Neue Einsichten in die orale Antikoagulationstherapie mit Cumarinen

J. Oldenburg; H. Seidel; B. Pötzsch; M. Watzka

doi:10.1055/s-0037-1616921

Hämostaseologie, Inhaltsverzeichnis

Hamostaseologie 2008; 28(01/02): 44-50
DOI: 10.1055/s-0037-1616921

Original Article

Schattauer GmbH

Neue Einsichten in die orale Antikoagulationstherapie mit Cumarinen

New insight in therapeutic anticoagulation by coumarin derivatives

Autoren

J. Oldenburg

¹Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn
H. Seidel

¹Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn
B. Pötzsch

¹Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn
M. Watzka

¹Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn

Abstract

Zusammenfassung

Die Identifizierung der Vitamin-K-Epoxid-Reduktase (VKORC1) hat maßgeblich zu einem besseren Verständnis des Vitamin-K-Zyklus beigetragen. Das VKORC1-Protein konnte als das molekulare Target der Cumarine charakterisiert werden und stellt das geschwindigkeitsbestimmende Enzym des Vitamin-K-Zyklus und möglicherweise die alleinige Komponente der VKOR-Aktivität dar. Mutationen und Polymorphismen innerhalb der translatierten und nicht translatierten Regionen des VKORC1-Gens verursachen partielle bis totale Cumarin-Resistenz und -Sensitivität. Die Verfügbarkeit einer molekulargenetischen Diagnostik (VKORC1, CYP2C9) und einer Laboranalytik mittels HPLC (zur Bestimmung des Cumarin-, Vitamin-K- und Vitamin- K-Epoxidspiegels) ist hilfreich in der Detektion hereditärer und erworbener Einflussgrößen der Cumarintherapie und könnte zukünftig für eine individualisierte, risikoärmere orale Antikoagulationstherapie zum Einsatz kommen.

Eine niedrig dosierte tägliche Vitamin-K-Supplementierung scheint geeignet, die Sicherheit einer oralen Antikoagulationstherapie mit Cumarinen zu verbessern. Bei der Entwicklung neuer und auf molekularer Ebene selektiv wirkender oraler Antikoagulanzien wird sich somit die Frage nach gleich guter Effektivität und Sicherheit im Vergleich zu den ˶alten“ Antikoagulanzien stellen. Gerade auch unter dem Aspekt der Ökonomie könnten die bewährten Cumarine durch eine pharmakogenetisch und nutritiv adaptierte Therapieoptimierung eine Renaissance erfahren.

Summary

The recent identification of vitamin K epoxid-reductase complex (VKORC1) contributed significantly to our mechanistic understanding of the vitamin K cycle. VKORC1 protein is targeted by Coumarins. Its enzymatic activity represents the rate-limiting step in the vitamin K cycle and γ-carboxylation of vitamin K dependent proteins. Possibly, VKORC1 is the only component of VKOR activity. Mutations as well as polymorphisms in coding and non-coding regions of the VKORC1 gene have been shown to cause both partial to total coumarin resistance and coumarin sensitivity. Availability of molecular diagnostics (VKORC1, CYP2C9) and laboratory analysis by HPLC (determination of coumarin, vitamin K and vitamin K epoxide levels) is helpful in detection of hereditary and acquired factors influencing coumarin therapy.

In the future, these tools might lead to an individualized and safer oral anticoagulation therapy. Furthermore, daily low-dose vitamin K supplementation may improve stability of coumarin-based anticoagulation. In the perspective of the coming new oral anticoagulants, the efficacy and safety profile of the ˶old“ anticoagulants is of major importance. The well established and oeconomic coumarin drugs will benefit from a pharmacogenetic and nutritive adjusted optimization of therapy.

Schlüsselwörter

VKORC1 - Vitamin-K-Zyklus - Cumarin

Keywords

VKORC1 - vitamin K cycle - coumarin

Volltext

Referenzen

References
1 Kaufman DW, Kelly JP, Rosenberg L. et al. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002; 287: 337-344.
2 Wittkowsky AK, Boccuzzi SJ, Wogen J. et al. Frequency of concurrent use of warfarin with potentially interacting drugs. Pharmacotherapy 2004; 24: 1668-1674.
3 Abusaada K, Sharma SB, Jaladi R. et al. Epidemiology and management of new-onset atrial fibrillation. Am J Manag Care 2004; 10: S50-S57.
4 Palareti G, Leali N, Coccheri S. et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 1996; 348: 432-438.
5 Kuijer PM, Hutten BA, Prins MH. et al. Prediction of the risk of bleeding during anticoagulation treatment for venous thromboembolism. Arch Intern Med 1999; 159: 457-460.
6 Prandoni P. Low rate of warfarin-related major bleeding in patients with recurrent venous thromboembolism. Thromb Haemost 1999; 82: 158-159.
7 Levine M, Gary R, Landefeld S. et al. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119: 108-121.
8 Beyth RJ, Milligan PE, Gage BF. Risk factors for bleeding in patients taking coumarins. Curr Hematol Rep 2002; 1: 41-49.
9 Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta- analysis. Ann Intern Med 2003; 139: 893-900.
10 Agnelli G. Long-term low-dose warfarin use is effective in the prevention of recurrent venous thromboembolism: no. J Thromb Haemost 2004; 2: 1036-1040.
11 Wilkinson TJ, Sainsbury R. Evaluation of a warfarin initiation protocol for older people. Intern Med J 2003; 33: 465-467.
12 Kamali F, Khan TI, King BP. et al. Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clin Pharmacol Ther 2004; 75: 204-212.
13 Geisen C, Watzka M, Sittinger K. et al. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost 2005; 94: 773-779.
14 Rieder MJ, Reiner AP, Gage BF. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352: 2285-2293.
15 Rost S, Fregin A, Ivaskevicius V. et al. Mutations in VKORC1 cause wafarin resistance and multiple coagulation factor deficiency type 2. Nature 2004; 427: 537-541.
16 Li T, Chang CY, Jin DY. et al. Identification of the gene for vitamin K epoxide reductase. Nature 2004; 427: 541-544.
17 Yuan HY, Chen JJ, Lee MT. et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 2005; 14: 1745-1751.
18 Oldenburg J, Bevans CG, Müller CR. et al. Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle. Antioxid Redox Signal 2006; 8: 347-353.
19 Oldenburg J, Watzka M, Rost S. et al. VKORC1: molecular target of coumarins. J Thromb Haemost 2007; 5 (Suppl. 01) 1-6.
20 Chan E, McLachlan A, O’Reilly R. et al. Stereochemical aspects of warfarin drug interactions: use of a combined pharmacokinetic-pharmacodynamic model. Clin Pharmacol Ther 1990; 56: 286-294.
21 Hignite C, Uetrecht J, Tschanz C. et al. Kinetics of R and S warfarin enantiomers. Clin Pharmacol Ther 1980; 28: 99-105.
22 Rettie AE, Korzekwa KR, Kunze KL. et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 1992; 5: 54-59.
23 Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther 1997; 73: 67-74.
24 Ufer M. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet 2005; 44: 1227-1246.
25 Zhang Z, Fasco MJ, Huang Z. et al. Human cytochromes P4501A1 and P4501A2: R-warfarin metabolism as a probe. Drug Metab Dispos 1995; 23: 1339-1346.
26 Zhou S, Chan E, Lim LY. et al. Therapeutic drugs that behave as mechanism-based inhibitors of cytochrome P450 3A4. Curr Drug Metab 2004; 5: 415-442.
27 Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet 2001; 40: 587-603.
28 Thijssen HH, Flinois JP, Beaune PH. Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes. Drug Metab Dispos 2000; 28: 1284-1290.
29 Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 2002; 12: 251-263.
30 Gage BF, Eby C, Milligan PE. et al. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost 2004; 91: 87-94.
31 Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarintreated patients: a HuGEnet systematic review and meta-analysis. Genet Med 2005; 7: 97-104.
32 D’Andrea G, D’Ambrosio RL, Di Perna P. et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 2005; 105: 645-649.
33 Wadelius M, Chen LY, Eriksson N. et al. Association of warfarin dose with genes involved in its action and metabolism. Hum Genet 2007; 121: 23-34.
34 Wadelius M, Chen LY, Downes K. et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 2005; 5: 262-270.
35 Herman D, Peternel P, Stegnar M. et al. The influence of sequence variations in factor VII, gammaglutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. Thromb Haemost 2006; 95: 782-787.
36 Kimura R, Miyashita K, Kokubo Y. et al. Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients. Thromb Res 2007; 120: 181-186.
37 Rieder MJ, Reiner AP, Rettie AE. Gamma-Glutamyl carboxylase (GGCX) tagSNPs have limited utility for predicting warfarin maintenance dose. J Thromb Haemost 2007; 5: 2227-2234.
38 Kohnke H, Sörlin K, Granath G. et al. Warfarin dose related to apolipoprotein E (APOE) genotype. Eur J Clin Pharmacol 2005; 61: 381-388.
39 Sconce EA, Daly AK, Khan TI. et al. APOE genotype makes a small contribution to warfarin dose requirements. Pharmacogenet Genomics 2006; 16: 609-611.
40 Kimmel SE, Christie J, Kealey C. et al. Apolipoprotein E genotype and warfarin dosing among Caucasians and African Americans. Pharmacogenomics J 2008; 8: 53-60.
41 Loebstein R, Vecsler M, Kurnik D. et al. Common genetic variants of microsomal epoxide hydrolase affect warfarin dose requirements beyond the effect of cytochrome P450 2C9. Clin Pharmacol Ther 2005; 77: 365-372.
42 Wajih N, Sane DC, Hutson SM. et al. The inhibitory effect of calumenin on the vitamin K-dependent gamma-carboxylation system. Characterization of the system in normal and warfarin-resistant rats. J Biol Chem 2004; 279: 25276-25283.
43 Vecsler M, Loebstein R, Almog S. et al. Combined genetic profiles of components and regulators of the vitamin K-dependent gamma-carboxylation system affect individual sensitivity to warfarin. Thromb Haemost 2006; 95: 205-211.
44 Sconce EA, Khan TI, Wynne HA. et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005; 106: 2329-2333.
45 Reitsma PH, van der Heijden JF, Groot AP. et al. A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk. PLoS Med 2005; 2: e312.
46 Quteineh L, Verstuyft C, Descot C. et al. Vitamin K epoxide reductase (VKORC1) genetic polymorphism is associated to oral anticoagulant overdose. Thromb Haemost 2005; 94: 690-691.
47 Schalekamp T, Brassé BP, Roijers JF. et al. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Ther 2006; 80: 13-22.
48 Fukuda T, Tanabe T, Ohno M. et al. Warfarin dose requirement for patients with both VKORC1 3673A/A and CYP2C9*3/*3 genotypes. Clin Pharmacol Ther 2006; 80: 553-554.
49 Veenstra DL, You JH, Rieder MJ. et al. Association of vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population. Pharmacogenet Genomics 2005; 15: 687-691.
50 Harrington DJ, Underwood S, Morse C. et al. Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1. Thromb Haemost 2005; 93: 23-26.
51 Bodin L, Horellou MH, Flaujac C. et al. A vitamin K epoxide reductase complex subunit-1 (VKORC1) mutation in a patient with vitamin K antagonist resistance. J Thromb Haemost 2005; 3: 1533-1535.
52 D’Ambrosio RL, D’Andrea G, Cafolla A. et al. A new vitamin K epoxide reductase complex subunit- 1 (VKORC1) mutation in a patient with decreased stability of CYP2C9 enzyme. J Thromb Haemost 2007; 5: 191-193.
53 Loebstein R, Dvoskin I, Halkin H. et al. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood 2007; 109: 2477-2480.
54 Myszka DG, Swenson RP. Synthesis of the photoaffinity probe 3-(p-azidobenzyl)-4-hydroxycoumarin and identification of the dicoumarol binding site in rat liver NAD(P)H:quinone reductase (EC 1.6.99.2). J Biol Chem 1991; 266: 4789-4797.
55 Rost S, Fregin A, Hünerberg M. et al. Site-directed mutagenesis of coumarin-type anticoagulant-sensitive VKORC1: evidence that highly conserved amino acids define structural requirements for enzymatic activity and inhibition by warfarin. Thromb Haemost 2005; 94: 780-786.
56 Wajih N, Sane DC, Hutson SM. et al. Engineering of a recombinant vitamin K-dependent gammacarboxylation system with enhanced gammacarboxyglutamic acid forming capacity: evidence for a functional CXXC redox center in the system. J Biol Chem 2005; 280: 10540-10547.
57 Jin DY, Tie JK, Stafford DW. The conversion of vitamin K epoxide to vitamin K quinone and vitamin K quinone to vitamin K hydroquinone uses the same active site cysteines. Biochemistry 2007; 46: 7279-7283.
58 Sconce EA, Kamali F. Appraisal of current vitamin K dosing algorithms for the reversal of overanticoagulation with warfarin: the need for a more tailored dosing regimen. Eur J Haematol 2006; 77: 457-462.
59 Tham LS, Goh BC, Nafziger A. et al. A warfarindosing model in Asians that uses single-nucleotide polymorphisms in vitamin K epoxide reductase complex and cytochrome P450 2C9. Clin Pharmacol Ther 2006; 80: 346-355.
60 Carlquist JF, Horne BD, Muhlestein JB. et al. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Thrombolysis 2006; 22: 191-197.
61 Hamberg AK, Dahl ML, Barba M. et al. A PK-PD model for predicting the impact of age CYP2C9 and VKORC1 genotype on individualization of warfarin therapy. Clin Pharmacol Ther 2007; 81: 185-193.
62 Reitsma PH, van der Heijden JF, Groot AP. et al. A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk. PLoS Med 2005; 2: e312.
63 Schalekamp T, Brassé BP, Roijers JF. et al. VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clin Pharmacol Ther 2007; 81: 185-193.
64 Higashi MK, Veenstra DL, Kondo LM. et al. Association between CYP2C9 genetic variants and anticoagulation- related outcomes during warfarin therapy. JAm MedAssoc 2002; 287: 1690-1698.
65 Visser LE, van Schaik RH, van Vliet M. et al. Allelic variants of cytochrome P450 2C9 modify the interaction between nonsteroidal anti-inflammatory drugs and coumarin anticoagulants. Clin Pharmacol Ther 2005; 77: 479-485.
66 Anderson JL, Horne BD, Stevens SM. et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007; 116: 2563-2570.
67 Herman D, Peternel P, Stegnar M. et al. The influence of sequence variations in factor VII, γ-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. Thromb Haemost 2006; 95: 782-787.
68 Takahashi H, Wilkinson G, Nutescu EA. et al. Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenet Genomics 2006; 16: 101-110.
69 Millican EA, Lenzini PA, Milligan PE. et al. Genetic- based dosing in orthopedic patients beginning warfarin therapy. Blood 2007; 110: 151-155.
70 Sconce E, Khan T, Mason J. et al. Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation. Thromb Haemost 2005; 93: 872-875.
71 Oldenburg J. Vitamin K intake and stability of oral anticoagulant treatment. Thromb Haemost 2005; 93: 799-800.
72 Sun YM, Jin DY, Camire RM. et al. Vitamin K epoxide reductase significantly improves carboxylation in a cell line overexpressing factor X. Blood 2005; 106: 3811-3815.
73 Schurgers LJ, Shearer MJ, Halmujak K. et al. Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose-response relationships in healthy subjects. Blood 2004; 104: 2682-2689.
74 Sconce E, Avery P, Wynne H. et al. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood 2007; 109: 2419-2423.
75 Reese AM, Farnett LE, Lyons RM. et al. Low-dose vitamin K to augment anticoagulation control. Pharmacotherapy 2005; 25: 1746-1751.
76 Rombouts EK, Rosendaal FR, van der Meer FJM. The effect of vitamin K supplementation on anticoagulant treatment. J Thromb Haemost 2006; 4: 691-692.
77 Rombouts EK, Rosendaal FR, van der Meer FJM. Daily vitamin K supplementation improves anticoagulant stability. J Thromb Haemost 2007; 5: 2043-2048.