravenous infusion with or without supplementary plasma infusion. Vitamin K is a cofactor for the posttranslational carboxylation of glutamate residues to λ-carboxyglutamates on the N-terminal regions of vitamin K dependent proteins.1Whitlon DS Sadowski JA Suttie JW Mechanisms of coumarin action: significance of vitamin K epoxide reductase inhibition.Biochemistry. 1978; 17: 1371-1377Crossref PubMed Scopus (306) Google Scholar, 2Fasco MJ Hildebrandt EF Suttie JW Evidence that warfarin anticoagulant action involves two distinct reductase activities.J Biol Chem. 1982; 257: 11210-11212PubMed Google Scholar, 3Choonara IA Malia RG Haynes BP et al.The relationship between inhibition of vitamin K 1,2,3-epoxide reductase and reduction of clotting factor activity with warfarin.Br J Clin Pharmacol. 1988; 25: 1-7Crossref PubMed Scopus (78) Google Scholar, 4Trivedi LS Rhee M Galivan JH et al.Normal and warfarin-resistant rat hepatocyte metabolism of vitamin K 2,3-epoxide: evidence for multiple pathways of hydroxyvitamin K formation.Arch Biochem Biophys. 1988; 264: 67-73Crossref PubMed Scopus (24) Google Scholar, 5Stenflo J Fernlund P Egan W et al.Vitamin K dependent modifications of glutamic acid residues in prothrombin.Proc Natl Acad Sci USA. 1974; 71: 2730-2733Crossref PubMed Scopus (614) Google Scholar, 6Nelsestuen GL Zytkovicz TH Howard JB The mode of action of vitamin K.Identification of gamma-carboxyglutamic acid as a component of prothrombin. J Biol Chem. 1974; 249: 6347-6350Google Scholar The process of λ-carboxylation is necessary for the biologic activity of vitamin K-dependent clotting factors, because it is required for calcium dependent complexing of the clotting proteins to their cofactors on phospholipid surfaces. During the carboxylation reaction the reduced form of vitamin K (vitamin KH2) is oxidized to vitamin K epoxide, which is recycled to vitamin K by vitamin K epoxide reductase, which in turn is reduced to vitamin KH2 by vitamin K reductase (Fig 1). Warfarin exerts its anticoagulant effect by inhibiting vitamin K epoxide reductase1Whitlon DS Sadowski JA Suttie JW Mechanisms of coumarin action: significance of vitamin K epoxide reductase inhibition.Biochemistry. 1978; 17: 1371-1377Crossref PubMed Scopus (306) Google Scholar, 2Fasco MJ Hildebrandt EF Suttie JW Evidence that warfarin anticoagulant action involves two distinct reductase activities.J Biol Chem. 1982; 257: 11210-11212PubMed Google Scholar, 3Choonara IA Malia RG Haynes BP et al.The relationship between inhibition of vitamin K 1,2,3-epoxide reductase and reduction of clotting factor activity with warfarin.Br J Clin Pharmacol. 1988; 25: 1-7Crossref PubMed Scopus (78) Google Scholar and to a lesser extent vitamin K reductase.2Fasco MJ Hildebrandt EF Suttie JW Evidence that warfarin anticoagulant action involves two distinct reductase activities.J Biol Chem. 1982; 257: 11210-11212PubMed Google Scholar This process leads to the depletion of vitamin KH2 and as a result, limits the λ-carboxylation of the vitamin K-dependent coagulant proteins (prothrombin, factor VII, factor IX, and factor X) and the regulatory anticoagulant proteins (protein C and protein S). The anticoagulant effect of warfarin can be overcome by vitamin K1 (both dietary and medicinal) because this oxidized form of the vitamin can be reduced through a warfarin resistant vitamin K reductase enzyme system (Fig 1). Dietary vitamin K17O'Reilly R Rytand D "Resistance" to warfarin due to unrecognized vitamin K supplementation.N Engl J Med. 1980; 303: 160-161PubMed Google Scholar,8Suttie JW Mummah-Schendel LL Shah DV et al.Vitamin K deficiency from dietary vitamin K restriction in humans.Am J Clin Nutr. 1988; 47: 475-480Crossref PubMed Scopus (109) Google Scholar is obtained predominantly from phylloquinone in plant material.8Suttie JW Mummah-Schendel LL Shah DV et al.Vitamin K deficiency from dietary vitamin K restriction in humans.Am J Clin Nutr. 1988; 47: 475-480Crossref PubMed Scopus (109) Google Scholar Increased intake of dietary vitamin K sufficient to reduce the anticoagulant response to warfarin7O'Reilly R Rytand D "Resistance" to warfarin due to unrecognized vitamin K supplementation.N Engl J Med. 1980; 303: 160-161PubMed Google Scholar occurs in patients on weight reduction diets (rich in green vegetables) and those treated with intravenous nutritional fluid supplements rich in vitamin K. Therapeutic Vitamin to Reduce the International Normalized Ratio in Anticoagulated PatientsThere is a strong relationship between the level of the international normalized ratio (INR) and the risk of bleeding. The risk of bleeding rises sharply when the INR exceeds 5.0, but the risk of bleeding is likely to be increased in high-risk patients (such as those having surgery) even when the INR is 1.5 to 2.0. If a patient has an elevated INR and is not bleeding or does not require surgery, then it is reasonable to reduce the INR to a safer level of <5.0 within 24 h. If the patient has serious bleeding the INR should be reduced to 1.0 as soon as possible. If the patient requires elective or urgent surgery it is reasonable to reduce the INR to 1.0 to 1.5 at the time of surgery.Three approaches can be used to reduce the INR. The first, and least rapid, is to discontinue treatment, the second is to use vitamin K1, and the third and most rapid, is to transfuse the patient with fresh plasma or prothrombin concentrate. The choice of these approaches is based largely on clinical judgment since randomized trials using clinical end points have not been performed. There is a strong relationship between the level of the international normalized ratio (INR) and the risk of bleeding. The risk of bleeding rises sharply when the INR exceeds 5.0, but the risk of bleeding is likely to be increased in high-risk patients (such as those having surgery) even when the INR is 1.5 to 2.0. If a patient has an elevated INR and is not bleeding or does not require surgery, then it is reasonable to reduce the INR to a safer level of <5.0 within 24 h. If the patient has serious bleeding the INR should be reduced to 1.0 as soon as possible. If the patient requires elective or urgent surgery it is reasonable to reduce the INR to 1.0 to 1.5 at the time of surgery. Three approaches can be used to reduce the INR. The first, and least rapid, is to discontinue treatment, the second is to use vitamin K1, and the third and most rapid, is to transfuse the patient with fresh plasma or prothrombin concentrate. The choice of these approaches is based largely on clinical judgment since randomized trials using clinical end points have not been performed. Discontinuation of Warfarin TherapyWhite and colleagues9White RH McCurdy SA von Marensdorff H et al.Home prothrombin time monitoring after initiation of warfarin therapy.A randomized, prospective study. Ann Intern Med. 1989; 111: 730-737Crossref PubMed Scopus (183) Google Scholar reported that it takes about 4 days for the INR to return to the normal range when warfarin is stopped in patients whose INR is between 2.0 and 3.0. White and colleagues9White RH McCurdy SA von Marensdorff H et al.Home prothrombin time monitoring after initiation of warfarin therapy.A randomized, prospective study. Ann Intern Med. 1989; 111: 730-737Crossref PubMed Scopus (183) Google Scholar reported that it takes about 4 days for the INR to return to the normal range when warfarin is stopped in patients whose INR is between 2.0 and 3.0. Use of Vitamin K1Vitamin K1 is available as an injectable solution, an oral solution, or as a tablet. It is able to reduce an elevated INR in anticoagulated patients within 24 h. Vitamin K1 may be indicated to lower the INR in anticoagulated patients in three different clinical circumstances. These are in patients: (1) with an elevated INR who are not bleeding, but are considered at increased risk, when it would be reasonable to reduce the INR to less than 5.0 within 24 h; (2) who require surgery, in which case it is reasonable to reduce the INR to 1.0 to 1.5 at the time of surgery; and (3) in those with serious bleeding, who should have their INR reduced to 1.0 as soon as possible.Ideally, vitamin should be administered in a dosage that rapidly reduces the INR into a safe range without: (1) exposing the patient to an unnecessary risk of thrombosis; (2) rendering the patient resistant to warfarin when it is restarted; and (3) exposing the patient to a risk of an anaphylactoid reaction.The optimal dosage and the optimal route of administration of vitamin K have never been evaluated using a rigorous study design. Consequently, recommendations vary from doses ranging from less than 1 mg to up to 10 mg and all three routes of administration; intravenous, subcutaneous, and oral have been advocated.High doses of vitamin K1 (≥10 mg) are effective but can lead to warfarin resistance for days after they are discontinued. The intravenous route is likely to give the most predictable response, but can be complicated by anaphylactoid reactions, and there is no definitive evidence that this rare, but serious complication can be avoided by using low doses intravenously.The risk of over-correction and warfarin resistance can be reduced by using low doses of vitamin K1 and the risk of anaphylactoid reactions avoided by using the oral route of administration. A number of recent studies have confirmed older reports that both low doses of vitamin K1 and the oral route are effective.The effectiveness of low-dose oral vitamin K1 was demonstrated in a randomized trial by Pengo and colleagues10Pengo V Banzato A Garelli E et al.Reversal of excessive effect of regular anticoagulation: low oral dose of phytonadion (vitamin K1) compared with warfarin discontinuation.Blood Coagul Fibrinolysis. 1993; 4: 739-741Crossref PubMed Scopus (80) Google Scholar in 1993 who showed that 2.5 mg oral vitamin K1 was more effective than withholding warfarin for correcting the INR to 9.0, since it failed to lower the INR to 5.0 and who were not bleeding. Oral vitamin K1 was administered as a scored 5 mg tablet. Patients who required reversal of their INR prior to minor surgery or a dental procedure took vitamin K1 36 h before the procedure and continued their daily dose of warfarin: the aim was to reduce their INR to between 1.5 and 2.0. Patients whose INR was >5.0 held their dose of warfarin and received a dose of vitamin K1 that was predicted (from the formula) to lower their INR into the targeted therapeutic range. There was a strong correlation between the actual and predicted change in the INR. The mean dose of oral vitamin for the first (preoperative) group was 5 mg and for the over-anticoagulated group it was 10 mg.Taken together, the results of these studies indicate that oral vitamin K1 is effective for reducing the INR in patients treated with warfarin. A dose of 1.0 to 2.5 mg is effective when the initial INR is between 5.0 and 9.0, but a larger oral dose (eg, 5 mg) is required when the INR is >9.0. A formula for vitamin K1 dosage has been developed to aid in dosage selection, but as pointed out by the authors, the validity of their formulas should be confirmed by other laboratories using thromboplastins with different International Sensitivity Index values.Since oral vitamin K1 is effective for lowering the INR, it is the route of choice unless very rapid reversal of the INR is considered to be critical, in which case vitamin K1 can be administered by slow intravenous infusion with or without supplementary plasma infusion. Vitamin K1 is available as an injectable solution, an oral solution, or as a tablet. It is able to reduce an elevated INR in anticoagulated patients within 24 h. Vitamin K1 may be indicated to lower the INR in anticoagulated patients in three different clinical circumstances. These are in patients: (1) with an elevated INR who are not bleeding, but are considered at increased risk, when it would be reasonable to reduce the INR to less than 5.0 within 24 h; (2) who require surgery, in which case it is reasonable to reduce the INR to 1.0 to 1.5 at the time of surgery; and (3) in those with serious bleeding, who should have their INR reduced to 1.0 as soon as possible. Ideally, vitamin should be administered in a dosage that rapidly reduces the INR into a safe range without: (1) exposing the patient to an unnecessary risk of thrombosis; (2) rendering the patient resistant to warfarin when it is restarted; and (3) exposing the patient to a risk of an anaphylactoid reaction. The optimal dosage and the optimal route of administration of vitamin K have never been evaluated using a rigorous study design. Consequently, recommendations vary from doses ranging from less than 1 mg to up to 10 mg and all three routes of administration; intravenous, subcutaneous, and oral have been advocated. High doses of vitamin K1 (≥10 mg) are effective but can lead to warfarin resistance for days after they are discontinued. The intravenous route is likely to give the most predictable response, but can be complicated by anaphylactoid reactions, and there is no definitive evidence that this rare, but serious complication can be avoided by using low doses intravenously. The risk of over-correction and warfarin resistance can be reduced by using low doses of vitamin K1 and the risk of anaphylactoid reactions avoided by using the oral route of administration. A number of recent studies have confirmed older reports that both low doses of vitamin K1 and the oral route are effective. The effectiveness of low-dose oral vitamin K1 was demonstrated in a randomized trial by Pengo and colleagues10Pengo V Banzato A Garelli E et al.Reversal of excessive effect of regular anticoagulation: low oral dose of phytonadion (vitamin K1) compared with warfarin discontinuation.Blood Coagul Fibrinolysis. 1993; 4: 739-741Crossref PubMed Scopus (80) Google Scholar in 1993 who showed that 2.5 mg oral vitamin K1 was more effective than withholding warfarin for correcting the INR to 9.0, since it failed to lower the INR to 5.0 and who were not bleeding. Oral vitamin K1 was administered as a scored 5 mg tablet. Patients who required reversal of their INR prior to minor surgery or a dental procedure took vitamin K1 36 h before the procedure and continued their daily dose of warfarin: the aim was to reduce their INR to between 1.5 and 2.0. Patients whose INR was >5.0 held their dose of warfarin and received a dose of vitamin K1 that was predicted (from the formula) to lower their INR into the targeted therapeutic range. There was a strong correlation between the actual and predicted change in the INR. The mean dose of oral vitamin for the first (preoperative) group was 5 mg and for the over-anticoagulated group it was 10 mg. Taken together, the results of these studies indicate that oral vitamin K1 is effective for reducing the INR in patients treated with warfarin. A dose of 1.0 to 2.5 mg is effective when the initial INR is between 5.0 and 9.0, but a larger oral dose (eg, 5 mg) is required when the INR is >9.0. A formula for vitamin K1 dosage has been developed to aid in dosage selection, but as pointed out by the authors, the validity of their formulas should be confirmed by other laboratories using thromboplastins with different International Sensitivity Index values. Since oral vitamin K1 is effective for lowering the INR, it is the route of choice unless very rapid reversal of the INR is considered to be critical, in which case vitamin K1 can be administered by slow intravenous infusion with or without supplementary plasma infusion.