Eric Pautas

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.

Risk Factors for Deep Vein Thrombosis in Inpatients Aged 65 and Older: A Case-Control Multicenter Study

Objectives: To identify independent risk factors of symptomatic deep vein thrombosis (DVT) in geriatric inpatients and to define high‐risk patients likely to benefit from preventive treatment.

Safety profile of tinzaparin administered once daily at a standard curative dose in two hundred very elderly patients.

AbstractObjectives: Too few very elderly patients with an age-related renal impairment are included in clinical trials. We conducted a study in order to evaluate the safety profile of tinzaparin, a low molecular weight heparin (LMWH), given at a curative dose (175 IU/kg once daily) in very elderly patients treated for up to 30 days. Setting: An 800-bed geriatric hospital. Design: A 1-year prescribing study. Patients: Consecutive in-patients older than age 70, whose creatinine clearance was above 20 ml/min, and requiring full anticoagulation with LMWH were included. Measurements: Safety parameters (major bleeding/heparin-induced thrombocytopenia/death) were recorded. Plasma anti-Xa activity levels were regularly measured throughout the treatment period. Results: Two-hundred in-patients, mean age 85.2 ± 6.9 years (70 to 102), mean creatinine clearance 51.2 ± 22.9 ml/min, were given tinzaparin. Six patients died during the treatment period: only one could be related to the anticoagulation treatment. Three major bleeding episodes (1.5%) were reported. Antithrombotic drug interactions likely contributed to the bleeding event in two of them. Heparin-induced thrombocytopenia was confirmed in two patients (1%). No correlation was found between anti-Xa activity and creatinine clearance or age. Conclusions: Tinzaparin can be used safely at a curative dose in very elderly patients as long as (i) the accurate bodyweight-adjusted dose is given; (ii) platelet counts and anti-Xa levels are regularly monitored and; (iii) the interaction with other antithrombotic drugs is correctly managed.

Safety Profile of Different Low-Molecular Weight Heparins Used at Therapeutic Dose

Low-molecular weight heparins (LMWHs) have been shown to be as safe and effective as unfractionated heparin (UFH) for the treatment of acute venous thrombosis and non-life-threatening pulmonary embolism. Different reports have shown that LMWHs may also be used to treat patients with unstable angina or non-Q-wave infarction. The safety of LMWHs used at therapeutic dose has been widely studied in pivotal clinical trials and analysed in several meta-analyses. However, despite the wide development and use of LMWHs, several issues regarding the safety and optimal use of LMWHs remain unanswered.The main adverse effect of LMWHs is bleeding and it is uncertain whether a weight-adjusted dosage regimen without laboratory monitoring can be used in patients with a high risk of bleeding, such as patients with renal failure, elderly patients, obese patients or pregnant women. These patients are usually excluded from clinical trials and only a few studies, not sufficiently powered to estimate efficacy and safety, have been carried out in these special populations. Most of the available data comes from pharmacokinetic or population pharmacodynamic studies or clinical reports. Results in patients with renal impairment who are not undergoing haemodialysis suggest that a reduction in calculated creatinine clearance levels is associated with an increased risk of accumulation of anti-Xa activity, the extent of which differs depending on the individual LMWH and the extent to which the compound is cleared by the kidney. The limited data available regarding the use of therapeutic doses of LMWHs in obese patients suggest that there is no need to cap the dose at a maximal allowable dose. Long-term (3-month) treatment with LMWHs appears to be as effective and safe as oral anticoagulant therapy for the treatment of venous thromboembolism. It appears that each LMWH is a distinct compound with unique pharmacokinetic and pharmacodynamic profiles. Until more data are available regarding these special populations, periodic monitoring of anti-Xa activity levels may be recommended to detect accumulation and/or an overdose and minimise the bleeding risk.The non-haemorrhagic adverse effects of the LMWHs include heparin-induced thrombocytopenia (HIT) and osteoporosis. The incidence of HIT appears to be lower with LMWHs than with UFH; there is currently not enough data to compare the frequency of HIT between the various LMWHs. LMWHs also appear to carry a lower risk of causing osteoporosis than UFH.In conclusion, studies that include special population patients are required to make conclusive recommendations concerning the safety and monitoring of the different LMWHs.

Elderly Medical Patients Treated with Prophylactic Dosages of Enoxaparin Influence of Renal Function on Anti-Xa Activity Level

BackgroundThe safety and optimal use of prophylactic treatment with low-molecular-weight heparins in elderly patients with impaired renal function remain undefined.MethodsThe primary aim of this study was to analyse, in ‘real life’, the influence of renal function, as assessed by Creatinine clearance (CLcr), on the level of anti-Xa activity in medical hospitalised elderly patients receiving prophylactic dosages of enoxaparin. Consecutive hospitalised acutely ill medical patients aged ≥75 years receiving daily dosages of enoxaparin 4000IU for up to 10 days were prospectively enrolled in two centres. Peak anti-Xa activity was measured at the beginning and during the course of therapy.ResultsOne hundred and twenty-five patients (31 men, 94 women), mean age 87.5 ± 6.3 years, mean bodyweight 56.4±11.9kg and mean CLcr 39.8 ± 16.1 mL/min, were enrolled in the study. The mean maximum anti-Xa activity (day 1 to day 10) [anti-Xamaxl–l0] was 0.64 ± 0.23 IU/mL (range 0.24–1.50 IU/mL). Weak negative correlations were found between CLcr and anti-Xamax and between bodyweight and anti-Xamax. Mean anti-Xamax was slightly but significantly higher in patients with CLcr of 20–30 mL/min compared with patients with CLcr of 31–40,41–50 or 51–80 mL/min (0.72 versus 0.61, 0.61 and 0.60 IU/ mL, respectively), and in patients weighing <50kg compared with patients weighing 50–60kg or >60kg (0.74 vs 0.64 and 0.52 IU/mL, respectively). Serious bleeding occurred in five patients, but anti-Xamax values in these patients were not different to those in patients without bleeding (p = 0.77). Individual anti-Xamax at the beginning or during the course of treatment was measured in the subgroup of 58 patients in whom anti-Xa activity was measured at least once during the study. The mean anti-Xamax value was slightly but significantly higher during the course of the therapy than at the beginning of the study (0.63 ± 0.26 IU/mL vs 0.56±0.23 IU/mL, p = 0.012).ConclusionOnly CLcr <30 mL/min and bodyweight <50kg were associated with significantly higher anti-Xamax values. The clinical relevance of these increases remains questionable. No conclusions about the safety of enoxaparin in elderly medical patients can be drawn from these findings.

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.

Improving Anticoagulation Control in Hospitalized Elderly Patients on Warfarin

OBJECTIVES: To determine the effect of patient characteristics and of specific guidelines that were developed for managing warfarin therapy in older adults and included in an in‐house computer program on anticoagulation quality.

Inflammation and disability as risk factors for mortality in elderly acute care patients.

Although the role of inflammation has been studied in specific diseases or in community living elderly, data in hospitalized acute care elderly patients are scarce. The present study was designed to determine the predictive value of sociodemographic, clinical and biological factors for mortality in acute care geriatric wards. Retrospective study was conducted in two acute care wards in a university-based geriatric hospital with elderly patients (n=224) consecutively admitted to acute care wards with available medical files. Sociodemographic variables, primary medical diagnosis and number of associated conditions, dementia, depression, pressure sores, functional status (measure by the activities of daily living=ADL scale), weight, and plasma levels of albumin, transthyretin, C-reactive protein (CRP) and orosomucoid were recorded at admission. Patients who died in the acute care wards were compared to those who survived. The mean length of stay was 16+/-13 days; mortality was 12%. Univariate analysis revealed that disability, no anti-depressant drug, pressure ulcers, a higher number of associated conditions, living with another person, and biological markers of malnutrition (albumin <35g/l, transthyretin <200mg/l) and inflammation (CRP < or =30mg/l, orosomucoid > or =1.25g/l) were significantly associated with an increase in the risk of death. The logistic regression model retained CRP > or =30mg/l (odds ratio (OR)=3.72, 95% confidence interval (CI)=1.34-10.31; p=0.009) and disability for at least one ADL item (OR=2.16, 95% CI=1.55-2.99; p<0.001) as independent risk factors for death. We conclude that CRP and disability are strong independent risk factors for death in this population, and special attention should be paid to these patients in an integrated therapeutic approach to geriatric care.

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.

Anticoagulation du sujet âgé : nouveautés thérapeutiques

Vitamin-K antagonists (VKA) are the current standard for oral anticoagulation. However, they carry several problems in older patients: frequent bleeding complications, complex management, risk of interactions with multiple drugs. Two new classes of oral anticoagulants (NOA) are now available: direct thrombin inhibitors (dabigatran); and direct factor Xa inhibitors (rivaroxaban, apixaban) and others. Their management is easier: quickly effective after administration, they are given at fixed doses and do not need regular laboratory monitoring. Several randomized trials have shown that NOA are non-inferior to heparins and VKA for treating venous thromboembolic disease (prophylactic or curative treatment) and atrial fibrillation (prevention of associated embolisms). NOA are also being studied for long-term treatment after acute coronary syndromes. Data regarding older people is still sparse. No trial has specifically studied older patients. In the context of atrial fibrillation, subgroup analysis show similar results between patients above and below 75 years old, except for dabigatran which seems to carry more bleeding complications in people older than 75 years, specially with the highest dose employed. All NOA are eliminated at least partly by kidneys. Their dose must be reduced in moderate renal failure (filtration glomerular rate (FGR) 30 to 50 ml/min) and they are contra-indicated in severe renal failure (FGR<30 ml/min). Doses of dabigatran and apixaban should be reduced in older people too. NOA also have other unresolved problems: drug interactions are still possible, specific coagulation test to assess them must be developed, and no specific antidote is currently available in case of hemorrhagic complication.