Acta med. scand. Vol. 198, pp. 269-270, 1975
Predictable Reduction in Anticoagulant Activity of Warfarin by Small Amounts of Vitamin K P. Andersen and H. C. Godal From the Haematological Research Laboratory and Medical Department IX, VlIevdl Hospital, University Clinic, Oslo, Norway
ABSTRACT. After withdrawal of warfarin (Marevan), 48-72 hours are required to raise the Thrombotest values from a therapeutic level (range %lo%) to 12% or higher. By i.v. administration of 1 mg vitamin K1 (Konakion@)and without changing the dose of the anticoagulant, this effect could be obtained within 24 hours. Furthermore, the effect of vitamin K vanished within 2-5 days. The use of small amounts of vitamin K may therefore be a simple and reliable way of obtaining a rapid, temporary reduction in anticoagulant effect.
without altering the dose of warfarin. In the remaining 5 patients, anticoagulant treatment was withdrawn. There-
after, all patients were followed by repeated TT readings during 48 hours. Reagents Vitamin K1, Konakion@ (Hoffmann-La Roche, Bade, Switzerland). Sodium warfarin, Marevan (Nyegaard & Co A/S, Oslo, Norway). Thrombotest (Nyegaard & Co A/S, Oslo, Norway) was carried out according t o the manufacturer.
RESULTS Anticoagulant therapy with vitamin K antagonists is widely used to prevent thrombosis. Episodes of spontaneous bleeding are therefore not uncommon. Severe bleeding is treated with large doses of vitamin K and transfusions of blood or plasma. During minor bleeding, or when surgical intervention is necessary, only a moderate reduction in anticoagulant effect is desirable, in order to reduce the risk of rethrombosis (2, 3). Generally, this is achieved by partial or total withdrawal of the anticoagulant drug (1). From the study of van der Meer et al. (6). it emerges that i.v. administration of small amounts of vitamin K1, without changing the dose of anticoagulant, might afford a simple and reliable alternative. The data presented below are in accordance with this concept. MATERIAL AND METHODS Twenty-five patients, who had been treated with warfarin (Marevan) for various periods (2 weeks to 3 years) were studied. They were all in a steady state with respect to hypocoagulability , their Thrombotest (TT) values being within the therapeutic range (5-10% of normal). Twenty of the patients received 1 mg vitamin K1 (Konakion") i.v.,
In all patients receiving 1 mg vitamin K l , this amount proved sufficient to raise the T T level above 12 % within 24 hours (Fig. 1 above). In contrast, total withdrawal of warfarin did not influence TT appreciably during this period (Fig. 1 below). The effect of vitamin K1 did not seem to depend on the dose of warfarin used to achieve adequate anticoagulant effect (Table I). In 4 of the 5 patients tested, the effect of vitamin K1 vanished within 2-5 days (Fig. 2).
DISCUSSION With the TT method for the control of anticoagulant therapy with vitamin K antagonists, values of 510% of normal are recommended as optimal (4, 5 ) , whereas values above 12% are considered sufficient to prevent excessive bleeding following surgery (7). In the present study, the effect of 1 mg vitamin K1 (and sustained dose of anticoagulant) varied considerably from patient to patient, but invariably, a T T value of at least 12% was achieved within 24 hours, the highest value being 32 % (Table I). The effect of vitamin K1 disappeared within 2-5 Acra med. scand. 198
210
P . Andersen and H . C. Godal
40
Table I. Effect on Thrombotest of I mg vitamin K 1 , in 20 putients treuted with warfarin
30
- 20 c E
PI
u 10
Pat. no."
L
Marevan for steady state (mg/d.)
TT(%) Before K1
24 h after K I
0)
-n 5 v)
2 3 4
0 L
0
n
5
6 7 8 9
7.5 3.75 3.75 10 11.25 5 8.75
10
10
I1 I2 13 14 I 15 I6 17 18 19 20
11.25 7.5 2 12.75 7.5 5 5 3.25 5 6 6.25
5 5
5 O
-'%'% hours
Fig. 1 . The effect on Thrombotest of I mg vitamin KI (Konakionm) given i.v. to 20 patients treated with Marevan (upper curve) as compared with the effect obtained in 5 patients by simple withdrawal of the anticoagulant drug (lower curve).
days and was not related to the dose of anticoagulant used. These observations fit in well with those of v a n der Meer et al. (6). who found that the magnitude and duration of the effect of agiven dose of vitamin K I depended on the intensity of anticoagulant treatment, but not o n the dose of anticoagulant required to obtain a given degree of hypocoagulability. Since 2-3 days are required to raise the TT value above 12% after withdrawal of warfarin (but without administration of vitamin K), it seems preferable to administer small amounts of vitamin K in order to obtain rapid and predictable coagulability
.--.
A Br c*-d B G A-A G R 0-0 H 0, S N m-¤
i Vit K1
I , -2
-1
0
1
2
3
4
5
Days
Fig. 2. Duration of the effect on Thrombotest of 1 mg vitamin K1 (Konakionm) given i.v. to 5 patients treated with Marevan, without changing the dose of anticoagulant. Actu med. scund. 198
3 5.5 5.5 7 7 6 7 5 6.5 6.5 6.5 6.5 7 9 9 9
7.5 6.25
1
c
10
9.5 7 9 9 12.5
12 12 13 13 13 15 15.5 16 16 16 16 16 17 19 20 21 22 23 25 30 30 32
Pat. 1 and 5 studied twice
changes in anticoagulated patients. In addition, the unchanged dosage of anticoagulant represents a simplification.
REFERENCES I . Eskeland, G.: Thromboembolism and anticoagulant therapy in surgical patients. Summary in English. Farmacoterapi 1, vol. XX, 1964. 2. Gormsen, J. & Haxholdt, B. F.: Operative and postoperative changes in blood coagulation. Acta chir. scand. 121: 377, 1961. 3. Ingram, G. I. C.: Anticoagulant therapy. Pharmacol. Rev. 13:279, 1961. 4. Loeliger, E. A . : Progress in the control of oral anticoagulation. Thrombos. Diathes. haemorrh. 28: 109, 1972. 5. Loeliger, E. A . , Hensen, A., Kroes, F., van Dijk, L. M., Fekkes, N., de Jonge, H. & Hernker, H. C.: A double-blind trial of long-term anticoagulant treatment after myocardial infarction. Acta med. scand. 182: 549, 1967. 6. van der Meer, J., Hemker, H. C. & Loeliger, E. A.: Pharmacological aspects of vitamin K1. A clinical and experimental study in man. Thrombos. Diathes. haemorrh., Suppl 29, 1968. 7. Wieberdink, J. : Safe peroperative anticoagulation. Thorax 22: 567. 1967.
Predictable Reduction in Anticoagulant Activity of Warfarin by Small Amounts of Vitamin K P. Andersen and H. C. Godal From the Haematological Research Laboratory and Medical Department IX, VlIevdl Hospital, University Clinic, Oslo, Norway
ABSTRACT. After withdrawal of warfarin (Marevan), 48-72 hours are required to raise the Thrombotest values from a therapeutic level (range %lo%) to 12% or higher. By i.v. administration of 1 mg vitamin K1 (Konakion@)and without changing the dose of the anticoagulant, this effect could be obtained within 24 hours. Furthermore, the effect of vitamin K vanished within 2-5 days. The use of small amounts of vitamin K may therefore be a simple and reliable way of obtaining a rapid, temporary reduction in anticoagulant effect.
without altering the dose of warfarin. In the remaining 5 patients, anticoagulant treatment was withdrawn. There-
after, all patients were followed by repeated TT readings during 48 hours. Reagents Vitamin K1, Konakion@ (Hoffmann-La Roche, Bade, Switzerland). Sodium warfarin, Marevan (Nyegaard & Co A/S, Oslo, Norway). Thrombotest (Nyegaard & Co A/S, Oslo, Norway) was carried out according t o the manufacturer.
RESULTS Anticoagulant therapy with vitamin K antagonists is widely used to prevent thrombosis. Episodes of spontaneous bleeding are therefore not uncommon. Severe bleeding is treated with large doses of vitamin K and transfusions of blood or plasma. During minor bleeding, or when surgical intervention is necessary, only a moderate reduction in anticoagulant effect is desirable, in order to reduce the risk of rethrombosis (2, 3). Generally, this is achieved by partial or total withdrawal of the anticoagulant drug (1). From the study of van der Meer et al. (6). it emerges that i.v. administration of small amounts of vitamin K1, without changing the dose of anticoagulant, might afford a simple and reliable alternative. The data presented below are in accordance with this concept. MATERIAL AND METHODS Twenty-five patients, who had been treated with warfarin (Marevan) for various periods (2 weeks to 3 years) were studied. They were all in a steady state with respect to hypocoagulability , their Thrombotest (TT) values being within the therapeutic range (5-10% of normal). Twenty of the patients received 1 mg vitamin K1 (Konakion") i.v.,
In all patients receiving 1 mg vitamin K l , this amount proved sufficient to raise the T T level above 12 % within 24 hours (Fig. 1 above). In contrast, total withdrawal of warfarin did not influence TT appreciably during this period (Fig. 1 below). The effect of vitamin K1 did not seem to depend on the dose of warfarin used to achieve adequate anticoagulant effect (Table I). In 4 of the 5 patients tested, the effect of vitamin K1 vanished within 2-5 days (Fig. 2).
DISCUSSION With the TT method for the control of anticoagulant therapy with vitamin K antagonists, values of 510% of normal are recommended as optimal (4, 5 ) , whereas values above 12% are considered sufficient to prevent excessive bleeding following surgery (7). In the present study, the effect of 1 mg vitamin K1 (and sustained dose of anticoagulant) varied considerably from patient to patient, but invariably, a T T value of at least 12% was achieved within 24 hours, the highest value being 32 % (Table I). The effect of vitamin K1 disappeared within 2-5 Acra med. scand. 198
210
P . Andersen and H . C. Godal
40
Table I. Effect on Thrombotest of I mg vitamin K 1 , in 20 putients treuted with warfarin
30
- 20 c E
PI
u 10
Pat. no."
L
Marevan for steady state (mg/d.)
TT(%) Before K1
24 h after K I
0)
-n 5 v)
2 3 4
0 L
0
n
5
6 7 8 9
7.5 3.75 3.75 10 11.25 5 8.75
10
10
I1 I2 13 14 I 15 I6 17 18 19 20
11.25 7.5 2 12.75 7.5 5 5 3.25 5 6 6.25
5 5
5 O
-'%'% hours
Fig. 1 . The effect on Thrombotest of I mg vitamin KI (Konakionm) given i.v. to 20 patients treated with Marevan (upper curve) as compared with the effect obtained in 5 patients by simple withdrawal of the anticoagulant drug (lower curve).
days and was not related to the dose of anticoagulant used. These observations fit in well with those of v a n der Meer et al. (6). who found that the magnitude and duration of the effect of agiven dose of vitamin K I depended on the intensity of anticoagulant treatment, but not o n the dose of anticoagulant required to obtain a given degree of hypocoagulability. Since 2-3 days are required to raise the TT value above 12% after withdrawal of warfarin (but without administration of vitamin K), it seems preferable to administer small amounts of vitamin K in order to obtain rapid and predictable coagulability
.--.
A Br c*-d B G A-A G R 0-0 H 0, S N m-¤
i Vit K1
I , -2
-1
0
1
2
3
4
5
Days
Fig. 2. Duration of the effect on Thrombotest of 1 mg vitamin K1 (Konakionm) given i.v. to 5 patients treated with Marevan, without changing the dose of anticoagulant. Actu med. scund. 198
3 5.5 5.5 7 7 6 7 5 6.5 6.5 6.5 6.5 7 9 9 9
7.5 6.25
1
c
10
9.5 7 9 9 12.5
12 12 13 13 13 15 15.5 16 16 16 16 16 17 19 20 21 22 23 25 30 30 32
Pat. 1 and 5 studied twice
changes in anticoagulated patients. In addition, the unchanged dosage of anticoagulant represents a simplification.
REFERENCES I . Eskeland, G.: Thromboembolism and anticoagulant therapy in surgical patients. Summary in English. Farmacoterapi 1, vol. XX, 1964. 2. Gormsen, J. & Haxholdt, B. F.: Operative and postoperative changes in blood coagulation. Acta chir. scand. 121: 377, 1961. 3. Ingram, G. I. C.: Anticoagulant therapy. Pharmacol. Rev. 13:279, 1961. 4. Loeliger, E. A . : Progress in the control of oral anticoagulation. Thrombos. Diathes. haemorrh. 28: 109, 1972. 5. Loeliger, E. A . , Hensen, A., Kroes, F., van Dijk, L. M., Fekkes, N., de Jonge, H. & Hernker, H. C.: A double-blind trial of long-term anticoagulant treatment after myocardial infarction. Acta med. scand. 182: 549, 1967. 6. van der Meer, J., Hemker, H. C. & Loeliger, E. A.: Pharmacological aspects of vitamin K1. A clinical and experimental study in man. Thrombos. Diathes. haemorrh., Suppl 29, 1968. 7. Wieberdink, J. : Safe peroperative anticoagulation. Thorax 22: 567. 1967.
