Publications by authors named "Stefanos Bonovas"

188 Publications

The use of thromboelastography (TEG) and rotational thromboelastometry (ROTEM) in neonates: a systematic review.

Eur J Pediatr 2021 Jun 16. Epub 2021 Jun 16.

Laboratory of Haematology and Blood Bank Unit, School of Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.

"Developmental hemostasis" refers to the dynamic process of gradual hemostatic maturation. Conventional coagulation tests seem to fail to accurately depict the in vivo hemostasis, while viscoelastic tests, thromboelastography (TEG), and rotational thromboelastometry (ROTEM) appear very promising as they provide insight more rapidly and accurately into the hemostatic potential. We systematically reviewed the literature in PubMed to examine the use of TEG and ROTEM in neonates. Our search yielded 34 studies, of which 18 concerned healthy neonates and 16 sick neonates. These viscoelastic tests have shown accelerated initiation of coagulation, increased clot strength, and increased fibrinolysis in healthy neonates compared to children and adults. Cord blood leads to a hypercoagulable state as compared to whole blood when testing is performed with TEG. Pre-term neonates have a more hypocoagulable profile, but balanced hemostasis, related to term neonates, that evolves to a more procoagulant phenotype over the first month of life. Critically ill neonates exhibit a more hypocoagulable profile as compared to healthy neonates. TEG and ROTEM have shown predictive value for bleeding events in critically ill neonates and neonates undergoing cardiopulmonary bypass or therapeutic hypothermia.Conclusion: TEG and ROTEM need to become part of the standard coagulation assessment in clinical settings in which hemostatic abnormalities are involved, as they seem to provide more rapid and accurate information regarding the hemostatic profile of the neonates. Their predictive value for bleeding events in critically ill neonates could lead to a more targeted therapy optimizing utilization of blood products. What is Known: • Conventional coagulation tests seem to fail to accurately depict the in vivo hemostasis. • TEG and ROTEM delineate more rapidly and accurately the hemostatic potential. What is New: • TEG and ROTEM have shown predictive value for bleeding events. • TEG and ROTEM may lead to a more targeted transfusion therapy optimizing utilization of blood products.
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http://dx.doi.org/10.1007/s00431-021-04154-4DOI Listing
June 2021

Rotational Thromboelastometry in Neonates Admitted to a Neonatal Intensive Care Unit: A Large Cross-sectional Study.

Semin Thromb Hemost 2021 Jun 15. Epub 2021 Jun 15.

Laboratory of Haematology and Blood Bank Unit, "Attikon" Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

The aim of the present study was to assess the coagulation profile in neonatal critical illness using rotational thromboelastometry (ROTEM), and to investigate its association with disease severity and its potential prognostic role in this clinical setting. Over a period of 67 months (July 2014-February 2020) 423 critically ill neonates with confirmed or suspected sepsis, perinatal hypoxia, or respiratory distress syndrome, hospitalized in our neonatal intensive care unit were included in the study. Demographic, clinical, and laboratory data were recorded on admission day and arterial blood was analyzed on ROTEM analyzer using the standard extrinsically activated rotational thromboelastometry assay (EXTEM). Neonatal illness severity scores (Modified NEOMOD [Neonatal Multiple Organ Dysfunction] and SNAPPE [Score for Neonatal Acute Physiology with Perinatal Extension]) were calculated at the same time as ROTEM analysis. Mortality during in-hospital stay was the main outcome measure. Multivariable analyses showed that a 10 mm decrease in EXTEM clot amplitude recorded at 10 minutes (A10) is significantly associated with a higher mortality (odds ratio [OR] = 1.69, 95% confidence interval [CI]: 1.33-2.08). Higher modified NEOMOD (OR = 1.36, 95% CI: 1.26-1.47) and higher SNAPPE scores (OR = 1.06, 95% CI: 1.04-1.08) were also associated with increased mortality. The CT and A10 variables demonstrated the best prognostic performance among the EXTEM parameters for mortality (area under the curve [AUC] = 0.78; 95% CI: 0.69-0.86 and AUC = 0.76; 95% CI: 0.66-0.85, respectively), showing an optimal cut-off CT ≥63 seconds and A10 ≤37 mm. Using optimal cut-off values of the EXTEM parameters for prediction of mortality, neonates with CT ≥63 seconds were 7.4 times more likely to die (OR = 7.40, 95% CI: 3.50-15.65), while neonates with A10 ≤37 mm were 5.8 times more likely to die (OR = 5.88, 95% CI: 2.94-12.50). An EXTEM hypocoagulable profile on disease onset was shown to be an independent risk factor for in-hospital mortality in neonatal critical illness.
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http://dx.doi.org/10.1055/s-0041-1729964DOI Listing
June 2021

Rotational Thromboelastometry Findings Are Associated with Symptomatic Venous Thromboembolic Complications after Hip Fracture Surgery.

Clin Orthop Relat Res 2021 06 2. Epub 2021 Jun 2.

A. G. Tsantes, A. Gialeraki, A. E. Tsantes, Laboratory of Haematology and Blood Bank Unit, Attiko Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Background: Venous thromboembolism is a common complication after hip fractures. However, there are no reliable laboratory assays to identify patients at risk for venous thromboembolic (VTE) events after major orthopaedic surgery.

Question/purposes: (1) Are rotational thromboelastometry (ROTEM) findings associated with the presence or development of symptomatic VTE after hip fracture surgery? (2) Were any other patient factors associated with the presence or development of symptomatic VTE after hip fracture surgery? (3) Which ROTEM parameters were the most accurate in terms of detecting the association of hypercoagulability with symptomatic VTE?

Methods: This retrospective study was conducted over a 13-month period. In all, 354 patients with femoral neck and peritrochanteric fractures who underwent hip hemiarthoplasty or cephallomedullary nailing were assessed for eligibility. Of those, 99% (349 of 354) were considered eligible for the study, 1% (3 of 354) of patients were excluded due to coagulation disorders, and another 1% (2 of 354) were excluded because they died before the postoperative ROTEM analysis. An additional 4% (13 of 354) of patients were lost before the minimum study follow-up of 3 months, leaving 95% (336 of 354) for analysis. A ROTEM analysis was performed in all patients at the time of their hospital admission, within hours of the injury, and on the second postoperative day. The patients were monitored for the development of symptoms indicative of VTE, and the gold standard tests for diagnosing VTE, such as CT pulmonary angiography or vascular ultrasound, were selectively performed only in symptomatic patients and not routinely in all patients. Therefore, this study evaluates the association of ROTEM with only clinically evident VTE events and not with all VTE events. ROTEM results did not affect the clinical surveillance of the study group and the decision for further work up. To determine whether ROTEM findings were associated with the presence or development of symptomatic VTE, ROTEM parameters were compared between patients with and without symptomatic VTE. To establish whether any other patient factors were associated with the presence or development of symptomatic VTE after hip fracture surgery, clinical parameters and conventional laboratory values were also compared between patients with and without symptomatic VTE. Finally, to determine which ROTEM parameters were the most accurate in terms of detecting the association of hypercoagulability with symptomatic VTE, the area under the curve (AUC) for certain cut off values of ROTEM parameters was calculated.

Results: We found several abnormal ROTEM values to be associated with the presence or development of symptomatic VTE. The preoperative maximum clot firmness was higher in patients with clinically evident VTE than in patients without these complications (median [interquartile range] 70 mm [68 to 71] versus 65 mm [61 to 68]; p < 0.001). The preoperative clot formation time was lower in patients with clinically evident VTE than those without clinically evident VTE (median 61 seconds [58 to 65] versus 70 seconds [67 to 74]; p < 0.001), and also the postoperative clot formation time was lower in patients with clinically evident VTE than those without these complications (median 52 seconds [49 to 59] versus 62 seconds [57 to 68]; p < 0.001). Increased BMI was also associated with clinically evident VTE (odds ratio 1.26 [95% confidence interval 1.07 to 1.53]; p < 0.001). We found no differences between patients with and without clinically evident VTE in terms of age, sex, smoking status, comorbidities, and preoperative use of anticoagulants. Lastly, preoperative clot formation time demonstrated the best performance for detecting the association of hypercoagulability with symptomatic VTE (AUC 0.89 [95% CI 0.81 to 0.97]), with 81% (95% CI 48% to 97%) sensitivity and 86% (95% CI 81% to 89%) specificity for clot formation time ≤ 65 seconds.

Conclusion: ROTEM's performance in this preliminary study was promising in terms of its association with symptomatic VTE. This study extended our earlier work by demonstrating that ROTEM has a high accuracy in detecting the level of hypercoagulability that is associated with symptomatic VTE. However, until its performance is validated in a study that applies a diagnostic gold standard (such as venography, duplex/Doppler, or chest CT) in all patients having ROTEM to confirm its performance, ROTEM should not be used as a regular part of clinical practice.

Level Of Evidence: Level IV, diagnostic study.
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http://dx.doi.org/10.1097/CORR.0000000000001832DOI Listing
June 2021

Seeking Strategies to Optimize Blood Utilization: The Preliminary Experience with Implementing a Patient Blood Management Program in a Greek Tertiary Hospital.

J Clin Med 2021 May 15;10(10). Epub 2021 May 15.

Laboratory of Haematology and Blood Bank Unit, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece.

Objectives: Our aim was to assess blood utilization after implementation of a patient blood management (PBM) program in a Greek tertiary hospital.

Methods: An electronic transfusion request form and a prospective audit of transfusion practice were implemented. After the one-year implementation period, a retrospective review was performed to assess transfusion practice in medical patients.

Results: Pre-PBM, a total of 9478 RBC units were transfused (mean: 1.75 units per patient) compared with 9289 transfused units (mean: 1.57 units per patient) post-PBM. Regarding the post-PBM period, the mean hemoglobin (Hb) level of the 3099 medical patients without comorbidities transfused was 7.19 ± 0.79 gr/dL. Among them, 2065 (66.6%) had Hb levels >7.0 gr/dL, while 167 (5.3%) had Hb levels >8.0 gr/dL. In addition, 331 (25.3%) of the transfused patients with comorbidities had Hb >8.0 gr/dL. The Hb transfusion thresholds significantly differed across the clinics ( < 0.001), while 21.8% of all medical non-bleeding patients received more than one RBC unit transfusion.

Conclusion: A poor adherence with the restrictive transfusion threshold of 7.0 gr/dL was observed. The adoption of a less strict threshold might be a temporary step to allow physicians to become familiar with the program and be informed on the safety and advantages of the restrictive transfusion strategy.
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http://dx.doi.org/10.3390/jcm10102141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157216PMC
May 2021

Predictive Value of Bowel Ultrasound in Crohn's Disease: A 12-Month Prospective Study.

Clin Gastroenterol Hepatol 2021 Apr 22. Epub 2021 Apr 22.

Istituti di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.

Background & Aims: Mucosal healing is associated with better outcomes in Crohn's disease (CD). Colonoscopy is invasive and poorly tolerated. Bowel ultrasound (US) is a noninvasive tool that increasingly is being used for CD assessment. We assessed the predictive role of baseline bowel US findings on disease course in a large prospective cohort of CD patients for 12 months.

Methods: Ileocolonic CD consecutive patients were followed up for 12 months after performing bowel US. The negative course of CD, defined as the need for steroids and/or change of therapy and/or hospitalization and/or the need for surgery, was assessed. We evaluated this composite end point and subsequently considered each individual end point separately. Predictors of negative disease course were analyzed by logistic regression analysis.

Results: There were 225 ileal and/or colonic CD consecutive patients included in the study. We analyzed the association between baseline bowel US parameters and endoscopic activity (defined as a Simplified Endoscopic Activity score for CD > 2) to set up a noninvasive quantitative ultrasound-based score (bowel ultrasound score). The multivariable analysis identified the following independent predictors of a worse outcome throughout the 12-month period as follows: bowel ultrasound score greater than 3.52 (odds ratio [OR], 6.97; 95% CI, 2.87-16.93; P < .001), presence of at least 1 disease complication (stricture, fistula, abscess) at baseline bowel US (OR, 3.90; 95% CI, 1.21-12.53; P = .021), fecal calprotectin value of 250 μg/g or greater at baseline (OR, 5.43; 95% CI, 2.25-13.11; P < .001), and male sex (OR, 2.60; 95% CI, 1.12-6.02; P = .025).

Conclusions: Bowel US predicts the 12-month course in CD.
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http://dx.doi.org/10.1016/j.cgh.2021.04.029DOI Listing
April 2021

Mental Health and Perceived Access to Care among People Who Inject Drugs in Athens, Greece.

J Clin Med 2021 Mar 12;10(6). Epub 2021 Mar 12.

Medical School, University of Cyprus, Nicosia 2029, Cyprus.

Poor mental health among human immunodeficiency virus (HIV)-positive people who inject drugs (PWID) may contribute to stigma, and together they act as barriers to medical care. This analysis aims to examine factors associated with the mental health of PWID and their network contacts, and the association of poor mental health with the experience of HIV-related stigmatizing events, with HIV-related social support, and with perceived access to care. Data were collected during the Transmission Reduction Intervention Project (TRIP) conducted in Athens, Greece (2013-2015). PWID ( = 292; = 122 HIV-positive) were interviewed both at baseline and follow-up. Items of depression, anxiety, and general positive affect subscales of the Mental Health Inventory were used to explore the psychological distress and well-being of participants at follow-up. Items of the Access to Care Scale were used to evaluate perceived access to medical care at baseline and follow-up. Linear regression showed that unemployment was positively related to depression (β = 1.49, = 0.019), while injecting drug use was a risk factor for a low general positive affect score (β = -3.21, = 0.015). Poor mental health was not linked to HIV-related stigma or social support. Positive perception of access to care was associated in multivariable analyses with low depression (β = -0.22, = 0.049). The perceived access to care score improved from baseline to follow-up ( = 0.019) and HIV-positive participants had a higher score than HIV-negative participants. Future interventions should include targets to improve the mental well-being of participants, reduce psychosocial distress, and minimize perceived barriers to accessing medical care.
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http://dx.doi.org/10.3390/jcm10061181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002050PMC
March 2021

Drug Injection-Related and Sexual Behavior Changes in Drug Injecting Networks after the Transmission Reduction Intervention Project (TRIP): A Social Network-Based Study in Athens, Greece.

Int J Environ Res Public Health 2021 03 1;18(5). Epub 2021 Mar 1.

Medical School, University of Cyprus, Nicosia 2029, Cyprus.

The Transmission Reduction Intervention Project (TRIP) was a network-based, enhanced contact tracing approach, targeting recently HIV-infected people who inject drugs (PWID) in Athens, Greece (2013-2015). This analysis examines behavioral changes of participants in TRIP and their determinants between baseline and follow-up visits to the program. All participants of TRIP were tested for HIV and interviewed using a questionnaire with items on drug injection-related and sexual behaviors. Multivariable logistic regression models were used to examine potential relationships between participants' behaviors and sociodemographic or other characteristics. The analysis included 292 participants. At follow-up, the percentage of participants who injected drugs decreased [92.5%, = 270 versus 72.3%, = 211 ( < 0.001)], and more participants adopted safer behaviors. Employment, age, and gender were significantly associated with some behavioral changes. For instance, unemployed participants were half as likely as the employed to stop drug injection [adjusted odds ratio (aOR): 0.475, 95% confidence interval (CI): 0.228, 0.988]. Increasing age was associated with lower probability of sharing syringes at follow-up (aOR: 0.936, 95%CI: 0.887, 0.988). Finally, females were less likely than males to improve their behavior related to sharing cookers, filters, or rinse water (aOR: 0.273, 95% CI: 0.100, 0.745). In conclusion, adoption of safer behaviors was observed following TRIP implementation. Future prevention programs should focus on younger PWID and especially females. Social efforts to support employment of PWID are also important.
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http://dx.doi.org/10.3390/ijerph18052388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967732PMC
March 2021

Ethnic Differences in the Smoking-Related Risk of Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

J Crohns Colitis 2021 Mar 15. Epub 2021 Mar 15.

Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.

Background And Aims: The association between smoking and inflammatory bowel disease (IBD) relies on old meta-analyses including exclusively non-Jewish White populations. Uncertainty persists regarding the role of smoking in other ethnicities.

Methods: We systematically searched Medline/PubMed, Embase and Scopus for studies examining tobacco smoking and the risk of developing IBD, i.e., Crohn's disease (CD) or ulcerative colitis (UC). Two authors independently extracted study data and assessed each study's risk-of-bias. We examined heterogeneity and small-study effect, and calculated summary estimates using random-effects models. Stratified analyses and meta-regression were employed to study the association between study-level characteristics and effect estimates. The strength of epidemiological evidence was assessed through prespecified criteria.

Results: We synthesized 57 studies examining the smoking-related risk of developing CD and UC. Non-Jewish White smokers were at increased risk of CD (29 studies; RR: 1.95, 95% CI: 1.69‒2.24; moderate evidence). No association was observed in Asian, Jewish and Latin-American populations (11 studies; RR: 0.97; 95% CI: 0.83-1.13), with no evidence of heterogeneity across these ethnicities. Smokers were at reduced risk of UC (51 studies; RR: 0.55, 95% CI: 0.48-0.64; weak evidence) irrespectively of ethnicity; however, cohort studies, large studies and those recently published showed attenuated associations.

Conclusions: This meta-analysis did not identify any increased risk of CD in smokers in ethnicities other than non-Jewish Whites, and confirmed the protective effect of smoking on UC occurrence. Future research should characterize the genetic background of CD patients across different ethnicities to improve our understanding on the role of smoking in CD pathogenesis.
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http://dx.doi.org/10.1093/ecco-jcc/jjab047DOI Listing
March 2021

Safety of S1P Modulators in Patients with Immune-Mediated Diseases: A Systematic Review and Meta-Analysis.

Drug Saf 2021 Jun 5;44(6):645-660. Epub 2021 Mar 5.

Department of Hepatogastroenterology, INSERM NGERE, Nancy University Hospital, Lorraine University, Allée du Morvan, 54511, Vandoeuvre-lès-Nancy, France.

Introduction: Sphingosine-1-phosphate modulators are approved for the treatment of multiple sclerosis and are under development for other immune-mediated conditions; however, safety concerns have arisen.

Objective: The objective of this systematic review was to investigate the safety profile of S1P modulators in patients with multiple sclerosis, ulcerative colitis, Crohn's disease, psoriasis, and systemic lupus erythematosus.

Methods: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from 1 January, 1990 through 1 April, 2020. We also performed a manual review of conference databases from 2017 through 2020. The primary outcome was the occurrence of adverse events and serious adverse events. We also estimated the occurrence of serious infections, herpes zoster infection, malignancy, bradycardia, atrio-ventricular block, and macular edema. We performed a meta-analysis of controlled studies to assess the risks of such events.

Results: We identified 3843 citations; of these, 26 studies were finally included, comprising 9604 patients who were exposed to a sphingosine-1-phosphate modulator. A meta-analysis of randomized controlled trials showed an increased risk in herpes zoster infection [risk ratio, 1.75 (95% confidence interval 1.09-2.80)], bradycardia [2.64 (1.77-3.96)], and atrio-ventricular block [1.73 (1.03-2.91)] among subjects exposed to sphingosine-1-phosphate modulators as compared with a placebo or an active comparator.

Conclusions: We found an increased risk of herpes zoster infection, and transient cardiovascular events among patients treated with sphingosine-1-phosphate modulators.

Clinical Trial Registration: PROSPERO CRD42020172575.
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http://dx.doi.org/10.1007/s40264-021-01057-zDOI Listing
June 2021

The Brain-Gut Axis: Psychological Functioning and Inflammatory Bowel Diseases.

J Clin Med 2021 Jan 20;10(3). Epub 2021 Jan 20.

Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy.

The brain-gut axis represents a complex bi-directional system comprising multiple interconnections between the neuroendocrine pathways, the autonomous nervous system and the gastrointestinal tract. Inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, is a chronic, relapsing-remitting inflammatory disorder of the gastrointestinal tract with a multifactorial etiology. Depression and anxiety are prevalent among patients with chronic disorders characterized by a strong immune component, such as diabetes mellitus, cancer, multiple sclerosis, rheumatoid arthritis and IBD. Although psychological problems are an important aspect of morbidity and of impaired quality of life in patients with IBD, depression and anxiety continue to be under-diagnosed. There is lack of evidence regarding the exact mechanisms by which depression, anxiety and cognitive dysfunction may occur in these patients, and whether psychological disorders are the result of disease activity or determinants of the IBD occurrence. In this comprehensive review, we summarize the role of the brain-gut axis in the psychological functioning of patients with IBD, and discuss current preclinical and clinical data on the topic and therapeutic strategies potentially useful for the clinical management of these patients. Personalized pathways of psychological supports are needed to improve the quality of life in patients with IBD.
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http://dx.doi.org/10.3390/jcm10030377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863941PMC
January 2021

Letter to the Editor Intestinal Ultrasound to Assess Disease Activity in Ulcerative Colitis: Development of a novel UC-Ultrasound index.

J Crohns Colitis 2021 Jan 25. Epub 2021 Jan 25.

Humanitas Clinical and Research Center - IRCCS -, via Manzoni, Rozzano (Mi) - Italy.

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http://dx.doi.org/10.1093/ecco-jcc/jjab018DOI Listing
January 2021

Prospective Temporal Validation of the Neonatal Bleeding Risk (NeoBRis) Index.

Thromb Haemost 2020 Dec 24. Epub 2020 Dec 24.

Laboratory of Haematology and Blood Bank Unit, "Attiko" Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

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http://dx.doi.org/10.1055/a-1343-3342DOI Listing
December 2020

Milan ultrasound criteria are accurate in assessing disease activity in ulcerative colitis: external validation.

United European Gastroenterol J 2021 May 16;9(4):438-442. Epub 2021 Feb 16.

Department of Gastroenterology, Humanitas Clinical and Research Center - IRCCS, Milan, Italy.

Introduction: The aim of this study was to provide an external validation of bowel ultrasound (US) predictors of activity in ulcerative colitis (UC) and quantitative Milan Ultrasound Criteria (MUC).

Methods: Forty-three consecutive patients with UC (16 in endoscopic remission and 27 with endoscopic activity) underwent bowel US and colonoscopy in a tertiary referral inflammatory bowel disease unit.

Results: An MUC score >6.2 discriminated patients with active versus non-active UC with a sensitivity of 0.85 (95% confidence interval (CI) 0.66-0.96), specificity of 0.94 (95% CI 0.70-0.99) and an area under the curve of 0.902 (95% CI 0.772-0.971) in complete agreement with the derivation study.

Conclusion: The external validation of MUC confirms that it is an accurate tool for assessing disease activity in patients with UC.
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http://dx.doi.org/10.1177/2050640620980203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259285PMC
May 2021

Reply to Ghirardello et al Letter to the Editor.

Thromb Haemost 2020 Dec 9. Epub 2020 Dec 9.

Laboratory of Haematology and Blood Bank Unit, "Attiko" Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

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http://dx.doi.org/10.1055/a-1333-7387DOI Listing
December 2020

Confounding and bias in observational studies in inflammatory bowel disease: a meta-epidemiological study.

Aliment Pharmacol Ther 2021 03 9;53(6):712-721. Epub 2020 Dec 9.

Department of Biomedical Sciences, Humanitas University, Milan, Italy.

Background: Observational research concerning inflammatory bowel disease (IBD) is highly susceptible to spurious findings because of confounding and bias.

Aim: To investigate how these issues were reported in this research field.

Methods: We identified and appraised a random sample of 160 observational studies concerning IBD published in high-impact gastroenterology journals and the most respected specialty journals of the condition. We applied a standardised methodology to assess how confounding and bias were reported and discussed, and investigated the association between yearly citations and study characteristics using mixed-effect multivariable regression analysis.

Results: The authors of 67 out of 160 articles (41.9%) mentioned confounding, and in 89 cases (55.6%) reported any bias. Although most authors applied strategies to minimise confounding or bias (n = 139; 86.9%) and acknowledged at least one unadjusted confounder (n = 116; 72.5%), a minority commented about whether the main findings could have been affected (n = 60; 37.5%). Very few authors (n = 7; 4.4%) called for caution in interpreting the results in the discussion. Reporting of confounding and bias was particularly lacking for case-control studies, those not using routinely collected data, those employing laboratory analyses as the primary method of assessment and studies investigating non-modifiable exposures. In adjusted analyses, mentioning or alluding to confounding was positively associated with yearly citations (P = 0.010), whereas calling for a cautious interpretation of the findings was not.

Conclusions: Reporting of confounding is inadequate and its acknowledgement is often neglected in interpreting high-impact observational research in IBD. These results encourage a more careful evaluation of the consequences of confounding and bias.
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http://dx.doi.org/10.1111/apt.16222DOI Listing
March 2021

Effect of early application of social distancing interventions on COVID-19 mortality over the first pandemic wave: An analysis of longitudinal data from 37 countries.

J Infect 2021 Jan 1;82(1):133-142. Epub 2020 Dec 1.

Medical School, University of Cyprus, Nicosia, Cyprus.

Objectives: To estimate the effect of early application of social distancing interventions on Covid-19 cumulative mortality during the first pandemic wave.

Methods: Ecological longitudinal study using multivariable negative binomial regression for panel data. Daily numbers of Covid-19 cases and deaths, and data on social distancing interventions, for the 37 member countries of the Organization for Economic Cooperation and Development (OECD) were analysed.

Results: Covid-19 cumulative mortality over the first pandemic wave varied widely across countries (range, 4.16 to 855 deaths per million population). On average, one-day delay in application of mass gatherings ban was associated with an adjusted increase in Covid-19 cumulative mortality by 6.97% (95% CI, 3.45 to 10.5), whilst a one-day delay in school closures was associated with an increase of 4.37% (95% CI, 1.58 to 7.17) over the study period. We estimated that if each country had enacted both interventions one week earlier, Covid-19 cumulative mortality could have been reduced by an average of 44.1% (95% CI, 20.2 to 67.9).

Conclusions: Early application of mass gatherings ban and school closures in outbreak epicentres was associated with an important reduction in Covid-19 cumulative mortality during the first pandemic wave. These findings may support policy decision making.
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http://dx.doi.org/10.1016/j.jinf.2020.11.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706420PMC
January 2021

Higher coagulation activity in hip fracture patients: A case-control study using rotational thromboelastometry.

Int J Lab Hematol 2021 Jun 24;43(3):477-484. Epub 2020 Nov 24.

Laboratory of Haematology and Blood Bank Unit, "Attiko" Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Introduction: Trauma-induced coagulopathy has been extensively investigated in the multitrauma setting, but only sparsely following moderate orthopedic trauma. The purpose of this study was to evaluate changes in the hemostatic profile of patients with hip fractures, using rotational thromboelastometry (ROTEM).

Methods: 198 patients with hip fractures who underwent surgery were included in the study. A matched group of 52 healthy individuals was also enrolled. Demographics, conventional laboratory assays, and ROTEM parameters were recorded and compared between patients and healthy adults. The preoperative and postoperative ROTEM values of fractured patients were also compared.

Results: The conventional coagulation assays were similar for the 2 groups. However, several ROTEM parameters including EXTEM MCF (P < .001), EXTEM alpha angle (P < .001), INTEM MCF (P < .001), INTEM A10 (P < .001), and INTEM alpha angle (P < .001) significantly differed between the 2 groups indicating a higher coagulation potential following hip fractures. Also, fractured patients had significantly lower INTEM and EXTEM CT values (P = .008 and P = .012, respectively) and significantly lower INTEM and EXTEM CFT values (P < .001). Adjusted analysis for confounders further confirmed the direct relationship between hip fracture and higher coagulation activity. Last, INTEM CT and CFT significantly decreased (P = .008 and P < .001, respectively), while INTEM MCF, A10, and alpha angle significantly increased (P < .001) postoperatively, indicating that surgery further increases the coagulation potential.

Conclusion: A higher coagulation activity following hip fractures and surgical treatment can be detected by ROTEM shortly after the injury, even when this is undetectable by conventional coagulation assays.
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http://dx.doi.org/10.1111/ijlh.13409DOI Listing
June 2021

The haemostatic profile in critically ill COVID-19 patients receiving therapeutic anticoagulant therapy: An observational study.

Medicine (Baltimore) 2020 Nov;99(47):e23365

Second Department of Critical Care, "Attikon" University Hospital, National and Kapodistrian University of Athens, Medical School.

Hypercoagulability and thrombosis remain a challenge in severe coronavirus disease 2019 (COVID-19) infections. Our aim is to investigate the hemostatic profile of critically ill COVID-19 patients on therapeutic anticoagulant treatment.Forty one patients were enrolled into the study. We recruited 11 consecutive, COVID-19, patients who received therapeutic anticoagulant treatment on intensive care unit (ICU) admission. Disease severity indexes, biochemical, hematological and haemostatic parameters, endogenous thrombin potential (ETP), plasminogen activator inhibitor-1 (PAI-1) activity and extrinsically activated rotational thromboelastometry assay (EXTEM) were recorded on days 1, 3, 7. We also enrolled 9 ICU non-COVID-19, 21 non-ICU COVID-19 patients and 20 healthy blood donors as control populations.Critically ill COVID-19 patients demonstrated a more hypercoagulable and hypofibrinolytic profile related to those with COVID-19 mild illness, based on EXTEM amplitude at 10 min (A10), maximum clot firmness (MCF) and lysis index at 60 min (LI60) variables (p = 0.020, 0.046 and 0.001, respectively). Similarly, a more hypercoagulable state was detected in COVID-19 ICU patients related to non-COVID-19 ICU patients based on A10 and MCF parameters (p = 0.03 and 0.04, respectively). On the contrary, ETP and EXTEM (clotting time) CT values were similar between patients with severe and mild form of the COVID-19 infection, probably due to anticoagulant treatment given.Critically ill COVID-19 patients showed a hypercoagulable profile despite the therapeutic anticoagulant doses given. Due to the small sample size and the study design, the prognostic role of the hypercoagulability in this clinical setting remains unknown and further research is required in order to be assessed.
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http://dx.doi.org/10.1097/MD.0000000000023365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676559PMC
November 2020

Macrophage expression and prognostic significance of the long pentraxin PTX3 in COVID-19.

Nat Immunol 2021 01 18;22(1):19-24. Epub 2020 Nov 18.

Humanitas Clinical and Research Center-IRCCS, Milan, Italy.

Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation. The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19). RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.
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http://dx.doi.org/10.1038/s41590-020-00832-xDOI Listing
January 2021

Evaluating Non-Statistically Significant Results From Trials in Practice.

JAMA 2020 10;324(16):1679

Humanitas University: Humanitas Clinical and Research Center, IRCCS, Milan, Italy.

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http://dx.doi.org/10.1001/jama.2020.15645DOI Listing
October 2020

COVID-19 Infection-Related Coagulopathy and Viscoelastic Methods: A Paradigm for Their Clinical Utility in Critical Illness.

Diagnostics (Basel) 2020 Oct 14;10(10). Epub 2020 Oct 14.

Intensive Care Unit, Excela Health Westmoreland Hospital, Greensburg, PA 15601, USA.

Hypercoagulability and thrombosis remain a challenge to diagnose and treat in severe COVID-19 infection. The ability of conventional global coagulation tests to accurately reflect in vivo hypo- or hypercoagulability is questioned. The currently available evidence suggests that markedly increased D-dimers can be used in identifying COVID-19 patients who may need intensive care unit (ICU) admission and close monitoring or not. Viscoelastic methods (VMs), like thromboelastography (TEG) and rotational thromboelastometry (ROTEM), estimate the dynamics of blood coagulation. The evaluation of coagulopathy by VMs in severe COVID-19 infection seems an increasingly attractive option. Available evidence supports that COVID-19 patients with acute respiratory failure suffer from severe hypercoagulability rather than consumptive coagulopathy often associated with fibrinolysis shutdown. However, the variability in definitions of both the procoagulant profile and the clinical outcome assessment, in parallel with the small sample sizes in most of these studies, do not allow the establishment of a clear association between the hypercoagulable state and thrombotic events. VMs can effectively provide insight into the pathophysiology of coagulopathy, detecting the presence of hypercoagulability in critically ill COVID-19 patients. However, it remains unknown whether the degree of coagulopathy can be used in order to predict the outcome, establish a diagnosis or guide anticoagulant therapy.
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http://dx.doi.org/10.3390/diagnostics10100817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602239PMC
October 2020

The role of ROTEM variables based on clot elasticity and platelet component in predicting bleeding risk in thrombocytopenic critically ill neonates.

Eur J Haematol 2021 Feb 27;106(2):175-183. Epub 2020 Oct 27.

Laboratory of Haematology and Blood Bank Unit, "Attiko" Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Background: Our aim was to investigate the role of thromboelastometry (ROTEM) parameters, including maximum clot elasticity (MCE) and platelet component (PLTEM MCE and PLTEM MCF), in early prediction of bleeding events in thrombocytopenic critically ill neonates.

Material And Methods: This single-center, prospective cohort study included 110 consecutive thrombocytopenic neonates with sepsis, suspected sepsis, or hypoxia. On the first day of disease onset, ROTEM EXTEM and FIBTEM assays were performed and the neonatal bleeding assessment tool was used for the evaluation of bleeding events.

Results: Most EXTEM and FIBTEM ROTEM parameters significantly differed between neonates with (n = 77) and without bleeding events (n = 33). Neonates with bleeding events had significantly lower PLTEM MCE and PLTEM MCF values compared to those without bleeding events (P < .001). Platelet count was found to be strongly positively correlated with EXTEM A5 (Spearman's rho = 0.61, P < .001) and A10 (rho = 0.64, P < .001). EXTEM A10 demonstrated the best prognostic performance (AUC = 0.853) with an optimal cutoff value (≤37 mm) (sensitivity = 91%, specificity = 76%) for prediction of bleeding events in thrombocytopenic neonates.

Conclusions: EXTEM A5 and EXTEM A10 were found to be strong predictors of hemorrhage, compared to most ROTEM variables quantifying clot elasticity and platelet component in thrombocytopenic critically ill neonates.
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http://dx.doi.org/10.1111/ejh.13534DOI Listing
February 2021

Study of critically ill patients with COVID-19 in New York City.

Lancet 2020 10;396(10257):1064

Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(20)32072-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544488PMC
October 2020

Validation of the Red Flags Index for Early Diagnosis of Crohn's Disease: A Prospective Observational IG-IBD Study Among General Practitioners.

J Crohns Colitis 2020 Sep 28. Epub 2020 Sep 28.

Humanitas University, Biomedical Sciences, Pieve Emanuele, Italy.

Introduction: Diagnostic delay >12 months is frequent in Crohn's disease [CD]. Recently, the International Organization for Inflammatory Bowel Disease [IO-IBD] developed a tool to identify early CD and reduce diagnostic delay. Subjects with an index ≥8 are more likely to have suspected CD (odds ratio [OR] 205, p <0.0001). We aimed to validate this questionnaire at the community level in patients seen by the general practitioners [GPs] in two large areas of Lombardy, Italy.

Methods: Consecutive adult patients referring to the GP were screened. The GPs administered the Red Flags [RF] questionnaire to the eligible patients. All patients were referred to the nearest participating centre to confirm or exclude the diagnosis of CD. Sensitivity, specificity, and positive and negative predictive values [PPV, NPV] of the RF index [RFI] were calculated. Patients lost to follow-up after the first gastroenterological visit were analysed using a non-responder imputation, assuming they were negative for CD diagnosis.

Results: From November 2016 to November 2019, 112 patients were included. A total of 66 subjects [59%] completed the study after the first gastroenterological visit. The prevalence of CD was 3.6% in the study population [4/112]. The RF index had 50% sensitivity, 58% specificity, 4% PPV, and 97% NPV. A combined diagnostic strategy with faecal calprotectin [FC] [RFI ≥8 and/or FC >250 ng/g] resulted in significantly improved accuracy: sensitivity 100% [29-100%], specificity 72% [55-85%], PPV = 21% [5-51%], NPV = 100% [88-100%].

Conclusions: The RF Index combined with FC is a valid tool to identify patients with high probability of having CD at early stage.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa111DOI Listing
September 2020

TNF Inhibitors and Risk of Malignancy in Patients with Inflammatory Bowel Diseases: A Systematic Review.

J Crohns Colitis 2021 May;15(5):840-859

Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France.

Background And Aims: The association between tumour necrosis factor inhibitors [TNFi] and malignancy in patients with inflammatory bowel disease [IBD] is not well understood. Our aim was to systematically evaluate the impact of TNFi use on risk of malignancy in IBD patients in daily clinical practice.

Methods: We searched Pubmed, Embase and Scopus until March 1, 2020 for observational cohort studies on adult IBD patients reporting malignancy occurrence and TNFi use.

Results: Twenty-eight studies [20 retrospective and eight prospective] were included, involving 298 717 IBD patients. Mean age at inclusion ranged from 28 to >65 years. Mean follow-up varied from 7 to 80 months. Infliximab was the most frequently used TNFi [13/28 studies, 46.4%], followed by adalimumab [3/28, 10.7%], while both infliximab and adalimumab were evaluated in five studies [17.8%]. In total, 692 malignancies were diagnosed in IBD patients treated with TNFi, accounting for an overall occurrence of 1.0%. The most frequent malignancies were non-melanoma skin cancers [123/692, 17.8%], digestive malignancies [120/692, 17.3%] and haematological malignancies [106/692, 15.3%]. The association between TNFi and malignancy was evaluated in 11 studies [39.3%]: no significant association was found in ten studies, while an increased risk of lymphoma in patients exposed to TNFi was reported in one study.

Conclusion: TNFi treatment is not associated with an increased risk of malignancy in IBD patients in real-life settings. Further large studies are needed to assess the prognosis of patients exposed to TNFi and risk of recurrence or new cancers in subjects with personal malignancy history.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa186DOI Listing
May 2021

UEG framework for the development of high-quality clinical guidelines.

United European Gastroenterol J 2020 10 2;8(8):851-864. Epub 2020 Sep 2.

Centre for Colorectal Disease, St Vincent's University Hospital and School of Medicine, University College Dublin, Dublin, Ireland.

The 48 national member societies and 17 specialist member societies which operate under the umbrella of United European Gastroenterology (UEG) increasingly develop clinical practice guidelines for both national and international implementation. The methodologies and strategies used in these guidelines vary considerably. The UEG Quality of Care Taskforce aimed to provide a framework for quality guidelines in order to assist member societies in the process of developing guidelines, and to provide a tool for readers of guidelines to critically appraise their quality. We outline the steps necessary to begin the guideline development process, how to build working groups, how to search for evidence, how to grade the quality of the evidence, how to reach consensus on statements and how to write the guideline document. We believe that using this framework will increase the potential to produce a high-quality guideline which is transparent, independent, reproducible and implementable.
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http://dx.doi.org/10.1177/2050640620950854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707865PMC
October 2020

A Risk Score for Predicting the Incidence of Hemorrhage in Critically Ill Neonates: Development and Validation Study.

Thromb Haemost 2021 Feb 24;121(2):131-139. Epub 2020 Aug 24.

Laboratory of Haematology and Blood Bank Unit, "Attiko" Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

The aim of the study was to develop and validate a prediction model for hemorrhage in critically ill neonates which combines rotational thromboelastometry (ROTEM) parameters and clinical variables. This cohort study included 332 consecutive full-term and preterm critically ill neonates. We performed ROTEM and used the neonatal bleeding assessment tool (NeoBAT) to record bleeding events. We fitted double selection least absolute shrinkage and selection operator logit regression to build our prediction model. Bleeding within 24 hours of the ROTEM testing was the outcome variable, while patient characteristics, biochemical, hematological, and thromboelastometry parameters were the candidate predictors of bleeding. We used both cross-validation and bootstrap as internal validation techniques. Then, we built a prognostic index of bleeding by converting the coefficients from the final multivariable model of relevant prognostic variables into a risk score. A receiver operating characteristic analysis was used to calculate the area under curve (AUC) of our prediction index. EXTEM A10 and LI60, platelet counts, and creatinine levels were identified as the most robust predictors of bleeding and included them into a Neonatal Bleeding Risk (NeoBRis) index. The NeoBRis index demonstrated excellent model performance with an AUC of 0.908 (95% confidence interval [CI]: 0.870-0.946). Calibration plot displayed optimal calibration and discrimination of the index, while bootstrap resampling ensured internal validity by showing an AUC of 0.907 (95% CI: 0.868-0.947). We developed and internally validated an easy-to-apply prediction model of hemorrhage in critically ill neonates. After external validation, this model will enable clinicians to quantify the 24-hour bleeding risk.
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http://dx.doi.org/10.1055/s-0040-1715832DOI Listing
February 2021

A snapshot of the ongoing clinical research on COVID-19.

F1000Res 2020 18;9:373. Epub 2020 May 18.

Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milano, 20090, Italy.

The pandemic of coronavirus disease 2019 (COVID-19) presents an unprecedented challenge to rapidly develop new diagnostic, preventive and therapeutic strategies. Currently, thousands of new COVID-19 patients are quickly enrolled in clinical studies. We aimed to investigate the characteristics of the COVID-19 studies registered in ClinicalTrials.gov and report the extent to which they have incorporated features that are desirable for generating high-quality evidence. On April 28, 2020, a total of 945 studies on COVID-19 have been registered in ClinicalTrials.gov; 586 studies are interventional (62.0%), the most frequent allocation scheme is the parallel group assignment (437; 74.6%), they are open-label and the most common primary purpose is the research on treatment. Too many of the ongoing interventional studies have a small expected sample size and may not generate credible evidence at completion. This might lead to a delayed recognition of effective therapies that are urgently needed, and a waste of time and resources. In the COVID-19 pandemic era, it is crucial that the adoption of new diagnostic, preventive and therapeutic strategies is based upon evidence coming from well-designed, adequately powered and carefully conducted clinical trials.
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http://dx.doi.org/10.12688/f1000research.23843.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256468PMC
June 2020

Erratum: Thromboelastometry Variables in Neonates with Perinatal Hypoxia.

Semin Thromb Hemost 2020 Jun 3;46(4):e1. Epub 2020 Jun 3.

Neonatal Department, National and Kapodistrian University of Athens School of Medicine, Aretaieion Hospital, Athens, Greece.

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http://dx.doi.org/10.1055/s-0040-1713395DOI Listing
June 2020

ROTEM diagnostic capacity for measuring fibrinolysis in neonatal sepsis.

Thromb Res 2020 08 20;192:103-108. Epub 2020 May 20.

Laboratory of Haematology and Blood Bank Unit, "Attiko" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. Electronic address:

Background: Hypofibrinolysis has been demonstrated in several studies in adult sepsis. Although fibrinolysis is an important and integral part of the hemostatic system, few data are available regarding its role in neonatal sepsis. Our purpose was to define fibrinolytic profiles across neonatal sepsis spectrum using rotational thromboelastometry (ROTEM).

Material And Methods: This study was performed in a Greek tertiary General Hospital during an 18 month-period and included 44 neonates with confirmed sepsis and 22 with suspected sepsis; 110 healthy neonates served as controls. Whenever sepsis was suspected, EXTEM and APTEM assays were performed, clinical findings and laboratory data were recorded.

Results: Although most EXTEM parameters were significantly different among the 3 groups, Maximal Lysis (ML) and Lysis Index at 60 min (LI60) levels were similar (p = 0.11 and p = 0.20, respectively). Hyperfibrinolysis, as defined by ROTEM parameters, did not significantly differ among the study populations (p = 0.41). On the contrary, fibrinolysis shutdown, defined as an EXTEM LI60 ≥98%, was more common in septic neonates than in healthy (p < 0.001) and neonates with suspected sepsis (p = 0.042). A weak to moderate correlation of LI60 and ML with mortality (Spearman rho = 0.43 and - 0.40, p = 0.005 and 0.007, respectively) and SNAPE score (Spearman rho = 0.35 and - 0.33, p = 0.02 and 0.03, respectively) was noticed in sepsis group.

Conclusions: ROTEM, based on fibrinolytic parameters, showed a more frequent fibrinolysis shutdown in neonatal sepsis, but it could neither effectively discriminate septic neonates, nor predict their clinical outcome. The considerable overlap among numerical ROTEM values probably compromises their diagnostic clinical utility in neonatal sepsis.
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http://dx.doi.org/10.1016/j.thromres.2020.05.028DOI Listing
August 2020
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