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Postoperative use of platelet function testing to rule out microvascular bleeding due to platelet dysfunction after cardiac surgery still lacks strong reference data and reliable cutoff values, yielding a clinically adequate sensitivity and specificity. The present study aims to investigate the performance of two different point-of-care viscoelastic devices and platelet aggregometry in expressing surgery-dependent platelet dysfunction and anticipating postoperative major bleeding in a cohort of high-risk patients.Prospective cohort study of 50 adult patients who were on antiplatelet drugs discontinued for no more than 7 days (clopidogrel and prasugrel) or 5 days (ticagrelor) undergoing cardiac surgery with cardiopulmonary bypass (CPB). Coagulation and platelet function testing, including QUANTRA, ROTEM, and Multiplate, were assessed preoperatively and postoperatively. Chest drain blood loss was measured in the first 12 postoperative hours. Perioperative bleeding was assessed using a modified version of the Universal Definition of Perioperative Bleeding (UDPB) in cardiac surgery, modified to not consider anemia-correcting packed red cells transfusions in the absence of bleeding600 mL/12 h. Major bleeding was identified as UDPB class II or higher.Multiplate adenosine diphosphate (ADPtest) was significantly ( P = .001) reduced after CPB, whereas TRAPtest was not. The platelet component (PC) as extrapolated by ROTEM data (EXTEM MCF-FIBTEM MCF) was unchanged after CPB, while the A10 PC (PC at 10 minutes) was significantly ( P = .001) reduced. The QUANTRA platelet contribution to clot stiffness (PCS) was significantly ( P = .001) reduced, as well. At the ROC analysis for the predictive ability of the post-CPB platelet function testing, the best discrimination was obtained by the QUANTRA PCS, with an area under the curve (AUC) (95% confidence interval [CI]) of 0.80 (0.66-0.91), P = .001, followed by the ROTEM A10 PC with AUC (95% CI) of 0.75 (0.51-0.99), P = .004, and PC with AUC (95% CI) of 0.74 (0.50-0.99), P = .009. The Multiplate ADPtest had an AUC (95% CI) of 0.67 (0.42-0.91), and the TRAPtest had an AUC (95% CI) of 0.62 (0.37-0.86). The cutoff values identified were 13 hPa for the QUANTRA PCS, 40 mm for the ROTEM A10, and 48.5 mm for the ROTEM PC, with negative predictive values of 84%, 81%, and 86%, respectively, and positive predictive values of 55%, 53%, and 69%, respectively.QUANTRA PCS, ROTEM A10 PC, and Multiplate ADPtest showed a significant decrease after CPB, whereas ROTEM PC and Multiplate TRAPtest did not. Major bleeding was predicted with a moderate to good discrimination by the post-CPB viscoelastic tests (PCS, PC, and A10 PC).

The assessment of platelet function in cardiac surgery patients who recently received dual-antiplatelet therapy is considered in the existing guidelines. Among available devices, Multiplate (MP) and ROTEM Platelet (RP) are both based on electrical impedance. This study aimed to determine the agreement between MP and RP in cardiac surgery patients under dual-antiplatelet therapy discontinued before surgery. Secondarily, it compared the ability of the MP and RP in predicting postoperative bleeding and the need for platelet transfusion.A prospective cohort study.A hospital in Milan, Italy.Fifty adult patients preoperatively and postoperatively tested.None.Patients were studied with adenosine diphosphate (ADP) and thrombin receptor-activating peptide (TRAP) testing on both of the devices. The mean preoperative ADP tests were below the respective lower limit of the reference value, thus reflecting a good ability of these tests to detect the residual or ongoing effects of antiplatelet drugs acting on the P2YBoth technologies seemed to offer potential benefits in the surgical approach to patients who preoperatively received antiplatelet drugs. However, the results of these tests are not interchangeable, and different cut-off values should be applied.

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.

Supplementary Tables S1-S3 from Molecular Alterations in Spontaneous Sputum of Cancer-Free Heavy Smokers: Results from a Large Screening Program

Resistance to the pharmacological effect of clopidogrel in patients undergoing dual antiplatelet therapy for carotid stenting may increase the risk of periprocedural neurological events. The purpose of the study was to describe the phenomenon of clopidogrel resistance in a series of patients undergoing carotid stenting.Data of patients who consecutively underwent carotid stenting from November 2016 to December 2020 for a significant stenosis and who underwent a dual antiplatelet therapy using acetyl-salicylic acid and clopidogrel were prospectively collected. Patients who were already taking a different thienopyridine were excluded. The effectiveness of antiplatelet drugs was assessed by the impedance aggregometry test. Primary endpoint was to evaluate the incidence of clopidogrel resistance and the effectiveness of ticagrelor as alternative therapy. P values 0.05 were considered statistically significant.Two-hundred patients (80 females, 40%) underwent stenting for carotid stenosis (94% asymptomatic). The phenomenon of clopidogrel resistance was observed in 38 patients (19%), in whom clopidogrel was replaced by ticagrelor (90 mg/bis in die) with 100% effectiveness at aggregometry test. Platelet counts was associated to clopidogrel resistance (P = 0.001). There was no stent thrombosis at 30 days, neither major hemorrhagic events; a total of 12/200 major adverse cardiovascular events occurred (6%), including 1 in the group of patients who took ticagrelor and 11 in group of patients under clopidogrel (2.6% versus 6.7%, P = 0.55).Clopidogrel was ineffective in 19% of patients undergoing carotid stenting. Platelet count seemed to affect this phenomenon. In these patients, clopidogrel was effectively replaced by ticagrelor.

Objective Preoperative anemia is a risk factor for transfusions, morbidity and mortality in cardiac surgery. The aim of this study is to assess if an anemia intervention strategy before cardiac surgery is associated with reduced red blood cell (RBC) transfusion. Design Retrospective, propensity matched study Setting. University Clinical Research Hospital. Participants: two-hundred-twenty-eight adult cardiac surgery patients. Propensity matching was based on demographics, pre-treatment hemoglobin value, congestive heart failure, active endocarditis, serum creatinine, serum bilirubin, redo surgery, non-elective surgery, non-isolated surgery. Interventions Patients in the treated group received an anemia correction treatment at the pre-admission anesthesia clinic examination. The treatment included ferric carboxymaltose and/or erythropoietin based on the anemia diagnosis (absolute sideropenic; functional sideropenic; anemia of chronic disease). Treatment was single shot, at a median of 13 preoperative days (interquartile range 9-17 days. Patients in the control group were selected by propensity matching and did not receive any treatment. Measurements and Main Results Patients in the treated group received RBC transfusion in 61.4% of the cases vs. 76.3% in control group (odds ratio 0.49, 95% confidence interval 0.26-0.84, P=0.010) and a median units load of 1 unit (interquartile range 0-2) vs. 2 units (interquartile range 1-3) in control group (P=0.001). Patients in the treated group had significantly lower chest drain output, postoperative low cardiac output rate, and shorter intensive care and hospital stay. Conclusions Anemia correction before cardiac surgery is associated with a reduction in both the RBC transfusion rate and the amount of units transfused.

Modern four-factor prothrombin complex concentrate was designed originally for rapid targeted replacement of the coagulation factors II, VII, IX and X. Dosing strategies for the approved indication of vitamin K antagonist-related bleeding vary greatly. They include INR and bodyweight-related protocols as well as fixed dose regimens. Particularly in the massively bleeding trauma and cardiac surgery patient, four-factor prothrombin complex concentrate is used increasingly for haemostatic resuscitation. Members of the Transfusion and Haemostasis Subcommittee of the European Association of Cardiothoracic Anaesthesiology performed a systematic literature review on four-factor prothrombin complex concentrate. The available evidence has been summarised for dosing, efficacy, drug safety and monitoring strategies in different scenarios. Whereas there is evidence for the efficacy of four-factor prothrombin concentrate for a variety of bleeding scenarios, convincing safety data are clearly missing. In the massively bleeding patient with coagulopathy, our group recommends the administration of an initial bolus of 25 IU.kg-1 . This applies for: the acute reversal of vitamin K antagonist therapy; haemostatic resuscitation, particularly in trauma; and the reversal of direct oral anticoagulants when no specific antidote is available. In patients with a high risk for thromboembolic complications, e.g. cardiac surgery, the administration of an initial half-dose bolus (12.5 IU.kg-1 ) should be considered. A second bolus may be indicated if coagulopathy and microvascular bleeding persists and other reasons for bleeding are largely ruled out. Tissue-factor-activated, factor VII-dependent and heparin insensitive point-of-care tests may be used for peri-operative monitoring and guiding of prothrombin complex concentrate therapy.

Acquired fibrinogen deficiency is a major determinant of severe bleeding in different clinical conditions, including cardiac surgery, trauma, postpartum hemorrhage, liver surgery, and transplantation. The existing guidelines recommend to supplement fibrinogen in patients with severe bleeding when the fibrinogen concentration is

According to the World Health Organization’s definition, long COVID is the persistence or development of new symptoms 3 months after the initial infection. Various conditions have been explored in studies with up to one-year follow-up but very few looked further. This prospective cohort study addresses the presence of a wide spectrum of symptoms in 121 patients hospitalized during the acute phase of COVID-19 infection, and the association between factors related to the acute phase of the disease and the presence of residual symptoms after one year or longer from hospitalization. The main results are as follows: (i) post-COVID symptoms persist in up to 60% of the patient population at a mean follow-up of 17 months; (ii) the most frequent symptoms are fatigue and dyspnea, but neuropsychological disturbances persist in about 30% of the patients (iii) when corrected for the duration of follow-up with a freedom-from-event analysis; only complete (2 doses) vaccination at the time of hospital admission remained independently associated with persistence of the major physical symptoms, while vaccination and previous neuropsychological symptoms remained independently associated with persistence of major neuropsychological symptoms.

Minimally invasive extracorporeal perfusion technologies are based on the use of a minimally invasive extracorporeal circulation (MiECC) system. This includes a closed CPB circuit; biologically inert blood contact surfaces; reduced priming volume; a centrifugal pump; a membrane oxygenator; a heat exchanger; a cardioplegia system; a venous bubble trap/venous air removing device; and a shed blood management system. Some of these items, alone or in combination, are able to modify the blood activation usually elicited by cardiopulmonary bypass (CPB). The hemostatic system activation is less activated and lower degrees of thrombin generation and platelet activation have been found in numerous studies. Additionally, the reduced level of hemodilution plays an important role in preserving clot firmness after CPB with MiECC. These biochemical changes are reflected by a blood loss containment, a reduced need for allogeneic blood transfusions, and, in some studies, by a lower thromboembolic complications rate. The activation of the inflammatory cascade is in turn limited by MiECC, both directly (through a blunting of the contact-phase activation) and indirectly (through a limited thrombin generation, platelet activation, and consequent lower release of pro-inflammatory cytokines). The clinical consequences of this are mainly demonstrated by a lower rate of postoperative atrial fibrillation; other inflammation-derived outcomes appear favorably affected by MiECC (lung function, acute kidney injury) but the multi-factorial nature of these complications makes difficult to clearly attribute this pattern to a lower degree of inflammation. Overall, the existing body of evidence is in favor of MiECC with respect to standard CPB.

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: COVID-19 associated coagulopathy is characterized by a pro-thrombotic state. However, the nature of this pattern has not been comprehensively studied. We investigated the coagulation pattern of patients with COVID-19 acute respiratory distress syndrome (ARDS) comparing survivors to not survivors. Methods: Prospective cohort study conducted in the Intensive Care Unit (ICU) of a University Hospital . Twenty COVID-19 ARDS patients received measurements of markers of thrombin generation (prothrombin fragment 1+2, PF 1+2); fibrinolysis activation (tissue plasminogen activator, tPA) and inhibition (plasminogen activator inhibitor-2, PAI-2); fibrin synthesis (fibrinopeptide A) and fibrinolysis magnitude (plasmin-antiplasmin complex, PAP, and D-dimers). Measurements were done at the ICU admission and after 10-14 days. Results: The general pattern showed an increased thrombin generation, modest or null release of t-PA, and increased levels of PAI-2, Fibrinopeptide A, PAP and D-dimers. At baseline, non survivors had a significantly (P=0.014) higher PAI-2/PAP ratio than survivors (109, interquartile range [IQR] 18.1-216, vs. 8.7, IQR 2.9-12.6). At follow-up, thrombin generation was significantly (P=0.025) reduced in survivors (PF 1+2 from 396 pg/mL, IQR 185-585 to 237 pg/mL, IQR 120-393), whereas it increased in non-survivors. Fibrinolysis inhibition at follow-up remained stable in survivors, and increased in non-survivors, leading to a significant (P=0.026) difference in PAI-2 levels (161 pg/mL, IQR 50-334, vs. 1,088 pg/mL, IQR 177-1,565). Conclusions: Severe patterns of COVID-19 infection (ARDS) are characterized by a thrombin burst, triggered by the release of IL-6 and other cytokines, and the consequent release of Tissue Factor. Mechanisms of fibrinolysis regulation appear unbalanced toward fibrinolysis inhibition. In survivors, this pattern ameliorates, whereas in non-survivors it worsens, leading to the environment for clinically relevant thrombi generation, that was found in 58% of non-surviving patients. Trial registration: clinicaltrials.gov (NCT04441502).

Background The increased use of antidepressant treatment during pregnancy occurred without firm evidence on safety/efficacy. The present study investigated the correlation among S100B and paroxetine blood levels with the occurrence of short-term post-natal neurological abnormalities. Methods We conducted a cross-sectional study in 50 pregnant women using paroxetine because of depression and in 150 controls. Standard laboratory parameters and S100B were measured at seven monitoring time-points (maternal blood: T1, 16–20 wks; T2, 27–30 wks; T3, 35–40 wks; T4, at delivery; amniotic fluid, T5; venous and arterial cord blood, T6-T7). Paroxetine levels were measured at T1-T6. Neurological outcome was set at 7th day from birth. Results Higher S100B concentrations at T1-T7 were found in the paroxetine-treated group. S100B correlated with paroxetine blood levels. The paroxetine/S100B ratio cut-off of 1.31 at T2 achieved sensitivity 100%, specificity 96.5% and positive/negative predictive values 87.5–100, respectively, as a single marker to predict adverse neonatal neurological outcome. Conclusions The present study offers additional support to the usefulness of longitudinal S100B and drug level monitoring in depressed pregnant women and in the early detection of cases at risk for short-term neurological abnormalities. Results open the way at further investigations correlating antidepressant drugs and neurobiomarkers in the maternal bloodstream.

Viscoelastic tests provide a dynamic assessment of coagulation, by exploring the time to clot formation and the clot strength. Using specific activators or inhibitors, additional factors can be explored, like the fibrinogen contribution to clot strength. Since the early days, various attempts have been done to measure platelet function with viscoelastic test. In general, the difference between the maximum clot strength and the fibrinogen contribution is considered an index of platelet contribution. However, this parameter does not clearly split platelet count from function; additionally, the extensive thrombin generation of standard activated viscoelastic tests activates platelet through the protease activated receptors, bypassing the other pathways. For this reason, standard viscoelastic tests cannot be used to assess platelet reactivity under the effects of aspirin or P2Y12 inhibitors. To overcome this limitation, a specific test was developed (thromboelastography platelet mapping). This test has been compared with the gold standard of light transmission aggregometry and with other point-of-care tests, with conflicting results. In general, the use of viscoelastic tests to assess the effects of antiplatelet agents is still limited. Conversely, platelet contribution to clot strength in the setting of coagulopathic bleeding is considered an important parameter to trigger platelet transfusion or desmopressin.

Background: Presently, a number of specific observations have been performed on microcirculatory function in a coronavirus disease-19 (COVID-19) setting. We hypothesized that, in the critically ill, endothelial dysfunction secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the subsequent inflammation and coagulopathy may lead to microcirculatory alterations, further exacerbated by the hypoxemic state. A dysfunctional microcirculation may represent the hidden motor underlying the development of COVID-19’s clinical manifestations. Methods: A single center, prospective, observational study. We analyzed bedside sublingual microcirculation in twenty-four consecutive COVID-19-associated acute respiratory distress syndrome (ARDS) patients mechanically ventilated in an Intensive Care Unit (ICU), together with macro-hemodynamics, clinical parameters, echocardiography, and laboratory data at a single time-point after ICU admission. All participants were recruited between March and May 2020. Results: The microcirculatory pattern was characterized by increased values of total vessel density and perfused vessel density, a reduced value of proportion of perfused vessels and microvascular flow index, and high values of heterogeneity index. The duration of mechanical ventilation before microcirculation assessment was inversely associated with the proportion of perfused vessels (p = 0.023). Within the macro-hemodynamic parameters, the right ventricle end-diastolic diameter was inversely associated with proportion of perfused vessels and microvascular flow index (p = 0.039 and 0.014, respectively) and directly associated with the heterogeneity index (p = 0.033). Conclusions: In COVID-19-associated ARDS patients, the microcirculation showed impaired quality of flow parameters coupled with a high vessel density.

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.

Direct oral anticoagulants (DOACs) exert similar anticoagulant effects to vitamin K antagonists and are increasingly used worldwide. Nevertheless, an evidence-based approach to patients receiving DOACs when any unplanned urgent surgery or bleeding (either spontaneous or traumatic) occurs is still missing. In this review, we investigate the role of point-of-care coagulation tests when other, more specific tests are not available. Indeed, thromboelastography and activated clotting time can detect dabigatran-induced coagulopathy, while their accuracy is limited for apixaban and rivaroxaban, mostly in cases of low drug plasma concentrations. These tests can also be used to guide the reversal of DOAC-induced coagulopathy providing a quick, before-and-after picture in case of therapeutic use of hemostatic compounds.

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.

Introduction:Low-weight (Methods:Prospective cohort study on 77 patients weighing 30 ml kg-1/24h).Results:Factors being independently associated with severe bleeding were the international normalized ratio and the fibrinogen levels at the arrival in the intensive care unit. Once corrected for other confounders, fibrinogen levels had an odds ratio of 0.2 (95% confidence interval = 0.011-0.54) per 1 gL-1for severe bleeding. The discrimination power was fair (area under the curve = 0.770). The best cut-off value was identified at a fibrinogen level of 150 mg dL-1, with a sensitivity of 52%, a specificity of 85% and a positive predictive value of 60% for severe bleeding.Conclusion:Both a prolonged international normalized ratio and low fibrinogen levels were predictive for severe bleeding, underscoring the role of coagulation factors dilution and consumption in this specific patient population.

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 Fibrinogen supplementation has been proposed both to prevent and treat postoperative bleeding in cardiac surgery. The optimal fibrinogen concentration trigger and target values and the fibrinogen concentrate dose required remain uncertain. This subanalysis of data from the Zero-Plasma Trial (ZEPLAST) assessed target fibrinogen values and the corresponding fibrinogen concentrate dose for supplementation. Methods We performed a post hoc analysis of 116 subjects included in the randomized, placebo-controlled ZEPLAST trail. Data considered were fibrin-based thromboelastometry (FIBTEM) maximum clot firmness (MCF) determined by whole-blood thromboelastometry (ROTEM) before and after placebo or fibrinogen concentrate, Clauss fibrinogen concentration after placebo or fibrinogen concentrate, postoperative bleeding and severe bleeding (SB). The association between FIBTEM MCF and Clauss fibrinogen concentration was tested with linear regression analyses. The predictive value for SB of FIBTEM MCF and Clauss fibrinogen concentration was tested with receiver operating characteristic analyses. Results There was a good association between FIBTEM MCF and Clauss fibrinogen concentration in the baseline study population (r2 + 0.66), which worsened in fibrinogen-supplemented subjects. Both FIBTEM MCF and Clauss fibrinogen concentration yielded a good discriminative power for SB (area under the curve 0.721 and 0.767, respectively). The negative predictive value for SB was 100% for a Clauss fibrinogen concentration of 287 mg dl−1 and 98% for an FIBTEM MCF of 14 mm. Based on these newly defined target values, the dose of fibrinogen concentrate needed would be 3 g lower than the dose used in ZEPLAST. Conclusions A dose of fibrinogen concentrate rarely exceeding 2 g might be sufficient to prevent bleeding in cardiac surgery.

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

Background Pre-operative fibrinogen levels are negatively associated with postoperative bleeding in cardiac surgery patients. The guidelines of the European Society of Anaesthesiology consider the possibility of a prophylactic pre-operative supplementation in patients with fibrinogen levels 1 l/12 h. Diagnostic accuracy for prediction of SB was tested at three cutoff values of pre-operative fibrinogen (2.5 g/l, 3.0 g/l, and 3.8 g/l). Results At all the three cutoff values, pre-operative fibrinogen levels had an excellent negative predictive value, ranging from 86% to 100%. Conversely, the positive predictive value was poor at all the cutoff levels: 12% (3.8 g/l), 14% (3.0 g/l), and 19% (2.5 g/l). Overall, the accuracy of pre-operative fibrinogen levels for the prediction of SB was poor. A strategy based on pre-operative fibrinogen supplementation would lead to inappropriate treatment in > 80% of the treated patients. Overall, a trigger value of 3.8 g/l would result in an inappropriate treatment in 52% of the patients, of 3.0 g/l in 20% of the patients, and of 2.5 g/l in 4% of the patients. Conclusion Correction of pre-operative fibrinogen levels below 3.8 g/l would lead to an excessive rate of inappropriate interventions. Values below 2.5 g/l could be considered.

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.

A rational management of perioperative and postoperative bleeding in modern cardiac surgery requires a thorough application of point-of-care (POC) monitoring in order to prevent and readily treat alterations of the haemostatic process. Preoperative platelet dysfunction, residual heparin after extracorporeal circulation, coagulation factors, and/or fibrinogen deficiency could be ruled out and specifically addressed with an appropriate treatment. Our approach includes preoperative platelet function testing of patients administered with thienopyridines or ticagrelor within 7–10 days before planned surgery and platelet function testing-based surgery timing. In the case of postoperative bleeding, residual heparin is tested and additional protamine is eventually administered. Simultaneously, an overall activity of coagulation factors (except fibrinogen) is assessed and, if significantly reduced, correction with prothrombotic complex concentrate is considered. If fibrinogen deficiency is suspected, a specific test is run, and in the case of severe reduction, the deficiency is compensated by fibrinogen concentrate or appropriate volume of fresh-frozen plasma. If both coagulation factors and fibrinogen activity are reduced, fibrinogen is usually considered for correction as first line, followed by prothrombin complex concentrate in the case of further bleeding. It is our clinical practice not to test nor to treat patients until postoperative bleeding appears clinically relevant. At IRCCS Policlinico San Donato, we firmly believe in the importance of the POC-based strategy for haemostatic treatment and constantly update our knowledge through research projects targeted in answering clinically relevant questions.

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.

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 aim of this study was to assess the association of the coagulation point-of-care (POC) tests activated clotting time (ACT) and thromboelastography-derived parameters reaction time (R-time) and maximum amplitude (MA) with the standard coagulation tests during postcardiotomy extracorporeal membrane oxygenation (ECMO), finding adequate values predictive for the target range of the standard coagulation tests.Thirty-one patients undergoing postcardiotomy ECMO with heparin anticoagulation were analyzed. Paired data of the POC tests and standard coagulation tests were analyzed for association and positive predictive value (PPV).The following target range values for standard coagulation test were settled: activated partial thromboplastin time (aPTT) 50-70 seconds; international normalized ratio (INR) 1.5-2.5; platelet count50,000 cells/µL; fibrinogen150 mg/dL. The best predictor for the desired aPTT range was an ACT of 162-185 seconds. A combination of an ACT162 seconds with an R-time10 minutes had an 83% PPV for a short aPTT. A combination of an ACT185 seconds with an R-time27 minutes had a 71% PPV for a long aPTT. No predictive ability of the POC tests was found in terms of the optimal INR range. An MA value41 mm had a 75% PPV for a low platelet count or fibrinogen level.Diagnostic-therapeutic algorithms based on coagulation POC-tests may be useful to manage anticoagulation during postcardiotomy ECMO. The best PPV for prompting therapeutic decision is provided by a combination of ACT and visco-elastic tests.

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.

A point-of-care (POC) device is a kind of diagnostic testing placed and performed at or in proximity of the site where the patient is receiving medical care. The ideal POC assay should be rapid with results readily available to the healthcare personnel and applicable to the clinical setting, poorly influenced by environmental factors, simple to perform and understand, and convenient and cost efficient if compared to the traditional laboratory technologies. This kind of device is normally positioned outside the laboratory, generally in intensive care units, clinical wards, or operating rooms. Multiple attempts have been made in order to achieve these characteristics in the field of coagulation monitoring, both for hemostasis and for anticoagulation purposes. Some of the devices gained success and acknowledgment and are now widely used in the hospitals, many more have been proposed in the past, and others are just at the beginning of their development and recognition route. The present chapter will address coagulation POC devices not treated in Chaps. 2 and 3.