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Objectives Coagulation point-of-care tests for the diagnosis and management of bleeding commonly are used in cardiac surgery. Recently, a new viscoelastic point-of-care device, Quantra (HemoSonics, Charlottesville, VA), which is based on sonic estimation of elasticity via resonance sonorheometry, entered the market. Prior studies have compared the Quantra parameters with conventional coagulation tests and thromboelastography or rotational thromboelastography, but no study has assessed the correlation of the platelet-derived Quantra parameter platelet contribution to stiffness (PCS) with platelet function assays. The present study compared the Quantra-derived coagulation parameters with conventional coagulation tests, rotational thromboelastography–derived parameters, and platelet function measured using multiplate aggregometry. Design Prospective cohort study. Setting University research hospital. Participants The study comprised 30 cardiac surgery patients before and after cardiopulmonary bypass. Interventions None. Measurements and Main Results Quantra clot stiffness showed a very strong correlation with the EXTEM maximum clot firmness before and after cardiopulmonary bypass and in the overall samples (r values 0.94-0.96). Quantra fibrinogen contribution to stiffness was compared with the corresponding FIBTEM and Clauss fibrinogen levels, which also showed a strong level of correlation (r values between 0.74 and 0.87). Quantra PCS strongly correlated with platelet count (r = 0.71) in the overall samples and moderately with adenosine diphosphate–dependent platelet function (r = 0.67). In a multivariable model, both the adenosine diphosphate test value and the platelet count remained independently associated with Quantra PCS. Conclusions Fibrinogen-dependent clot stiffness properties are well-reflected by the Quantra fibrinogen contribution to stiffness parameter, and PCS incorporates platelet count and function.

In thromboelastometry (ROTEMTM) the difference in amplitude between the EXTEM and the FIBTEM is considered an index of platelet contribution to clot strength (PCSamp). The difference in elasticity (PCSel) is rarely used. We investigated the ability of PCSamp and PCSel in reflecting platelet count and function in 103 patients undergoing cardiac surgery, simultaneously measuring ROTEM and platelet function tests (multiple electrode aggregometry ADPtest and TRAPtest, MultiplateTM). PCSamp and PCSel were tested for association with platelet count and function. The PCSamp showed a low (R coefficient 0.32-0.39) association with platelet count and function (ADPtest), whereas the PCSel showed higher values of association (R coefficient 0.55-0.71) with the same variables. No association was found between PCS and TRAPtest. In a multivariable model, both the platelet count (R coefficient 0.60, P = 0.001) and the ADPtest (R coefficient 0.36, P = 0.001) were independently associated with the PCSel. The discrimination properties of the PCSel for the prediction of a low platelet count/function were very good (c-statistics 0.837). In clinical practice, the difference in elasticity between EXTEM and FIBTEM should replace the difference in amplitude.

Background Perinatal asphyxia is a major cause of mortality and morbidity in neonates: The aim of the present study was to investigate, by means of longitudinal assessment of urinary S100B, the effectiveness of hypothermia, in infants complicated by perinatal asphyxia and hypoxic-ischemic encephalopathy. Methods We performed a retrospective case-control study in 108 asphyxiated infants, admitted to nine tertiary departments for neonatal intensive care from January 2004 to July 2017, of whom 54 underwent hypothermia treatment and 54 did not. The concentrations of S100B protein in urine were measured using an immunoluminometric assay at first urination and 4, 8, 12, 16, 20, 24, 48, 72, 96, 108 and 120 h after birth. The results were correlated with the achievement of S100B levels within normal ranges at 72 h from hypothermia treatment. Routine laboratory parameters, longitudinal cerebral function monitoring, cerebral ultrasound and neurologic patterns were assessed according to standard protocols. Results Higher S100B concentrations were found in hypothermia-treated infants in both moderate (up to 12 h) and severe (up to 24 h) hypoxic-ischemic encephalopathy. S100B levels returned to normal ranges starting from 20 h of hypothermia treatment in moderate and from 36 h in severe hypoxic-ischemic encephalopathy. Conclusions The present results offer additional support to the usefulness of longitudinal neuro-biomarkers monitoring in asphyxiated infants treated by hypothermia. The pattern of S100B concentrations during hypothermia supports the need for further investigations aimed at reconsidering the time-window for patient recruitment and treatment, and the optimal duration of the cooling and rewarming phases of the hypothermia procedure.

Background Cardiac surgery with cardiopulmonary bypass is associated with important changes in the microcirculation, usually attributed to endothelial dysfunction. Another common finding of cardiac surgery is postoperative thrombocytopenia and platelet loss of function. Objective To investigate the association between microvascular flow pattern and postoperative changes in platelet count and function in cardiac surgery patients. Methods Twelve adult cardiac surgery patients received microvascular circulation (sidestream darkfield sublingual mucosa analysis) and platelet count and function (multiple electrode aggregometry ADPtest and TRAPtest) assessment before and after cardiopulmonary bypass. Results After cardiopulmonary bypass, sublingual microcirculation showed a significantly (P = 0.001) decreased microvascular flow index and increased heterogeneity index (P = 0.006). Platelet function significantly decrease after cardiopulmonary bypass both at ADPtest (P = 0.011) and TRAPtest (P = 0.002). Preoperative patterns of poor microvascular perfusion (low perfused vessels density and total vessels density) were significantly associated with lower values of post-cardiopulmonary bypass platelet function (ADPtest, P = 0.009, TRAPtest, P = 0.031) and count (P = 0.048). Conclusions A preoperative disturbance of the microcirculation is associated with a greater postoperative platelet dysfunction. Endothelial damage, chemical and mechanical stimuli are the possible link between the two patterns.

Platelet dysfunction after cardiac surgery is a determinant of postoperative bleeding. The existing guidelines suggest the use of desmopressin and/or platelet concentrate transfusions in case of platelet dysfunction in bleeding patients, but no cut-off values for platelet activity exist in the literature. The Platelet Function in the Operating Room (PLATFORM) study aims to identify the relationship between platelet function after cardiopulmonary bypass and severe bleeding, finding adequate predictive values of platelet function for severe bleeding. The PLATFORM is a prospective cohort study on 490 adult patients receiving cardiac surgery with cardiopulmonary bypass. Patients received platelet function tests (multiple electrode aggregometry ADPtest and TRAPtest) before surgery and after cardiopulmonary bypass, and routine coagulation tests before surgery and at the arrival in the intensive care unit. The post-cardiopulmonary bypass ADPtest and TRAPtest were significantly (

The study presents a model of shear-stress-based platelet activation. Twenty-eight patients (22 free from anticoagulants and major antiplatelet agents, and six under the effects of P2Y12 platelet inhibitors) participated. The main purpose was to verify the hypothesis that a model of shear-dependent blood activation does not require artificial activators to trigger clot formation. Whole blood collected from the patients received platelet function tests [ADPtest and thrombin receptor-activating peptide (TRAP)test] and was tested with a cone-on-plate viscosimeter at a shear rate of 100 s. Changes in blood viscosity were characterized by a time-to-gel point (TGP), a maximum clot viscosity and a steady clot viscosity (SCV). In patients free from major antiplatelet effects, the TGP was 180 s (interquartile range 148-290 s), while in patients under double antiplatelet therapy the TGP was significantly (P = 0.039) longer (345 s, interquartile range 250-452 s). The SCV was 16 centipoise (cP) (interquartile range 11-47 cP) in the patients free from major antiplatelet agents, significantly (P = 0.012) higher than in patients under double antiplatelet therapy (10 cP, interquartile range 6-11 cP). There was a significant (P = 0.011) association between platelet function at the TRAPtest and the maximum clot viscosity, and between TRAPtest and the SCV (P = 0.021). A shear rate of 100 s triggers clot formation through a primary role of platelet activation in this model of blood activation.

Aims: S100B has been proposed as a consolidated marker of brain damage in infants with congenital heart disease (CHD) undergoing cardiac surgery and cardiopulmonary bypass (CPB). The present study aimed to investigate whether S100B blood levels in the perioperative period differed in infants complicated or not by cyanotic CHD (CHDc) and correlated with oxygenation status (PaO2). Methods: We conducted a case-control study of 48 CHD infants without pre-existing neurological disorders undergoing surgical repair and CPB. 24 infants were CHDc and 24 were CHD controls. Blood samples for S100B assessment were collected at six monitoring time-points: before the surgical procedure (T0), after sternotomy but before CPB (T1), at the end of the cross-clamp CPB phase (T2), at the end of CPB (T3), at the end of the surgical procedure (T4), at 24 h postsurgery (T5). Results: In the CHDc group, S100B multiples of median (MoM) were significantly higher (p .05, for all) were found at T2, T3, T5. Linear regression analysis showed a positive correlation between S100B MoM at T3 and PaO2 (R = 0.84; p

Objective Hemodilution has been associated with both hypocoagulability and hypercoagulability in studies based on thromboelastography (TEG). Severe hemodilution during cardiopulmonary bypass (CPB) is a risk factor for morbidity in cardiac surgery. This study investigated the effects of different degrees of hemodilution with CPB on post-CPB TEG parameters and coagulation-related outcomes. Design Retrospective cohort study. Setting University research hospital. Participants The study comprised 793 cardiac surgery patients. Interventions None. Measurements and Main Results The patient population was divided into low (LH), moderate (MH), and severe (SH) hemodilution groups based on the hemodilution degree on CPB. Differences in TEG parameters and coagulation-related outcomes were assessed. Patients with SH experienced significantly (p = 0.019) prolonged clotting times (median r-time 6.1 min, interquartile range 5.1-7.4 min) with respect to patients with MH (median r-time 5.8 min, interquartile range 4.8-7 min) and LH (median r-time 5.9 min, interquartile range 4.8-7.2 min). Clot firmness was significantly (p = 0.001) lower in patients with SH (median maximum amplitude 63 mm, interquartile range 57-68 mm) compared with patients with MH (median maximum amplitude 65 mm, interquartile range 61-71 mm) and LH (median maximum amplitude 67 mm, interquartile range 62-74 mm). Patients with SH had higher chest drain blood loss and required more fresh frozen plasma and platelet concentrate transfusions than did patients with MH or LH. Postoperative thromboembolic complications were significantly (p = 0.006) more common in patients with SH (2.6%) than in patients with MH (0%) or LH (0.4%). Conclusions SH on CPB is associated with hypocoagulation, bleeding, and thrombosis-associated worse outcomes.

Choices for monitoring of unfractionated heparin (UFH) anticoagulation in extracorporeal membrane oxygenation (ECMO) patients include activated clotting time, activated partial thromboplastin time, reaction times of viscoelastic tests, and anti-factor Xa activity (between 0.3 and 0.7 IU/mL). Recent studies propose the anti-factor Xa to be the gold standard for monitoring UFH anticoagulation in ECMO. However, many extraneous factors combined question the utility of anti-factor Xa as the sole method of monitoring of UFH effects in ECMO. Anti-factor Xa is a chromogenic assay, which may be biased by the frequently elevated values of bilirubin and free hemoglobin in ECMO patients. The test may alternatively underestimate UFH effects in cases of low antithrombin values. More importantly, the anti-factor Xa assay is a plasma-based test which does not take into account the role of platelets and fibrinogen in forming a stable clot. Thrombocytopenia and platelet dysfunction are common features in ECMO patients, and underestimating their role may lead to over-anticoagulation, should only anti-factor Xa guiding be used to adjust the UFH dose. Conversely, fibrinogen is an acute phase protein, and some patients may experience high levels of fibrinogen during the ECMO course. In this case, an UFH monitoring based on anti-factor Xa is insensitive to this condition, although it may potentially be associated with thrombotic complications. Finally, the generally suggested range of 0.3 to 0.7 IU/mL is a somewhat arbitrary estimate, based on the desired range for treating and preventing thrombotic events in non-ECMO patients. In conclusion, anti-factor Xa may offer useful information on the real effects of UFH only when combined with a whole blood test capable of assessing the relative contribution of platelets and fibrinogen to clot formation.

Background Low fibrinogen levels immediately after cardiac surgical procedures have been associated with postoperative bleeding and transfusions. However, no sound data on the adequate trigger values for fibrinogen supplementation and target values for fibrinogen concentration exist. Methods This retrospective study examined prospectively collected data, including data on 2,800 adult patients undergoing cardiac operations. Standard coagulation parameters at the arrival in the intensive care unit were retrieved, inclusive of fibrinogen levels. Postoperative bleeding was assessed based on the chest drain output (mL/12 h). Severe bleeding (SB) was defined as chest drain output greater than 1,000 mL/12 h. Results Postoperative blood loss was associated with low values of fibrinogen and platelet count, as well as with a prolonged activated partial thromboplastin time and international normalized ratio. At multivariable analysis, fibrinogen levels lower than 220 mg/dL remained independently associated with SB (odds ratio: 2.25; 95% confidence interval: 1.54 to 3.28). A cutoff value of 115 mg/dL yielded a positive predictive value for SB of 50% and may be proposed as a trigger value for fibrinogen supplementation, with a target value of 280 mg/dL (98% negative predictive value for SB). In actively bleeding patients, these values are increased to 215 and 375 mg/dL, respectively. Conclusions These data confirm the independent role of fibrinogen levels as determinants of SB after cardiac surgical procedures and suggest adequate cutoff values and fibrinogen concentrate doses to prevent or treat SB. However, the identified trigger and target values should be confirmed in prospective series of patients undergoing fibrinogen supplementation.

Background Previous studies showed that desmopressin decreases post-operative blood loss in patients undergoing cardiac surgery. These studies were small and never studied the effect of desmopressin in patients with active bleeding. Objective of the study was to determine whether desmopressin reduces red blood cells transfusion requirements in patients with active bleeding after cardiac surgery who had been pre-treated with tranexamic acid. Methods This multicenter, randomized, double-blind, placebo-controlled, parallel-group study randomized elective patients with bleeding after cardiac surgery despite pre-treatment with tranexamic acid, to receive placebo (saline solution) or a single administration of desmopressin (0.3 μg/kg in saline solution). The primary endpoint was the number of patients requiring red blood cells transfusion after randomization and during hospital stay. Secondary end points were: blood loss from chest tubes during the first 24 h after study drug administration, hours of mechanical ventilation, intensive care unit stay, and in-hospital mortality. Results The study was interrupted after inclusion of 67% of the planned patients for futility. The number of patients requiring red blood cells transfusion after randomization was 37/68 (54%) in desmopressin group and 33/67 (49%) in placebo group (P = 0.34) with no difference in blood loss: 575 (interquartile 422–770) ml in desmopressin group and 590 (476–1013) ml in placebo group (P = 0.42), mechanical ventilation, intensive care unit stay or mortality. Conclusions This multicenter randomized trial demonstrated that, in patients pre-treated with tranexamic acid, desmopressin should not be expected to improve treatment of patients who experience bleeding after cardiac surgery.

Body mass index (BMI) and specifically overweight and obesity have been associated with an increased platelet reactivity in different series of patients. This information is derived by different laboratory platelet function tests (PFTs) like mean platelet volume (MPV), platelet microparticles, thromboxane B2 metabolites, and others. Point-of-care PFT, which are often used in cardiac surgery, are rarely addressed. The present study aims to verify platelet reactivity using multiple-electrode aggregometry (MEA) as a function of BMI in cardiac surgery patients. One-hundred ninety-eight cardiac surgery patients free from the effects of drugs acting on the P2Y

After cardiopulmonary bypass (CPB) thrombocytopenia is a relatively common pattern which may trigger postoperative bleeding. The purpose of this study is to verify if the endogenous fibrinogen levels are independent determinants of chest drain blood loss and need for allogeneic blood products transfusions in a clinical model of post-CPB thrombocytopenia.Retrospective analysis on 445 consecutive patients having a platelet count100×1000cells/μL after CPB. Based on the fibrinogen levels the patients were divided into three groups with similar platelet count and low (LF, median 170mg/dL), intermediate (IF, median 215mg/dL), and high (HF, median 280mg/dL), fibrinogen levels. Chest drain blood loss (mL/12h), transfusion rate of red blood cells (RBC), fresh frozen plasma (FFP) and platelet concentrates were assessed and compared between groups.There was a significant (P=0.001) difference in chest drain blood loss with higher values in the LF group (487mL/12h, IQR 300-600mL/12h) than in the IF group (350mL/12h, IQR 200-500mL/12h) and the HF group (300mL/12h, IQR 200-475mL/12h). Transfusion rates of FFP significantly (P=0.014) differed between groups (LF: 18.4%, IF: 7.9%, HF: 9.2%) and platelet concentrate transfusions significantly (P=0.020) differed between groups (LF: 23.5%, IF: 16.5%, HF: 10.7%). In multivariable models, these differences were confirmed. Thromboelastography parameters showed an effective compensation of clot firmness in group HF vs. IF and LF.Levels of fibrinogen240mg/dL compensate the decrease in clot firmness observed in thrombocytopenic patients following CPB, and reduce bleeding and transfusion needs.

Platelet function tests (PFTs) before cardiac surgery are predictive of postoperative bleeding and can guide a correct timing of surgery in patients under P2Y12 inhibitors. Thrombocytopenia affects PFT and may determine postoperative bleeding. The present study aims to investigate the relationship between platelet count and function, and its role in determining postoperative bleeding in cardiac surgery patients pre-treated with P2Y12 inhibitors. The study includes 589 consecutive cardiac surgery patients, tested before surgery with platelet count and multiple electrode aggregometry (MEA) ADPtest (investigating P2Y12 receptor platelet reactivity) and TRAPtest (investigating the thrombin-dependent platelet reactivity). Platelet function was linearly associated (P = 0.001) with platelet count at the ADPtest and the TRAPtest, demonstrating a positive association in the whole spectrum of platelet count. The ADPtest (P = 0.001) and platelet count (P = 0.001) were negatively associated with postoperative bleeding, whereas the TRAPtest was not. At a multivariable analysis, the ADPtest (P = 0.026) and platelet count (P = 0.006) remained independent predictors of postoperative bleeding. The platelet transfusion rate was 5.7% in patients with ADPtest ≥30 U and platelet count ≥150 000 cells/µL, 14.3% in patients with ADPtest ≥30 U and platelet count

Background:S100B is a well-established biomarker of central nervous system (CNS) development and damage in the perinatal period. Because the fetal CNS induces an overproduction of S100B measurable in the maternal bloodstream we evaluated S100B protein in healthy pregnancies in order to provide a reference curve of the protein in the second and third trimesters and to provide information on CNS development when standard monitoring procedures could be silent or unavailable.Methods:Between July 2012 and December 2014 we conducted a prospective study in 1213 healthy pregnancies delivering healthy newborns. Maternal blood samples were collected for standard monitoring procedures and S100B assessment. S100B correlations with selected outcomes (gestational age at sampling, gender of fetus, gestational age and weight at birth, delivery mode) were calculated using multiple forward stepwise regression analysis.Results:S100B concentrations in the second and third trimesters of pregnancy were found to be gestational age-, gender- and delivery mode-dependent (pConclusions:The present findings offering a S100B protein reference curve in maternal blood suggest that non-invasive fetal CNS monitoring is becoming feasible and open the way to further research in neuro-biomarker assessment in the maternal bloodstream.

Background Gender influences platelet biology. Women have a larger platelet count, but gender-based differences in platelet function remain debated. We performed a study addressing gender-based differences in platelet function using point-of-care platelet function tests (PFT). Methods The patient population consisted of 760 cardiac surgery patients where preoperative PFT (multiple-electrode aggregometry [MEA]) were available. Platelet count and function at the ADPtest and TRAPtest were compared in the overall population and separately in patients with or without residual effects of P2Y12 inhibitors. Results Women had a significantly (P = 0.001) higher platelet count but a non-significantly higher platelet reactivity to ADP. In clopidogrel-treated patients, the platelets ADP reactivity was significantly (P = 0.031) higher in women, and platelet count was the main determinant of platelet hyper-reactivity. Within patients under full clopidogrel effects, women with a platelet count ≥ 200,000 cells/μL had a significantly (P = 0.023) higher rate of high-on-treatment platelet reactivity (HTPR, 45.5%) with respect to males with a platelet count < 200,000 cells/μL (11.9%), with a relative risk of 6.2 (95% confidence interval 1.4–29). Conclusions Our findings confirm that women have a larger platelet count than men, and that this is associated to a trend towards a higher platelet reactivity. HTPR is largely represented in women with a high platelet count. This generates the hypothesis that women requiring P2Y12 inhibitors could potentially benefit from larger doses of drug or should be treated with anti-platelet agents with a low rate of HTPR.

OBJECTIVES: Patients who undergo cardiac operations under the effects of thienopyridines have a greater risk of major postoperative bleeding, transfusions and surgical revision due to bleeding. Discontinuation of thienopyridine is suggested but an adequate recovery period following discontinuation is still under debate, with opinions ranging from 3 to 7 days. The aim of this study was to assess the rate of recovery of thienopyridine-resistant patients and the time taken for resumption of platelet function after discontinuation of thienopyridine, in the setting of patients scheduled for cardiac operations. METHODS: This was a retrospective study, based on 344 patients screened for platelet aggregation before cardiac operations. All the patients received thienopyridines within 7 days prior to the test. Multiple electrode aggregometry adenosine diphosphate test was used to assess platelet aggregation before the operation. RESULTS: Thienopyridine resistance rate was 28%. Patients receiving clopidogrel had a significantly higher rate (32%) of resistance, compared with those receiving ticlopidine (14%) and thienopyridine resistance was significantly associated with platelet count (P= 0.006). The time taken to recover platelet function after thienopyridine discontinuation was variable between individuals; the only factor associated with a faster recovery time was the serum bilirubin value (P= 0.002). Platelet aggregation values high enough to avoid major bleeding were reached 3 days after discontinuation (95% confidence interval: 2–4 days); however, a complete recovery of platelet function was reached only after 8 days (95% confidence interval: 7–9 days). CONCLUSIONS :P atient-specific factors determine the effectiveness of thienopyridine treatment and platelet function recovery rate. Among these, platelet count (for thienopyridine resistance) and serum bilirubin values (for platelet function recovery rate) should be considered.

ObjectivesPurified antithrombin supplementation in cardiac surgery has been suggested for the treatment of heparin resistance and the prevention of thromboembolic complications. This study is a randomized controlled trial of preoperative purified antithrombin supplementation, with the primary end point of avoiding low (

The effects of cardiac surgery on the microcirculation of children are unknown. The aim of this study was to assess the microcirculatory changes in children undergoing surgery for correction of congenital heart disease.We used a videomicroscope (Sidestream Dark Field, SDF) in a convenience sample of 24 childrenfive yr old. Total vascular density (TVD, vessels mm(-2)), microvascular flow index (MFI, arbitrary units), proportion of perfused small vessels (PPV, percentage), and perfused vessel density (PVD) were obtained after induction of anaesthesia (T1), at the end of the surgical procedure (T2), after intensive care unit (ICU) admission (T3), and at six h (T4) and 12h (T5) after ICU admission.Microcirculatory variables did not significantly change over time. Haemodynamic parameters and microcirculatory variables were not correlated. In a subanalysis conducted for cyanotic (n=7) and acyanotic (n=17) children, repeated measures ANOVA showed a significant interaction between time and the presence of cyanosis for PPV (P=0.03), TVD (P=0.03), and PVD (P=0.03). Weak inverse correlations were found between storage time of transfused red blood cell (RBCs) and MFI at T3 (r=-0.63, P=0.01) and T4 (r=-0.53, P=0.03).Microcirculatory variables have a different time-related trend in cyanotic and acyanotic children undergoing cardiac surgery. The storage time of transfused RBCs seems to negatively impact the microcirculation. Further and larger studies are warranted to prove the potential implications of this study.

During cardiopulmonary bypass (CPB), red blood cell transfusions may be required to correct dilutional anemia. The decision-making process for transfusions is usually based on the level of hemoglobin.This study investigates the hypothesis that oxygen-derived variables (mixed venous oxygen saturation, SvO2, and oxygen extraction rate, O2ER) may be more reliable predictors of the efficacy of the transfusion. Thirty-six patients for 41 transfusion episodes during CPB were retrospectively analyzed. For each patient, oxygen-derived variables, including SvO2 and O2ER, were measured before and after the transfusion. No changes in pump flow were allowed between the two measurements. The efficacy of transfusion was defined as an increase in SvO2 of at least 5%. We identified 11 transfusion episodes leading to an efficacious SvO 2 increase. Factors associated with the efficacy of the transfusion were a low SvO2 and a high O2ER. No association was found with hemoglobin values, unless for a trend for efficacy of transfusion in patients with very low (2 and 39% for O2ER were predictive for the efficacy of red blood cell transfusions, with a high accuracy (c-statistics 0.856 and 0.848, respectively) and negative and positive predictive values exceeding 82%. In conclusion, SvO2 and O2ER are better than the hemoglobin value for guiding the decision-making process of red blood cell transfusions to correct hemodilutional anemia during CPB.

Background. Preoperative treatment with thienopyridines is associated with increased postoperative bleeding in cardiac surgery patients. Patients under treatment with thienopyridines have different levels of platelet dysfunction and the effects of discontinuation are not totally predictable. The present study aimed to determine if a preoperative assessment of platelet function in these patients could provide clinically relevant information regarding the risks of excessive postoperative bleeding and transfusion requirements. Methods. This is a retrospective analysis of prospectively collected data. Patients (n 87) under thienopyridine treatment until at least one week before cardiac surgery were enrolled in the study. Platelet function was assessed preoperatively with multiple electrode aggregometry: the adenosine diphosphate (ADP) test and TRAP (thrombin receptor-associated peptide) test were performed for all patients. Results. Univariate analysis revealed that postoperative bleeding was associated (p < 0.1) with preoperative serum creatinine level, platelet count, CPB (cardiopulmonary bypass) duration, and results from the ADP test and the TRAP test. Multivariable linear regression analysis confirmed the CPB duration (p 0.049) and ADP test (p 0.007) as independently associated with postoperative bleeding. The relationship between the ADP test and postoperative bleeding was investigated with polynomial regression analysis, and a logarithmic equation provided the best fit. The accuracy of prediction was good (area under the curve 0.71, p 0.013), with a cutoff value for the ADP test at 31 U (sensitivity 72%, specificity 66%, negative predictive value 92%, and positive predictive value 29%). Conclusions. The multiple electrode aggregometry ADP test in patients under thienopyridine treatment and undergoing cardiac surgery is associated with postoperative bleeding and platelet transfusion and provides an accurate preoperative prediction of postoperative bleeding risk.

Platelet function tests are suggested to assess platelet reactivity before cardiac and major non-cardiac surgery. Different point-of-care platelet function tests are available. Among these, electric impedance platelet aggregometry (EIPA) (Multiplate®, MP) is one of the most widely used techniques. Recently, a new EIPA system (Rotem Platelet®, RP) was released. This is a comparative study of platelet function measured with MP and RP. Fifty cardiac surgery patients were admitted to this study. All the patients received a preoperative platelet function test with both the MP and the RP; for each technology, two tests were performed: the ADPtest (investigating P2Y12 receptor platelet reactivity) and the TRAPtest (investigating the thrombin-dependent platelet reactivity). ADP-based platelet reactivity values demonstrated a significant (p = 0.019) correlation between the MP and the RP; and a marginally significant (p = 0.042) correlation for TRAP-based tests. The Bland-Altman analysis of the ADPtest demonstrated a positive bias of 5.94 units (MP > RP) and a percentage error of 88%. For the TRAPtest, there was a positive bias of 12 units (MP > RP) and a percentage error of 89%. In patients who were preoperatively treated with P2Y12 receptor inhibitors, only the MP ADPtest was positively associated with the days from drug discontinuation (p = 0.003). Platelet function assessment with RP greatly differs from the equivalent MP measure, and no correction value can be applied due to the low level of precision. This applies both to ADPtest and TRAPtest. The MP ADPtest is more reliable for platelet reactivity after discontinuation of P2Y12 receptor inhibitors.

Background Postoperative bleeding after heart operations is still a common finding, leading to allogeneic blood products transfusion. Fibrinogen and coagulation factors deficiency are possible determinants of bleeding. The experimental hypothesis of this study is that a first‐line fibrinogen supplementation avoids the need for fresh frozen plasma ( FFP ) and reduces the need for any kind of transfusions. Methods and Results This was a single‐center, prospective, randomized, placebo‐controlled, double‐blinded study. One‐hundred sixteen patients undergoing heart surgery with an expected cardiopulmonary bypass duration >90 minutes were admitted to the study. Patients in the treatment arm received fibrinogen concentrate after protamine administration; patients in the control arm received saline solution. In case of ongoing bleeding, patients in the treatment arm could receive prothrombin complex concentrates ( PCC s) and those in the control arm saline solution. The primary endpoint was avoidance of any allogeneic blood product. Patients in the treatment arm had a significantly lower rate of any allogeneic blood products transfusion (odds ratio, 0.40; 95% confidence interval, 0.19 to 0.84, P =0.015). The total amount of packed red cells and FFP units transfused was significantly lower in the treatment arm. Postoperative bleeding was significantly ( P =0.042) less in the treatment arm (median, 300 mL; interquartile range, 200 to 400 mL) than in the control arm (median, 355 mL; interquartile range, 250 to 600 mL). Conclusions Fibrinogen concentrate limits postoperative bleeding after complex heart surgery, leading to a significant reduction in allogeneic blood products transfusions. No safety issues were raised. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01471730.

Drugs that act on the platelet P2Y12 receptor are responsible for postoperative bleeding in cardiac surgery. However, protease-activated receptor (PAR) that reacts to thrombin stimulation might still be active in patients treated with P2Y12 inhibitors. Preoperative platelet function testing could possibly guide the timing of surgery. We investigated the association between P2Y12 receptor and PAR inhibition and bleeding after cardiac surgery.A retrospective cohort study of 361 patients undergoing cardiac surgery and treated with P2Y12 anti-platelet agents was undertaken. All patients received a preoperative multiplate electrode aggregometry testing of platelet P2Y12 receptor activity (ADPtest) and PAR reactivity with thrombin receptor-activating peptide (TRAP) stimulation. ADPtest and TRAPtest data measured before surgery were analysed for association with postoperative bleeding (ml per 12 h) and severe postoperative bleeding.Both the ADPtest and the TRAPtest were significantly (P=0.001) associated with postoperative bleeding. A threshold of 22 U for the ADPtest yielded a negative predictive value (NPV) of 94% and a positive predictive value (PPV) of 20%, and a threshold of 75 U for the TRAPtest yielded an NPV of 95% and a PPV of 23%. In the subgroup of patients with ADPtest22 U, TRAPtest ≥75 U was not associated with severe bleeding (NPV of 100% and PPV of 37%).In patients taking P2Y12 receptor inhibitors, residual platelet reactivity to thrombin stimulation limits the risk of severe postoperative bleeding.

Introduction Unfractionated heparin (UFH) is the anticoagulant of choice for extracorporeal membrane oxygenation (ECMO), but bivalirudin can be used as an alternative. The purpose of the present study is to investigate the existence of a heparin-like effect (HLE) during heparin-free ECMO. Methods This is a retrospective study on patients treated with ECMO and receiving bivalirudin as the sole anticoagulant. Thromboelastography (TEG) tests with and without heparinase were recorded during the ECMO duration. A total of 41 patients (22 pediatrics and 19 adults) treated with ECMO after cardiac surgery procedures and receiving only bivalirudin-based anticoagulation were studied. Based on the presence of a different reaction time (R-time) between the TEG test with heparinase or without heparinase we defined the presence of a HLE. Survival to hospital discharge, liver failure, sepsis, bleeding and transfusion rate were analyzed for association with HLE with univariate tests. Results HLE was detected in 56.1% of the patients. R-times were significantly shorter in tests done with heparinase versus without heparinase during the first seven days on ECMO. Patients with HLE had a significantly (P = 0.046) higher rate of sepsis (30%) than patients without HLE (5.6%) at a Pearson’s chi-square test. Conclusions A heparin-like effect is common during ECMO, and most likely due to a release of heparinoids from the glycocalyx and the mast cells, as a consequence of sepsis or of the systemic inflammatory reaction triggered by the contact of blood with foreign surfaces.

The viscoelastic functional fibrinogen (FF) and FIBTEM assays measure the contribution of fibrin to clot strength. Inhibition of platelet function is a necessary precondition for these tests to work. We investigated a novel test for measuring fibrin-based clotting, FIBTEM PLUS, in cardiac surgery and compared it with FF and FIBTEM.A prospective, observational study was performed which included 30 patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Blood samples were drawn at the beginning of surgery (pre-CPB), approximately 20 minutes before weaning from CPB and 5 minutes after heparin neutralization. FF, FIBTEM, and FIBTEM PLUS tests were performed in duplicate for all blood samples. Additional coagulation parameters, including platelet count, plasma fibrinogen levels, factor XIII activity, and heparin concentration, were also recorded for each sample.At all time points, the lowest mean maximum clot firmness (MCF) was observed with FIBTEM PLUS, although a statistically significant difference between FIBTEM and FIBTEM PLUS was observed only at baseline (mean values 22 vs 19 mm, P = 0.01; FF value for comparison: 27.7 mm). FF maximum amplitude (MA) values were significantly higher than FIBTEM MCF and FIBTEM PLUS MCF pre-CPB, during CPB and after heparin neutralization (P ≤ 0.001 for FF MA versus FIBTEM MCF and for FF MA versus FIBTEM PLUS MCF at all time points). The difference between FIBTEM MCF and FIBTEM PLUS MCF correlated with platelet count (r = 0.46;P0.001), whereas differences between FF MA and FIBTEM MCF, or FF MA and FIBTEM PLUS MCF did not (r = -0.07, P = 0.51; r = 0.16, P = 0.12, respectively). Differences between the assays were unrelated to heparin levels, which decreased considerably after protamine administration compared with heparin levels recorded before weaning from CPB (decrease from 2.1 to 0.1 U/mL and from 2.8 to 0.2 U/mL for anti-factor IIa and anti-factor Xa, respectively). Agreement between duplicate measurements was similar with FIBTEM and FIBTEM PLUS assays and lower with FF. Significant positive correlations were found between MCF or MA and fibrinogen concentration (all P0.001); the highest correlation was with FIBTEM PLUS MCF (r = 0.70).The FIBTEM PLUS assay produces precise results. At baseline, it provides greater inhibition of platelets than FIBTEM, but there is no meaningful difference between FIBTEM PLUS and FIBTEM in patients with low platelet counts.

Postoperative bleeding is common after cardiac surgery. Major bleeding (MB) is a determinant of red blood cell (RBC) transfusion, especially in patients with preoperative anemia. Preoperative anemia and RBC transfusions are recognized risk factors for operative mortality. The present study investigates the role of MB as an independent determinant of operative mortality in cardiac surgery.A single-center retrospective study based on the institutional database of cardiac surgery in the period 2000-2012 was conducted. Sixteen thousand one hundred fifty-four (16,154) consecutive adult patients undergoing cardiac surgery were analyzed. The impact of postoperative bleeding and MB on operative (30 days) mortality was analyzed univariately and after correction for preoperative anemia, RBC transfusions, and other confounders.Postoperative bleeding was significantly (p0.001) associated with operative mortality, both in univariate and multivariable models. The main complications associated with MB were thromboembolic complications, infections, and surgical reexploration. In a multivariable model, MB remained an independent predictor of operative mortality (odds ratio, 3.45; 95% confidence interval, 2.78 to 4.28). Preoperative anemia and RBC transfusions coexist in the model, acting with a multiplying effect when associated with MB.Major bleeding is per se a risk factor for operative mortality. However, its deleterious effects are strongly enhanced by RBC transfusions and, to a lesser extent, preoperative anemia. Major bleeding is a partially modifiable risk factor, and adequate preemptive and treatment strategies should be applied to limit this event.

Objectives Postoperative bleeding in cardiac surgery remains an important complication, leading to increased morbidity and mortality. Different interventions are possible to prevent/treat postoperative bleeding. The present study aims to investigate the effectiveness of these interventions in a real-world scenario. Methods This is a retrospective study based on 19 670 consecutive adult cardiac surgery patients operated from 2000 to 2015. During the study period, the following interventions have been applied and tested for effectiveness with a before versus after analysis: thromboelastography (TEG)-based diagnosis and treatment in actively bleeding patients; platelet function tests (PFTs); timing of surgery based on PFTs; fresh frozen plasma (FFP)-free strategy using prothrombin complex concentrate and fibrinogen concentrate. Results TEG-based diagnostic and therapeutic approach resulted in a significant (P = 0.006) reduction of postoperative bleeding and significant (P = 0.001) increase in platelet concentrate transfusion rate. Timing of surgery based on PFTs resulted in a significant reduction of postoperative bleeding (P = 0.001), surgical re-exploration rate (P = 0.002), FFP (P = 0.001) and platelet concentrate (P = 0.016) transfusion rate. FFP-free strategy was associated with a significant decrease in postoperative bleeding (P = 0.005) and FFP transfusions (P = 0.001). The combination of all the interventions was associated with a significant (P = 0.001) reduction in postoperative bleeding, surgical re-exploration rate and FFP transfusions, whereas platelet concentrate transfusion rate was significantly (P = 0.001) higher. Conclusions Despite a continuous increase in the bleeding risk profile, the application of a bundle of interventions is effective in controlling postoperative bleeding and related complications. Platelet transfusions remain unreplaceable in the present scenario.

The impact of diabetes mellitus (DM) on the outcome of patients requiring cardiac surgery has been investigated in previous decades. However, the profile of cardiac surgical practice is changing in addition to changes in patients' risk profile, making the results inconclusive. In this study we sought to investigate the impact of DM on operative mortality and morbidity in patients undergoing cardiac surgery and adjust for patient and disease characteristics. In total 10,709 patients (9,229 nondiabetics and 1,480 diabetics) were admitted to the study; 5,557 patients (1,012 diabetics) underwent an isolated coronary operation, 1,775 patients (278 diabetics) underwent coronary plus valve operations, and 3,337 patients (209 diabetics) underwent valve operations. To control for differences in patient and disease characteristics, a propensity score (for DM) was performed. DM increased crude morbidity and this difference was maintained after risk adjustment for propensity score; conversely, the crude operative mortality risk was higher in diabetics but not significantly after adjustment for propensity score. Thereafter, DM remained independently associated to operative mortality risk in the valve population only (odds ratio 2.53, 95% confidence interval 1.45 to 4.4, p = 0.001). In conclusion, DM has a significant impact on operative mortality of patients undergoing heart valve surgery. Although diabetic patients undergoing coronary operations are not at increased risk of operative mortality, morbidity is significantly affected in the overall population.

Purpose: The high mortality rate for lung cancer is likely to be reduced by the development of a panel of sensitive biological markers able to identify early-stage lung cancers or subjects at high risk. The aim of this study was to establish the frequency of K-ras and p53 mutations and p16INK4A, RASSF1A, and NORE1A hypermethylation in sputum of a large cohort of cancer-free heavy smokers and to assess whether these markers are suitable for a routine use in the clinical practice for the early diagnosis of pulmonary cancer. Experimental Design: Sputum samples were collected from 820 heavy smokers. Inclusion criteria consisted of radiologic and cytologic absence of pulmonary lesions, age at least 60 years, male gender, and a smoking history of at least 20 pack-years. Results: The analysis identified 56 individuals (6.9%) with one molecular alteration. p53 mutation and p16INK4A, RASSF1A, and NORE1A methylation frequencies were 1.9%, 5.1%, 0.8%, and 1.0%, respectively; no K-ras mutations were found. One patient with p53 mutations was diagnosed with an early-stage lung cancer after 3-years of follow-up. The molecular analysis of bronchoscopy samples confirmed in half of the cases alterations present in sputum without revealing additional molecular changes. Conclusions: Genetic and epigenetic abnormalities can be detected in cancer-free heavy smokers. Although the predictive value of the cancer risk is still to be established as it requires not less than 5 years of follow-up, p53 and p16INK4A are more promising candidates than K-ras, RASSF1A, and NORE1A for the pulmonary molecular screening of heavy smokers healthy individuals.

Summary Methylation of tumor suppressor genes is among the most frequent alterations in patients with malignant pleural mesothelioma (MPM). The aim of this study was to analyze the promoter methylation status of four tumor suppressor genes, p15INK4B, p16INK4A, RASSF1A and NORE1A in MPM. Samples of 79 MPM patients were analyzed using a methylation-specific PCR method. Associations between methylation status, clinico-pathological parameters (including proliferation index) and overall survival (OS) were examined. The analysis documented methylation in 30 cases (38%). The methylation frequency for individual genes was 19% for p15INK4B (n = 15), 11.4% for p16INK4A (n = 9), 20.2% for RASSF1A (n = 16) and 5.1% for Nore1A (n = 4). In the whole series methylation was associated to an increased proliferation index (P = 0.05). In patients treated with extrapleural pneumonectomy, methylated MPM showed a trend to a poorer OS in comparison to unmethylated cases (median OS 16 months vs. 35 months, P = 0.06, HR = 2.01, 95% CI 0.95–4.30). In the overall population, methylation did not correlate to patient outcome but a trend to an improved survival was detectable in ummethylated MPM treated with extrapleural pneumonectomy. This result suggests the need to select homogeneously treated and staged patients with MPM to address whether their methylation profile may impact on patient's survival.

Postoperative bleeding is a major problem in pediatric cardiac surgery with cardiopulmonary bypass (CPB). It recognizes a multifactorial cause, inclusive of coagulation factors consumption, hyperfibrinolysis, incomplete heparin reversal, and platelet consumption. Limited information on platelet function is available. This pilot study investigates platelet function changes in pediatric cardiac operations and their relationship with postoperative bleeding.A cohort of 22 patients aged four years or less were prospectively analyzed. Besides the usual coagulation tests, they were studied for platelet function at four points in time: preoperative, arrival in the intensive care unit, first and second postoperative day. Platelet function was measured with multiple electrode aggregometry TRAP-test.After the cardiac operation there was a non-significant decrease in platelet function, with 36% of the patients demonstrating increased aggregability. Platelet count demonstrated a significant (P=0.001) decrease related to the CPB duration. The International Normalized Ratio (INR) was significantly (P=0.001) increased after the operation. Postoperative bleeding was associated with the degree of thrombocytopenia (P=0.014), the increase in INR (P=0.001), and the prolongation of the activated partial thromboplastin time (P=0.002).In this pilot study, platelet function in pediatric patients undergoing cardiac surgery demonstrates a variable pattern and no association with postoperative bleeding. Confounding factors like age and cyanosis should be addressed with larger patient populations.