247 research outputs found
Pharmacogenetics of warfarin
Warfarin is one of the most commonly used oral anticoagulants worldwide
and is highly efficacious for the treatment and prevention of thromboembolic
disorders. However, due to its narrow therapeutic index and large interindividual
variability, it remains a challenging drug to prescribe. Genetic factors (CYP2C9 and
VKORCI), together with clinical factors (age and body weight), account for up to
60% of warfarin dose variance but the remaining ~40% variability remains
unexplained.
A polymorphism rs2108622 in CYP4F2, a vitamin K oxidase, has previously
been associated with increased warfarin stable dose requirements, accounting for
1-7% dose variability. In our cohort of prospectively recruited patients (n = 311), we
were unable to confirm these results. Interestingly, after fine mapping of the CYP4F2
gene region, we found a SNP rs2189784, which is in LD with rs2108622, to be
associated with time to therapeutic INR (Pc = 0.03). Further fine mapping of the
CYP4F gene cluster together with the utilisation a bank of well characterized
Caucasian surgical liver samples (n = 149) and data from a genome-wide association
study (n = 714), showed that CYP4F2 rs2108622 and rs2189784 SNPs were found to
be associated with increasing CYP4F2 and decreasing CYP4FII or CYP4Fl2 mRNA
expression, respectively. Interestingly, a CYP4Fll variant rsl060467 (in LD with
rs2108622) was associated with reduced CYP4F2 rnRNA expression. Furthermore,
rsl060467 contributes to 2.5% of warfarin dose variability and was associated with
reduced warfarin dose requirement (~1 mg/day, Pc = 0.003), an effect in the opposite
direction previously reported with CYP4F2 rs2108622 by Caldwell et al. (2008) and
other studies.
Warfarin-resistant patients have been reported to harbour VKORCI missense
mutations. Extended regions of VKORCI were sequenced in our patients (n = 65)
with resistance to warfarin, defined by clinical and pharmacodynamic criteria. Seven
novel heterozygous mutations were identified and in silica analyses predicted the
promoter c.-160G>C mutation creates a putative Spl transcription factor binding site
and that the missense mutation c.79C>G to be deleterious. To confirm these
predictions, in vitro functional studies were carried out using EMSA, transient
transfection assays, and DNA methylation. c.-160G>C was found to create a weak
binding site for Spl transcription factor, and caused an increase in promoter activity
by ~20% (P = 0.003). The c.79C>G mutation reduced levels of PIVKA-II by ~10%.
Associations of VKORCI genotypes with DNA methylation did not remain
significant after correction for multiple testing.
The effect of warfarin on the rate of decline of vitamin K-dependent clotting
factors, and the role of SNPs in the clotting factor genes, is not known. Using a large
prospective cohort of patients (n = 619), SNPs in F7 and F 10 genes showed
association with variability in factor VII levels. The rate at which the plasma levels
of factors II, X and protein C decline affect how patients respond to warfarin, in
particular the achievement of warfarin stable dose and time to therapeutic INR.
Furthermore, the change in clotting factor X level accounted for 1.4% of warfarin
dose variability.
In conclusion, the results presented in this thesis demonstrate that multiple
genetic, clinical and biochemical factors account for the variability in warfarin
response. Further understanding of such complex interactions, along with the advent
of genomics technologies and development of new computational and conceptual
tools, will yield insights to the accurate prediction of drug efficacy and toxicity,
which will hopefully translate into improved outcomes for patients
Operation Warp Speed: Projects responding to the COVID-19 pandemic
The 2020 COVID-19 pandemic has profound socio-economic consequences. Extraordinary times call for extraordinary measures, so this paper focuses on radical changes to accepted practice in project organizing in response. In particular, we focus on schedule compression to deliver outputs to mitigate the immediate impact of the pandemic on health. In the spirit of engaged scholarship, which is problem-driven rather than theory-driven, we address directly the evidence of what happened in two empirical vignettes and one more substantial case study ā the CoronavirusUY app; emergency field hospitals; and vaccine development. We then suggest the implications for project management theory in discussion
Being precise with anticoagulation to reduce adverse drug reactions: are we there yet?
Anticoagulants are potent therapeutics widely used in medical and surgical settings, and the amount spent on anticoagulation is rising. Although warfarin remains a widely prescribed oral anticoagulant, prescriptions of direct oral anticoagulants (DOACs) have increased rapidly. Heparin-based parenteral anticoagulants include both unfractionated and low molecular weight heparins (LMWHs). In clinical practice, anticoagulants are generally well tolerated, although interindividual variability in response is apparent. This variability in anticoagulant response can lead to serious incident thrombosis, haemorrhage and off-target adverse reactions such as heparin-induced thrombocytopaenia (HIT). This review seeks to highlight the genetic, environmental and clinical factors associated with variability in anticoagulant response, and review the current evidence base for tailoring the drug, dose, and/or monitoring decisions to identified patient subgroups to improve anticoagulant safety. Areas that would benefit from further research are also identified. Validated variants in VKORC1, CYP2C9 and CYP4F2 constitute biomarkers for differential warfarin response and genotype-informed warfarin dosing has been shown to reduce adverse clinical events. Polymorphisms in CES1 appear relevant to dabigatran exposure but the genetic studies focusing on clinical outcomes such as bleeding are sparse. The influence of body weight on LMWH response merits further attention, as does the relationship between anti-Xa levels and clinical outcomes. Ultimately, safe and effective anticoagulation requires both a deeper parsing of factors contributing to variable response, and further prospective studies to determine optimal therapeutic strategies in identified higher risk subgroups
Warfarin dosing algorithms: A systematic review
AIMS:Numerous algorithms have been developed to guide warfarin dosing and improve clinical outcomes. We reviewed the algorithms available for various populations and the covariates, performances and risk of bias of these algorithms. METHODS:We systematically searched MEDLINE until 20 May 2020 and selected studies describing the development, external validation, or clinical utility of a multivariable warfarin dosing algorithm. Two investigators conducted data extraction and quality assessment. RESULTS:Of 10,035 screened records, 266 articles were included in the review, describing the development of 433 dosing algorithms, 481 external validations and 52 clinical utility assessments. Most developed algorithms were for dose-initiation (86%), developed by multiple linear regression (65%) and mostly applicable to Asians (49%) or Whites (43%). The most common demographic/clinical/environmental covariates were age (included in 401 algorithms), concomitant medications (270 algorithms) and weight (229 algorithms) while CYP2C9 (329 algorithms), VKORC1 (319 algorithms) and CYP4F2 (92 algorithms) variants were the most common genetic covariates. Only 26% and 7% algorithms were externally validated and evaluated for clinical utility, respectively, with less than 2% of algorithm developments and external validations being rated as having a low risk of bias. CONCLUSION:Most warfarin dosing algorithms have been developed in Asians and Whites and may not be applicable to under-served populations. Few algorithms have been externally validated, assessed for clinical utility, and/or have a low risk of bias which makes them unreliable for clinical use. Algorithm development and assessment should follow current methodological recommendations to improve reliability and applicability, and under-represented populations should be prioritized
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