Perioperative Hyper-coagulation and Thrombosis: Cost Analysis After Congenital Heart Surgery.

Thrombosis, a major adverse event of congenital heart surgery, has been associated with poor outcomes. We hypothesized that in CHD patients undergoing cardiac surgery, increased perioperative use of pro-coagulant products may be associated with postoperative thrombosis in the setting of hyperfibrinogenemia, leading to greater hospital and blood product costs. Single-center retrospective study. Data from Boston Children's Hospital's electronic health record database was used in this study. All patients undergoing congenital heart surgery between 2015 and 2018 with postoperative fibrinogen levels above 400 mg/dl were reviewed. Of 334 patients with high plasma fibrinogen levels, 28 (8.4%) developed postoperative thrombosis (median age: one year, 59% male). In our cohort, 25 (7%) demonstrated evidence of baseline hypercoagulability by one or more panel test results. Thrombosis was associated with greater hospital and blood product costs, longer ventilation times, and longer hospital and ICU length of stays. Preoperative hypercoagulable state (odds ratio: 2.58, 95% CI [1.07, 9.99], p = 0.002), postoperative red blood cell transfusion (odds ratio: 1.007, 95% CI [1.000, 1.015], p = 0.04), and single ventricle physiology (univariate odds ratio: 2.94, 95% CI [1.09, 7.89], p = 0.03) were predictors of postoperative thrombosis. Preoperative hypercoagulable state and intraoperative platelet transfusion were predictors of hospital cost. Thrombosis was associated with worse in-hospital outcomes and higher costs. Preoperative hypercoagulable state and postoperative red blood cell transfusion were significant predictors of thrombosis. Risk prediction models that can guide thrombosis prevention are needed to improve outcomes of patients undergoing congenital heart surgery.

Implications of Transfusion in Adults with Congenital Heart Disease Undergoing Cardiac Surgery.

The number of adults with congenital heart disease (CHD) requiring cardiovascular (CV) surgery is increasing rapidly in today's era. We hypothesized that exposure to perioperative blood products is associated with worse outcomes in adults. All adults (≥ 18 years old) undergoing CV surgery with Cardio-Pulmonary Bypass (CPB) between 2015 and 2020 were reviewed retrospectively. Associations between transfusion and outcomes were studied by univariable logistic regression and Wilcoxon rank sum tests. Cox/ logistic regression was used to assess (a) postoperative ventilation time and length of stay, and (b) major complications, respectively. Of 323 patients, 170 (53%) received blood products perioperatively. The median age was 27 (interquartile range [IQR]: 22-36) years, there were 181 (46%) males, and 16 (5%) patients had single ventricle anatomy. Patients receiving products experienced more complications (OR: 6.6, 95% CI: [2.9, 14.7], p < 0.001) specifically, cardiac arrest (OR: 8.8, 95% CI: [1.1, 71.9], p = 0.04). Transfusion was associated with greater frequency of thrombosis ((OR: 7.8, 95% CI: [1.8, 34.7], p = 0.01)), longer ventilation time (HR: 3.0, 95% CI: [2.4, 3.9], p < 0.001), and longer hospital length of stay (HR: 2.7, 95% CI: [2.1, 3.4], p < 0.001). Longer CPB time (OR: 1.0, 95% CI: [1.0, 1.1], p < 0.001) and prior cardiac surgery (OR: 1.6, 95% CI: [1.3, 2.1], p < 0.001) were independent predictors of perioperative blood product transfusion. Adults who received perioperative blood products experienced more complications and worse in-hospital outcomes. Future research on optimizing blood product transfusion based on risk prediction is needed to optimize outcomes in adults with CHD.

Clinical implications of acute shunt thrombosis in paediatric patients with systemic-to-pulmonary shunt re-interventions.

PURPOSE: Systemic-to-pulmonary shunts are used as a source of pulmonary blood flow in palliated Congenital Heart Disease in neonates and young infants. Shunt thrombosis, often requiring shunt interventions during index hospitalisation, is associated with poor outcomes. We hypothesised that extensive use of perioperative pro-coagulant products may be associated with shunt thrombosis. METHODS: Children (≤18 years) undergoing systemic-to-pulmonary shunts with in-hospital shunt reinterventions between 2016 and 2020 were reviewed retrospectively. Perioperative associations to shunt thrombosis were examined by univariate logistic regression and Wilcoxon rank sum tests as appropriate. Cox and log transformed linear regression were used to analyse postoperative ventilation duration, length of stay, and cost. RESULTS: Of 71 patients requiring in-hospital shunt intervention after systemic-to-pulmonary shunts, 10 (14%) had acute shunt thrombosis, and among them five (50%) died. The median age was four (interquartile range: 0-15) months. There were 40 (56%) males, 41 (58%) had single ventricle anatomy, and 29 (40%) were on preoperative anticoagulants. Patients with acute shunt thrombosis received greater volume of platelets (p = 0.04), cryoprecipitate (p = 0.02), and plasma (p = 0.04) postoperatively in the ICU; experienced more complications (p = 0.01) including re-exploration for bleeding (p = 0.008) and death (p = 0.02), had longer hospital length of stays (p = 0.004), greater frequency of other arterial/venous thrombosis (p = 0.02), and greater hospital costs (p = 0.002). CONCLUSIONS: Patients who develop acute shunt thrombosis receive more blood products perioperatively and experience worse hospital outcomes and higher hospital costs. Future research on prevention/early detection of shunt thrombosis is needed to improve outcomes in infants after systemic-to-pulmonary shunt surgery.

Comparison of Thromboelastography Devices TEG®6S Point of Care Device vs. TEG®5000 in Pediatric Patients Undergoing Cardiac Surgery.

Thromboelastography (TEG) can predict bleeding in pediatric patients undergoing cardiac surgery. We hypothesized that results obtained from TEG®5000 correlate with the new point-of-care TEG®6S system and that TEG®6S rewarming maximum amplitude (MA) is associated with surrogate endpoints for perioperative bleeding in pediatric patients who underwent complex cardiac surgery. We describe a retrospective study of pediatric (≤18 years) patients who underwent complex cardiac surgery on cardiopulmonary bypass. Citrate whole-blood samples were used to compared TEG®5000 vs.TEG®6S and TEG®6S-FLEV (with fibrinogen measurement) vs. Clauss-fibrinogen methods. TEG®6S parameters obtained during rewarming were compared to the surrogate endpoints for perioperative bleeding using linear regression analysis. Among 100 patients, 225 TEG®5000 vs.TEG®6S comparisons and 54 TEG®6S-FLEV were analyzed. Good correlation was observed for all parameters comparing TEG®5000 to TEG®6S and TEG®6S-FLEV to the Clauss-fibrinogen method (Pearson r ≥ .7). Similar to rewarming TEG®5000 MA, rewarming TEG®6S MA was the only parameter independently associated with risk for perioperative bleeding (median [interquartile range {IQR}] in bleeding vs. nonbleeding patients: 35 [29, 48] vs. 37 [32, 55]; p = .02). A platelet transfusion calculator was developed based on TEG®6S results by determining the relationship between platelet transfusion volume (mL/kg) and percent change in MA using linear regression analysis. TEG®6S is a good alternative point-of-care method to analyze a patient's coagulation profile and it is comparable to TEG®5000 in pediatric patients undergoing cardiac surgery on cardiopulmonary bypass. Lower TEG®6S MA during rewarming is associated with increased risk for perioperative bleeding. TEG analysis during rewarming may be useful in customizing platelet transfusion therapy by reducing the risk of bleeding while minimizing excessive blood product transfusions.

Coagulation profiles and viscoelastic testing in multisystem inflammatory syndrome in children.

OBJECTIVE: To characterize viscoelastic testing profiles of children with multisystem inflammatory syndrome in children (MIS-C). METHODS: This single-center retrospective review included 30 patients diagnosed with MIS-C from March 1 to September 1, 2020. Thromboelastography (TEG) with platelet mapping was performed in 19 (63%) patients and compared to age- and sex-matched controls prior to cardiac surgery. Relationships between TEG parameters and inflammatory markers were assessed using correlation. RESULTS: Patients with MIS-C had abnormal TEG results compared to controls, including decreased kinetic (K) time (1.1 vs. 1.7 minutes, p < .01), increased alpha angle (75.0° vs. 65.7°, p < .01), increased maximum amplitude (70.8 vs. 58.3 mm, p < .01), and decreased lysis in 30 minutes (Ly30) (1.1% vs. 3.7%, p = .03); consistent with increased clot formation rate and strength, and reduced fibrinolysis. TEG maximum amplitude was moderately correlated with erythrocyte sedimentation rate (ESR) (r = 0.60, p = .02), initial platelet count (r = 0.67, p < .01), and peak platelet count (r = 0.51, p = .03). TEG alpha angle was moderately correlated with peak platelet count (r = 0.54, p = .02). Seventeen (57%) patients received aspirin (ASA) and anticoagulation, five (17%) received only ASA, and three (10%) received only anticoagulation. No patients had a symptomatic thrombotic event. Six (20%) patients had a bleeding event, none of which was major. CONCLUSIONS: Patients with MIS-C had evidence of hypercoagulability on TEG. Increased ESR and platelets were associated with higher clot strength. Patients were prophylactically treated with ASA or anticoagulation with no symptomatic thrombosis or major bleeding. Further multicenter study is required to characterize the rate of thrombosis and optimal thromboprophylaxis algorithm in this patient population.

Stratification of Bleeding Risk Using Thromboelastography in Children on Extracorporeal Membrane Oxygenation Support.

OBJECTIVES: Patients undergoing extracorporeal membrane oxygenation are at high risk for bleeding and thrombotic complications. Current laboratory methods for assessing the coagulation system may be imprecise and complicate clinical decision-making. We hypothesize that thromboelastography may be more strongly associated with bleeding events than traditional methods and can aid extracorporeal membrane oxygenation coagulation management. DESIGN: In a retrospective study, 40 patients with congenital heart disease requiring extracorporeal membrane oxygenation support yielded a total of 159 patient days of data for thromboelastography analysis. SETTING: Pediatric cardiac ICU at a single institution. SUBJECTS: Pediatric patients (≤ 18 yr) with congenital heart disease requiring extracorporeal membrane oxygenation support. INTERVENTIONS: None. METHODS: Thromboelastography was performed on whole blood samples collected 6-12 hours following extracorporeal membrane oxygenation initiation and daily for the duration of extracorporeal membrane oxygenation. Bleeding during each 24-hour period was defined as need for re-exploration or need for blood transfusion. Associations between thromboelastography variables and bleeding over each 24-hour period (bleeding vs nonbleeding days) were assessed using mixed effects logistic regression and classification and regression tree analysis. MEASUREMENTS AND MAIN RESULTS: Bleeding occurred in 25 patients (63%), contributing 87 bleeding days (55% extracorporeal membrane oxygenation days) for analysis. The probability of bleeding within the 24-hour period was not associated with activated partial thromboplastin time (p = 0.6) or anti-Xa levels (p = 0.3) on that day. The strongest correlate of bleeding was a maximum amplitude less than 55.4 mm on thromboelastography (odds ratio, 3.28; 95% CI, 1.63-6.60; p < 0.001). Bleeding occurred on 73% versus 35% of extracorporeal membrane oxygenation days for maximum amplitude less than 55.4 mm versus greater than or equal to 55.4 mm, respectively. Bleeding occurred on all days when a combination of maximum amplitude less than 55.4 mm and a reaction time greater than 12.9 minutes was present. The lowest risk of bleeding (28% of patient days) was associated with maximum amplitude greater than or equal to 55.4 mm and plasma fibrinogen greater than 345 mg/dL. CONCLUSIONS: Thromboelastography-derived variables maximum amplitude and reaction time, along with plasma fibrinogen levels, can help predict bleeding events in children on extracorporeal membrane oxygenation support. Research based on larger patient samples is needed to confirm the specific thresholds identified for bleeding risk stratification for extracorporeal membrane oxygenation anticoagulation management.

Platelet Inhibition With IV Glycoprotein IIb/IIIa Inhibitor to Prevent Thrombosis in Pediatric Patients Undergoing Aortopulmonary Shunting.

OBJECTIVES: Shunt thrombosis, a potential complication of aortopulmonary shunting, is associated with high mortality. Commonly used oral antiplatelet drugs such as aspirin demonstrate variable absorption and inconsistent antiplatelet effect in critically ill patients early after surgery. IV glycoprotein IIb/IIIa inhibitors are antiplatelet agents with rapid and reproducible effect that may be beneficial as a bridge to oral therapy. DESIGN: Retrospective review of pediatric patients undergoing treatment with IV tirofiban. Discarded blood samples were used to determine pharmacokinetic parameters. SETTING: Pediatric cardiac ICU at a single institution. PATIENTS: Fifty-two pediatric patients (< 18 yr) undergoing surgical aortopulmonary shunt procedure who received tirofiban infusion as a bridge to oral aspirin. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome measures were shunt thrombosis and bleeding events, whereas secondary outcomes included measurement of platelet inhibition by thromboelastography with platelet mapping and pharmacokinetic analysis (performed in a subset of 15 patients). Shunt thrombosis occurred in two of 52 patients (3.9%) after prophylaxis treatment with tirofiban; both thrombosis events occurred after discontinuation of the drug. One patient (1.9%) experienced bleeding complication during the infusion. A tirofiban bolus of 10 µg/kg and infusion of 0.15 µg/kg/min resulted in significantly increased platelet inhibition via adenosine diphosphate pathway (median 66% [43-96] pre-tirofiban compared with 97% [92-99%] at 2 hr; p < 0.05). Half-life of tirofiban in plasma was 142 ± 1.5 minutes, and the average steady-state concentration was 112 ± 62 ng/mL. Age and serum creatinine were significant covariates associated with systemic clearance. Dosing simulations were generated based upon one compartment model. CONCLUSIONS: IV glycoprotein IIb/IIIa inhibitor as a bridge to oral antiplatelet therapy is safe in pediatric patients after aortopulmonary shunting. Dosing considerations should include both age and renal function. Randomized trials are warranted to establish efficacy compared with current anticoagulation practices.

Transition from Hemochron Response to Hemochron Signature Elite Activated Clotting Time Devices in a Congenital Cardiac Surgery Practice.

Heparin is the primary anticoagulant used during cardiac surgery to prevent thrombosis due to cardiopulmonary bypass (CPB)-related activation of the hemostatic system. The efficacy of heparin in the operating room is generally determined by activated clotting time (ACT) point-of-care tests performed throughout the procedure. In an effort to transition to the Hemochron Elite which requires approximately 1/10th the sampling volume of blood, we conducted a prospective study in 260 pediatric patients undergoing CPB. ACT tests were performed during CPB with a total of 260 pre-bypass and 1,117 on-bypass ACT values recorded. All samples were run simultaneously on both ACT devices. Several therapeutic cut-off possibilities ranging from >380 to >480 seconds were evaluated to ascertain the ACT level on the Elite device which best correlated with results from the Response device. Linear regression was used to determine correlation. The correlation between the two methods was moderate with a Pearson r of .6 and .4 for pre-bypass bolus ACT values and on-bypass ACT values, respectively. As the therapeutic ACT cut-off values were lowered from 480 to 380 seconds on the Elite device relative to the Response device (>480 seconds) for the on-bypass heparin samples, more patients would be under-dosed (incidence rising from 1 to 2%) and fewer patients would be overdosed (incidence decreasing from 32 to 5%) and the percent correlation between devices increased from 67 to 93%. A similar trend was observed with the pre-bypass heparin bolus samples. There was no significant effect of temperature on the ACT values comparing both devices. A therapeutic ACT value of >400 seconds for CPB with the Hemochron Elite device reasonably approximates a therapeutic ACT value of >480 seconds on the Hemochron Response device in our congenital cardiac surgery practice. Transitioning to the Elite device significantly reduces the overall sampling volume required for ACT monitoring during cardiac surgery.

Preoperative Thromboelastographic Profile of Patients with Congenital Heart Disease: Association of Hypercoagulability and Decreased Heparin Response.

OBJECTIVE: To describe the demographic and thromboelastographic characteristics of patients with congenital heart disease presenting with decreased heparin response before cardiac surgery. DESIGN: Retrospective, observational study. SETTING: Single institution, tertiary, academic, university hospital. PARTICIPANTS: The study comprised 496 pediatric and adult patients undergoing cardiac surgery for congenital heart disease. INTERVENTIONS: Retrospective review of medical records. MEASUREMENTS AND MAIN RESULTS: Data on preoperative thromboelastography (TEG), demographics, and response to heparin were collected retrospectively. Logistic regression analysis was used to study the association between TEG and response to heparin. Decreased heparin response (defined as activated clotting time <480 s initial bolus of 300 U/kg heparin) was observed in 23.6% of patients presenting for surgery. Age distribution and preoperative coagulation profiles were similar for both nonresponders and responders to heparin. Preoperatively, nonresponders demonstrated all thromboelastrographic characteristics consistent with a hypercoagulable profile (shorter reaction time, K value, wider angle, and maximum amplitude). Univariate logistic regression identified all TEG variables significantly associated with decreased heparin response. After adjustment for age, procedure type, and the presence of cyanosis, a multivariate logistic regression model identified the TEG variable K (≤1.3 min) as being significantly associated with decreased heparin response (odds ratio 3.7; confidence interval 2.3-5.8; p < 0.0001). CONCLUSIONS: Decreased response to heparin before cardiac surgery in patients with congenital heart disease is associated with preoperative hypercoagulability identified using a viscoelastic test. Additional studies are needed to better understand the etiology of decreased heparin response and potential clinical strategies to improve anticoagulation management.

Relationship Between Transfusion of Blood Products and the Incidence of Thrombotic Complications in Neonates and Infants Undergoing Cardiac Surgery.

OBJECTIVES: The authors hypothesized that transfusion of blood products in neonates and infants undergoing high-risk cardiac surgery in the absence of intraoperative coagulation monitoring increases the risk of thrombotic complications. DESIGN: Prospective observational study. SETTING: Neonates and infants undergoing cardiac surgery at a tertiary pediatric center. PARTICIPANTS: Neonates weighing >2.5 kg and infants ≤12 months of age undergoing elective cardiac surgery with cardiopulmonary bypass were included in this prospective observational study. INTERVENTION: None. MEASUREMENTS AND RESULTS: Demographic data, surgical characteristics, transfusion data, and coagulation parameters (thromboelastography and thromboelastometry) were collected. Logistic regression analysis was performed to identify potential determinants of postoperative thrombotic complications. Among the 138 neonates and infants included in the study, 12 (9%) developed a postoperative thrombotic complication. Unadjusted logistic regression analysis confirmed that the number and volume of blood products transfused were associated significantly with the increased incidence of thrombotic complication (odds ratio: 2.78, 95% confidence interval: 1.30-5.94, p = 0.008). This association persisted after adjustment for patient's age, the need for deep hypothermic cardiac arrest, and bypass time (odds ratio: 2.23, 95% confidence interval: 1.02-4.87, p = 0.044). The number of blood products transfused was associated with a significant increase in parameters of clot amplitudes measured at cardiac intensive care unit admission, while no difference was reported when measured after the administration of protamine. CONCLUSIONS: This prospective observational study reports a significant association between transfusion of blood products in neonates and young infants undergoing cardiac surgery and an increased incidence of thrombotic complications in the absence of intraoperative coagulation monitoring.

Hypercoagulability panel testing predicts thrombosis in neonates undergoing cardiac surgery.

Thrombosis contributes to morbidity and mortality in neonates following cardiac surgery. Alterations in hemostatic factors following cardiac surgery have been described, but there is no data correlating these changes with risk of thrombosis in neonates. The aim of this study is to predict thrombosis in neonates undergoing cardiac surgery by assessment of a panel of hypercoagulability markers. Neonates undergoing cardiac surgery were enrolled preoperatively and prospectively followed. Preoperative hypercoagulability panel testing included thrombin generation assay (TGA), immunoassays for antithrombin III, protein C, protein S, factor VIII, thrombin-activatable fibrinolytic inhibitor (TAFI), plasminogen activator inhibitor-1 (PAI-1), and cardiolipin antibody. Postoperative thrombosis was defined by clinical events (shunt thrombosis, limb ischemia, and stroke) or imaging (intravascular or intracardiac thrombus). Risk factors for thrombosis were assessed. One hundred neonates were enrolled in the study over a two-year period. The incidence of postoperative in-hospital thrombosis was 20%. The only significant clinical risk factor associated with thrombosis was the single ventricle physiology. Hypercoagulability factors associated with increased risk of thrombosis by univariate analysis were elevated PAI-1, TAFI, and TGA, and presence of anticardiolipin antibodies. Multivariable logistic regression analysis demonstrated that elevated PAI-1 (P = 0.015), TAFI (P = 0.028), and TGA (P = 0.007) were independent predictors of thrombosis. Hypercoagulability panel testing may help identify neonates at high risk for thrombosis following cardiac surgery. Future studies are warranted to determine if high risk patients benefit from targeted anticoagulation therapies.

Neutrophil extracellular traps formation is associated with postoperative complications in neonates and infants undergoing congenital cardiac surgery.

Pediatric patients with congenital heart diseases (CHD) often undergo surgical repair on cardiopulmonary bypass (CPB). Despite a significant medical and surgical improvement, the mortality of neonates and infants remains high. Damage-associated molecular patterns (DAMPs) are endogenous molecules released from injured/damaged tissues as danger signals. We examined 101 pediatric patients who underwent congenital cardiac surgery on CPB. The mortality rate was 4.0%, and the complication rate was 31.6%. We found that neonates/infants experienced multiple complications most, consistent with the previous knowledge. Neonates and infants in the complication group had received more transfusion intraoperatively than the non-complication arm with lower maximum amplitude (MA) on rewarming CPB thromboelastography (TEG). Despite TEG profiles were comparable at ICU admission between the two groups, the complication arm had higher postoperative chest tube output, requiring more blood transfusion. The complication group showed greater neutrophil extracellular traps (NETs) formation at the end of CPB and postoperatively. Plasma histones and high mobility group box 1 (HMGB1) levels were significantly higher in the complication arm. Both induced NETs in vitro and in vivo . As histones and HMGB1 target Toll-like receptor (TLR)2 and TLR4, their mRNA expression in neutrophils was upregulated in the complication arm. Taken together, NETs play a major role in postoperative complication in pediatric cardiac surgery and would be considered a target for intervention. Key points: Neonates and infants showed highest postoperative complications with more upregulation of inflammatory transcriptomes of neutrophils.Neonates and infants with organ dysfunction had more NETs formation with higher plasma histones and HMGB1 levels.

Thromboelastography During Rewarming for Management of Pediatric Cardiac Surgery Patients.

BACKGROUND: Thromboelastography (TEG) predicts bleeding in pediatric patients undergoing cardiac surgical procedure. We hypothesize that TEG indicators at rewarming correlate with postprotamine values and that rewarming TEG is associated with surrogate end points for postoperative bleeding in pediatric patients undergoing complex cardiac surgical procedure. METHODS: In a retrospective study of 703 pediatric (≤18 years) patients undergoing complex cardiac surgical procedures, TEG results obtained during rewarming and after protamine administration were compared using linear regression. A composite end point of extended blood product transfusion or surgical reexploration for bleeding was used as a surrogate for postoperative bleeding. RESULTS: By multivariable analysis, longer cardiopulmonary bypass time and lower TEG maximal amplitude (MA) during rewarming were independently associated with the risk of the composite end point in the operating room or in the intensive care unit (P < .05). Among patients with an MA of less than 45 mm during rewarming, those who received a platelet transfusion in the operating room compared with those who did not were less likely to reach the composite end point within the subsequent 24 hours (8% vs 32%, respectively; P < .01). Good correlation was observed between TEG variables at rewarming vs after protamine administration (Pearson r ≥ 0.7). The relationship between platelet transfusion volume (mL/kg) and the percentage change in the MA was determined using linear regression, and a platelet transfusion calculator was generated. CONCLUSIONS: A lower MA during rewarming is associated with an increased risk of perioperative bleeding. In patients with a rewarming MA of less than 45 mm, an intraoperative platelet transfusion may reduce the risk of subsequent bleeding. Individualized platelet transfusion therapy based on rewarming TEG may reduce the risk of bleeding while minimizing unnecessary platelet transfusion.

Low-Fouling Zwitterionic Polymeric Colloids as Resuscitation Fluids for Hemorrhagic Shock.

Colloids, known as volume expanders, have been used as resuscitation fluids for hypovolemic shock for decades, as they increase plasma oncotic pressure and expand intravascular volume. However, recent studies show that commonly used synthetic colloids have adverse interactions with human biological systems. In this work, a low-fouling amine(N)-oxide-based zwitterionic polymer as an alternative volume expander with improved biocompatibility and efficacy is designed. It is demonstrated that the polymer possesses antifouling ability, resisting cell interaction and deposition in major organs, and is rapidly cleared via renal filtration and hepatic circulation, reducing the risk of long-term side effects. Furthermore, in vitro and in vivo studies show an absence of adverse effects on hemostasis or any acute safety risks. Finally, it is shown that, in a head-to-head comparison with existing colloids and plasma, the zwitterionic polymer serves as a more potent oncotic agent for restoring intravascular volume in a hemorrhagic shock model. The design of N-oxide-based zwitterionic polymers may lead to the development of alternative fluid therapies to treat hypovolemic shock and to improve fluid management in general.

Magnetic Resonance-Based Diagnostics for Bleeding Assessment in Neonatal Cardiac Surgery.

PURPOSE: Infants undergoing a cardiac operation are at high risk for postsurgical bleeding. To date, there are no highly predictive models for postsurgical bleeding in this population. This study's objective was to assess the predictive ability of T2 magnetic resonance (T2MR). DESCRIPTION: T2MR uses magnetic resonance to detect clot formation characteristics on a small blood sample and provides hemostatic indicators that can assess bleeding risk. EVALUATION: This prospective, single-institution study enrolled 100 patients younger than 12 months old undergoing a cardiac operation from April 27, 2015, to September 21, 2016. The primary end point was postsurgical bleeding within 24 hours after the procedure. T2MR data were modeled with a binary recursive partitioning algorithm with randomized cross-validation. The tight clot metric produced the highest univariate discrimination of bleeding (receiver operator characteristic curve, 0.64; classification accuracy, 72%), and along with the platelet function metric, demonstrated highest relative importance based on Gini index splitting (Salford Systems, San Diego, CA). Multivariate modeling with cross-validation showed mean receiver operator characteristic curve area of 0.74 and classification accuracy of 82%. CONCLUSIONS: T2MR tight clot and platelet function metrics were associated with bleeding events.

Multipotency of mouse trophoblast stem cells.

BACKGROUND: In a number of disease processes, the body is unable to repair injured tissue, promoting the need to develop strategies for tissue repair and regeneration, including the use of cellular therapeutics. Trophoblast stem cells (TSCs) are considered putative stem cells as they differentiate into other subtypes of trophoblast cells. To identify cells for future therapeutic strategies, we investigated whether TSCs have properties of stem/progenitor cells including self-renewal and the capacity to differentiate into parenchymal cells of fetal organs, in vitro and in vivo. METHODS: TSCs were isolated using anti-CD117 micro-beads, from embryonic day 18.5 placentas. In vitro, CD117+ TSCs were cultured, at a limiting dilution in growth medium for the development of multicellular clones and in specialized medium for differentiation into lung epithelial cells, cardiomyocytes, and retinal photoreceptor cells. CD117+ TSCs were also injected in utero into lung, heart, and the sub-retinal space of embryonic day 13.5 fetuses, and the organs were harvested for histological assessment after a natural delivery. RESULTS: We first identified CD117+ cells within the labyrinth zone and chorionic basal plate of murine placentas in late pregnancy, embryonic day 18.5. CD117+ TSCs formed multicellular clones that remained positive for CD117 in vitro, consistent with self-renewal properties. The clonal cells demonstrated multipotency, capable of differentiating into lung epithelial cells (endoderm), cardiomyocytes (mesoderm), and retinal photoreceptor cells (ectoderm). Finally, injection of CD117+ TSCs in utero into lungs, hearts, and the sub-retinal spaces of fetuses resulted in their engraftment on day 1 after birth, and the CD117+ TSCs differentiated into lung alveolar epithelial cells, heart cardiomyocytes, and retina photoreceptor cells, corresponding with the organs in which they were injected. CONCLUSIONS: Our findings demonstrate that CD117+ TSCs have the properties of stem cells including clonogenicity, self-renewal, and multipotency. In utero administration of CD117+ TSCs engraft and differentiate into resident cells of the lung, heart, and retina during mouse development.

Monitoring of blood coagulation with non-contact drop oscillation rheometry.

BACKGROUND: Thromboelastography is widely used as a tool to assess the coagulation status of critical-care patients. It allows observation of changes in the material properties of whole blood brought about by clot formation and clot lysis. However, contact activation of the coagulation cascade at surfaces of thromboelastographic systems leads to inherent variability and unreliability in predicting bleeding or thrombosis risks, while also requiring large sample volumes. OBJECTIVES: To develop a non-contact drop oscillation rheometry (DOR) method to measure the viscoelastic properties of blood clots and to compare the results with current laboratory standard measurements. METHODS: Drops of human blood and plasma (5-10 µL) were acoustically levitated. Acoustic field modulation induced drop shape oscillations, and the viscoelastic properties of the sample were calculated by measuring the resonance frequency and damping ratio. RESULTS: DOR showed sensitivity to coagulation parameters. An increase in platelet count resulted in an increase in the maximum clot stiffness. An increase in the calcium ion level enhanced the coagulation rate prior to saturation. An increase in hematocrit resulted in a higher rate of clot formation and increased clot stiffness. Comparison of the results with those obtained with thromboelastography showed that coagulation started sooner with DOR, but with a lower rate and lower maximum stiffness. CONCLUSIONS: DOR can be used as a monitoring tool to assess blood coagulation status. The advantages of small sample size, the lack of contact and small strain (linear viscoelasticity) makes this technique unique for real-time monitoring of blood coagulation.

Evaluation of Placental Mesenchymal Stem Cell Sheets for Myocardial Repair and Regeneration.

IMPACT STATEMENT: This work explores placental tissue as a cell source for fabrication of tissue-engineered surgical patches for myocardial repair of congenital heart defects. This study demonstrates promising findings for the clinically driven evaluation of the cell source as defined by potential cardiac benefit, compatibility, cell source availability, and implant deliverability. It documents methods for the isolation of mesenchymal stem cells from human placental amnion and chorion tissues, characterization of these cells, and eventual cell sheet growth that can be leveraged going forward for patch fabrication. It establishes support to continue pursuing the placenta as a valuable cell source for myocardial repair.

Thromboelastography Is Associated With Surrogates for Bleeding After Pediatric Cardiac Operations.

BACKGROUND: Perioperative bleeding is a common complication in pediatric patients undergoing cardiac operation. Although thromboelastography (TEG) has been used in patients undergoing adult cardiac operation, limited data are available in pediatric patients. We hypothesize that TEG variables may be associated with surrogate end points for postoperative bleeding in pediatric patients undergoing complex cardiac operation. METHODS: In a retrospective study, TEG was obtained after protamine administration and on admission to the intensive care unit (ICU) in pediatric patients (≤18 years) undergoing cardiac operation that required cardiopulmonary bypass. A composite end point of extended blood product transfusion or surgical re-exploration for bleeding was used as a surrogate for perioperative bleeding. TEG variables were compared between patients who did or did not reach the composite end point. RESULTS: The study included 511 pediatric patients undergoing complex cardiac operation. The composite end point was reached in 52% of patients with maximum amplitude (MA) less than 45 mm compared with 31% with MA of 45 mm or more (p < 0.001). With the use of multivariable regression analysis, MA less than 45 mm was independently associated with the composite end point (p < 0.001). Patients with MA less than 45 mm who received platelet transfusion in the operating room (OR) were less likely to reach the composite end point within the subsequent 24 hours (8%) compared with patients who did not receive intraoperative platelet transfusion (24%) (p = 0.02). CONCLUSIONS: Intraoperative TEG MA less than 45 mm is associated with a surrogate end point for intraoperative bleeding in pediatric patients undergoing complex cardiac operation. In patients with MA less than 45 mm, prophylactic platelet transfusion in the OR may be associated with reduction in bleeding end points in the ICU.

Platelet testing to guide aspirin dose adjustment in pediatric patients after cardiac surgery.

OBJECTIVES: Thrombosis is associated with increased morbidity and mortality in pediatric patients undergoing cardiac surgery. Although aspirin commonly is used for thromboprophylaxis, the utility of laboratory-based tests that assess aspirin efficacy have not been evaluated. We sought to determine the relationship between platelet aggregation testing and aspirin dose adjustment on thrombosis rates in this population. METHODS: Pediatric patients undergoing cardiac surgery who received aspirin and underwent platelet testing were studied retrospectively. Patients were excluded if they were treated with multiple agents or experienced thrombosis before the initiation of aspirin. Thrombosis events within 30 days after initiation of aspirin were recorded. Associations between aspirin responsiveness and thrombosis rate and aspirin dose adjustment and thrombosis rate were assessed with the use of multivariable logistic regression analysis. RESULTS: Suboptimal platelet response to aspirin was detected in 64 of 430 patients (15%) and thrombosis was detected in 11 patients (2.6%). Lack of aspirin responsiveness on initial testing was a significant risk factor for thrombosis (P < .001) independent of age, weight, diagnosis, and initial aspirin dose. Dose escalation based on aspirin testing was performed in 40 of 64 patients, and significantly lower rate of thrombosis was observed in patients who underwent dose escalation compared with those without dose escalation (0/40 vs 9/24, P < .001). By multivariable analysis, the only significant independent risk factor for thrombosis was failure to increase aspirin dose after initial unresponsiveness (P < .001). CONCLUSIONS: Current practice of weight-based aspirin dosing may lead to subtherapeutic platelet inhibition in some children. Aspirin unresponsiveness is associated with increased risk of thrombosis after specific pediatric cardiac surgical procedures. Aspirin dose increase in unresponsive patients is associated with reduced risk of thrombosis.