bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coagulation Profile of Children on Extracorporeal Membrane Oxygenation (ECMO) - Is FXIII the Missing Link?
Authors: Haas Thorsten , Doell Carsten , Schmugge Markus , Cushing Melissa M. , Cannizzaro Vincenzo 
Published: November 2019

Abstract
Background
Published data about bleeding management on extracorporeal membrane oxygenation (ECMO) in children is sparse and to date no global transfusion algorithm has been established. Viscoelastic testing can be effective for determining the etiology and management of coagulopathic bleeding during cardiothoracic procedures, but data regarding its usefulness in ECMO patients are scarce. Recently, low factor XIII levels were determined to be a frequent finding in adult ECMO patients(Kalbhenn et al; Perfusion 2015;30:675-82).
Methods
This is a retrospective analysis of thromboelastometry (ROTEM®) and factor XIII data obtained in children (ages 0 to 18 years) undergoing ECMO since 2013 in a single center children's hospital. Acute bleeding treatment was based on daily ROTEM testing, complete blood count and routine plasmatic coagulation testing. The transfusion algorithm targeted a hemoglobin level >13g dL-1, a Quick's value >50%, a plasma fibrinogen level >1.5g L-1, and a platelet count of >100,000 µL-1. Red blood cells (RBC), solvent detergent (S/D) plasma and platelet apheresis concentrates were exclusively used to maintain hemostasis. Measurement of FXIII levels is not part of routine testing, but was assessed when unexplained bleeding was observed.
Results
Laboratory and transfusion data from sixteen patients, age 4 (1-15) months [median(IQR)] with a body weight of 6 (3-8) kg were included. Median time on ECMO was 7 (4-9) days. Large volumes of allogeneic blood were transfused to all children, meeting criteria for massive transfusion each individual day on ECMO (Tab.1). Overall, median daily ROTEM measurements were within reference ranges (Tab.2), while median levels of FXIII were decreased despite massive transfusion [FXIII levels 42% (28-51%)].
Conclusion
Pediatric ECMO was almost always combined with daily massive transfusion, which led to correction of overall ROTEM values. Notably, despite transfusion of large amounts of plasma, decreased FXIII levels were noted. This finding is supported by results of a study in adult ECMO patients, where FXIII levels <50% were observed in 88% of all patients. Although inherited homozygous FXIII deficiency is usually defined by levels <5%, even mildly to moderately reduced FXIII levels have been reported to contribute to increased bleeding after cardiac surgery(Ternström et al; Thromb Res 2010;126:e128-33). Further studies should be performed to assess the impact of FXIII substitution in pediatric ECMO patients and to investigate whether substitution of FXIII may decrease bleeding without increasing thrombotic complications.

Disclosures
Haas: CSL Behring: Speakers Bureau; TEM International: Speakers Bureau; Octapharma: Consultancy.
Perioperative Management for Congenital Factor XI Deficiency; A Systematic Review
Authors: Chai-Adisaksopha Chatree , Rattanathammethee Thanawat , Drakulic Milana , Matino Davide , Iorio Alfonso 
Published: November 2019

Abstract
Background: Congenital Factor XI (FXI) deficiency is the most common rare bleeding disorder, characterized by production defect of FXI. Bleeding manifestation is usually mild and associated with trauma or surgery. The treatment options during surgery include plasma, FXI concentrate, recombinant activated factor VII (rFVIIa), etc. This study aimed to investigate the efficacy of hemostatic control and thrombotic complications in patients with congenital FXI deficiency who underwent surgery or an invasive procedure.
Methods: We conducted a systematic search in MEDLINE, EMBASE and CENTRAL database from inception to March 2016. We included the case reports and case series of patients with congenital FXI deficiency. Studies must report the perioperative treatment regimen, hemostatic outcome and thromboembolic complication. The pre- and post-FXI levels were collected. The primary outcome was the efficacy of hemostatic control and the safety outcome was thromboembolic complication.
Results: There were 87 studies included in this review, involving 310 patients with congenital FXI deficiency. Median age was 49.5 years (range 0.3 to 94). Forty percent of the patients were male. Median baseline FXI level was 6.0% (range <1 to 75.0). FXI concentrate was the most common treatment (48.39%), following by plasma (21.61%), rFVIIa (12.90%) and others (FEIBA, DDAVP, tranexamic acid and no treatment; 17.1%). Hemostatic control was found to be good or excellent in 118 patients (88.06%) who had major surgery, 65 patients (92.85%) in minor surgery and 47 patients (97.91%) in dental procedure, Table 1. Thromboembolic events were reported in 7/150 (4.67%) patients treated with FXI concentrate and 4/34 (11.76%) patients treated with rFVIIa, Table 2. None of patients receiving plasma, FEIBA, DDAVP or tranexamic acid had thrombosis.
Conclusion: Hemostatic control during perioperative periodwas achieved in majority of patients with congenital FXI. Peak plasma FXI should be obtained in patients treated with plasma or FXI concentrate with the target FXI of 60-70% for major surgery and 40-50% for minor surgery. With respect to the higher risk of thromboembolic complication, we recommend plasma over FXI concentrate and rFVIIa for perioperative treatment in patients with FXI deficiency.

Disclosures
No relevant conflicts of interest to declare.
Risk of Bleeding from Primary Thromboprophylaxis (PTP) in Patients with Solid Cancer Receiving Chemotherapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (RCT)
Authors: Thein Kyaw Zin , Tun Aung M , Yeung Sai-Ching J , Oo Thein H. 
Published: November 2019

Abstract
Introduction: Thrombosis is the second leading cause of death in cancer patients. Hypothetically, prognosis might be improved by preventing thrombotic events by PTP. PTP has to be outweighed with the bleeding risk from PTP benefit. Moreover, PTP in ambulatory cancer patients remains uncertain. We performed a systematic review and meta-analysis of RCTs to determine the risk of major bleeding (MB) and clinically relevant non-major (CRNM) bleeding from PTP with low-molecular weight heparins (LMWH) in solid cancer patients receiving chemotherapy.
Methods: We systematically conducted a comprehensive literature search using MEDLINE and EMBASE databases through May 31, 2016. The RCTs with MB and CRNM bleeding as safety outcomes were included in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Random effects model was applied.
Results: 12 RCTs with a total of 8643 patients were eligible for analysis. Dalteparin, nadroparin, certoparin, semuloparin and bemiparin were used in the studies. 9 studies utilized prophylactic doses, while one used intermediate doses and 2 employed therapeutic dose. The PTP duration was from 6 weeks to 6 months. MB events were reported in 67 (1.486%) patients on PTP compared to 46 (1.112%) in control group. The pooled RR for MB was statistically nonsignificant at 1.341 (95% CI: 0.917 to 1.960, P = 0.130). CRNM bleeding events were noted in 209 (4.637%) in PTP group and 106 (2.563%) in control group. The RR for CRNM bleeding was statistically significant at 1.729 (95% CI: 1.017 to 2.938, P = 0.043). The absolute RD in CRNM bleeding was 0.020 (95% CI: 0.004 to 0.035, P = 0.012) with an estimated number needed to harm (NNH) of 48 to cause one CRNM bleeding event.
Conclusions: Approximately 60 patients are needed to be treated with PTP to prevent one symptomatic venous thrombosis among all ambulatory unselected cancer patients on chemotherapy in a previous meta-analysis. Our meta-analysis revealed that PTP contributed an increase in CRNM bleeding events with NNH of 48. The risk of bleeding should not be underestimated and more RCTs are required before making any recommendations.
Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures
Oo: Daiichi Sankyo: Research Funding.
A Systematic Review and Meta-Analysis of Randomized Controlled Trials (RCT) in Ambulatory Thromboprophylaxis (ATP) in Patients with Lung Cancer Receiving Chemotherapy
Authors: Thein Kyaw Zin , Yeung Sai-Ching J , Oo Thein H. 
Published: November 2019

Abstract

Introduction: Lung cancer (LC) is the commonest cause of cancer mortality in USA. Thromboembolism (TE) is the second leading cause of death in cancer patients. The ambulatory thromboprophylaxis (ATP) in solid cancer patients remains uncertain. However, LC is at least an intermediate risk for TE according to Khorana scoring system. We conducted a systematic review and meta-analysis of RCTs to determine the benefit and risk of ATP with low-molecular weight heparins (LMWH) in LC patients receiving chemotherapy.
Methods: We performed a comprehensive literature search using MEDLINE and EMBASE databases through June 30, 2016. The RCTs with reduction in TE as a primary or secondary endpoint and the major bleeding (MB) as a safety outcome were included in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Fixed effects model was applied.
Results: A total of 4315 patients with LC from 4 RCTs and a subgroup of another 2 RCTs were included in our analysis. The prophylactic doses of dalteparin, nadroparin, certoparin, semuloparin and bemiparin were used in the studies. The ATP duration ranged from 3 to 6 months. The randomization ratio was 2 to 1 in PROTECHT study and 1 to 1 in other studies. The TE incidence was 89 (4.007%) in ATP group and 166 (7.927%) in control group with a RR of 0.510 (95% CI: 0.397 to 0.654, P < 0.001). The absolute RD was -0.039 (95% CI: -0.053 to -0.025, P < 0.001) with an estimated number needed to treat (NNT) of 25 to prevent one TE event. MB events were 24 (1.506%) in ATP group compared to 15 (1.019%) in control group according to an analysis of 4 RCTs. The pooled RR for MB was statistically nonsignificant at 1.468 (95% CI: 0.785 to 2.746, P = 0.229). Clinically relevant nonmajor (CRNM) bleeding events were 80 (5.571%) in ATP group and in 24 (1.674%) in control group on an analysis of 4 RCTs. The RR for CRNM bleeding was statistically significant at 3.253 (95% CI: 2.092 to 5.059, P < 0.001).
Conclusions: In our study, the relative risk reduction for TE is 49% with a NNT of 25 to prevent one TE without increasing MB. Nevertheless, CRNM bleeding episodes were significant at a ratio of 3.253. Based on the findings, selection of LC patients who are at high TE risk is important. Further studies are necessary to define a subset of LC patients who may benefit from ATP.
Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures
Oo: Daiichi Sankyo: Research Funding.
Novel Class of Direct Thrombin Inhibitors Prevent Thrombosis By Inhibiting Fibrinogen Cleavage While Preserving Platelet Function
Authors: Sivaraja Mohan , Sizikov Sivan , Sandoval Nichole , Lin Kenneth , Igoudin Lev , Dash Subhadra , Xu Chengpei , Clemens Daniel , Estiarte Angels , Shiau Timothy , Short Kevin , Williams David , Datta Anirban , Kita David 
Published: November 2019

Abstract
We have developed a new class of direct thrombin inhibitors (VE-DTIs) that act through reversible covalent enzyme inhibition. These compounds inhibit thrombin with high potency (IC50 < 10 nM) and with better than 100× selectivity against related serine proteases. In rodents, VE-DTIs show dose-dependent efficacy in preventing arterial and venous thromboses respectively in arteriovenous shunt thrombosis and venous stasis thrombosis models. They also prevent thrombin-induced pulmonary embolism in rodents. Despite their strong anticoagulation properties, VE-DTIs are associated with significantly lower bleeding times than other approved anticoagulants dabigatran, argatroban or apixaban in rodent bleeding models (tail bleeding time and saphenous vein bleeding time).
We compared the effect of VE-DTIs and the DTIs argatroban and dabigatran on the coagulation cascade. In vitro, VE-DTIs inhibited thrombin-mediated fibrinogen cleavage with similar potency. Inhibition of thrombin/thrombomodulin complex-mediated activation of TAFI and protein C by VE-DTIs were also comparable. In contrast, VE-DTIs were more than 1000-fold less potent in inhibiting thrombin-mediated platelet activation than the other DTIs. Additionally, and also in contrast to argatroban and dabigatran, VE-DTIs protect rodents from the effects of thrombin-induced pulmonary embolism without significantly inhibiting platelet activation. The ability of VE-DTIs to prevent thrombosis without significantly impacting platelet function could lead to a new anticoagulant therapy with lower bleeding risk.

Disclosures
Sivaraja: Verseon Corporation: Employment, Equity Ownership. Sizikov:Verseon Corporation: Employment, Equity Ownership. Sandoval:Verseon Corporation: Employment, Equity Ownership. Lin:Verseon Corporation: Employment, Equity Ownership. Igoudin:Verseon Corporation: Employment, Equity Ownership. Dash:Verseon Corporation: Employment, Equity Ownership. Xu:Verseon Corporation: Employment, Equity Ownership. Clemens:Verseon Corporation: Employment, Equity Ownership. Estiarte:Verseon Corporation: Employment, Equity Ownership. Shiau:Verseon Corporation: Employment, Equity Ownership. Short:Verseon Corporation: Employment, Equity Ownership. Williams:Verseon Corporation: Employment, Equity Ownership. Datta:Verseon Corporation: Employment, Equity Ownership. Kita:Verseon Corporation: Employment, Equity Ownership.
The Effect of Platelet Transfusion on Death in the Intensive Care Unit
Authors: Arnold Donald M. , Ning Shuoyan , Barty Rebecca , Liu Yang , Cook Richard , Rochberg Bram , Iorio Alfonso , Shih Andrew W. , Heddle Nancy M 
Published: November 2019

Abstract

Background: Thrombocytopenia is a common complication of critical illness and an independent risk factor for death in the intensive care unit (ICU). Whether platelet transfusions modify the risk of death in critically ill patients is unknown.
Methods: Adult patients admitted to ICU who received one or more platelet transfusion over a 10-year period (2006 - 2015) from 3 academic hospitals in Canada were analyzed from a blood transfusion registry. Oncology patients were excluded. Contemporaneous non-transfused ICU patients were used as controls. Data from the registry were validated by integrity checks with medical records and laboratory information systems. We estimated the effect of platelet transfusion on mortality in ICU adjusted for baseline and time-varying covariates including multi-organ dysfunction score (MODS) and severity of thrombocytopenia using a stratified cox proportional hazards model. Significance was set at p<0.05 for all analyses.
Results: Of 43,234 non-oncology patients admitted to ICU, 5,621 (13.0%) received one or more platelet transfusion. Compared with non-transfused controls, transfused patients had lower platelet counts (median, 82 x109/L vs. 163 x109/L); were more often admitted after surgery (90.7% vs. 46.9%) especially cardiac surgery (86.8% of surgeries vs. 60.6%); and had higher unadjusted mortality (10.7% vs. 6.5%). Using regression analysis adjusted for covariates (nadir platelet count, red blood cell transfusion, need for hemodialysis) and stratified by age, baseline MODS score (available for 66.2% of patients) and need for invasive mechanical ventilation, platelet transfusions were associated with a lower risk of death in ICU [hazard ratio (HR)= 0.66; 95% confidence interval (CI), 0.46 - 0.96; p= 0.028; n= 26,404 with all available data]. A similar effect was observed in the subgroup of cardiac surgery patients (HR= 0.50; 95% CI, 0.26 - 0.98; p=0.044; n= 10,676) but not all surgical patients (HR = 0.73; 95% CI, 0.46 - 1.17; p= 0.188; n= 14,461).
Conclusion:After adjusting for illness severity, thrombocytopenia and other confounders common among critically ill patients, platelet transfusions were associated with improved survival in the population of mostly cardiac surgery patients. This potential protective effect of platelet transfusions requires further evaluation in prospective studies.

Disclosures
Arnold: Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; UCB: Consultancy; Amgen: Consultancy, Research Funding.
Blood Management Strategies to Reduce Transfusions after Elective Lower-Extremity Joint Arthroplasty Surgeries: One Tertiary Care Hospital's Early Experience with an Alternative Payment Model - a Total Joint 'Bundle
Authors: Kansagra Ankit J. , Dahiya Saurabh , Andrzejewski Chester , Krushell Robert , Lehman Andrew , Greenbaum Jordan , Ehresman Alice , Visintainer Paul , McGirr Joan , Mahoney Kathleen , Cloutier Darlene , Stefan Mihaela 
Published: November 2019

Abstract

Background and objective: Blood loss associated with total lower-extremity joint arthroplasty (TJA) often results in postoperative anemia and need for red blood cell transfusions (RBCT).
We report the results of a quality improvement initiative to improve blood management and decrease transfusions in patients undergoing TJA in one tertiary hospital.
Methods: Pre and post analysis after the implementation of a multifaceted intervention which included preoperative assessment for anemia, use of tranexamic acid, discouragement of autologous pre-operative blood collection and institution of more restrictive RBCT protocols. The results were stratified into three periods: I - pre-interventional (01/01/2013 -09/30/2013); II - peri-interventional (10/01/2013 -04/30/2014); and III - post-interventional (05/01/2014 -12/31/2014). We used fractional logistic regression with robust standard errors and regression modeling was configured using a segmented, or "piecewise", approach in which slope coefficients in each period were estimated.
Results: During the study period 2511 patients underwent surgery. Compared with the pre-intervention period, the total number of RBC units transfused decreased from a total of 587 in the pre- to 107 in the post-intervention period (81.8% decrease). The percentage of patients receiving transfusion declined from 36.7% in pre-implementation period to 8.8% to post-intervention period. Depending upon the costing methodology used, annualized savings in RBC expenditure between time period 1 and 3 ranged from a low of $108,000 using the acquisition cost per unit (~$225/unit) to $480,000 when using activity based costing (~$1000/unit). Mean length of stay (days) and 30-day readmission rates remained stable during the study period.
Conclusions: A multidisciplinary approach with proactive involvement of all the interested parties can be successful and sustainable in reducing RBCT and its associated costs, in patients undergoing TJA.

Disclosures
No relevant conflicts of interest to declare.
Inhibiting IL-2 Signaling and the Regulatory T-Cell Pathway Using Computationally Designed Novel Peptides
Authors: Price-Troska Tammy , Diller David , Bayden Alexander , Jarosinski Mark , Audies Joseph , Yang Zhi-Zhang , Ansell Stephen M 
Published: November 2019

Abstract
Regulatory T-cells (TREG) are the gateway to immune function and typically regulate immune cell activation. Cytokines, including interleukin-2 (IL-2), induce T-cell differentiation and promote a regulatory phenotype. Once activated via the IL-2 receptor (IL-2R), a cascade of events in T-cells initiate signal transducer and activator of transcription 5 (STAT5) and Forkhead box P3 (FOXP3) activation which appear to function as important regulators of this immunologic pathway and promote the development and function of TREG cells. In non-Hodgkin lymphoma (NHL), we have found that intratumoral TREG cells are increased in number and suppress immune function. In previous work, we have found that TREG cells inhibit T-cell proliferation, suppress cytokine production and limit effector cell cytotoxicity. We have also shown that increased serum levels of soluble sIL-2Rα is a prognostic factor in NHL and that sIL-2Rα can bind to IL-2 and promote its signaling thereby increasing TREG cell numbers. In this study, we developed a strategy to inhibit the binding of IL-2 to sIL-2Rα with the goal of suppressing the induction of FOXP3 and decreasing TREG cell numbers. To do this, we developed peptides designed to disrupt the interaction between IL2 and sILRα.
In collaboration with CMDBioscienceSM, we developed and analyzed 22 peptide compounds derived by structure-based computational design. Initially, we screened each peptide at increasing concentrations using an ELISA assay to test the inhibition of IL-2/IL-2Rα binding by the solubilized peptide. Candidate peptides were then further tested using upregulation of pSTAT5 and FOXP3 in T-cells measured by flow cytometry as a measure of inhibition of IL-2 signaling. The peptides were developed according to different design hypotheses and grouped into different families; the screening ELISA results indicated 4 promising peptides that inhibited IL2/IL2Rα binding (up to 100% inhibition; max peptide concentration of 100uM). These peptides were then used to determine their effect on STAT5 and FOXP3 expression. A lead candidate peptide consistently reduced the expression of FOXP3 and STAT5 expression compared to cells not exposed to peptide. Use of the peptide to disrupt IL-2 signaling inhibited the development of cells with a TREG phenotype.
We conclude that structure-based peptide design can be used to identify novel peptide inhibitors that block IL-2/IL-2Rα signaling and inhibit STAT5 and FOXP3 upregulation. These peptides could be used as new therapeutic agents to limit immune suppression by TREG cells and promote a more effective anti-tumor immune response in NHL.

Disclosures
No relevant conflicts of interest to declare.