The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon

2004 ◽  
Vol 92 (07) ◽  
pp. 61-66 ◽  
Author(s):  
Loes Visser ◽  
Ron van Schaik ◽  
Martin van Vliet ◽  
Paul Trienekens ◽  
Peter De Smet ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Bleeding Risk ◽  
Bleeding Complications ◽  
Wild Type ◽  
Bleeding Events ◽  
Initiation Phase ◽  
Cyp2c9 Genotype ◽  
Fatal Bleeding ◽  
Increased Risk ◽  
Variant Genotype

SummaryThe principal enzyme involved in coumarin metabolism is CYP2C9. Allelic variants of CYP2C9, CYP2C9*2 and CYP2C9*3, code for enzymes with reduced activity. Despite increasing evidence that patients with these genetic variants require lower maintenance doses of anticoagulant therapy, there is lack of agreement among studies on the risk of bleeding and CYP2C9 polymorphisms. It was, therefore, our objective to study the effect of the CYP2C9 polymorphisms on bleeding complications during initiation and maintenance phases of coumarin anticoagulant therapy. The design of the study was a population-based cohort in a sample of the Rotterdam Study, a study in 7,983 subjects. All patients who started treatment with acenocoumarol or phenprocoumon in the study period from January 1, 1991 through December 31, 1998 and for whom INR data were available were included. Patients were followed until a bleeding complication, the end of their treatment, death or end of the study period. Proportional hazards regression analysis was used to estimate the risk of a bleeding complication in relation to CYP2C9 genotype after adjustment for several potentially confounding factors such as age, gender, target INR level, INR, time between INR measurements, and aspirin use. The effect of variant genotype on bleeding risk was separately examined during the initiation phase of 90 days after starting therapy with coumarins. The 996 patients with analysable data had a mean follow-up time of 481 days (1.3 years); 311 (31.2%) had at least 1 variant CYP2C9 allele and 685 (68.8%) had the wild type genotype. For patients with the wild type genotype, the rate of minor bleeding, major bleeding and fatal bleeding was 15.9, 3.4 and 0.2 per 100 treatmentyears, respectively. For patients with a variant genotype, the rate of minor, major and fatal bleeding was 14.6, 5.4 and 0.5 per 100 treatment-years. Patients with a variant genotype on acenocoumarol had a significantly increased risk for a major bleeding event (HR 1.83, 95% CI: 1.01-3.32). During the initiation phase of therapy we found no effect of variant genotype on bleeding risk. In this study among outpatients of an anticoagulation clinic using acenocoumarol or phenprocoumon, having a variant allele of CYP2C9 was associated with an increased risk of major bleeding events in patients on acenocoumarol, but not in patients on phenprocoumon. Although one might consider the assessment of the CYP2C9 genotype of a patient for dose adjustment before starting treatment with acenocoumarol, a prospective randomised trial should demonstrate whether this reduces the increased risk of major bleeding events.

scholarly journals Long-term outcomes in high-bleeding risk patients undergoing PCI for acute coronary syndromes: results from a large single-center pci registry

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J Nicolas ◽  
D Cao ◽  
B Claessen ◽  
S Sartori ◽  
R Chandiramani ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Acute Coronary Syndromes ◽  
Bleeding Risk ◽  
Bleeding Complications ◽  
Major Adverse Cardiovascular Events ◽  
Bleeding Events ◽  
Increased Risk ◽  
Risk Patients ◽  
Coronary Syndromes ◽  
High Bleeding Risk

Abstract Introduction Current clinical guidelines recommend prolonged dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndromes (ACS). However, an extended DAPT duration in high-bleeding risk (HBR) patients amplifies the risk of post procedural complications. Hence, clinicians often face the dilemma of prolonging DAPT duration to prevent recurrent ischaemic events at the expense of increasing the incidence of bleeding in high-risk patients. The actual incidence of ischaemic and bleeding events in this particular population is not well elucidated. Purpose To evaluate one-year ischemic and bleeding outcomes following PCI for ACS in a real-world HBR population as defined by the Academic Research Consortium (ARC) consensus document. Methods We included all patients who presented with ACS to a high-volume single PCI centre from 2012 to 2017 and underwent PCI with 2nd generation drug-eluting stent implantation. Patients were classified as HBR if they met ≥1 major or ≥2 minor criteria according to the recent ARC-HBR consensus. The outcomes of interest were major adverse cardiovascular events (MACE), a composite of all-cause death, myocardial infarction (MI), and target lesion revascularization (TLR), and major bleeding events, including both peri-procedural and post-discharge bleeding. All outcomes were assessed at 1-year follow-up. The Kaplan-Meier method was used for time-to-event analyses. Results Out of 6,097 ACS patients included in this analysis, 2,717 (44.6%) fulfilled the ARC-HBR definition. Compared to non-HBR group, HBR patients were more frequently female, older, more likely to have cardiovascular risk factors (e.g., diabetes, hypertension, and hyperlipidemia) and complex coronary artery disease (e.g., multi-vessel disease, bifurcation lesions, and calcification). The 1-year incidence of MACE was significantly higher in HBR patients (16.3% vs. 8.1%, HR 2.16, 95% CI [1.81–2.59], p<0.001) (Figure 1A). This finding was driven by higher rates of all-cause death and MI (Figure 1B). The 1-year incidence of major bleeding was also significantly higher in HBR patients compared to non-HBR (11.1% vs. 3.1%, HR: 3.92, 95% CI 3.10–4.95; p<0.001). Conclusions HBR patients undergoing PCI for ACS are not only subject to bleeding complications but are also at an increased risk for ischemic events and all-cause mortality. Figure 1 Funding Acknowledgement Type of funding source: None

Abstract 299: Association of Chronic Lung Disease with Treatments and Outcomes of Acute Coronary Syndromes: Results from the NCDR®

2012 ◽  
Vol 5 (suppl_1) ◽  
Author(s):  
Jonathan R Enriquez ◽  
James A de Lemos ◽  
Ramin Farzaneh-Far ◽  
Anand Rohatgi ◽  
S. A Peng ◽  
...  
Keyword(s):  
Hospital Mortality ◽  
Lung Disease ◽  
Major Bleeding ◽  
Chronic Lung Disease ◽  
Beta Blockers ◽  
Bleeding Risk ◽  
Bleeding Complications ◽  
Processes Of Care ◽  
Increased Risk ◽  
The Impact

Background: Previous reports are conflicting regarding outcomes, treatments, and processes of care after acute myocardial infarction (MI) for patients with chronic lung disease (CLD). Methods: Using the NCDR ACTION Registry ® -GWTG ™ (AR-G), demographics, clinical characteristics, treatments, processes of care, and in-hospital adverse events after NSTEMI and STEMI were compared between patients with (n= 22,624; 14.2%) and without (n= 136,266; 85.8%) CLD. CLD was defined by a history of COPD, chronic bronchitis, or emphysema. Multivariable adjustment using published AR-G in-hospital mortality and major bleeding risk adjustment models was performed to quantify the impact of CLD on treatments and outcomes. Results: CLD was present in 10.1% of STEMI patients and 17.0% of NSTEMI patients. In both STEMI and NSTEMI, CLD patients were older, more likely to be female, and had more comorbidities including diabetes, renal disease, prior MI and heart failure, compared to those without CLD. Although on admission CLD patients were more likely to be on cardiovascular medications, by discharge slightly fewer CLD patients received composite core measures (aspirin, beta-blockers, ACE-inhibitors, and statins) (table). In NSTEMI, CLD was also associated with less use of invasive procedures and with increased risk of both death and major bleeding. In STEMI, major bleeding but not mortality was increased. Conclusions: CLD is a common comorbidity and is independently associated with an increased risk for major bleeding after MI. In NSTEMI, CLD is also associated with receiving fewer evidence-based medications, less timely angiography and revascularization, and increased in-hospital mortality. Close attention should be given to this high-risk subgroup for the prevention and management of bleeding complications after MI, and further investigation is needed to determine the reasons for treatment and outcome disparities in NSTEMI.

Calculation of HAS-BLED Score Is Useful for Early Identification of Venous Thromboembolism Patients at High Risk for Major Bleeding Events: A Prospective Outpatients Cohort Study

2017 ◽  
Vol 44 (04) ◽  
pp. 348-352 ◽  
Author(s):  
Reinhard Raggam ◽  
Franz Hafner ◽  
Alexander Avian ◽  
Gerald Hackl ◽  
Gerhard Cvirn ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Major Bleeding ◽  
Odds Ratio ◽  
Bleeding Complications ◽  
Minor Bleeding ◽  
Prospective Evaluation ◽  
Bleeding Events ◽  
Increased Risk ◽  
Major Bleeding Events

AbstractThe aim of this study was prospective evaluation of the performance of the HAS-BLED score in predicting major bleeding complications in a real-world outpatient cohort, during long-term anticoagulation for venous thromboembolism (VTE), treated with a broad spectrum of anticoagulants. We analyzed 111 outpatients objectively diagnosed with VTE and treated long-term with various anticoagulants. Patients were grouped in three cohorts based on the anticoagulant regimen. Calculation of the HAS-BLED score and documentation of bleeding events were performed every 6 months for 1 year. Patients with a HAS-BLED score ≥ 3 had an increased risk for major bleeding events (odds ratio [OR]: 13.05, 95% confidence interval [CI]: 0.96–692.58, p = 0.028) and a trend to higher risk for minor bleeding events as well (OR: 2.25, 95% CI: 0.87–5.85, p = 0.091) when compared with patients with a HAS-BLED score < 3.This indicates that a HAS-BLED score ≥ 3 allows for identification of patients with VTE on long-term anticoagulation at an increased risk for major bleeding events, irrespective of the anticoagulant agent used.

scholarly journals Bleeding Risk in a Cohort of Ambulatory Cancer Patients Receiving Outpatient Prophylactic Anticoagulation for Venous Thrombosis Prevention

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 709-709
Author(s):  
Andrew B Wilks ◽  
Daniel Douce ◽  
Steven Ades ◽  
Mary Cushman ◽  
Neil A. Zakai ◽  
...  
Keyword(s):  
Lung Cancer ◽  
High Risk ◽  
Cancer Patients ◽  
Major Bleeding ◽  
Bleeding Risk ◽  
Bleeding Events ◽  
Major Bleed ◽  
Prophylactic Dose ◽  
Increased Risk ◽  
Prophylactic Anticoagulation

Background: Recent clinical trials have evaluated the safety and efficacy of direct oral anticoagulant (DOAC) therapy for venous thromboembolism (VTE) prophylaxis in cancer outpatients at high risk for thrombosis. Bleeding risk in these trials were approximately 2% over the first 6 months of therapy. For individual patients, the utility of prophylactic anticoagulation (AC) depends on an acceptable safety profile between bleeding and thrombosis. We investigated whether ambulatory cancer patients on contemporary cancer-directed therapies and prophylactic AC had an increased risk of major bleeds over the first 6 months of therapy. Methods: As part of a single-center prospective cohort study, we assessed consecutive ambulatory patients initiating cancer-directed treatment, risk-stratified these patients for VTE using the Khorana score and educated them about VTE. High risk patients (Khorana score ≥3) were offered prophylactic AC. Major bleeding events and minor bleeding events (based on ISTH standard definitions) were prospectively captured via billing code screening and confirmed by physician review of the medical record. Logistic regression was used to compare the odds of developing a major bleed within 6 months in those who received prophylactic AC compared to those that did not. Results: A total of 1,210 patients were enrolled from October 2015 - June 2018, of which, 640 were women (52.9%). The most common cancers were gastrointestinal 270 (22%), lung 213 (18%), and breast 198 (16%). There were 393 patients (32%) with a Khorana score of 0, 706 (58%) with a Khorana score of 1-2, and 111 (9%) with a score of ≥3. A total of 421 patients received any AC (LMWH or DOAC). Of these, 282 received a prophylactic dose anticoagulant and 139 were receiving a full dose anticoagulant prior to enrolling for other medical reasons. Prophylactic dose anticoagulants prescribed included apixaban in 107 (41%), rivaroxaban in 6 (2.3%), enoxaparin in 119 (45.7%), and other heparin products in 50 (19.2%). A total of 27 (2.33%) major bleeds and 22 (1.81%) minor bleeds occurred within the first 6 months of starting therapy. Of these bleeding events, 8 (2.8%) occurred in those on prophylactic AC, and 6 (4.3%) occurred in those on full dose AC. The odds ratio (OR) of developing a major bleed on any type of AC was 1.78 [CI 0.817-3.88]. The OR of major bleeding on prophylactic AC was 1.49 [CI 0.64-3.479]. The OR of major bleed was highest in lung cancer patients on prophylactic AC (OR 2.81, CI 1.27-6.25). Men, when compared to women, were more likely to bleed on prophylactic AC in the first six month (OR 0.2; CI 0.07-0.52). The OR for major bleed with each 1 year increase in age was 1.02 (CI 0.99, 1.06). The OR of bleeding with a high risk Khorana score (≥3) compared to a lower score was 1.04 (CI 0.73-1.50). Conclusion: During the first six months of therapy, prophylactic AC was associated with an increased risk of major bleeding events in patients on cancer-directed therapy. In this study, the rate of major bleeding was similar as compared to published clinical trials. Neither age nor higher Khorana score were associated with an increased risk of major bleeds in patients on prophylactic AC. The finding that men, when compared to women, and patients with lung cancer may have an increased risk of major bleeding while on prophylactic AC and cancer-directed chemotherapy suggests these groups may warrant both increased education and monitoring to ensure safety while on prophylactic AC. Disclosures No relevant conflicts of interest to declare.

scholarly journals An Exploratory Association Analysis of ABCB1 rs1045642 and ABCB1 rs4148738 with Non-Major Bleeding Risk in Atrial Fibrillation Patients Treated with Dabigatran or Apixaban

2020 ◽  
Vol 10 (3) ◽  
pp. 133
Author(s):  
Adela-Nicoleta Roşian ◽  
Mihaela Iancu ◽  
Adrian Pavel Trifa ◽  
Ştefan Horia Roşian ◽  
Cristina Mada ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Major Bleeding ◽  
Statistical Significance ◽  
Oral Anticoagulants ◽  
Positive Association ◽  
Bleeding Risk ◽  
Protective Role ◽  
Bleeding Complications ◽  
Variant Genotype ◽  
Risk Patients

(1) Background: The approach of bleeding complications in patients treated with non-vitamin K oral anticoagulants (NOACs) represents an important issue in clinical practice. Both dabigatran and apixaban are substrates for P-glycoprotein and, therefore, ABCB1 gene variations may be useful in individualizing NOACs treatment, especially in high-risk patients. (2) Methods: ABCB1 rs1045642 and rs4148738 were determined in 218 atrial fibrillation patients treated with dabigatran or apixaban (70.94 ± 9.04 years; 51.83% men). (3) Results: Non-major bleeding appeared in 7.34% NOACs–treated patients. The logistic tested models based on the four genetic models revealed no significant association between the variant genotype of two ABCB1 SNPs and the risk of bleeding (p > 0.05). Among the four two-locus haplotypes, TA and CA haplotypes had the highest frequency in NOACs-treated patients with bleeding, involving a possible positive association with the susceptibility of bleeding complications (OR = 1.04 and OR = 1.91, respectively). The logistic model found no significant association of estimated haplotypes with bleeding (p > 0.05) except for the TG haplotype which had a trend toward statistical significance (p = 0.092). Among the risk factors for bleeding, only age > 70 years and stroke/TIA showed a tendency toward statistical significance. (4) Conclusions: We found no significant associations between the studied ABCB1 variant genotypes with non-major bleeding risk in NOACs-treated patients. A trend of association between TG haplotype with bleeding risk was observed, implying a protective role of this haplotype against bleeding in patients treated with dabigatran or apixaban.

External validation of the VTE-BLEED score for predicting major bleeding in stable anticoagulated patients with venous thromboembolism

2017 ◽  
Vol 117 (06) ◽  
pp. 1164-1170 ◽  
Author(s):  
Frederikus A. Klok ◽  
Stefano Barco ◽  
Stavros V. Konstantinides
Keyword(s):  
Venous Thromboembolism ◽  
High Risk ◽  
Major Bleeding ◽  
External Validation ◽  
Chronic Phase ◽  
Bleeding Risk ◽  
Bleeding Events ◽  
Risk Of Bleeding ◽  
Increased Risk ◽  
Study Population

SummaryOne of the main determinants of establishing the optimal treatment duration of patients with venous thromboembolism (VTE) is the risk of major bleeding during long-term anticoagulant therapy. The 6-variable VTE-BLEED score was recently developed to enable estimation of this bleeding risk. This study aimed at externally validating VTE-BLEED. This was a post-hoc study of the randomised, double-blind, double-dummy, Hokusai-VTE study that compared edoxaban versus warfarin for treatment of VTE. VTE-BLEED was calculated in all 8,240 study patients. The numbers of adjudicated major bleeding events during ‘stable anticoagulation’, i. e. occurring after day 30, in patients with low (total score <2 points) and high risk of bleeding (total score ≥2 points) were compared for the overall study population, patients randomised to edoxaban or warfarin, and for important patient subcategories. During ‘stable’ anticoagulation, major bleeding occurred in 1.02% (40/3,903) and 0.82% (32/3,899) of patients treated with warfarin and edoxaban, respectively. For the overall study population, the risks of bleeding in the low and high risk groups were 0.51% and 2.03%, respectively, for an odds ratio (OR) of 4.04 (95% confidence interval [CI]: 2.51–6.48). ORs were 5.04 (95%CI: 2.62–9.69) and 3.09 (95%CI: 1.54–6.22) for warfarin and edoxaban, respectively. VTE-BLEED was consistently able to identify patients at a 2.5- to 11-fold higher bleeding risk across all the predefined subcategories, as well as for the treatment period between day 30 to day 180, and beyond day 180. In conclusion, patients identified as high risk by VTE-BLEED had a four-fold increased risk of bleeding during the chronic phase of treatment.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Treatment algorithm in cancer-associated thrombosis: Canadian expert consensus

2018 ◽  
Vol 25 (5) ◽  
Author(s):  
M. Carrier ◽  
N. Blais ◽  
M. Crowther ◽  
P. Kavan ◽  
G. Le Gal ◽  
...  
Keyword(s):  
Anticoagulant Therapy ◽  
Treatment Algorithm ◽  
Bleeding Risk ◽  
Bleeding Complications ◽  
Bleeding Events ◽  
Web Based ◽  
Patients With Cancer ◽  
Increased Risk ◽  
Recurrent Vte ◽  
Cancer Associated Thrombosis

Management of anticoagulant therapy for the treatment of venous thromboembolism (vte) in cancer patients is complex because of an increased risk of recurrent vte and major bleeding complications in those patients relative to the general population. Subgroups of patients with cancer also show variation in their risk for recurrent vte and adverse bleeding events. Accordingly, a committee of 10 Canadian clinical experts developed the consensus risk- stratification treatment algorithm presented here to provide guidance on tailoring anticoagulant treatment choices for the acute and extended treatment of symptomatic and incidental vte, to prevent recurrent vte, and to minimize the bleeding risk in patients with cancer.During a 1-day live meeting, a systematic review of the literature was performed, and a draft treatment algorithm was developed. The treatment algorithm was refined through the use of a Web-based platform and a series of online teleconferences.Clinicians using this treatment algorithm should consider the bleeding risk, the type of cancer, and the potential for drug–drug interactions in addition to informed patient preference in determining the most appropriate treatment for patients with cancer-associated thrombosis. Anticoagulant therapy should be regularly reassessed as the patient’s cancer status and management change over time.

scholarly journals Major Bleeding and Adverse Outcome following Percutaneous Coronary Intervention

2015 ◽  
Vol 10 (1) ◽  
pp. 22 ◽  
Author(s):  
Eric W Holroyd ◽  
Ahmad HS Mustafa ◽  
Chee W Khoo ◽  
Rob Butler ◽  
Douglas G Fraser ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Major Adverse Cardiovascular Event ◽  
Bleeding Risk ◽  
Therapeutic Interventions ◽  
Bleeding Complications ◽  
Bleeding Events ◽  
Adverse Cardiovascular Event ◽  
Access Site ◽  
Percutaneous Coronary ◽  
Major Bleeding Events

Advances in anti-thrombotic and anti-platelet therapies have improved outcomes in patients undergoing percutaneous coronary interventions (PCIs) through a reduction in ischaemic events, at the expense of peri-procedural bleeding complications. These may occur through either the access site through which the PCI was performed or through non-access-related sites. There are currently over 10 definitions of major bleeding events consisting of clinical events, changes in laboratory parameters and clinical outcomes, where different definitions will differentially influence the reported incidence of major bleeding events. Use of different major bleeding definitions has been shown to change the reported outcome of a number of therapeutic strategies in randomised controlled trials but as yet a universal bleeding definition has not gained widespread adoption in assessing the efficacy of such therapeutic interventions. Major bleeding complications are independently associated with adverse mortality and major adverse cardiovascular event (MACE) outcomes, irrespective of the definition of major bleeding used, with the worst outcomes associate with non-access-site related bleeds. We consider the mechanisms through which bleeding complications may affect longer-term outcomes and discuss bleeding avoidance strategies, including access site choice, pharmacological considerations and formal bleeding risk assessment to minimise such bleeding events.

scholarly journals The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis

Blood ◽  
2014 ◽  
Vol 124 (15) ◽  
pp. 2450-2458 ◽  
Author(s):  
Chatree Chai-Adisaksopha ◽  
Mark Crowther ◽  
Tetsuya Isayama ◽  
Wendy Lim
Keyword(s):  
Systematic Review ◽  
Gastrointestinal Bleeding ◽  
Major Bleeding ◽  
Meta Analysis ◽  
Oral Anticoagulants ◽  
Bleeding Complications ◽  
Fatal Bleeding ◽  
Increased Risk ◽  
Key Points ◽  
The Impact

Key Points TSOACs are associated with less major bleeding, fatal bleeding, clinically relevant nonmajor bleeding, and total bleeding. The meta-analysis does not show increased risk of major gastrointestinal bleeding in patients who received TSOACs compared with warfarin.

Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparin-induced thrombocytopenia treated with lepirudin

Blood ◽  
2006 ◽  
Vol 108 (5) ◽  
pp. 1492-1496 ◽  
Author(s):  
Bernard Tardy ◽  
Thomas Lecompte ◽  
Françoise Boelhen ◽  
Brigitte Tardy-Poncet ◽  
Ismaïl Elalamy ◽  
...  
Keyword(s):  
Predictive Factors ◽  
Major Bleeding ◽  
Severe Renal Impairment ◽  
Bleeding Event ◽  
Bleeding Risk ◽  
Bleeding Complications ◽  
Routine Practice ◽  
Heparin Induced Thrombocytopenia ◽  
Increased Risk ◽  
Antithrombotic Efficacy

The antithrombotic efficacy of lepirudin in patients with heparin-induced thrombocytopenia (HIT) is compromised by an increased risk for bleeding. A retrospective observational analysis in 181 patients (median age, 67 years) with confirmed HIT treated in routine practice with lepirudin was performed to identify predictive factors for thrombotic and bleeding complications. Lepirudin was administered at a mean (± SD) dose of 0.06 ± 0.04 mg/kg/h (compared with a recommended initial dose of 0.15 mg/kg/h). Mean activated partial thromboplastin time was greater than 1.5 times baseline value in 99.4% of patients. Median treatment duration was 7.7 days. Until discharge from the hospital, 13.8% and 20.4% of patients experienced a thrombotic or a major bleeding event, respectively. On multivariate analysis, mean lepirudin dose was not a significant predictive factor for thrombosis. In contrast, mean lepirudin dose greater than 0.07 mg/kg/h, long duration of lepirudin treatment, and moderate to severe renal impairment were significant positive factors for major bleeding. Overall, these results suggest that the recommended dose of lepirudin in patients with HIT is too high; the use of reduced doses may be safer with regard to bleeding risk and does not compromise antithrombotic efficacy.

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