Virginie Siguret

Human NK cells display major phenotypic and functional changes over the life span.

Aging is generally associated with an increased predisposition to infectious diseases and cancers, related in part to the development of immune senescence, a process that affects all cell compartments of the immune system. Although many studies have investigated the effects of age on natural killer (NK) cells, their conclusions remain controversial because the diverse health status of study subjects resulted in discordant findings. To clarify this situation, we conducted the first extensive phenotypic and functional analysis of NK cells from healthy subjects, comparing NK cells derived from newborn (cord blood), middle‐aged (18–60 years), old (60–80 years), and very old (80–100 years) subjects. We found that NK cells in cord blood displayed specific features associated with immaturity, including poor expression of KIR and LIR‐1/ILT‐2 and high expression of both NKG2A and IFN‐γ. NK cells from older subjects, on the other hand, preserved their major phenotypic and functional characteristics, but with their mature features accentuated. These include a profound decline of the CD56bright subset, a specific increase in LIR‐1/ILT‐2, and a perfect recovering of NK‐cell function following IL2‐activation in very old subjects. We conclude that the preservation of NK cell features until very advanced age may contribute to longevity and successful aging.

Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement.

Managing vitamin K antagonist (VKA) therapy is challenging in children because of a narrow therapeutic range and wide inter- and intra-individual variability in dose response. Only a few small studies have investigated the effect of nongenetic and genetic factors on the dose response to VKAs in children. In a cohort study including 118 children (median age 9 years; range, 3 months-18 years) mostly with cardiac disease, we evaluated by multivariate analysis the relative contribution of nongenetic factors and VKORC1/CYP2C9/CYP4F2 genotypes on warfarin (n = 83) or fluindione (n = 35) maintenance dose and the influence of these factors on the time spent within/above/below the range. The results showed that height, target international normalized ratio and VKORC1 and CYP2C9 genotypes were the main determinants of warfarin dose requirement, accounting for 48.1%, 4.4%, 18.2%, and 2.0% of variability, respectively, and explaining 69.7% of the variability. Our model predicted the warfarin dose within 7 mg/wk in 86.7% of patients. None of the covariates was associated with the time spent above or below the international normalized ratio range. Whether this model predicts accurately the effective maintenance dose is currently being investigated.

Impact of the CYP4F2 p.V433M polymorphism on coumarin dose requirement: systematic review and meta-analysis.

A systematic review and a meta‐analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC‐homozygotes, T‐allele carriers required an 8.3% (95% confidence interval (CI): 5.6–11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I2 = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.

Haemorrhagic complications of vitamin k antagonists in the elderly: risk factors and management.

In patients >75 years of age, the two main indications for oral anticoagulant therapy with vitamin K antagonists (VKAs) are treatment of venous thromboembolic disease and prevention of systemic embolism in patients with nonvalvular atrial fibrillation. In both indications, a target International Normalized Ratio of 2.5 (range 2.0–3.0) is recommended. Bleeding is the adverse effect feared by physicians that most limits the use of VKAs in older frail patients. In this paper, we discuss (i) the risk of VKA-related bleeding with advancing age; (ii) the severity of bleeding complications and particularly the risk of intracranial haemorrhage in older patients; (iii) the risk factors for bleeding related to patient characteristics; and (iv) the risk factors or determinants for bleeding related to treatment variables (warfarin induction and maintenance administration, instability of anticoagulation, poor compliance and patient’s education level, and concomitant use of drugs). Avoiding over-anticoagulation and/or reducing periods of overdosing in the course of oral anticoagulant treatment with tailored monitoring may help to minimise the risk of bleeding in older patients.

Warfarin Therapy: Influence of Pharmacogenetic and Environmental Factors on the Anticoagulant Response to Warfarin

Warfarin is difficult to use because of a marked inter- and intraindividual variability among patients in the required dosage. Recent advances in understanding the vitamin K cycle have been made. Besides well-known demographic or environmental factors (advanced age, vitamin K intake, concomitant drugs, comorbid conditions, and acute illnesses), genetic single nucleotide polymorphisms (SNPs) have been identified as strongly affecting the maintenance dosage and its variability. SNPs of vitamin K epoxide reductase complex subunit-1 (VKORC1) gene have been identified, affecting the enzyme shown as one of the target of vitamin K antagonist. SNPs of cytochrome P450 2C9 (CYP2C9) gene have been shown to decrease the catabolism of warfarin. The combined analysis of VKORC1, CYP2C9 SNPs, and age may account for more than 50% of the individual variability in the warfarin maintenance dosage. Predicting models of warfarin maintenance dosage taking into account these individual parameters are currently developed.

Reversal of Overanticoagulation in Very Elderly Hospitalized Patients with an INR above 5.0: 24-Hour INR Response after Vitamin K Administration

BACKGROUND Reversal of overanticoagulation to minimize the bleeding risk is important in elderly inpatients receiving vitamin K antagonist therapy. However, no study has specifically focused on this population. The objective of this study is to evaluate whether guidelines based on American College of Chest Physicians recommendations for the management of overanticoagulation (international normalized ratio [INR] ≥5.0) can apply to elderly inpatients, and notably allow 24-hour INRs to return to the 1.8-3.2 range in this population. The influence of different factors on the vitamin K response also was evaluated. METHODS Inpatients aged ≥75 years with INR ≥5.0 were included in this observational study. INRs were assessed on the day of the overdosage (Day 0) and on the following day (Day 1). RESULTS Of 385 Day 0 INRs ≥5.0 (239 patients; 86±6 years), 217 were managed according to recommendations, with a mean INR decreasing from 6.8±2.4 (range: 5.0-20.0) on Day 0 to 2.7±1.3 (range: 1.1-10.1) on Day 1 (P<.0001); 55% of INRs were within the 1.8-3.2 range, 20% <1.8, and 25% >3.2. In the subset of Day 0 INRs between 5.0 and 6.0, mean INR decreased from 5.5±0.3 to 2.7±1.0 (P<.0001) on Day 1 after oral administration of 1 mg vitamin K1 (n=121) and from 5.3±0.3 to 5.0±1.6 (P=.149) without vitamin K1 administration (n=48). Among covariates entered in the multivariate analysis, including co-medications, only the vitamin K1 dose influenced Day 1 INRs, with higher doses of vitamin K1 associated with Day 1 INRs <1.8 (P<.0001). CONCLUSION In elderly inpatients with INR ≥5.0, both vitamin K antagonist dose omission and vitamin K1 administration according to recommendations were effective in reversing overanticoagulation, allowing most INRs to return to the 1.8-3.2 range without excessive overcorrection. Therefore, American College of Chest Physicians recommendations may be applied to elderly inpatients.

Influence of genetics and non-genetic factors on acenocoumarol maintenance dose requirement in Moroccan patients

What is known and Objective:  Coumarin derivatives such as acenocoumarol represent the therapy of choice for the long‐term treatment and prevention of thromboembolic diseases. Many genetic, clinical and demographic factors have been shown to influence the anticoagulant dosage. Our aim was to investigate the contribution of genetic and non‐genetic factors to variability in response to acenocoumarol in Moroccan patients.

Bleeding risk of antiplatelet drugs compared with oral anticoagulants in older patients with atrial fibrillation: a systematic review and meta-analysis

Essentials Hemorrhagic risk of antiplatelet drugs is generally thought to be lower than anticoagulants. We systematically reviewed trials comparing antiplatelet and anticoagulant drugs in older patients. Overall, the risk of major bleeding was similar with antiplatelet and with anticoagulant drugs. In elderly patients, risks and benefits of antiplatelet drugs should be carefully weighted.

Pharmacogénétique et antivitamine K aujourd’hui : un débat ouvert

The use of vitamin K antagonists (VKA) is challenging because of their narrow therapeutic index and a high bleeding risk. These drugs are widely prescribed for the prophylaxis and treatment of many thrombo-embolic disorders. The management of patients with VKA represents a public health problem according to the high number of deaths and hospitalizations in relation to hemorrhagic complications. Monitoring is required because of the large inter-individual variability. The identification of factors, in particular genetic factors, influencing the response to VKA will improve the safety of VKA treatment. In addition to demographic, clinical, biological factors and drug interactions, genetic factors can explain a large part of the inter-individual variability. The main enzyme responsible for VKA metabolism is the hepatic cytochrome P450 2C9 (CYP2C9). Vitamin K epoxide reductase complex subunit I (VKORC1) is a key enzyme in the vitamin K cycle and is the pharmacological target of VKA. Genetic variations affecting both CYP2C9 and VKORC1 are associated with a significant decrease in the VKA dose requirement and an increased risk of bleeding. CYP2C9 and VKORC1 genotyping may identify a subgroup of patients with an early response at the induction of VKA therapy, potentially leading to a high bleeding risk. On the opposite, rare mutations in VKORC1 can explain high dose requirement and pharmacodynamic resistance. Genotyping CYP2C9 and VKORC1 variants before treatment initiation could allow the development of dosing protocols and the identification of patients at high risk of bleeding complications.

Genetic resistance to warfarin therapy masked by amiodarone in a 2-year-old girl with mitral valve replacement.

C. MOREAU,*†‡ F . BA JOLLE ,§ V. S IGURET ,‡ ¶ M.-A . LOR IOT*† and D . BONNET§ *Sorbonne Paris Cit e, INSERM UMR-S 775, Universit e Paris Descartes; †Assistance Publique Hôpitaux de Paris, Hôpital Europ een Georges Pompidou, Service de Biochimie, Unit e Fonctionnelle de Pharmacog en etique et Oncologie Mol eculaire; ‡Assistance Publique Hôpitaux de Paris, Hôpital Europ een Georges Pompidou, Service d’H ematologie Biologique; §Universit e Paris Descartes, M3C-Necker, Hôpital Necker Enfants Malades; and ¶Sorbonne Paris Cit e, Universit e Paris Descartes, INSERM UMR-S765, Paris, France