Publications by authors named "Argirios E Tsantes"

42 Publications

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

Haemostatic profile of riboflavin-treated apheresis platelet concentrates.

Blood Transfus 2021 May 21. Epub 2021 May 21.

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

Background: The haemostatic activity of platelet concentrates (PCs) treated with pathogen reduction technology (PRT) remains a subject of debate. Our aim was to investigate the effect of Mirasol PRT on the haemostatic properties of PCs stored in plasma.

Material And Methods: Untreated and Mirasol-treated platelets stored in plasma and derived from ten split double-dose apheresis PCs were evaluated in vitro on days 1, 3 and 5 post collection for functionality, microparticle procoagulation activity (MPA), endogenous thrombin potential (ETP), and haemostatic profile using rotational thromboelastometry (ROTEM).

Results: P-selectin expression was significantly higher in Mirasol-treated platelets compared with untreated counterparts on days 3 and 5 (p=0.003 and p=0.002, respectively). Clot strength, as shown by EXTEM maximum clot firmness (MCF), was significantly lower in the Mirasol-treated platelets at all time points (days 1, 3, 5) than in untreated platelets (p=0.009, p<0.001, p<0.001, respectively). There was a considerable increase in MPA over time (p<0.001) and this was significantly higher in the Mirasol-treated platelets on day 5 (p=0.015). A notable acceleration of decrease in ETP values was observed for Mirasol-treated PCs over time (p<0.001), with significant differences between PRT-treated and untreated PCs on days 3 and 5 (p=0.038 and p=0.019, respectively). Clot strength attenuation was significantly associated with pH reduction (p<0.001, Spearman's rho: 0.84), increased microparticle procoagulant activity (p<0.001, Spearman's rho: -0.75), and with decreased ETP (p<0.032, Spearman's rho: 0.41).

Discussion: Increased platelet activation induced by PRT treatment leads to a decrease in in vitro haemostatic capacity as seen by reduced clot strength and thrombin generation capacity over time. The clinical relevance of this needs to be investigated.
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http://dx.doi.org/10.2450/2021.0089-21DOI Listing
May 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

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

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

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

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

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

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

Effects of electronic cigarette on platelet and vascular function after four months of use.

Food Chem Toxicol 2020 Jul 25;141:111389. Epub 2020 Apr 25.

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

We examined the effects of electronic cigarette on platelet and vascular function after 4 months of use compared to tobacco smoking. Forty smokers without cardiovascular disease were randomized to smoke either conventional cigarettes or an electronic cigarette (nicotine concentration of 12 mg/ml). At baseline and after four months, we measured a) platelet function by Platelet Function Analyzer PFA-100 and Light Transmission Aggregometry, b) pulse wave velocity, c) plasma malondialdehyde levels as oxidative stress index and d) the exhaled CO level. After 4 months, continuation of conventional cigarette smoking further impaired platelet function compared to vaping as assessed by PFA (mean increase 27.1 vs 11.6 s, p for interaction = 0.048) and by LTA (decline 24.1 vs 9.4%, p for interaction = 0.045). Conversely, compared to smoking, vaping resulted in greater reduction of exhaled CO (6.9 ppm vs 2.6, p for interaction < 0.001), improvement of PWV (decrease of 0.8 m/s vs increase of 0.8 m/s, p for interaction = 0.020) and reduction of MDA (reduction 0.13 vs increase 0.19 nmol/L, p for interaction = 0.035). Switching to electronic cigarette for 4 months has a neutral effect on platelet function while it reduces arterial stiffness and oxidative stress compared to tobacco smoking.
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http://dx.doi.org/10.1016/j.fct.2020.111389DOI Listing
July 2020

β-Amyloid and mitochondrial-derived peptide-c are additive predictors of adverse outcome to high-on-treatment platelet reactivity in type 2 diabetics with revascularized coronary artery disease.

J Thromb Thrombolysis 2020 Apr;49(3):365-376

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

Background And Aims: Increased β-amyloid and decreased mitochondrial-derived peptide (MOTS-c), are reported in diabetes. We investigated their additive value to high on-clopidogrel platelet reactivity (HPR) for adverse outcome in type 2 diabetics after recent revascularization.

Patients And Methods: In 121 type II diabetics, treated with clopidogrel and aspirin, (93 males, mean age 67.2 years) we measured: (a) maximum platelet aggregation to adenosine diphosphate (ADP) by light transmission aggregometry (LTAmax), (b) malondialdehyde (MDA), as oxidative stress marker, (c) MOTS-c, (d) β-amyloid blood levels. Cardiac death and acute coronary syndromes (MACE) were recorded during 2 years of follow-up.

Results: Out of 121 patients, 32 showed HPR (LTAmax > 48%,). At baseline, HPR was associated with β-amyloid > 51 pg/ml (p = 0.006) after adjusting clinical variables, HbA1c, MOTS-c, MDA and medication. During follow-up, 22 patients suffered a MACE. HPR, β-amyloid > 51 pg/ml and MOTS-c < 167 ng/ml were predictors of MACE (relative risk 3.1, 3.5 and 3.8 respectively, p < 0.05) after adjusting for confounders and medication. There was significant interaction between HPR and β-amyloid or MOTS-c for the prediction of MACE (p < 0.05). Patients with HPR and β-amyloid > 51 mg/dl or HPR and MOTS-c concentration < 167 ng/ml had a fourfold higher risk for MACE than patients without these predictors (relative risk 4.694 and 4.447 respectively p < 0.01). The above results were confirmed in an external validation cohort of 90 patients with diabetes and CAD.

Conclusions: Increased β-amyloid or low MOTS-c are additive predictors to high on-clopidogrel platelet reactivity for adverse outcome in diabetics with CAD during 2-years follow-up. Clinical Trial Registration-URL: https://www.clinicaltrials.gov. Unique identifier: NCT04027712.
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http://dx.doi.org/10.1007/s11239-020-02060-4DOI Listing
April 2020

Impaired Arterial Elastic Properties and Endothelial Glycocalyx in Patients with Embolic Stroke of Undetermined Source.

Thromb Haemost 2019 Nov 17;119(11):1860-1868. Epub 2019 Aug 17.

Second Department of Neurology, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.

Background And Purpose:  Cardioembolism is a postulated mechanism of embolic stroke of undetermined source (ESUS). We investigated endothelial glycocalyx, aortic elastic properties, oxidative stress, and their association with left atrial (LA) function in ESUS and healthy individuals.

Methods:  In 90 ESUS patients (age 50.4 ± 13.2) and 90 controls with similar risk factors, we measured: (1) perfused boundary region (PBR) of the sublingual arterial microvessels (range 5-25 µm), a marker inversely related with glycocalyx thickness, (2) pulse wave velocity (PWV), central systolic blood pressure (cSBP), and augmentation index (AIx), (3) LA volume and strain using speckle-tracking imaging, and (4) malondialdehyde (MDA) and protein carbonyls (PCs), as oxidative stress markers.

Results:  Compared with controls, ESUS had higher PWV, PBR, MDA, and PC levels as well as higher LA volume and reduced reservoir LA strain ( < 0.05). PBR > 1.2 μm of microvessel ranging from 5 to 9 μm and PWV > 10.2 m/s were associated with ESUS on multivariable analysis (odds ratio: 2.374 and 5.429,  < 0.05, respectively) and increased the c-statistic of the initial model from 0.54 to 0.71. In ESUS, glycocalyx damage (increased PBR) was related with increased PWV ( < 0.01) which was linked with LA reservoir strain after controlling for age, sex, and risk factors ( = 0.03). Increased MDA and PC were related with glycocalyx damage, increased PWV ( = 0.67 and  = 0.52), AIx, cSBP, and aortic atheroma ( < 0.01).

Conclusion:  Arterial function and endothelial glycocalyx are severely impaired in ESUS and are linked to LA dysfunction suggesting their contribution to ESUS pathogenesis.

Clinical Trial Registration:  URL-http://www.clinicaltrials.gov. Unique identifier: NCT03609437.
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http://dx.doi.org/10.1055/s-0039-1694752DOI Listing
November 2019

The prognostic value of multiple electrode aggregometry and light transmittance aggregometry in stable cardiovascular patients with type 2 diabetes mellitus.

Thromb Res 2019 08 4;180:47-54. Epub 2019 Jun 4.

Second Cardiology Department, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Aim: Limited data are available regarding the clinical relevance of platelet function measurements in stable patients with coronary artery disease (CAD). Our aim is to evaluate the agreement between multiple electrode aggregometry (MEA) and light transmittance aggregometry (LTA) in detecting clopidogrel low responders and their prognostic value in CAD patients with type 2 diabetes mellitus (T2DM) on dual platelet inhibition.

Methods: LTA and MEA were performed in 122 stable cardiovascular patients with T2DM. The upper quartile of patients according to maximum LTA (LTAmax) and MEA measurements were defined as clopidogrel low responders. Agreement between the two methods was evaluated by kappa statistics. We assessed the potential correlation between antiplatelet response and clinical outcome and the optimal cutoff value according to ROC analysis to predict the occurrence of major adverse cardiovascular events (MACE), during 1-year follow-up period.

Results: Cohen's kappa coefficients (0.214) indicated fair agreement (70.2%) between LTA and MEA. A total of 25 MACE occurred in 108 patients (23.1%). Patients with MACE had higher LTAmax than those without (57.1 ± 16.5 vs 49.3 ± 18.3, respectively, p = 0.023). MEA measurements were similar between patients with and without MACE (30.1 ± 15.4 vs 30.6 ± 20.8, respectively; p = 0.84). Multiple logistic regression showed LTAmax response as an independent predictor of death from cardiovascular causes (Odds Ratio, adjusted:0.2;0.05-0.81). ROC analysis indicated that LTAmax cutoff of 62.5% best predicted death (AUC = 0.67, sensitivity = 78%, specificity = 61.5%).

Conclusions: The assessment of platelet responsiveness remains highly test-specific. Our results support the prognostic role of LTA, but not MEA testing, for death risk evaluation in stable cardiovascular T2DM patients.
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http://dx.doi.org/10.1016/j.thromres.2019.06.001DOI Listing
August 2019

Thromboelastometry: studying hemostatic profile in small for gestational age neonates-a pilot observational study.

Eur J Pediatr 2019 Apr 1;178(4):551-557. Epub 2019 Feb 1.

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

Scarce data exists about the hemostatic status of small for gestational age (SGA) neonates. We aimed at evaluating the hemostatic profile of SGA neonates, using thromboelastometry (TEM). This is an observational study performed in a Greek tertiary General Hospital during an 18-month period. Ninety-three neonates were included in the study: 48 appropriate for gestational age weight (AGA) neonates and 45 SGA neonates Extrinsically activated TEM (ex-TEM) parameters, such as clotting time, clot formation time, amplitude recorded at 5 and 10 min, a angle, maximum clot firmness, lysis index at 60 min, and also platelet count, were used for the evaluation of the hemostatic profile in all neonates. No statistically significant differences were noticed regarding all ex-TEM parameters between AGA and SGA neonates, while no event of hemorrhage or thrombosis was noticed in the study population.Conclusions: The coagulation system of SGA neonates seems to be fully functional, with no evident tendency toward coagulopathy or thrombosis, when compared with AGA neonates. TEM seems to provide a promising and valid assessment of coagulation and fibrinolysis systems and may be used as a valuable biomarker, in the future. Further studies, with large samples, are necessary to confirm our results. What is Known: • SGA neonates may present coagulation disorders mainly due to hepatic dysfunction, polycythemia, and thrombocytopenia owing to long-term intrauterine hypoxia. • In the literature, despite the statistically significant differences in laboratory results between SGA and AGA neonates, no clinical manifestations of significantly altered hemostasis were recorded. Data of TEM interpretation of hemostasis in SGA neonates are not available. What is New: • TEM seems to interpret coagulation mechanism of preterm and full-term SGA neonates and confirm previous relevant literature findings regarding hemostasis in these neonates.
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http://dx.doi.org/10.1007/s00431-019-03331-wDOI Listing
April 2019

Laboratory Assessment of the Anticoagulant Activity of Apixaban in Patients With Nonvalvular Atrial Fibrillation.

Clin Appl Thromb Hemost 2018 Dec 1;24(9_suppl):194S-201S. Epub 2018 Oct 1.

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

Our aim is to determine the most appropriate laboratory tests, besides anti-factor Xa (anti-FXa) chromogenic assays, to estimate the degree of anticoagulation with apixaban and compare it with that of rivaroxaban in real-world patients. Twenty patients with nonvalvular atrial fibrillation treated with apixaban 5 mg twice daily and 20 patients on rivaroxaban 20 mg once daily were studied. Conventional coagulation tests, thrombin generation assay (TGA), and thromboelastometry (nonactivated TEM [NATEM] assay) were performed in the 40 patients and 20 controls. The anti-FXa chromogenic assays were used to measure apixaban and rivaroxaban plasma levels. The NATEM measurements showed no significant difference between the 2 groups of patients. Concerning TGA, endogenous thrombin potential (ETP) was significantly decreased in patients on rivaroxaban as compared to those treated with apixaban ( < .003). A statistically significant, strong inverse correlation between apixaban plasma concentrations and ETP ( < .001) was observed. Apixaban significantly reduces ETP compared to controls, but to a lesser extent than rivaroxaban. Thrombin generation assay might provide additional information on apixaban exposure, which is required in order to individualize treatment especially for patients with a high bleeding risk. Our findings have to be further investigated in studies with larger sample sizes, in the entire range of apixaban exposure, with other direct oral anticoagulants, and in relation to clinical outcomes.
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http://dx.doi.org/10.1177/1076029618802364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714834PMC
December 2018

Platelet to lymphocyte and neutrophil to lymphocyte ratio as predictive indices of endometrial carcinoma: Findings from a retrospective series of patients and meta-analysis.

J Gynecol Obstet Hum Reprod 2018 Dec 25;47(10):511-516. Epub 2018 Aug 25.

Department of Pathology, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece.

Background: The purpose of the present study is to present new data concerning the diagnostic efficacy of neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios in detecting endometrial carcinoma and to summarize the existing knowledge by accumulating all the available data in the existing literature.

Materials And Methods: We retrospectively identified patients with evidence of endometrial pathology (vaginal bleeding or increased endometrial thickness) that undergone dilatation and curettage. For the meta-analysis we used the Medline, Scopus, Clinicaltrials.gov, EMBASE, Cochrane Central Register of Controlled Trials CENTRAL and Google Scholar databases to identify relevant articles in the field.

Results: In our retrospective series we identified 106 women with endometrioid endometrial carcinoma and 72 controls. PLR and NLR values were comparable among the two groups (p>.05). Eleven studies were included in the present systematic review with a total of 4168 patients. The meta-analysis included 1013 patients. PLR values were not significantly different among the two groups. On the other hand, NLR was significantly raised among patients with endometrial carcinoma (MD 0.73, 95% CI 0.01, 1.45).

Conclusion: The findings of our meta-analysis support that NLR values are significantly elevated in patients with endometrial cancer compared to controls. Moreover, there seem to be evidence to support that both PLR and NLR values increase in patients with advanced stage disease, including positive lymph nodes, lymphovascular space involvement and distant metastases. Future studies are needed in this field to reach firm conclusions and these should specifically target patients with advanced stage disease.
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http://dx.doi.org/10.1016/j.jogoh.2018.08.016DOI Listing
December 2018

Comparison between Nageotte and flow cytometric counting of residual leucocytes in freshly prepared leucocyte-reduced red blood cell components.

Transfus Apher Sci 2018 Aug 7;57(4):544-548. Epub 2018 Jun 7.

Laboratory of Haematology & Blood Bank Unit, "Attikon" Hospital, School of Medicine, National and Kapodistrian University of Athens, 1 Rimini Str., 12462, Athens, Greece. Electronic address:

Background: Flow cytometry (FC) and Nageotte hemocytometry represent the most widely accepted methods for counting residual white blood cells (rWBCs) in leucocyte-reduced (LR) blood components. Our aim was to study the agreement between the two methods, under real working blood bank conditions.

Materials And Methods: 94 freshly produced LR red blood cell (RBC) units were tested for rWBC concentrations by FC and Nageotte. To assess the precision of each method, we calculated the intra-assay coefficients of variation (CV), and followed the Bland-Altman methodology to study the agreement between the two methods.

Results: CV was 18.5% and 26.2% for the Nageotte and the FC, respectively. However, the agreement between the duplicate observations, using the binary cut-off threshold of 1 × 10 WBCs per unit to define the results as "pass/fail", was 71.9% for the Nageotte and 93.3% for the FC. Linear regression analysis did not show any correlation (R-squared = 0.01, p = 0.35) between the two methods, while the Bland-Altman analysis for the measuring agreement showed a bias toward a higher Nageotte count of 0.77 × 10 leucocytes per unit (p < 0.001) with the 95% limits of agreement (d ± 2 sd) ranging from -0.40 × 10 to 1.94 × 10 leucocytes per unit.

Conclusion: The absence of agreement between Nageotte and FC method, with the differences within d ± 2 sd being of high clinical importance, suggests that the two methods cannot be used for clinical purposes interchangeably. The Nageotte seems unsuitable for quality control even with a pass-fail criterion, under real working blood bank conditions.
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http://dx.doi.org/10.1016/j.transci.2018.06.002DOI Listing
August 2018

Thromboelastometry for diagnosis of neonatal sepsis-associated coagulopathy: an observational study.

Eur J Pediatr 2018 Mar 18;177(3):355-362. Epub 2017 Dec 18.

Laboratory of Haematology and Blood Bank Unit, School of Medicine, "Attiko" University Hospital, National and Kapodistrian University of Athens, 1 Rimini Str, 12462, Athens, Greece.

Our aim was to evaluate the potential role of standard extrinsically activated thromboelastometry (EXTEM) assay in the early detection of neonatal sepsis. We studied 91 hospitalized neonates categorized in two groups: group A included 35 neonates with confirmed sepsis, while group B included 56 neonates with suspected sepsis; 274 healthy neonates served as controls. Whenever sepsis was suspected, EXTEM assay was performed, Score for Neonatal Acute Physiology Perinatal Extension (SNAPPE) and Tοllner score were calculated, and clinical findings and laboratory results were recorded. Septic neonates had significantly prolonged clotting time (CT) and clot formation time (CFT), and reduced maximum clot firmness (MCF), compared to neonates with suspected sepsis (p values 0.001, 0.001, and 0.009, respectively) or healthy neonates (p values 0.001, 0.001, and 0.021, respectively). EXTEM parameters (CT, CFT, MCF) demonstrated a more intense hypocoagulable profile in septic neonates with hemorrhagic diathesis than those without (p values 0.021, 0.007, and 0.033, respectively). In septic neonates, CFT was correlated with platelet count, SNAPPE, Tollner score, and day of full enteral feeding (p values 0.01, 0.02, 0.05, and 0.03, respectively).

Conclusions: A ROTEM hypocoagulable profile at admission seems promising for the early detection of sepsis in neonates while the degree of hypocoagulation may be associated with sepsis severity. What is Known: • The early phase of septicemia might be difficult to be recognized in neonates. In adult septic patients, the diagnostic and prognostic role of thromboelastometry (ROTEM) have been extensively investigated. • Limited data are available on the role of ROTEM as an indicator of early neonatal sepsis. What is New: • ROTEM measurements indicate an early appearance of hypocoagulability in neonatal sepsis, while the degree of hypocoagulation might be associated with severity of sepsis. • ROTEM could be a useful tool in the early detection of sepsis in neonates.
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http://dx.doi.org/10.1007/s00431-017-3072-zDOI Listing
March 2018

Reference ranges of thromboelastometry in healthy full-term and pre-term neonates.

Clin Chem Lab Med 2017 Aug;55(10):1592-1597

.

Background: Rotational thromboelastometry (ROTEM) is an attractive method for rapid evaluation of hemostasis in neonates. Currently, no reference values exist for ROTEM assays in full-term and pre-term neonates. Our aim was to establish reference ranges for standard extrinsically activated ROTEM assay (EXTEM) in arterial blood samples of healthy full-term and pre-term neonates.

Methods: In the present study, EXTEM assay was performed in 198 full-term (≥37 weeks' gestation) and 84 pre-term infants (<37 weeks' gestation) using peripheral arterial whole blood samples.

Results: Median values and reference ranges (2.5th and 97.5th percentiles) for the following main parameters of EXTEM assay were determined in full-term infants: clotting time (seconds), 41 (range, 25.9-78); clot formation time (seconds), 70 (range, 40-165.2); maximum clot firmness (mm), 66 (range, 41-84.1); lysis index at 60 min (LI60, %), 97 (range, 85-100). The only parameter with a statistically significant difference between full-term and pre-term neonates was LI60 (p=0.006). Furthermore, it was inversely correlated with gestational age (p=0.002) and birth weight (p=0.016) in pre-term neonates.

Conclusions: In conclusion, an enhanced fibrinolytic activity in pre-term neonates was noted. For most EXTEM assay parameters, reference ranges obtained from arterial newborn blood samples were comparable with the respective values from studies using cord blood. Modified reagents, small size samples, timing of sampling, and different kind of samples might account for any discrepancies among similar studies. Reference values hereby provided can be used in future studies.
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http://dx.doi.org/10.1515/cclm-2016-0931DOI Listing
August 2017

Comparative Assessment of the Anticoagulant Activity of Rivaroxaban and Dabigatran in Patients With Nonvalvular Atrial Fibrillation: A Noninterventional Study.

Medicine (Baltimore) 2016 Apr;95(14):e3037

From the Laboratory of Haematology and Blood Bank Unit, "Attiko" Hospital(AET, EK, PD); Second Cardiology Department, "Attiko" Hospital(II, KK, IP, JL); Second Department of Critical Care Medicine, "Attiko" Hospital(PK, IT); Department of Microbiology (VK), School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; and Humanitas Clinical and Research Center (SB), Rozzano, Milan, Italy.

There is a shortage of data in everyday clinical practice about the anticoagulant effects caused by the new oral anticoagulants (NOAs). Our aim was to estimate the intensity of anticoagulant activity induced by rivaroxaban 20 mg qd and dabigatran 110 mg bid among patients with nonvalvular atrial fibrillation (NV-AF).We studied 20 patients with NV-AF treated with dabigatran, and 20 patients treated with rivaroxaban. We performed conventional coagulation tests, thrombin generation (TG) test, thromboelastometry (ROTEM), and epinephrine-induced light transmission aggregometry (LTA) in all 40 patients and 20 controls. Hemoclot Thrombin Inhibitors (HTI) and Factor Xa Direct Inhibitor (DiXaI) assay were used to measure dabigatran and rivaroxaban plasma levels, respectively.Measurements of all assays estimating anticoagulant activity across the 2 patient groups were similar, except for aPTT. Patients on dabigatran exhibited statistically significantly prolonged aPTT values (P < 0.001). In LTA, patients on dabigatran also showed decreased aggregation compared to those on rivaroxaban (P = 0.045). Regarding the TG test, there was no association between endogenous thrombin potential (ETP) and rivaroxaban plasma levels (P = 0.33) as opposed to dabigatran levels (P < 0.001), but significant correlations were observed between rivaroxaban plasma concentrations and kinetic parameters of TG assay (Tlag, P = 0.045; Tmax, P = 0.016; and Cmax, P = 0.003).Based on ROTEM and TG assays, the anticoagulant effects induced by the 2 drugs given in the specific dose regimens in real-world patients were comparable. Only platelet aggregation was found to be more affected by dabigatran as compared to rivaroxaban.
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http://dx.doi.org/10.1097/MD.0000000000003037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998746PMC
April 2016

Impact of dabigatran on platelet function and fibrinolysis.

J Neurol Sci 2015 Oct 23;357(1-2):204-8. Epub 2015 Jul 23.

Second Department of Neurology, "Attikon" University Hospital, School of Medicine, University of Athens, Athens, Greece; International Clinical Research Center, St. Anne's University Hospital in Brno, Brno, Czech Republic. Electronic address:

Background: We sought to evaluate the potential enhanced fibrinolytic and antiplatelet activity of dabigatran etexilate (DE) due to decreased thrombin levels in patients with stroke or transient ischemic attack and non-valvular atrial fibrillation (NVAF).

Methods: Consecutive patients with cerebrovascular diseases and NVAF that were treated with DE in a tertiary university hospital. Fibrinolysis and platelet function were assessed by thromboelastometry (ROTEM) and platelet function analyzer (PFA)-100, respectively, before and after treatment with DE. Conventional coagulation tests, endogenous thrombin potential (ETP) and hemoclot thrombin inhibitors (HTI), were also performed in order to detect any possible correlation between dabigatran plasma levels, its anticoagulant activity and the intensity of platelet dysfunction or fibrinolysis.

Results: A total of nineteen patients fulfilled our inclusion criteria (mean age 62.3±7.2years; 47% males; median CHADS2-score: 3; interquartile range: 2-4). DE treatment was associated with a significant reduction of the lysis index (LI60) at 60min (p=0.036), and prolongation of the PFA-100 CEPI closure time (p=0.024). After dabigatran treatment, abnormal PFA-100 results were obtained in two patients (11%, 95% CI: 2%-33%). DE levels (determined by HTI) were strongly inversely correlated (rho=-0.85; p<0.001) with the area under the curve (AUC) values in ETP assay. Νo association was found between HTI and PFA-100 CEPI CT (p=0.64), or LI60 measurements (p=0.60).

Conclusions: Our findings indicate that DE might affect platelet function and fibrinolysis and highlight the potential role of ETP as an alternative option in DE monitoring. The intensity and clinical relevance of DE antiplatelet and fibrinolytic effects require further investigation.
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http://dx.doi.org/10.1016/j.jns.2015.07.031DOI Listing
October 2015

Laboratory assessment of the anticoagulant activity of dabigatran.

Clin Appl Thromb Hemost 2015 Jul 18;21(5):434-45. Epub 2014 Dec 18.

Laboratory of Haematology & Blood Bank Unit, "Attiko" University Hospital, School of Medicine, University of Athens, Athens, Greece

Background: Our aim was to identify laboratory assays in order to assess the anticoagulant effects of dabigatran etexilate (DE).

Methods: Twenty patients with nonvalvular atrial fibrillation treated on DE (110 mg per os twice daily) and 20 on acenocoumarol were studied. Conventional coagulation tests, endogenous thrombin potential (ETP), thromboelastometry (ROTEM), epinephrine-induced light transmission aggregometry (LTA), and Hemoclot Thrombin Inhibitors (HTI) were performed in all patients.

Results: In ROTEM analysis, the lysis index at 60 minutes was significantly lower in patients receiving DE (P = .011). In LTA, patients on DE showed decreased aggregation compared to those on acenocoumarol, marginally insignificant (P = .068). Regarding ETP, acenocoumarol affected thrombin generation more than dabigatran (area under the curve [AUC], P < .001), while statistically significant associations were detected between dabigatran levels, as determined by the HTI assay, and almost all parameters of ETP assay (AUC, P < .001).

Conclusion: The role of ETP in estimating anticoagulant activity of dabigatran possibly requires further research.
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http://dx.doi.org/10.1177/1076029614564209DOI Listing
July 2015

Cost-effectiveness of leucoreduction for prevention of febrile non-haemolytic transfusion reactions.

Blood Transfus 2014 Apr;12(2):232-7

Blood Transfusion Centre, General Hospital of Nikaia, Athens, Greece.

Background: The cost-effectiveness of universal leucoreduction of blood components remains unclear. When using leucoreduced red blood cells, the decrease in the rate of febrile non-haemolytic transfusion reactions (FNHTR) is the only proven, meaningful clinical benefit, whose relationship to costs can be calculated relatively easily. The aim of this study was to evaluate the cost-effectiveness of leucoreduction in avoiding FNHTR.

Materials And Methods: Data were obtained from two large tertiary hospitals in Athens, Greece, over a 4-year period (2009-2012). The incidence of FNHTR in patients transfused with leucoreduced or non-leucodepleted red blood cells, the additional cost of leucoreduction and the cost to treat the FNHTR were estimated. The incremental cost-effectiveness ratio (ICER), which is the ratio of the change in costs to the incremental benefits of leucoreduction, was calculated.

Results: In total, 86,032 red blood cell units were transfused. Of these, 53,409 were leucodepleted and 32,623 were non-leucoreduced. Among patients transfused with leucodepleted units, 25 cases (0.047%) met the criteria for having a FNHTR, while in patients treated with non-leucoreduced components, 134 FNHTR were observed (0.411%). The ICER of leucoreduction was € 6,916 (i.e., the cost to prevent one case of FNHTR).

Conclusions: Leucoreduction does not have a favourable cost-effectiveness ratio in relation to the occurrence of FNHTR. However, many factors, which could not be easily and accurately assessed, influence the long-term costs of transfusion. It is imperative to undertake a series of large, meticulously designed clinical studies across the entire spectrum of blood transfusion settings, to investigate most of the parameters involved.
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http://dx.doi.org/10.2450/2014.0263-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039706PMC
April 2014

The association between plasminogen activator inhibitor type 1 (PAI-1) levels, PAI-1 4G/5G polymorphism, and myocardial infarction: a Mendelian randomization meta-analysis.

Clin Chem Lab Med 2014 Jul;52(7):937-50

Background: The circulating levels of plasminogen activator inhibitor type 1 (PAI-1) are increased in individuals carrying the 4G allele at position -675 of the PAI-1 gene. In turn, overexpression of PAI-1 has been found to affect both atheroma and thrombosis. However, the association between PAI-1 levels and the incidence of myocardial infarction (MI) is complicated by the potentially confounding effects of well-known cardiovascular risk factors. The current study tried to investigate in parallel the association of PAI-1 activity with the PAI-1 4G/5G polymorphism, with MI, and some components of metabolic syndrome (MetS).

Methods: Using meta-analytical Mendelian randomization approaches, genotype-disease and genotype-phenotype associations were modeled simultaneously.

Results: According to an additive model of inheritance and the Mendelian randomization approach, the MI-related odd ratio for individuals carrying the 4G allele was 1.088 with 95% confidence interval (CI) 1.007, 1.175. Moreover, the 4G carriers had, on average, higher PAI-1 activity than 5G carriers by 1.136 units (95% CI 0.738, 1.533). The meta-regression analyses showed that the levels of triglycerides (p=0.005), cholesterol (p=0.037) and PAI-1 (p=0.021) in controls were associated with the MI risk conferred by the 4G carriers.

Conclusions: The Mendelian randomization meta-analysis confirmed previous knowledge that the PAI-1 4G allele slightly increases the risk for MI. In addition, it supports the notion that PAI-1 activity and established cardiovascular determinants, such as cholesterol and triglyceride levels, could lie in the etiological pathway from PAI-1 4G allele to the occurrence of MI. Further research is warranted to elucidate these interactions.
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http://dx.doi.org/10.1515/cclm-2013-1124DOI Listing
July 2014

Impact of the proton pump inhibitors and CYP2C19*2 polymorphism on platelet response to clopidogrel as assessed by four platelet function assays.

Thromb Res 2013 Aug 2;132(2):e105-11. Epub 2013 Jul 2.

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

Background: Previous studies suggested a possible negative interference of proton pump inhibitors (PPIs) on clopidogrel's antiplatelet effect because of the competitive inhibition of the CYP 2C19 isoenzyme. Moreover, carriers of the loss-of-function allele of CYP2C19 polymorphism (CYP2C19*2) display significantly lower responses to clopidogrel. In this study, we investigated the association between CYP2C19*2 genotype, PPI intake and clopidogrel resistance in patients with coronary artery disease (CAD) and their effect on clinical outcome.

Methods: We recruited 95 patients with CAD receiving chronic clopidogrel therapy in combination with aspirin. Platelet reactivity was simultaneously assessed by INNOVANCE PFA-100 P2Y, ADP-induced light transmission aggregometry (LTA), flow-cytometric vasodilator-stimulated phosphoprotein (VASP)-phosphorylation assay and multiple electrode aggregometry (Multiplate). Cardiovascular outcomes were recorded during 1-year follow-up period.

Results: Only platelet reactivity assessed by measuring platelet phosphorylated-VASP demonstrated a significant higher platelet reactivity in carriers of CYP2C19*2 (p=0.023). The other methods displayed higher - but not statistically significant - platelet reactivity in patients carrying the CYP2C19*2 variant as compared with non-carriers. Patients on PPIs demonstrated almost similar suppression of platelet reactivity in comparison with those not treated with PPIs by all platelet function assays. In logistic regression analysis none of the platelet function assays measurements were related with clinical outcomes. Similarly neither CYP2C19*2 genetic variant nor PPI treatment were associated with adverse clinical events.

Conclusions: PPI co-administration did not influence clopidogrel's antiplatelet effect on laboratory testing by all platelet function assays used. On the contrary, patients carrying CYP2C19*2 genotype had significantly higher residual platelet reactivity as estimated by VASP-phosphorylation assay.
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http://dx.doi.org/10.1016/j.thromres.2013.06.015DOI Listing
August 2013

Red blood cell transfusion affects microdialysis-assessed interstitial lactate/pyruvate ratio in critically ill patients with late sepsis.

Intensive Care Med 2012 Nov 10;38(11):1843-50. Epub 2012 Jul 10.

Second Department of Critical Care Medicine, Attiko University Hospital, Medical School, National and Kapodistrian University of Athens, 1 Rimini Street, Haidari, 12462, Athens, Greece.

Purpose: The aim of this study was to explore the effect of red blood cell (RBC) transfusion on microdialysis-assessed interstitial fluid metabolic parameters in septic patients.

Methods: We conducted a retrospective study of 37 patients with severe sepsis/septic shock requiring transfusion of one to two RBC units. Interstitial fluid metabolic alterations were monitored by a microdialysis catheter inserted in the subcutaneous adipose tissue. Samples were collected before (T0) and after transfusion at two time-points: T1a and T1b; median post-transfusion times of 120 [interquartile range (IQR); 45-180] and 360 (IQR; 285-320) min. Lactate, pyruvate, glycerol and glucose concentrations were measured with a bedside analyzer, and the lactate/pyruvate (LP) ratio was calculated automatically.

Results: RBC transfusions decreased the LP ratio from (T0) 18.80 [interquartile range (IQR); 14.85-27.45] to (T1a) 17.80 (IQR; 14.35-25.20; P < 0.05) and (T1b) 17.90 (IQR; 14.45-22.75; P < 0.001), while there was also significant interindividual variation. Post-transfusion LP ratio changes at T1a [r = -0.42; 95 % confidence interval (CI), -0.66 to -0.098; P = 0.01] and T1b (r = -0.68; 95 % [CI], -0.82 to -0.44; P < 0.001) were significantly correlated with the pre-transfusion LP ratio, but not with baseline demographic characteristics, vital signs, severity scores, hemoglobin level and blood lactate. RBC storage time and leukocyte reduction had no influence on the tissue metabolic response to transfusion.

Conclusions: Tissue oxygenation is affected by RBC transfusion in critically ill septic patients. Monitoring of tissue LP ratio by microdialysis may represent a useful method for individual clinical management.
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http://dx.doi.org/10.1007/s00134-012-2635-8DOI Listing
November 2012
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