Summary
Background
The outbreak of chilblain‐like lesions (CLL) during the COVID‐19 pandemic has been reported extensively, potentially related to SARS‐CoV‐2 infection, yet its underlying ...pathophysiology is unclear.
Objectives
To study skin and blood endothelial and immune system activation in CLL in comparison with healthy controls and seasonal chilblains (SC), defined as cold‐induced sporadic chilblains occurring during 2015 and 2019 with exclusion of chilblain lupus.
Methods
This observational study was conducted during 9–16 April 2020 at Saint‐Louis Hospital, Paris, France. All patients referred with CLL seen during this period of the COVID‐19 pandemic were included in this study. We excluded patients with a history of chilblains or chilblain lupus. Fifty patients were included.
Results
Histological patterns were similar and transcriptomic signatures overlapped in both the CLL and SC groups, with type I interferon polarization and a cytotoxic–natural killer gene signature. CLL were characterized by higher IgA tissue deposition and more significant transcriptomic activation of complement and angiogenesis factors compared with SC. We observed in CLL a systemic immune response associated with IgA antineutrophil cytoplasmic antibodies in 73% of patients, and elevated type I interferon blood signature in comparison with healthy controls. Finally, using blood biomarkers related to endothelial dysfunction and activation, and to angiogenesis or endothelial progenitor cell mobilization, we confirmed endothelial dysfunction in CLL.
Conclusions
Our findings support an activation loop in the skin in CLL associated with endothelial alteration and immune infiltration of cytotoxic and type I IFN‐polarized cells leading to clinical manifestations.
What is already known about this topic?
Chilblain‐like lesions have been reported during the COVID‐19 pandemic.
They are associated with systemic type I interferon polarization, but the precise pathophysiology is still unclear.
What does this study add?
We demonstrate cutaneous and systemic immune activation and vascular alteration.
Histological patterns were similar and transcriptomic signatures overlapped in chilblain‐like lesions and a comparator group with seasonal chilblains.
A systemic immune response was associated with high prevalence of IgA antineutrophil cytoplasmic antibodies and an elevated type I interferon signature.
We confirmed endothelial dysfunction in chilblain‐like lesions.
What is the translational message?
Chilblain‐like lesions and seasonal chilblains seem to share a common pathophysiology.
The strong type I interferon response can be explained by a viral trigger.
Similar endothelial dysfunctions have been described during mild COVID‐19.
Local or systemic anti‐inflammatory treatment could reverse cutaneous manifestations.
Linked Comment: S.M. Pilkington and R.E.B. Watson. Br J Dermatol 2021; 185:1090–1091.
Plain language summary available online
Essentials
Rivaroxaban and dabigatran are substrates of the P‐glycoprotein (P‐gp) encoded by the ABCB1 gene.
We tested the effect of ABCB1 polymorphisms and of a P‐gp inhibitor on both drugs' ...pharmacokinetics.
The ABCB1 genotype was not a clinically relevant determinant of both drugs' pharmacokinetics.
Administration of P‐gp inhibitors with dabigatran or rivaroxaban should be exercised with caution.
Summary
Background
The direct oral anticoagulants (DOACs) dabigatran and rivaroxaban are both substrates of the P‐glycoprotein (P‐gp) transporter, encoded by the ABCB1 gene. Rivaroxaban is metabolized by cytochrome P450 A4 (CYP3A4). Interindividual variability in DOAC exposure and frequent P‐gp‐associated drug–drug interactions have been described in patients.
Objective
To assess the influence of ABCB1 polymorphisms on the pharmacokinetics of dabigatran and rivaroxaban, associated or not with clarithromycin, a P‐gp and CYP3A4 inhibitor.
Methods
Sixty healthy male volunteers, selected according to ABCB1 genotype (20 homozygous mutated, 20 heterozygous mutated, and 20 wild‐type for haplotype 2677‐3435), were included in this randomized, two‐center, crossover study. All received sequentially a single dose of dabigatran etexilate (300 mg) and rivaroxaban (40 mg) associated or not with clarithromycin. Peak plasma concentration and area under the curve (AUC) were compared across the three ABCB1 genotypes. The effect of clarithromycin on dabigatran or rivaroxaban pharmacokinetics was assessed.
Results
Interindividual coefficients of variation for AUC were 77% for dabigatran and 51% for rivaroxaban. ABCB1 genotype did not significantly affect drug pharmacokinetics: AUC ratios between mutant‐allele carriers and wild‐type volunteers were 1.27 (95% confidence interval CI 0.84–1.92) and 1.20 (95% CI 0.96–1.51) for dabigatran and rivaroxaban, respectively. Clarithromycin coadministration led to a two‐fold increase in both drugs’ AUC, irrespective of ABCB1 genotype: ratios of geometric means were 2.0 (95% CI 1.15–3.60) and 1.94 (95% CI 1.42–2.63) for dabigatran and rivaroxaban, respectively.
Conclusions
ABCB1 genotype is not a significant determinant of interindividual variability in dabigatran and rivaroxaban pharmacokinetics. The levels of one drug did not predict the levels of the other. Coadministration of a P‐gp/CYP3A4 inhibitor with dabigatran or rivaroxaban may warrant caution in patients at risk of overexposure.
Determining the optimal dose of warfarin for frail elderly patients is a challenging task because of the low dose requirements in such patients, the wide interindividual variability of response, and ...the associated risk of bleeding. The objective of this study was to address the influence of 13 common variations in eight genes on the maintenance dose of warfarin in a cohort of frail elderly inpatients. For our study, we enrolled 300 Caucasian subjects who were hospital inpatients, with a mean age of 86.7 ± 6 years. In addition to age, genetic variants of VKORC1, CYP2C9, CYP4F2, and EPHX1 were found to be significant predictor variables for the maintenance dose of warfarin, explaining 26.6% of dose variability. Among 132 patients in whom warfarin therapy was initiated with the same low‐dose regimen, we studied the relative influences of genetic and nongenetic factors. The time to first international normalized ratio (INR) ≥2 was influenced by VKORC1 and CYP2C9 genotypes (P = 0.0003 and P = 0.0016, respectively); individuals with multiple variant alleles were at highest risk for overanticoagulation (INR >4) (odds ratio, 12.8; 95% confidence interval, 2.73–60.0). In this special population of frail elderly patients with multiple comorbidities and polypharmacy, we demonstrated the main impact of genetic factors on warfarin response.
Clinical Pharmacology & Therapeutics (2010) 87 1, 57–64. doi:10.1038/clpt.2009.178
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.
Summary
Background
The hemorrhagic risk of antiplatelet drugs in older patients could be higher than is usually assumed.
Objective
To compare the bleeding risk of antiplatelet drugs and oral anticoagulants in elderly patients.
Methods
We carried out a systematic review and meta‐analysis. We searched PubMed, EMBASE and the Cochrane Library up to January 2016 for randomized and non‐randomized controlled trials (RCTs) and parallel cohorts comparing antiplatelet drugs and oral anticoagulants in patients aged 65 years or older. Two independent authors assessed studies for inclusion. The pooled relative risk (RR) of major bleeding was estimated using a random model.
Results
Seven RCTs (4550 patients) and four cohort studies (38 649 patients) met the inclusion criteria. The risk of major bleeding when on aspirin or clopidogrel was equal to that when on warfarin in RCTs (RR, 1.01; 95% confidence interval (95% CI), 0.69–1.48; moderate‐quality evidence), lower than when on warfarin in non‐randomized cohort studies (RR, 0.87; 95% CI, 0.77–0.99; low‐quality evidence) and not different when all studies were combined (RR, 0.86; 95% CI, 0.73–1.01). Bleeding of any severity (RR, 0.70; 95% CI, 0.57–0.86) and intracranial bleeding (RR, 0.46; 95% CI, 0.30–0.73) were less frequent with antiplatelet drugs than with warfarin. All‐cause mortality was similar (RR, 0.99). Subgroup analysis suggested that major bleeding might be higher with warfarin than with aspirin in patients over 80 years old.
Conclusion
Elderly patients treated with aspirin or clopidogrel suffer less any‐severity bleeding but have a risk of major bleeding similar to that of oral anticoagulants, with the exception of intracranial bleeding.
Coronavirus Disease-2019 (COVID-19) predisposes patients to thrombosis which underlying mechanisms are still incompletely understood. We sought to investigate the balance between procoagulant factors ...and natural coagulation inhibitors in the critically ill COVID-19 patient and to evaluate the usefulness of hemostasis parameters to identify patients at risk of venous thromboembolic event (VTE).
We conducted an observational study recording VTEs defined as deep vein thrombosis or pulmonary embolism using lower limb ultrasound (92% of the patients), computed tomography pulmonary angiography (6%) and both tests (2%). We developed a comprehensive analysis of hemostasis.
Ninety-two consecutive mechanically ventilated COVID-19 patients (age, 62 years 53-69 (median 25th-75th percentiles); M/F sex ratio, 2.5; body-mass index, 28 kg/m2 25-32; past hypertension (52%) and diabetes mellitus (30%)) admitted to the Intensive Care Unit (ICU) from 03/11/2020 to 5/05/2020, were included. When tested, patients were receiving prophylactic (74%) or therapeutic (26%) anticoagulation. Forty patients (43%) were diagnosed with VTE. Patients displayed inflammatory and prothrombotic profile including markedly elevated plasma fibrinogen (7.7 g/L 6.1-8.6), D-dimer (3,360 ng/mL 1668-7575), factor V (166 IU/dL 136-195) and factor VIII activities (294 IU/dL 223-362). We evidenced significant discrepant protein C anticoagulant and chromogenic activities, combined with slightly decreased protein S activity. Plasma D-dimer >3,300 ng/mL predicted VTE presence with 78% (95%-confidence interval (95% CI), 62-89) sensitivity, 69% (95% CI, 55-81) specificity, 66% (95% CI, 51-79) positive predictive value and 80% (95% CI, 65-90) negative predictive value area under the ROC curve, 0.779 (95%CI, 0.681-0.859), p=0.0001.
Mechanically ventilated COVID-19 patients present with an imbalance between markedly increased factor V/VIII activity and overwhelmed protein C/S pathway. Plasma D-dimer may be a useful biomarker at the bedside for suspicion of VTE.
Background: In the elderly, concerns have been raised regarding the risk of accumulation of low molecular weight heparins, owing to their renal elimination. Although data exist for tinzaparin, they ...are observational. Objectives: To assess whether: (i) there was an accumulation of anti‐factor Xa activity; and (ii) there was any relationship between anti‐FXa activity and age, weight, creatinine clearance or clinical outcomes in patients with moderate‐to‐severe renal impairment receiving tinzaparin (175 IU kg−1 per 24 h) for acute venous thromboembolism. Methods: In 38 centers participating in the Innohep in Renal Insufficiency Study (IRIS), peak plasma anti‐FXa activity was measured on day 2/day 3 and on day 5 or at visit S (VS) (end of tinzaparin treatment). There was considered to be absence of accumulation if the 90% confidence interval (CI) of the (anti‐FXa day 5/VS)/(anti‐FXa day 2/3) ratio did not exceed the predefined limit of 1.25. Results: Eighty‐seven patients, with a mean age of 83 ± 5 years (range: 75–99 years) and a mean creatinine clearance (CrCl) of 40.8 mL min−1, 24.1% of whom had severe renal impairment, were included. The mean duration of tinzaparin treatment was 8.4 days. No significant accumulation was detected: the mean accumulation ratio was 1.06 (90% CI 1.01–1.11). There was no correlation between the accumulation ratio and age, weight, or CrCl. The mean anti‐FXa activity did not differ significantly between the eight patients who experienced clinically relevant bleeding and those who did not. Conclusions: No accumulation of anti‐FXa activity was observed in elderly patients with renal impairment receiving therapeutic doses of tinzaparin, suggesting that there is no need for systematic anti‐FXa monitoring in these patients. The high proportion of high molecular weight moieties in tinzaparin may account for its reduced dependence on renal elimination.
Summary
Background
Non‐specific hemostatic agents, namely activated prothrombin complex concentrate (aPCC), PCC and recombinant activated factor (F) VII (rFVIIa), can be used, off‐label, to reverse ...the effects of FXa inhibitors in the rare cases of severe hemorrhages, as no approved specific antidote is available. We have evaluated the ability of aPCC, PCC and rFVIIa to reverse apixaban.
Methods
Healthy volunteer whole blood was spiked with therapeutic or supra‐therapeutic apixaban concentrations and two doses of aPCC, PCC or rFVIIa. Tests performed included a turbidimetry assay for fibrin polymerization kinetics analysis, scanning electron microscopy for fibrin network structure observation, thrombin generation assay (TGA), thromboelastometry, prothrombin time and activated partial thromboplastin time.
Results
aPCC generated a dense clot constituting thin and branched fibers similar to those of a control without apixaban, increased fibrin polymerization velocity and improved quantitative (endogenous thrombin potential and peak height) as well as latency (clotting and lag times) parameters. Adding PCC also improved the fibrin and increased quantitative parameters, but fibrin polymerization kinetics and latency parameters were not corrected. Finally, rFVIIa improved latency parameters but failed to restore the fibrin network structure, fibrin polymerization velocity and quantitative parameters.
Conclusion
aPCC was more effective than PCC or rFVIIa in reversing in vitro the effects of apixaban. aPCC rapidly triggered the development of an apparently normal fibrin network and corrected latency and quantitative parameters, whereas PCC or rFVIIa had only a partial effect.
Background: Initiating warfarin is challenging in frail elderly patients because of low‐dose requirements and interindividual variability. Objectives: We investigated whether incorporating VKORC1 and ...CYP2C9 genotype information in different models helped to predict the warfarin maintenance dose when added to clinical data and INR values at baseline (Day 0), and during warfarin induction. Patients: We prospectively enrolled 187 elderly inpatients (mean age, 85.6 years), all starting on warfarin using the same ‘geriatric dosing‐algorithm’ based on the INR value measured on the day after three 4‐mg warfarin doses (INR3) and on INR6 ± 1. Results: On Day 0, the clinical model failed to accurately predict the maintenance dose (R2 < 0.10). Adding the VKORC1 and CYP2C9 genotypes to the model increased R2 to 0.31. On Day 3, the INR3 value was the strongest predictor, completely embedding the VKORC1 genotype, whereas the CYP2C9 genotype remained a significant predictor (model‐ R2 0.55). On Day 6 ± 1, none of the genotypes predicted the maintenance dose. Finally, the simple ‘geriatric dosing‐algorithm’ was the most accurate algorithm on Day 3 (R2 0.77) and Day 6 (R2 0.81), under‐estimating (≥ 1 mg) and over‐estimating the dose (≥ 1 mg) in fewer than 10% and 2% of patients, respectively. Clinical models and the ‘geriatric dosing‐algorithm’ were validated on an independent sample. Conclusions: Before starting warfarin therapy, the VKORC1 genotype is the best predictor of the maintenance dose. Once treatment is started using induction doses tailored for elderly patients, the contribution of VKORC1 and CYP2C9 genotypes in dose refinement is negligible compared with two INR values measured during the first week of treatment.
Summary
Since low molecular weight heparins (LMWH) are partly eliminated by renal excretion, their pharmacodynamic profile may be modified in very elderly patients with age-related renal impairment. ...The aim of this prospective study was to determine whether tinzaparin (Innohep
®
) 175 anti-Xa IU/kg administered subcutaneously once daily over 10 days does accumulate in hospital patients greater than 70 years of age. Plasma anti-Xa and anti-IIa amidolytic levels and APTT were determined prior to the first injection (day 0), and then, at peak level i.e. 5 h after the second injection (day 2) and subsequently on days 5, 7 and 10.
Thirty consecutive inpatients (6 men, 24 women) requiring LMWHs at a curative dose for acute thromboembolic disease were included. Patients’ characteristics (mean ± SD) were: age 87.0 ± 5.9 years (range 71–96), body weight 62.7 ± 14.6 kg (range 38-90) and creatinine clearance 40.6 ± 15.3 mL/min (range 20–72). The mean actual dose of tinzaparin delivered was 174.8 anti-Xa IU/kg. Since no patient had an anti-Xa activity above 1.5 IU/mL, the dose of tinzaparin remained fixed over 10 days.
Anti-Xa and anti-IIa peak levels measured on day 2 were 0.66 ± 0.20 IU/mL (range 0.26–1.04) and 0.33 ± 0.10 IU/mL (range 0.18–0.55), respectively. Ex vivo anti-Xa/anti-IIa ratios were close to 2.1. APTT ratios (patient/control) were strongly correlated with anti-IIa activity (p <0.01). There was no progressive increase of the anti-Xa and anti-IIa activities after repeated administration of tinzaparin over the 10 day treatment period. No correlation was found between anti-Xa and anti-IIa activities and age, weight, or creatinine clearance. No major bleeding occurred during the study and only one minor haematoma at the injection site was reported. No thromboembolic complication or death occurred.
Tinzaparin may thus be administered safely at a treatment dose (175 anti-Xa IU/kg) in older patients with age-related renal impairment. Neither dose adjustment, nor serial anti-Xa activity monitoring seems to be required in patients with creatinine clearance above 20 mL/min during the first ten day treatment.
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