RESUMO
The dietary factor vitamin K has been found to protect against ferroptosis, a form of cell death driven by lipid peroxidation. This reveals new dietary links to cancers and degenerative conditions and a key factor involved in warfarin poisoning.
Assuntos
Ferroptose , Ferroptose/genética , Vitamina K , Varfarina , Peroxidação de Lipídeos , Morte Celular/fisiologiaRESUMO
Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation1, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers2. Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic and cell-intrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we show that the fully reduced forms of vitamin K-a group of naphthoquinones that includes menaquinone and phylloquinone3-confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for γ-glutamyl carboxylase. Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-44,5, was found to efficiently reduce vitamin K to its hydroquinone, a potent radical-trapping antioxidant and inhibitor of (phospho)lipid peroxidation. The FSP1-mediated reduction of vitamin K was also responsible for the antidotal effect of vitamin K against warfarin poisoning. It follows that FSP1 is the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle6. The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis.
Assuntos
Ferroptose , Vitamina K , Antídotos/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Carbono-Carbono Ligases/metabolismo , Coenzimas/metabolismo , Ferroptose/efeitos dos fármacos , Hidroquinonas/metabolismo , Hidroquinonas/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Oxirredução , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Vitamina K/metabolismo , Vitamina K/farmacologia , Varfarina/efeitos adversosRESUMO
Direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists, mostly warfarin, for the main indications for oral anticoagulation, prevention and treatment of venous thromboembolism, and prevention of embolic stroke in atrial fibrillation. While DOACs offer practical, fixed-dose anticoagulation in many patients, specific restrictions or contraindications may apply. DOACs are not sufficiently effective in high-thrombotic risk conditions such as antiphospholipid syndrome and mechanical heart valves. Patients with cancer-associated thrombosis may benefit from DOACs, but the bleeding risk, particularly in those with gastrointestinal or urogenital tumors, must be carefully weighed. In patients with frailty, excess body weight, and/or moderate-to-severe chronic kidney disease, DOACs must be cautiously administered and may require laboratory monitoring. Reversal agents have been developed and approved for life-threatening bleeding. In addition, the clinical testing of potentially safer anticoagulants such as factor XI(a) inhibitors is important to further optimize anticoagulant therapy in an increasingly elderly and frail population worldwide.
Assuntos
Fibrilação Atrial , Insuficiência Renal Crônica , Humanos , Idoso , Varfarina/uso terapêutico , Varfarina/efeitos adversos , Anticoagulantes/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Hemorragia/complicações , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/induzido quimicamente , Insuficiência Renal Crônica/tratamento farmacológico , Administração OralRESUMO
ABSTRACT: Direct oral anticoagulants (DOACs) that inhibit the coagulation proteases thrombin or factor Xa (FXa) have replaced warfarin and other vitamin K antagonists (VKAs) for most indications requiring long-term anticoagulation. In many clinical situations, DOACs are as effective as VKAs, cause less bleeding, and do not require laboratory monitoring. However, because DOACs target proteases that are required for hemostasis, their use increases the risk of serious bleeding. Concerns over therapy-related bleeding undoubtedly contribute to undertreatment of many patients who would benefit from anticoagulation therapy. There is considerable interest in the plasma zymogen factor XI (FXI) and its protease form factor XIa (FXIa) as drug targets for treating and preventing thrombosis. Laboratory and epidemiologic studies support the conclusion that FXI contributes to venous and arterial thrombosis. Based on 70 years of clinical observations of patients lacking FXI, it is anticipated that drugs targeting this protein will cause less severe bleeding than warfarin or DOACs. In phase 2 studies, drugs that inhibit FXI or FXIa prevent venous thromboembolism after total knee arthroplasty as well as, or better than, low molecular weight heparin. Patients with heart disease on FXI or FXIa inhibitors experienced less bleeding than patients taking DOACs. Based on these early results, phase 3 trials have been initiated that compare drugs targeting FXI and FXIa to standard treatments or placebo. Here, we review the contributions of FXI to normal and abnormal coagulation and discuss results from preclinical, nonclinical, and clinical studies of FXI and FXIa inhibitors.
Assuntos
Fator XI , Trombose , Humanos , Fator XIa/farmacologia , Varfarina/uso terapêutico , Varfarina/farmacologia , Trombose/tratamento farmacológico , Trombose/etiologia , Trombose/prevenção & controle , Coagulação Sanguínea , Anticoagulantes/efeitos adversos , Hemorragia/induzido quimicamente , Fibrinolíticos/uso terapêuticoRESUMO
Disulfide bond formation has a central role in protein folding of both eukaryotes and prokaryotes. In bacteria, disulfide bonds are catalyzed by DsbA and DsbB/VKOR enzymes. First, DsbA, a periplasmic disulfide oxidoreductase, introduces disulfide bonds into substrate proteins. Then, the membrane enzyme, either DsbB or VKOR, regenerate DsbA's activity by the formation of de novo disulfide bonds which reduce quinone. We have previously performed a high-throughput chemical screen and identified a family of warfarin analogs that target either bacterial DsbB or VKOR. In this work, we expressed functional human VKORc1 in Escherichia coli and performed a structure-activity-relationship analysis to study drug selectivity between bacterial and mammalian enzymes. We found that human VKORc1 can function in E. coli by removing two positive residues, allowing the search for novel anticoagulants using bacteria. We also found one warfarin analog capable of inhibiting both bacterial DsbB and VKOR and a second one antagonized only the mammalian enzymes when expressed in E. coli. The difference in the warfarin structure suggests that substituents at positions three and six in the coumarin ring can provide selectivity between the bacterial and mammalian enzymes. Finally, we identified the two amino acid residues responsible for drug binding. One of these is also essential for de novo disulfide bond formation in both DsbB and VKOR enzymes. Our studies highlight a conserved role of this residue in de novo disulfide-generating enzymes and enable the design of novel anticoagulants or antibacterials using coumarin as a scaffold.
Assuntos
Proteínas de Bactérias , Proteínas de Escherichia coli , Escherichia coli , Vitamina K Epóxido Redutases , Varfarina , Varfarina/metabolismo , Varfarina/química , Vitamina K Epóxido Redutases/metabolismo , Vitamina K Epóxido Redutases/química , Vitamina K Epóxido Redutases/genética , Humanos , Escherichia coli/metabolismo , Escherichia coli/genética , Escherichia coli/enzimologia , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Dissulfetos/química , Dissulfetos/metabolismo , Cumarínicos/metabolismo , Cumarínicos/química , Isomerases de Dissulfetos de Proteínas/metabolismo , Isomerases de Dissulfetos de Proteínas/química , Isomerases de Dissulfetos de Proteínas/genética , Anticoagulantes/química , Anticoagulantes/metabolismo , Benzoquinonas/metabolismo , Benzoquinonas/química , Relação Estrutura-Atividade , Ligação Proteica , Proteínas de MembranaRESUMO
BACKGROUND: The efficacy and safety of non-vitamin-K antagonist oral anticoagulants (NOACs) across the spectrum of body mass index (BMI) and body weight (BW) remain uncertain. METHODS: We analyzed data from COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation), which pooled patient-level data from the 4 pivotal randomized trials of NOAC versus warfarin in patients with atrial fibrillation. The primary efficacy and safety outcomes were stroke or systemic embolic events (stroke/SEE) and major bleeding, respectively; secondary outcomes were ischemic stroke/SEE, intracranial hemorrhage, death, and the net clinical outcome (stroke/SEE, major bleeding, or death). Each outcome was examined across BMI and BW. Because few patients had a BMI <18.5 kg/m2 (n=598), the primary analyses were restricted to those with a BMI ≥18.5 kg/m2. RESULTS: Among 58 464 patients, the median BMI was 28.3 (interquartile range, 25.2-32.2) kg/m2, and the median BW was 81.0 (interquartile range, 70.0-94.3) kg. The event probability of stroke/SEE was lower at a higher BMI irrespective of treatment, whereas the probability of major bleeding was lower at a higher BMI with warfarin but relatively unchanged across BMI with NOACs. NOACs reduced stroke/SEE overall (adjusted hazard ratio [HRadj], 0.80 [95% CI, 0.73-0.88]; P<0.001), with a generally consistent effect across BMI (Ptrend across HRs, 0.48). NOACs also reduced major bleeding overall (HRadj, 0.88 [95% CI, 0.82-0.94]; P<0.001), but with attenuation of the benefit at a higher BMI (trend test across BMI [Ptrend], 0.003). The overall treatment effects of NOACs versus warfarin for secondary outcomes were consistent across BMI, with the exception of the net clinical outcome and death. While these outcomes were overall reduced with NOACs (net clinical outcome, HRadj, 0.91 [95% CI, 0.87-0.95]; P<0.001; death, HRadj, 0.91 [95% CI, 0.86-0.97]; P=0.003), these benefits were attenuated at higher BMI (Ptrend, 0.001 and 0.08, respectively). All findings were qualitatively similar when analyzed across BW. CONCLUSIONS: The treatment effect of NOACs versus warfarin in atrial fibrillation is generally consistent for stroke/SEE across the spectrum of BMI and BW, whereas the reduction in major bleeding is attenuated in those with higher BMI or BW. Death and the net clinical outcome are overall reduced with NOACs over warfarin, although there remain uncertainties for these outcomes at a very high BMI and BW.
Assuntos
Fibrilação Atrial , Acidente Vascular Cerebral , Humanos , Varfarina/efeitos adversos , Anticoagulantes/efeitos adversos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/induzido quimicamente , Índice de Massa Corporal , Administração Oral , Ensaios Clínicos Controlados Aleatórios como Assunto , Hemorragia/complicações , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Peso Corporal , Resultado do TratamentoRESUMO
BACKGROUND: Testing of factor Xa inhibitors for the prevention of cardiovascular events in patients with rheumatic heart disease-associated atrial fibrillation has been limited. METHODS: We enrolled patients with atrial fibrillation and echocardiographically documented rheumatic heart disease who had any of the following: a CHA2DS2VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating a higher risk of stroke), a mitral-valve area of no more than 2 cm2, left atrial spontaneous echo contrast, or left atrial thrombus. Patients were randomly assigned to receive standard doses of rivaroxaban or dose-adjusted vitamin K antagonist. The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular (cardiac or noncardiac) or unknown causes. We hypothesized that rivaroxaban therapy would be noninferior to vitamin K antagonist therapy. The primary safety outcome was major bleeding according to the International Society of Thrombosis and Hemostasis. RESULTS: Of 4565 enrolled patients, 4531 were included in the final analysis. The mean age of the patients was 50.5 years, and 72.3% were women. Permanent discontinuation of trial medication was more common with rivaroxaban than with vitamin K antagonist therapy at all visits. In the intention-to-treat analysis, 560 patients in the rivaroxaban group and 446 in the vitamin K antagonist group had a primary-outcome event. Survival curves were nonproportional. The restricted mean survival time was 1599 days in the rivaroxaban group and 1675 days in the vitamin K antagonist group (difference, -76 days; 95% confidence interval [CI], -121 to -31; P<0.001). A higher incidence of death occurred in the rivaroxaban group than in the vitamin K antagonist group (restricted mean survival time, 1608 days vs. 1680 days; difference, -72 days; 95% CI, -117 to -28). No significant between-group difference in the rate of major bleeding was noted. CONCLUSIONS: Among patients with rheumatic heart disease-associated atrial fibrillation, vitamin K antagonist therapy led to a lower rate of a composite of cardiovascular events or death than rivaroxaban therapy, without a higher rate of bleeding. (Funded by Bayer; INVICTUS ClinicalTrials.gov number, NCT02832544.).
Assuntos
Anticoagulantes , Fibrilação Atrial , Inibidores do Fator Xa , Cardiopatia Reumática , Rivaroxabana , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/etiologia , Ecocardiografia , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/uso terapêutico , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Cardiopatia Reumática/complicações , Cardiopatia Reumática/diagnóstico , Cardiopatia Reumática/diagnóstico por imagem , Rivaroxabana/efeitos adversos , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Resultado do Tratamento , Vitamina K/antagonistas & inibidores , Varfarina/efeitos adversos , Varfarina/uso terapêuticoRESUMO
BACKGROUND: There is uncertainty surrounding the use of direct oral anticoagulants (DOACs) in patients with kidney dysfunction. METHODS: Using the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database (data from RE-LY [Randomized Evaluation of Long-term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], and ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48]), we performed an individual patient-level network meta-analysis to evaluate the safety and efficacy of DOACs versus warfarin across continuous creatinine clearance (CrCl). A multivariable Cox model including treatment-by-CrCl interaction with random effects was fitted to estimate hazard ratios for paired treatment strategies (standard-dose DOAC, lower-dose DOAC, and warfarin). Outcomes included stroke and systemic embolism (S/SE), major bleeding, intracranial hemorrhage (ICH), and death. RESULTS: Among 71 683 patients (mean age, 70.6±9.4 years; 37.3% female; median follow-up, 23.1 months), the mean CrCl was 75.5±30.5 mL/min. The incidence of S/SE, major bleeding, ICH, and death increased significantly with worsening kidney function. Across continuous CrCl values down to 25 mL/min, the hazard of major bleeding did not change for patients randomized to standard-dose DOACs compared with those randomized to warfarin (Pinteraction=0.61). Compared with warfarin, standard-dose DOAC use resulted in a significantly lower hazard of ICH at CrCl values <122 mL/min, with a trend for increased safety with DOAC as CrCl decreased (6.2% decrease in hazard ratio per 10-mL/min decrease in CrCl; Pinteraction=0.08). Compared with warfarin, standard-dose DOAC use resulted in a significantly lower hazard of S/SE with CrCl <87 mL/min, with a significant treatment-by-CrCl effect (4.8% decrease in hazard ratio per 10-mL/min decrease in CrCl; Pinteraction=0.01). The hazard of death was significantly lower with standard-dose DOACs for patients with CrCl <77 mL/min, with a trend toward increasing benefit with lower CrCl (2.1% decrease in hazard ratio per 10-mL/min decrease in CrCl; Pinteraction=0.08). Use of lower-dose rather than standard-dose DOACs was not associated with a significant difference in incident bleeding or ICH in patients with reduced kidney function but was associated with a higher incidence4 of death and S/SE. CONCLUSIONS: Standard-dose DOACs are safer and more effective than warfarin down to a CrCl of at least 25 mL/min. Lower-dose DOACs do not significantly lower the incidence of bleeding or ICH compared with standard-dose DOACs but are associated with a higher incidence of S/SE and death. These findings support the use of standard-dose DOACs over warfarin in patients with kidney dysfunction.
Assuntos
Fibrilação Atrial , Embolia , Acidente Vascular Cerebral , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Masculino , Varfarina/efeitos adversos , Metanálise em Rede , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Fator Xa , Anticoagulantes/uso terapêutico , Acidente Vascular Cerebral/epidemiologia , Hemorragia/epidemiologia , Hemorragias Intracranianas/induzido quimicamente , Embolia/epidemiologia , Rim , Administração Oral , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: The benefit-risk profile of direct oral anticoagulants (DOACs) compared with warfarin, and between DOACs in patients with atrial fibrillation (AF) and chronic liver disease is unclear. METHODS: We conducted a new-user, retrospective cohort study of patients with AF and chronic liver disease who were enrolled in a large, US-based administrative database between January 1, 2011, and December 31, 2017. We assessed the effectiveness and safety of DOACs (as a class and individually) compared with warfarin, and between DOACs in patients with AF and chronic liver disease. The primary outcomes were hospitalization for ischemic stroke/systemic embolism and hospitalization for major bleeding. Inverse probability treatment weights were used to balance the treatment groups on measured confounders. RESULTS: Overall, 10 209 participants were included, with 4421 (43.2%) on warfarin, 2721 (26.7%) apixaban, 2211 (21.7%) rivaroxaban, and 851 (8.3%) dabigatran. The incidence rates per 100 person-years for ischemic stroke/systemic embolism were 2.2, 1.4, 2.6, and 4.4 for DOACs as a class, apixaban, rivaroxaban, and warfarin, respectively. The incidence rates per 100 person-years for major bleeding were 7.9, 6.5, 9.1, and 15.0 for DOACs as a class, apixaban, rivaroxaban, and warfarin, respectively. After inverse probability treatment weights, the risk of hospitalization for ischemic stroke/systemic embolism was significantly lower between DOACs as a class (hazard ratio [HR], 0.64 [95% CI, 0.46-0.90]) or apixaban (HR, 0.40 [95% CI, 0.19-0.82]) compared with warfarin, but not significantly different between rivaroxaban versus warfarin (HR, 0.76 [95% CI, 0.47-1.21]) or rivaroxaban versus apixaban (HR, 1.73 [95% CI, 0.91-3.29]). Compared with warfarin, the risk of hospitalization for major bleeding was lower with DOACs as a class (HR, 0.69 [95% CI, 0.58-0.82]), apixaban (HR, 0.60 [95% CI, 0.46-0.78]), and rivaroxaban (HR, 0.79 [95% CI, 0.62-1.0]). However, the risk of hospitalization for major bleeding was higher for rivaroxaban versus apixaban (HR, 1.59 [95% CI, 1.18-2.14]). CONCLUSIONS: Among patients with AF and chronic liver disease, DOACs as a class were associated with lower risks of hospitalization for ischemic stroke/systemic embolism and major bleeding versus warfarin. However, the incidence of clinical outcomes among patients with AF and chronic liver disease varied between individual DOACs and warfarin, and in head-to-head DOAC comparisons.
Assuntos
Fibrilação Atrial , Embolia , AVC Isquêmico , Hepatopatias , Acidente Vascular Cerebral , Humanos , Varfarina/efeitos adversos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/epidemiologia , Rivaroxabana/efeitos adversos , Anticoagulantes/efeitos adversos , Estudos de Coortes , Estudos Retrospectivos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/tratamento farmacológico , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Hemorragia/tratamento farmacológico , Dabigatrana/efeitos adversos , Hepatopatias/diagnóstico , Hepatopatias/epidemiologia , Embolia/epidemiologia , Embolia/prevenção & controle , Embolia/complicações , Administração OralRESUMO
Antiplatelets and anticoagulants are extensively used in cardiovascular medicine for the prevention and treatment of thrombosis in the venous and arterial circulations. Wide inter-individual variability has been observed in response to antiplatelets and anticoagulants, which triggered researchers to investigate the genetic basis of this variability. Data from extensive pharmacogenetic studies pointed to strong evidence of association between polymorphisms in candidate genes and the pharmacokinetics and pharmacodynamic action and clinical response of the antiplatelets clopidogrel and the anticoagulant warfarin. In this review, we conducted an extensive search on Medline for the time period of 2009-2023. We also searched the PharmGKB website for levels of evidence of variant-drug combinations and for drug labels and clinical guidelines. We focus on the pharmacogenetics of novel antiplatelets and anticoagulants while excluding acetylsalicylic acid, warfarin and heparins, and discuss the current knowledge with emphasis on the level of evidence.
Assuntos
Anticoagulantes , Varfarina , Humanos , Anticoagulantes/uso terapêutico , Anticoagulantes/farmacocinética , Varfarina/uso terapêutico , Varfarina/farmacocinética , Farmacogenética , Clopidogrel , Polimorfismo Genético , Inibidores da Agregação Plaquetária/uso terapêuticoRESUMO
OBJECTIVES: Genetic variation has been a major contributor to interindividual variability of warfarin dosage requirement. The specific genetic factors contributing to warfarin bleeding complications are largely unknown, particularly in Chinese patients. In this study, 896 Chinese patients were enrolled to explore the effect of CYP2C9 and VKORC1 genetic variations on both the efficacy and safety of warfarin therapy. METHODS AND RESULTS: Univariate analyses unveiled significant associations between two specific single nucleotide polymorphisms rs1057910 in CYP2C9 and rs9923231 in VKORC1 and stable warfarin dosage ( P â <â 0.001). Further, employing multivariate logistic regression analysis adjusted for age, sex and height, the investigation revealed that patients harboring at least one variant allele in CYP2C9 exhibited a heightened risk of bleeding events compared to those with the wild-type genotype (odds ratioâ =â 2.16, P â =â 0.04). Moreover, a meta-analysis conducted to consolidate findings confirmed the associations of both CYP2C9 (rs1057910) and VKORC1 (rs9923231) with stable warfarin dosage. Notably, CYP2C9 variant genotypes were significantly linked to an increased risk of hemorrhagic complications ( P â <â 0.00001), VKORC1 did not demonstrate a similar association. CONCLUSION: The associations found between specific genetic variants and both stable warfarin dosage and bleeding risk might be the potential significance of gene detection in optimizing warfarin therapy for improving patient efficacy and safety.
Assuntos
Anticoagulantes , Povo Asiático , Citocromo P-450 CYP2C9 , Polimorfismo de Nucleotídeo Único , Vitamina K Epóxido Redutases , Varfarina , Humanos , Citocromo P-450 CYP2C9/genética , Vitamina K Epóxido Redutases/genética , Varfarina/efeitos adversos , Varfarina/administração & dosagem , Feminino , Masculino , Pessoa de Meia-Idade , Anticoagulantes/efeitos adversos , Anticoagulantes/administração & dosagem , Idoso , Povo Asiático/genética , Hemorragia/induzido quimicamente , Hemorragia/genética , China , Adulto , Genótipo , Estudos de Associação Genética , População do Leste AsiáticoRESUMO
CYP2C9 encodes a cytochrome P450 enzyme responsible for metabolizing up to 15% of small molecule drugs, and CYP2C9 variants can alter the safety and efficacy of these therapeutics. In particular, the anti-coagulant warfarin is prescribed to over 15 million people annually and polymorphisms in CYP2C9 can affect individual drug response and lead to an increased risk of hemorrhage. We developed click-seq, a pooled yeast-based activity assay, to test thousands of variants. Using click-seq, we measured the activity of 6,142 missense variants in yeast. We also measured the steady-state cellular abundance of 6,370 missense variants in a human cell line by using variant abundance by massively parallel sequencing (VAMP-seq). These data revealed that almost two-thirds of CYP2C9 variants showed decreased activity and that protein abundance accounted for half of the variation in CYP2C9 function. We also measured activity scores for 319 previously unannotated human variants, many of which may have clinical relevance.
Assuntos
Citocromo P-450 CYP2C9/metabolismo , Mutação de Sentido Incorreto , Medicamentos sob Prescrição/metabolismo , Saccharomyces cerevisiae/enzimologia , Xenobióticos/metabolismo , Sítios de Ligação , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/genética , Ensaios Enzimáticos , Biblioteca Gênica , Ensaios de Triagem em Larga Escala , Humanos , Modelos Moleculares , Mutagênese Sítio-Dirigida , Fenitoína/química , Polimorfismo Genético , Medicamentos sob Prescrição/química , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Saccharomyces cerevisiae/genética , Transgenes , Varfarina/química , Varfarina/metabolismo , Xenobióticos/químicaRESUMO
Venous thromboembolism (VTE) remains a significant cause of morbidity and mortality among multiple myeloma patients. Chang and colleagues' findings indicate that factor Xa inhibitors are as effective as warfarin in preventing VTE without raising the risk of gastrointestinal or intracranial bleeding complications. Commentary on: Chang et al. The comparative efficacy and safety of factor Xa inhibitors and warfarin for primary thromboprophylaxis in multiple myeloma patients undergoing immunomodulatory therapy. Br J Haematol 2024;205:473-477.
Assuntos
Inibidores do Fator Xa , Mieloma Múltiplo , Tromboembolia Venosa , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/complicações , Humanos , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/efeitos adversos , Tromboembolia Venosa/prevenção & controle , Tromboembolia Venosa/etiologia , Anticoagulantes/uso terapêutico , Anticoagulantes/efeitos adversos , Varfarina/uso terapêutico , Varfarina/efeitos adversosRESUMO
There are limited data on the optimal choice of anticoagulation in multiple myeloma (MM) patients receiving immunomodulatory drugs (IMiDs). We conducted a propensity score-matched cohort study using the TriNetX database to compare the efficacy and safety of factor Xa inhibitors and warfarin in this patient population. Compared to warfarin, factor Xa inhibitors had a similar risk of deep vein thrombosis (hazard ratio [HR]: 1.11 [95% CI: 0.50-2.46]) or pulmonary embolism (HR: 1.08 [95% CI: 0.59-2.00]). There were no differences in the risk of gastrointestinal or intracranial bleeding. Factor Xa inhibitor-treated patients had lower all-cause mortality (HR: 0.56 [95% CI: 0.36-0.86]) compared with warfarin. These data suggest that factor Xa inhibitors had similar safety and efficacy compared with warfarin for MM patients on IMiDs.
Assuntos
Anticoagulantes , Inibidores do Fator Xa , Mieloma Múltiplo , Varfarina , Humanos , Varfarina/uso terapêutico , Varfarina/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/complicações , Mieloma Múltiplo/mortalidade , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/efeitos adversos , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Anticoagulantes/uso terapêutico , Anticoagulantes/efeitos adversos , Trombose Venosa/prevenção & controle , Trombose Venosa/etiologia , Agentes de Imunomodulação/uso terapêutico , Agentes de Imunomodulação/efeitos adversos , Idoso de 80 Anos ou mais , Embolia Pulmonar/prevenção & controle , Embolia Pulmonar/etiologiaRESUMO
BACKGROUND & AIMS: Reported rates of delayed bleeding (DB) after endoscopic resection using direct oral anticoagulants (DOACs) are high and heterogeneous. This large-scale multicenter study analyzed cases of DB after colorectal endoscopic submucosal dissection related to various types of DOACs in Japan (the ABCD-J study) with those associated with warfarin. METHODS: We retrospectively reviewed 1019 lesions in patients treated with DOACs and 459 lesions in patients treated with warfarin among 34,455 endoscopic submucosal dissection cases from 47 Japanese institutions between 2012 and 2021. The DB rate (DBR) with each DOAC was compared with that with warfarin. Risk factors for DB in patients treated with DOACs or warfarin were also investigated. RESULTS: The mean tumor sizes in the DOAC and warfarin groups were 29.6 ± 14.0 and 30.3 ± 16.4 mm, respectively. In the DOAC group, the DBR with dabigatran (18.26%) was significantly higher than that with apixaban (10.08%, P = .029), edoxaban (7.73%, P = .001), and rivaroxaban (7.21%, P < .001). Only rivaroxaban showed a significantly lower DBR than warfarin (11.76%, P = .033). In the multivariate analysis, heparin bridging therapy (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.27-3.73, P = .005), rectal location (2.01, 1.28-3.16, P = .002), and procedure time ≥55 minutes (2.43, 1.49-3.95, P < .001) were significant risk factors for DB in the DOAC group. The DB risk in the DOAC group (OR, (95% CI)) was 2.13 (1.30-3.50) and 4.53 (2.52-8.15) for 1 and 2 significant risk factors, respectively. CONCLUSIONS: Dabigatran was associated with a higher DBR than other DOACs, and only rivaroxaban was associated with a significantly lower DBR than warfarin.
Assuntos
Fibrilação Atrial , Neoplasias Colorretais , Ressecção Endoscópica de Mucosa , Humanos , Varfarina , Rivaroxabana/efeitos adversos , Dabigatrana/efeitos adversos , Japão , Ressecção Endoscópica de Mucosa/efeitos adversos , Estudos Retrospectivos , Hemorragia/induzido quimicamente , Anticoagulantes , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/complicações , Administração Oral , Fibrilação Atrial/complicaçõesRESUMO
Human serum albumin (HSA) is the most abundant plasma protein of the circulatory system. It is a multidomain, multifunctional protein that, combining diverse affinities and wide specificity, binds, stores, and transports a variety of biological compounds, pharmacores, and fatty acids. HSA is finding increasing uses in drug-delivery due to its ability to carry functionalized ligands and prodrugs. All this raises the question of competition for binding sites occupancy in case of multiple ligands, which in turn influences the protein structure/dynamic/function relationship and also has an impact on the biomedical applications. In this work, the effects of interactive binding of palmitic acid (PA), warfarin (War) and ibuprofen (Ibu) on the thermal stability of HSA were studied using DSC, ATR-FTIR, and EPR. PA is a high-affinity physiological ligand, while the two drugs are widely used for their anticoagulant (War) and anti-inflammatory (Ibu) efficacy, and are exogenous compounds that accommodate in the deputed drug site DS1 and DS2, respectively overlapping with some of the fatty acid binding sites. The results indicate that HSA acquires the highest thermal stability when it is fully saturated with PA. The binding of this physiological ligand does not hamper the binding of War or Ibu to the native state of the protein. In addition, the three ligands bind simultaneously, suggesting a synergic cooperative influence due to allosteric effects. The increased thermal stability subsequent to binary and multiple ligands binding moderates protein aggregation propensity and restricts protein dynamics. The biophysics findings provide interesting features about protein stability, aggregation, and dynamics in interaction with multiple ligands and are relevant in drug-delivery.
Assuntos
Ibuprofeno , Albumina Sérica Humana , Varfarina , Humanos , Sítios de Ligação , Ligação Competitiva , Ibuprofeno/química , Ibuprofeno/metabolismo , Ligantes , Ácido Palmítico/química , Ácido Palmítico/metabolismo , Ligação Proteica , Estabilidade Proteica/efeitos dos fármacos , Albumina Sérica Humana/metabolismo , Albumina Sérica Humana/química , Temperatura , Varfarina/química , Varfarina/metabolismo , Varfarina/farmacologiaRESUMO
BACKGROUND: In post-stroke atrial fibrillation (AF) patients who have indications for both oral anticoagulant (OAC) and antiplatelet agent (AP), e.g., those with carotid artery stenosis, there is debate over the best antithrombotic strategy. We aimed to compare the risks of ischemic stroke, composite of ischemic stroke/major bleeding and composite of ischemic stroke/intracranial hemorrhage (ICH) between different antithrombotic strategies. METHODS: This study included post-stroke AF patients with and without extracranial artery stenosis (ECAS) (n = 6390 and 28,093, respectively) identified from the Taiwan National Health Insurance Research Database. Risks of clinical outcomes and net clinical benefit (NCB) with different antithrombotic strategies were compared to AP alone. RESULTS: The risk of recurrent ischemic stroke was higher for patients with ECAS than those without (12.72%/yr versus 10.60/yr; adjusted hazard ratio [aHR] 1.104, 95% confidence interval [CI] 1.052-1.158, p < 0.001). For patients with ECAS, when compared to AP only, non-vitamin K antagonist oral anticoagulant (NOAC) monotherapy was associated with lower risks for ischaemic stroke (aHR 0.551, 95% CI 0.454-0.669), the composite of ischaemic stroke/major bleeding (aHR 0.626, 95% CI 0.529-0.741) and the composite of ischaemic stroke/ICH (aHR 0.577, 95% CI 0.478-0.697), with non-significant difference for major bleeding and ICH. When compared to AP only, warfarin monotherapy was associated with higher risks of major bleeding (aHR 1.521, 95% CI 1.231-1.880), ICH (aHR 2.045, 95% CI 1.329-3.148), and the composite of ischaemic stroke and major bleeding. With combination of AP plus warfarin, there was an increase in ischaemic stroke, major bleeding, and the composite outcomes, when compared to AP only. NOAC monotherapy was the only approach associated with a positive NCB, while all other options (warfarin, combination of AP-OAC) were associated with negative NCB. CONCLUSIONS: For post-stroke AF patients with ECAS, NOAC monotherapy was associated with lower risks of adverse outcomes and a positive NCB. Combination of AP with NOAC or warfarin did not offer any benefit, but more bleeding especially with AP-warfarin combination therapy.
Assuntos
Fibrilação Atrial , Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/complicações , Varfarina/uso terapêutico , Fibrilação Atrial/complicações , Anticoagulantes/uso terapêutico , Fibrinolíticos/uso terapêutico , Estudos de Coortes , Isquemia Encefálica/tratamento farmacológico , Constrição Patológica/induzido quimicamente , Constrição Patológica/complicações , Constrição Patológica/tratamento farmacológico , Hemorragia/induzido quimicamente , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/complicações , Hemorragias Intracranianas/tratamento farmacológico , AVC Isquêmico/tratamento farmacológico , Artérias , Administração OralRESUMO
Pharmacogenomics is the examination of how genetic variation influences drug metabolism and response, in terms of both efficacy and safety. In cardiovascular disease, patient-specific diplotypes determine phenotypes, thereby influencing the efficacy and safety of drug treatments, including statins, antiarrhythmics, anticoagulants and antiplatelets. Notably, polymorphisms in key genes, such as CYP2C9, CYP2C19, VKORC1 and SLCO1B1, significantly impact the outcomes of treatment with clopidogrel, warfarin and simvastatin. Furthermore, the CYP2C19 polymorphism influences the pharmacokinetics and safety of the novel hypertrophic cardiomyopathy inhibitor, mavacamten. In this review, we critically assess the clinical application of pharmacogenomics in cardiovascular disease and delineate present and future utilization of pharmacogenomics. This includes insights into identifying missing heritability, the integration of whole genome sequencing and the application of polygenic risk scores to enhance the precision of personalized drug therapy. Our discussion encompasses health economic analyses that underscore the cost benefits associated with pre-emptive genotyping for warfarin and clopidogrel treatments, albeit acknowledging the need for further research in this area. In summary, we contend that cardiovascular pharmacogenomic analyses are underpinned by a wealth of evidence, and implementation is already occurring for some of these gene-drug pairs, but as with any area of medicine, we need to continually gather more information to optimize the use of pharmacogenomics in clinical practice.
Assuntos
Doenças Cardiovasculares , Medicina de Precisão , Humanos , Varfarina/uso terapêutico , Testes Farmacogenômicos , Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/diagnóstico , Anticoagulantes/uso terapêutico , Farmacogenética , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Vitamina K Epóxido Redutases/genéticaRESUMO
BACKGROUND: Optimal first-trimester anticoagulation is still challenging in pregnant women with mechanical heart valves (MHVs) requiring high-dose warfarin. This multicenter prospective study aims to determine the optimal anticoagulation regimens for pregnant patients with MHVs. METHODS: All women were allocated to one of three treatment options during first trimester including lone low-molecular-weight heparin (LMWH), combination of LMWH + 2.5 mg warfarin, and LMWH+4 mg warfarin. Primary maternal outcome included a combination of death, thromboembolism, severe bleeding, and need for treatment of mechanical valve thrombosis (MVT). Any fetal loss was determined as primary fetal outcome. RESULTS: The study included 78 pregnancies in 65 women with MHVs. Primary maternal outcome rate was 44%, 12.5%, 3.5%, respectively. The rates of primary maternal outcome (44 vs 3.5%, P < .001), obstructive MVT (16 vs 0%, P = .04), MVT requiring treatment (28 vs 0%, P = .003), and cerebral embolism (24 vs 3.4%, P = .041) were found to be significantly higher in lone LMWH group compared to LMWH + 4 mg warfarin group. Moreover, the rates of primary maternal outcome (12.5 vs 44%, P = .015) and treatment for MHV thrombus (4.2 vs 28%, P = .049) were significantly lower in LMWH + 2.5 mg warfarin group compared to lone LMWH group. The incidences of fetal loss were 8 (32%) in the lone LMWH group, 8 (33.3%) in LMWH + 2.5 mg warfarin group, and 11 (37.9%) in LMWH + 4 mg warfarin group (P = .890 for 3-group).Warfarin related-embryopathy was not observed in any case. CONCLUSIONS: The combined anticoagulation strategy of LMWH plus low-dose warfarin during the first trimester of pregnancy may result in less maternal complications with comparable fetal outcomes in patients with MHVs. CONDENSED ABSTRACT: Low-molecular-weight heparin (LMWH) is thought to be safer for the fetus, however it is suspected to be less protective for the mother. To solve this dilemma, the authors suggested a novel anticoagulation strategy in pregnant women with prosthetic valves. Seventy-eight pregnancies of 65 women (median age 32 [27-35] years) were included in the study. A combination of LMWH and a reduced dose warfarin were associated with low rates of thrombus-related complications in pregnant patients with mechanical heart valves.
Assuntos
Anticoagulantes , Próteses Valvulares Cardíacas , Heparina de Baixo Peso Molecular , Complicações Cardiovasculares na Gravidez , Varfarina , Humanos , Feminino , Gravidez , Anticoagulantes/administração & dosagem , Adulto , Varfarina/administração & dosagem , Varfarina/efeitos adversos , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/uso terapêutico , Heparina de Baixo Peso Molecular/efeitos adversos , Estudos Prospectivos , Próteses Valvulares Cardíacas/efeitos adversos , Quimioterapia Combinada , Resultado da Gravidez , Primeiro Trimestre da Gravidez , Tromboembolia/prevenção & controle , Tromboembolia/etiologia , Tromboembolia/epidemiologia , Trombose/prevenção & controle , Trombose/etiologiaRESUMO
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.