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Anticoagulation
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
Louis M. Fink, Nicole A. Massoll, Alex A. Pappas
A frequently encountered clinical situation is when a patient who is either being initiated or maintained on warfarin has significant unexpected increases or decreases in the PT. These unexpected PT changes can be a result of increases or decreases of dietary vitamin K, which decreases or increases the warfarin effect respectively (see Table 8) (44,66). The marked PT variations often seen in patients receiving multiple drugs is often due to drug interactions, which can enhance or decrease warfarin metabolism (see Table 8) (44,66–68). A variety of antimicrobial agents have been associated with hypoprothrombinemia which may enhance warfarin anticoagulation (68). Failure of the PT to prolong after “appropriate” warfarin dosage is often misinterpreted as “warfarin resistance.” True warfarin resistance is rare, and low PT responses to seemingly appropriate doses of warfarin are usually related to altered vitamin K metabolism as described previously. True resistance to warfarin is most likely due to an autosomal-dominant mutant form of vitamin K reductase that displays either a decreased warfarin affinity or an increased vitamin K affinity. Current recommendations for oral anticoagulation therapy in patients with familiar warfarin resistance are to continue increasing until a therapeutic response is achieved. This could be 30 mg to over 600 mg daily (69). Acquired resistance is usually from drug interactions, decreased warfarin absorption, or a high-vitamin K diet (may be seen in patients treated with hyperalimentation regimes).
Anticoagulant Therapy
Published in Hau C. Kwaan, Meyer M. Samama, Clinical Thrombosis, 2019
Hau C. Kwaan, M. M. Samama, A. R. Kher
When hepatic enzymes are induced, increased metabolism of warfarin leads to warfarin resistance. Such “enzyme inducers” include several prescribed sedatives: ethchlorvynol, glutethimide, and meprobamate.121 Other enzyme inducers are the anticonvulsants, the barbiturates, primidone, and carbamazepine, and the antimicrobials, griseofulvin, rifampin,120 and nafcillin.131 Chlordiazepoxide (Librium), diazepam (Valium), and flurazepam (Dalmaine) do not ordinarily affect warfarin action unless there is also impairment of the liver function.
Future directions in stroke treatment
Published in Christos Tziotzios, Jesse Dawson, Matthew Walters, Kennedy R Lees, Stroke in Practice, 2017
Christos Tziotzios, Jesse Dawson, Matthew Walters, Kennedy R Lees
Warfarin is metabolised by the cytochrome P450 2C9 enzyme (CYP2C9) into its major inactive metabolite, 7-hydroxywarfarin (seeFigure 11.1).26 Genome-wide association studies (GWAS) have identified genetic polymorphisms of CYP2C9 as an important determinant of warfarin activity.27 The two common allelic variants, CYP2C9*2 and CYP2C9*3, result in poor metaboliser (PM) phenotypes and display reduced warfarin metabolism.28 These patients’ genotypes have been shown to have an increased risk of overcoagulation and haemorrhagic complications.2930 The therapeutic target for warfarin, Vitamin K epoxide reductase complex 1 (VKORC1), also displays genetic polymorphism and pharmacogenetic variability.27, 31 These mutations have been associated with both warfarin resistance and increased drug sensitivity.32 There has therefore been increasing interest in the role of genotype-guided warfarin therapy in clinical practice.33 The FDA approved warfarin genotype-testing in 2007 and has recently updated its label for warfarin pharmacogenetic testing (www.pharmgkb.org/clinical/warfarin.jsp). Various PCR-based genotyping methods are now available and some have been approved by the FDA.3435
ABCB1 2677G>T single nucleotide polymorphism influences warfarin dose requirement for warfarin maintenance therapy
Published in British Journal of Biomedical Science, 2019
Gopisankar Mg, Hemachandren M, Surendiran A
We accept certain limitations: we did not consider the effects of other relevant genes (e.g. CYP2C9 and VKORC1 and their polymorphisms). Indeed, the overall effect found from the study can be a net effect of other genes not assessed in this study. Increasing the dose without following any algorithms can result in adverse outcomes. In certain genotypes it is not the dose, but the time to reach target is prolonged as in CYP2C9 *1/*3, *2/*2, *2/*3 and *3/*3. This highlights the necessity and explains the rationale behind developing and validating algorithms with clinical and genetic parameters especially for drugs such as warfarin. Future studies are needed to evaluate the combined role of established genetic markers for warfarin such as CYP2C9 and VKORC1, and also the role of newer genetic polymorphisms including that of ABCB1 2677G>T polymorphism on various parameters related to warfarin such as dose requirement, time to achieve target INR and association with warfarin resistance. We also acknowledge potential effects of drugs (Table 1).
Regioselectivity significantly impacts microsomal glucuronidation efficiency of R/S-6, 7-, and 8-hydroxywarfarin
Published in Xenobiotica, 2019
So-Young Kim, Drew R. Jones, Ji-Yeon Kang, Chul-Ho Yun, Grover P. Miller
Coumadin (R/S-warfarin) metabolism plays a critical role in patient response to anticoagulant therapy. Warfarin is administered as an equal mixture of R and S enantiomers. Although both drug forms likely contribute to anticoagulation, S-warfarin is more potent than R-warfarin (Breckenridge et al., 1974). Once taken, warfarin is readily absorbed and undergoes essentially no first-pass metabolism. Over time, warfarin undergoes extensive metabolism in the liver such that ∼92% is excreted in the urine as metabolites (Bristol-Meyers Squib product literature, January, 2009). The primary route of metabolism is oxidation by several cytochrome P450s to generate 6-, 7-, 8-, 10, and 4′-hydroxywarfarin (Jones & Miller, 2011; Kaminsky & Zhang, 1997). Drug–drug interactions (Juurlink, 2007; Miller, 2010) and allelic variants of these enzymes (Cavallari & Limdi, 2009; Jorgensen et al., 2009) highlight the link between warfarin metabolism and patient response to therapy, because changes in metabolic activity lead to warfarin resistance or sensitivity in patients.
Deciphering DMET genetic data: comprehensive assessment of Northwestern Han, Tibetan, Uyghur populations and their comparison to eleven 1000 genome populations
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Jiayi Zhang, Huijuan Wang, Geng Niu, Yongkang Liu, Yanxia Wang, Lirong Zhang, Yanrui Pei, Hongli Zhu, Penggao Dai, Chao Chen
The VKORC1 gene encodes the catalytic subunit of the vitamin K epoxide reductase complex, which is responsible for reducing the inactive vitamin K 2, 3-epoxide into active vitamin K in the endoplasmic reticulum membrane. A comparative study on key pharmacogenomic variants in Sri Lankan and European populations found that the VKORC1 rs9923231 related to warfarin differed in the two populations [21]. A study in South Indians revealed that the allele frequencies of VKORC1 rs2359612 (T), rs8050894 (C), rs9934438 (T) and rs9923231 (A) were 11.0%, 11.8%, 11.7% and 12.0%, respectively. The allele, genotype and haplotype frequencies of the VKORC1 gene were distinct from that in other Hapmap populations (p < .0001) [22]. A study on a French strain of rats demonstrated that rats with different VKORC1 mutations exhibited varying degrees of warfarin resistance [23]. The current study showed that the minor allele frequencies of rs9934438 and rs8050894 in Uyghur were significantly higher than those in Han and Tibetan, suggesting that different selections and dosages must be considered with regard to the desired VKORC1-related drugs, such as acenocoumarol, coumarin, fluindione, phenprocoumon and warfarin [24–28].