Warfarin sensitivity

Vitamin K is the cofactor for the carboxylation of glutamate residues in the post-synthetic modification of proteins to form the unusual amino acid y-carboxygluta-mate (Gla), which chelates the calcium ion. Initially, vitamin K hydroquinone is oxidized to the epoxide (Figure 45-8), which activates a glutamate residue in the protein substrate to a carbanion, that reacts non-enzymically with carbon dioxide to form y-carboxyglut-amate. Vitamin K epoxide is reduced to the quinone by a warfarin-sensitive reductase, and the quinone is reduced to the active hydroquinone by either the same warfarin-sensitive reductase or a warfarin-insensitive... 

Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000 ... 

Taube, et al., "Influence of Cytochrome P-450 CYP2C9 Polymorphisms on Warfarin Sensitivity and Risk of Over-Anticoagulation in Patients on Long-Term Treatment," Blood, 96,1816-1819 (2000). 

T. M. Guenthner, D. Cai, R. Wallin, Co-Purification of Microsomal Epoxide Hydrolase with the Warfarin-Sensitive Vitamin Kx Oxide Reductase of the Vitamin K Cycle , Biochem. Pharmacol. 1998, 55, 169 - 175. 

Vitamin K cycle—metabolic interconversions of vitamin K associated with the synthesis of vitamin K-dependent clotting factors. Vitamin K1 or K2 is activated by reduction to the hydroquinone form (KH2). Stepwise oxidation to vitamin K epoxide (KO) is coupled to prothrombin carboxylation by the enzyme carboxylase. The reactivation of vitamin K epoxide is the warfarin-sensitive step (warfarin). The R on the vitamin K molecule represents a 20-carbon phytyl side chain in vitamin Ki and a 30- to 65-carbon polyprenyl side chain in vitamin K2. 

Shikata E, leiri I, Ishiguru S, et al. Association of pharmacokinetics (CYP2C9) and pharmacodynamics (factors II, VII, IX, and X protein S and C and gamma-glutamyl carboxylase) gene variants with warfarin sensitivity. Blood 2004 103 2630-2635. 

Khan T, Kamali F, Daly A, King B, Wynne HA. Warfarin sensitivity be aware of genetic influence. Age Ageing 2003 32 226-227. 

Haining RL, Steward DJ, Henne KR, et al. Correlation of the cytochrome-P450 2C9 Leu(359) defect with warfarin sensitivity. FASEB J 1997 11 130-139. 

Figure 5.2. Reaction of the vitamin K-dependent carboxylase (vitamin K epoxidase) and recycling of vitamin K epoxide to the hydroquinone. Vitamin K epoxidase, EC 1.14.99.20 warfarin-sensitive epoxide/quinone reductase, EC 1.1.4.1 and warfarin-insensitive quinone reductase, EC 1.1.4.2.

Patients with hypothyroidism and hyperthjroidism should all be carefully monitored because the response is greatly reduced in hypothyroidism and greatly enhanced in hyperthyroidism (103). The increased warfarin sensitivity is said to be related to increased degradation of clotting factors. When the thyroid disease is treated, the susceptibility of these patients to coumarins gradually normalizes. 

Chu K, Wu SM, Stanley T, Stafford DW, High KA. A mutation in the propeptide of Factor IX leads to warfarin sensitivity by a novel mechanism. J Clin Invest 1996 98(7) 1619-25. 

Grice GR, Milligan PE, Eby C, et al. Pharmacogenetic dose refinement prevents warfarin overdose in a patient who is highly warfarin-sensitive. Thromb Haemost 2008 6(l) 207-9. 

Yuan HY, Chen JJ, Lee MT, etal. A novel functional VKORCl promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 2005 14(13) 1745-5L... 

Shikata E, leiri I, Ishiguro S, et al. Multiple gene polymorphisms and warfarin sensitivity. Eur J Clin Pharmacol 2006 62(10) 881-3. 

Chern HD, Ueng TH, Fu YP, et al. CYP2C9 polymorphism and warfarin sensitivity in Taiwan Chinese. Clin Chim Acta 2006 367(l—2) 108—13. 

FIGURE 54-6 The vitamin K cycle y-glutamyl carboxy lotion of vitamin K-dependentpr( eins. The enzyme -glutamyl carboxylase couples the oxidation of the reduced hydroquinone form (KH2) of vitamin Kj or K2, to -carboxylation of Glu residues on vitamin K-dependent proteins, generating the epoxide of vitamin K (KO) and 7-carboxyglutamate (Gla) residues in vitamin K-dependent precursor proteins in the endoplasmic reticulum. A 2,3-epoxide reductase regenerates vitamin KH2 and is the warfarin-sensitive step. The R on tiie vitamin K molecule represents a 20-carbon phytyl side chain in vitamin and a 5- to 65-carbon prenyl side chain in vitamin K2. 

Approximately 10% of patients require <1.5 mg/day of warfarin to achieve an INR of 2—3. These patients are more likely to possess one or two polymorphic alleles of CYP2C9, the major enzyme responsible for converting the S-enantiomer warfarin to its inactive metabolites. In comparison with the wild-type CYP2C9 1 allele, the variant alleles CYP2C9 2 and CYP2C9 3 have been shown to inactivate S-warfarin much less efficiently in vitro. The variant alleles are present in 10-20% of Caucasians, but in <5% of African Americans or Asians. Polymorphic variations in VKORCl, which encodes a component of the Vitamin K reductase complex (see Figure 54-6), also determine warfarin sensitivity. 

Bachmann KA, Sullivan TJ. Dispositional and pharmacodynamic characteristics of brodifacoum in warfarin-sensitive rats. Pharmacol 1983 27 281-288. 

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