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BACKGROUND Heparan sulfate is an integral component of the glycocalyx that provides an anticoagulant layer close to the endothelium. Hypoperfusion, inflammation and sympathoadrenal activation following major trauma result in glycocalyx shedding and subsequent release of heparan sulfate into the bloodstream. The possible anticoagulant effect of this "auto-heparinization" has been suggested as a potential driver of trauma-induced coagulopathy. We investigated whether thromboelastometry can be used to detect trauma-induced auto-heparinization. METHODS This study comprised three parts. First, in a retrospective clinical study of 264 major trauma patients, the clotting time (CT) in the INTEM (intrinsic activation) and HEPTEM (intrinsic activation plus heparinase) assays were evaluated upon emergency room admission. Second, in an in-vivo experimental rat model of hemorrhagic-traumatic shock, the release of heparan sulfate was investigated with INTEM and HEPTEM analysis of whole blood. Third, in-vitro spiking of whole blood from healthy volunteers was undertaken to assess the effects of clinically relevant quantities of heparan sulfate and heparin on CT in the INTEM and HEPTEM assays. RESULTS In the first part, severe injury and hemorrhagic shock was not associated with any increases in INTEM CT versus HEPTEM CT. Part two showed that an approximate 3-fold increase in heparan sulfate resulting from hemorrhagic traumatic shock in rats did not prolong INTEM CT, and no significant differences between INTEM CT and HEPTEM CT were observed. Third, spiking of whole blood with heparan sulfate had no impact on INTEM CT, whereas heparin elicited significant prolongation of INTEM CT. CONCLUSIONS Despite structural similarity between heparan sulfate and heparin, the amounts of heparan sulfate shed in response to trauma did not exert an anticoagulant effect that was measurable by the intrinsically activated CT in thromboelastometry. The extent to which heparan sulfate contributes to trauma-induced coagulopathy is yet to be elucidated. LEVEL OF EVIDENCE III. Retrospective clinical analysis. Prospective preclinical study.

Only a very small portion of end-stage organ failures can be treated by transplantation because of the shortage of donor organs. Although artificial long-term organ support such as ventricular assist devices provide therapeutic options serving as a bridge-to-transplantation or destination therapy for end-stage heart failure, suitable long-term artificial lung systems are still at an early stage of development. Although a short-term use of an extracorporeal lung support is feasible today, the currently available technical solutions do not permit the long-term use of lung replacement systems in terms of an implantable artificial lung. This is currently limited by a variety of factors: biocompatibility problems lead to clot formation within the system, especially in areas with unphysiological flow conditions. In addition, proteins, cells, and fibrin are deposited on the membranes, decreasing gas exchange performance and thus, limiting long-term use. Coordinated basic and translational scientific research to solve these problems is therefore necessary to enable the long-term use and implantation of an artificial lung. Strategies for improving the biocompatibility of foreign surfaces, for new anticoagulation regimes, for optimization of gas and blood flow, and for miniaturization of these systems must be found. These strategies must be validated by in vitro and in vivo tests, which remain to be developed. In addition, the influence of long-term support on the pathophysiology must be considered. These challenges require well-connected interdisciplinary teams from the natural and material sciences, engineering, and medicine, which take the necessary steps toward the development of an artificial implantable lung.

Thrombosis and haemostasis 122(4), 552-559 (2022). doi:10.1055/a-1549-6556, Published by Thieme, Stuttgart

Purpose of review Posttraumatic bleeding following major trauma is life threatening for the patient and remains a major global health issue. Bleeding after major trauma is worsened by trauma-induced coagulopathy (TIC). TIC consists of acute trauma coagulopathy and resuscitation coagulopathy. The early diagnosis and management of prehospital TIC management are challenging. Recent findings Concepts for early diagnosis and management of civilian prehospital TIC management are evolving. The feasibility of prehospital blood component as well as coagulation factor transfusion has been proven. Summary Due to different national guidelines and regulations of blood component therapies there is a wide heterogeneity in concepts of prehospital damage control resuscitation. Tranexamic acid administration is widely accepted, whereas the transfusion of whole blood, blood components, or coagulations factors needs further examination in the civilian setting.

Background Viscoelastic coagulation testing is increasingly used to diagnose trauma-induced coagulopathy. Two fully automated analysers, TEG 6s and ROTEM Sigma, were launched recently. No previous studies have compared these devices in trauma paients. Objective The aim of this study was to evaluate whether both fully automatic devices deliver comparable results. Design Prospective observational study. Setting Level one trauma centre from August 2017 to September 2018. Patients A total of 105 blood samples from 67 trauma patients were analysed simultaneously on TEG 6s and ROTEM Sigma. Main outcome measures TEG 6s assays kaolin (CK), RapidTEG (CRT), kaolin with heparinase (CKH) and functional fibrinogen were compared with ROTEM Sigma assays INTEM, EXTEM, HEPTEM and FIBTEM. TEG 6s functional fibrinogen level was compared with plasma fibrinogen concentration, measured using the Clauss method. Correlations were classified as weak (Spearman correlation coefficient 0.20 to 0.39), moderate (0.40 to 0.59), strong (0.60 to 0.79) or very strong (≥0.80). Results The TEG 6s parameters reaction time, kinetic time and α-angle (CK, CRT and CKH assays) mostly showed strong correlations with the corresponding ROTEM parameters clotting time, clot formation time and α-angle (INTEM, EXTEM and HEPTEM assays). The exceptions were CRT reaction time vs. EXTEM clotting time, and CK α-angle vs. INTEM α-angle, which correlated moderately. Absolute values for many of these parameters showed significant differences between the two devices. Very strong correlations and similar absolute values were observed between TEG 6s maximum amplitude (CRT, CK and CKH assays) and ROTEM maximum clot firmness (EXTEM, INTEM and HEPTEM assays). Correlations were also very strong for functional fibrinogen maximum amplitude vs. FIBTEM maximum clot firmness and functional fibrinogen level vs. Clauss fibrinogen concentration, but absolute values were significantly different. Conclusion Strong to very strong correlations were observed between corresponding TEG 6s and ROTEM Sigma parameters. However, absolute values showed significant differences for most of the measurements.

Critical care 23(1), 1-4 (2019). doi:10.1186/s13054-019-2524-4, Published by Springer, Berlin ; Heidelberg

OBJECTIVE To assess the impact of direct oral anticoagulant (DOAC) intake compared with Coumadin (COU) in patients suffering hip fractures (HFs). DESIGN Retrospective cohort analysis. SETTING Level 1 Trauma Center. INTERVENTION Timing of surgical hip fixation. PATIENTS Three-hundred twenty patients 65 years of age or older with isolated HF were enrolled into the study: 207 (64.7%) without any antithrombotic therapy (no-ATT), 59 (18.4%) on COU, and 54 (16.9%) on DOACs. MAIN OUTCOME MEASUREMENTS Time to surgery, blood loss, mortality, hospital length of stay, red blood cell transfusion, use of reversal agents, and Charlson Comorbidity Index. RESULTS Patients on COU and DOACs had a higher Charlson Comorbidity Index compared with the no-ATT group (P < 0.0001). Despite the fact that significantly more patients received reversal agents in the COU group compared with DOAC medication (P < 0.0001), percentage of transfused patients were similar (54.2% vs. 53.7%). Time to surgery was significantly shorter in the no-ATT group when compared with DOAC patients (12-29.5 hours, respectively). No difference in postoperative hemorrhage, intensive care unit length of stay, and mortality was observed between groups. CONCLUSIONS DOAC medication in HF patients caused long elapse time until surgical repair. We found no evidence of higher bleeding rates in HF patients on DOACs compared with COUs. Earlier HF fixation might be indicated in DOAC patients. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Background Extracorporeal membrane oxygenation (ECMO) is a potential treatment option in critically ill COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) if mechanical ventilation (MV) is insufficient; however, thromboembolic and bleeding events (TEBE) during ECMO treatment still need to be investigated. Methods We conducted a retrospective, single-center study including COVID-19 patients treated with ECMO. Additionally, we performed a univariate analysis of 85 pre-ECMO variables to identify factors influencing incidences of thromboembolic events (TEE) and bleeding events (BE), respectively. Results Seventeen patients were included; the median age was 57 years (interquartile range [IQR]: 51.5–62), 11 patients were males (65%), median ECMO duration was 16 days (IQR: 10.5–22), and the overall survival was 53%. Twelve patients (71%) developed TEBE. We observed 7 patients (41%) who developed TEE and 10 patients (59%) with BE. Upper respiratory tract (URT) bleeding was the most frequent BE with eight cases (47%). Regarding TEE, pulmonary artery embolism (PAE) had the highest incidence with five cases (29%). The comparison of diverse pre-ECMO variables between patients with and without TEBE detected one statistically significant value. The platelet count was significantly lower in the BE group (n = 10) than in the non-BE group (n = 7) with 209 (IQR: 145–238) versus 452 G/L (IQR: 240–560), with p = 0.007. Conclusion This study describes the incidences of TEE and BE in critically ill COVID-19 patients treated with ECMO. The most common adverse event during ECMO support was bleeding, which occurred at a comparable rate to non-COVID-19 patients treated with ECMO.

Nature utilizes endothelium as a blood interface that perfectly controls hemostasis, preventing the uncontrolled formation of thrombi. The management of positive and negative feedback that finely tunes thrombosis and fibrinolysis is essential for human life, especially for patients who undergo extracorporeal circulation (ECC) after a severe respiratory or cardiac failure. The exposure of blood to a surface different from healthy endothelium inevitably initiates coagulation, drastically increasing the mortality rate by thromboembolic complications. In the present study, an ultrathin antifouling fibrinolytic coating capable of disintegrating thrombi in a self-regulated manner is reported. The coating system is composed of a polymer brush layer that can prevent any unspecific interaction with blood. The brushes are functionalized with a tissue plasminogen activator (tPA) to establish localized fibrinolysis that solely and exclusively is active when it is required. This interactive switching between the dormant and active state is realized through an amplification mechanism that increases (positive feedback) or restores (negative feedback) the activity of tPA depending on whether a thrombus is detected and captured or not. Thus, only a low surface density of tPA is necessary to lyse real thrombi. Our work demonstrates the first report of a coating that self-regulates its fibrinolytic activity depending on the conditions of blood.

Background The role of extracorporeal membrane oxygenation (ECMO) in the management of critically ill COVID‐19 patients remains unclear. Our study aims to analyze the outcomes and risk factors from patients treated with ECMO. Methods and Results This retrospective, single‐center study includes 17 COVID‐19 patients treated with ECMO. Univariate and multivariate parametric survival regression identified predictors of survival. Nine patients (53%) were successfully weaned from ECMO and discharged. The incidence of in‐hospital mortality was 47%. In a univariate analysis, only four out of 83 pre‐ECMO variables were significantly different; IL‐6, PCT, and NT‐proBNP were significantly higher in non‐survivors than in survivors. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score was significantly higher in survivors. After a multivariate parametric survival regression, IL‐6, NT‐proBNP and RESP scores remained significant independent predictors, with hazard ratios (HR) of 1.069 [95%‐CI: 0.986‐1.160], p= 0.016 1.001 [95%‐CI: 1.000‐1.001], p=0.012; and 0.843 [95%‐CI: 0.564‐1.260], p=0.040, respectively. A prediction model comprising IL‐6, NT‐proBNP, and RESP score showed an area under the curve (AUC) of 0.87, with a sensitivity of 87.5% and 77.8% specificity compared to an AUC of 0.79 for the RESP score alone. Conclusion The present study suggests that ECMO is a potentially lifesaving treatment for selected critically ill COVID‐19 patients. Considering IL‐6 and NT‐per‐BNP, in addition to the RESP score, may enhance outcome predictions.

BACKGROUND Many trauma centres have adopted the administration of fixed ratios of packed red blood cells (PRBCs), platelet concentrates and fresh frozen plasma (FFP) for bleeding patients. However, the haemostatic efficacy of this concept is not well proven. OBJECTIVE Our objective was to characterise the haemostatic profile of different ratios (2 : 1 : 1, 1 : 1 : 1 and 1 : 1 : 2) of PRBCs, platelet concentrates and FFP in comparison with coagulation factor concentrates (fibrinogen and/or prothrombin complex concentrate). DESIGN An in vitro study. SETTING Research laboratories of the department of transfusion medicine, Linz, Austria. MATERIALS Whole blood donations from a total of 20 male volunteers. INTERVENTION Reconstitution of blood at different ratios of PRBCs, platelet concentrates and FFP or coagulation factor concentrates. MAIN OUTCOME MEASURES Cell count, conventional and thromboelastometric coagulation parameters, single coagulation factor activities as well as endogenous thrombin potential. RESULTS Fibrinogen levels and haematocrit were lower in the FFP group at any ratio compared with the concentrate-based groups (P

Adequate plasma levels of fibrinogen are essential for clot formation, and in severe bleeding, fibrinogen reaches a critically low plasma concentration earlier than other coagulation factors. Although the critical minimum concentration of fibrinogen to maintain hemostasis is a matter of debate, many patients with coagulopathic bleeding require fibrinogen supplementation. Among the treatment options for fibrinogen supplementation, fibrinogen concentrate may be viewed by some as preferable to fresh frozen plasma or cryoprecipitate. The authors review major studies that have assessed fibrinogen treatment in trauma, cardiac surgery, end-stage liver disease, postpartum hemorrhage, and pediatric patients. Some but not all randomized controlled trials have shown that fibrinogen concentrate can be beneficial in these settings. The use of fibrinogen as part of coagulation factor concentrate based therapy guided by point-of-care viscoelastic coagulation monitoring (ROTEM [rotational thromboelastometry] or TEG [thromboelastography]) appears promising. In addition to reducing patients' exposure to allogeneic blood products, this strategy may reduce the risk of complications such as transfusion-associated circulatory overload, transfusion-related acute lung injury, and thromboembolic adverse events. Randomized controlled trials are challenging to perform in patients with critical bleeding, and more evidence is needed in this setting. However, current scientific rationale and clinical data support fibrinogen repletion in patients with ongoing bleeding and confirmed fibrinogen deficiency.

The first ever venous thrombotic condition associated with spaceflight, an internal jugular vein thrombus requiring anticoagulation, has recently been reported. Systematic investigation of space travel-associated thrombotic risk has not been conducted. Cellular, animal, and human studies performed in ground-based models and in actual weightlessness revealed influences of weightlessness and gravity on the blood coagulation system. However, human study populations were small and limited to highly selected participants. Evidence in individuals with medical conditions and older persons is lacking. Evidence for thrombotic risk in spaceflight is unsatisfactory. This issue deserves further study in heterogeneous, high risk populations to find prevention strategies and to enable safe governmental and touristic human spaceflight.

BACKGROUND In long-term left ventricular assist device (LVAD) therapy, recurrent bleeding events may justify cessation of anticoagulation therapy (AT). However, data about THE safety and risks of AT cessation in LVAD patients are scarce.Methods and Results:Between 2010 and 2015, 128 patients received a HeartMate II (HMII). Following recurrent bleeding events, we ceased vitamin K antagonist (VKA) therapy in 13 patients (10%) (no-VKA group). To characterize the hemostatic profile, we performed von Willebrand factor (vWF), platelet function (PF), and other hemostatic tests in all HMII patients. The incidence of pump thrombosis (PT), ischemic stroke (IS) and bleeding events in this HMII population was 4.7 %, 6.2% and 36.7%, respectively. Median survival without VKA was 435 days. No cases of PT and only 1 of IS occurred after AT discontinuation. All patients had impaired PF and acquired von Willebrand syndrome (AvWS). However, the vWF collagen-binding activity to antigen ratio before and after VKA cessation was significantly lower in the no-VKA group compared with the HMII population (0.60±0.12 vs. 0.73±0.14, P=0.006). The thrombin-antithrombin III complex (TAT) value was significantly higher in the no-VKA group (P=0.0005). CONCLUSIONS We experienced good results with AT cessation in specific HMII patients. The simultaneous onset of AvWS and high TAT values could explain at least in part the low thromboembolic rate in HMII patients without VKA.

Background Few data have been published to date on outcomes after the common clinical experience of severe hemorrhage in orally anticoagulated patients. Methods A prospective, multicenter observational study was carried out to investigate outcomes and management in a series of consecutive patients who sustained a severe hemorrhage under treatment with vitamin K antagonists (VKA) or direct oral anticoagulant drugs (DOAC). The primary endpoint was in-hospital death up to and including day 30 after hospital admission. The secondary endpoints were the duration of bleeding, in-hospital death due to hemorrhage (as defined by the study physician examining the patient's records), the use of antagonists, the extent of supportive measures used to stop the hemorrhage, and an assessment of causality. Consecutive patients were recruited until a predefined number of patients was reached in both groups. Results Among 193 patients with severe hemorrhage, 97 had been taking a VKA, and 96 had been taking a DOAC. 13.0 % (95% confidence interval [8.6; 18.5]; 25/193) of the overall group patients died in the first 30 days after hospital admission, including 17.5% ([10.6; 26.6]; 17/97) in the VKA group and 8.3% ([3.7; 15.8]; 8/96) in the DOAC group (p = 0.085). The median duration of bleeding was 19.8 hours in the VKA group and 27.8 hours in the DOAC group (p = 0.632). The in-hospital mortality due to hemorrhage was higher in the VKA group than in the DOAC group (15.5% [15/97] versus 4.2% [4/97]; p = 0.014). Only the use of prothrombin complex concentrates (PCCs) lowered the median duration of hemorrhage in the two patient groups. In 35% (68/193) of the patients, the hemorrhage was caused by an external influence, most commonly a fall. Conclusion The in-hospital mortality was higher among patients treated with VKA than among patients treated with DOAC, although the difference failed to reach statistical significance.

Factor Xa inhibitors prevent thrombosis but are associated with severe or life-threatening bleeding. Here, the authors present data on four-factor prothrombin complex concentrates in management of anticoagulation-associated bleeding and restoring hemostasis, including recent results from the UPRATE study.

Trauma care providers are facing an increasing number of elderly patients on direct oral anticoagulants prior to injury. For dabigatran etexilate (DAB), the specific antagonist idarucizumab (IDA) has been approved since 2015 as a reversal agent. However, only limited data regarding the use of IDA in trauma patients are available. We performed a retrospective analysis of trauma patients under DAB for whom IDA administration was deemed necessary to reverse DAB’s antithrombotic effect. A total of 15 (9 male) patients were treated with IDA during the study period. The mean age was 81 ± 10 years. Intracranial haemorrhage (n = 7) and long bone fractures (n = 5) were the most common types of injury. Three patients were diagnosed as polytrauma. In all but one patient, atrial fibrillation was the indication for DAB intake. The median dose of IDA was 2.5 g (IQR 2.5–5). IDA administration decreased DAB plasma levels from 112.4 (IQR 73.4–123.4) to 5 (IQR 4–12) ng/mL (p = 0.031), thrombin time from 114.8 ± 48.3 to 16.2 ± 0.5 s (p

The direct oral anticoagulants (DOACs) provide a number of clinical advantages over vitamin K antagonists for the treatment of thromboembolism, including improved efficacy and safety, as well as no need for regular monitoring of anticoagulant effect. However, as with all anticoagulants, bleeding complications may occur, and anticoagulant reversal may be required in specific clinical situations, such as in patients experiencing spontaneous or traumatic bleeds, or in anticoagulated patients requiring emergency surgery or other invasive procedures. Therefore, several reversal agents for the DOACs are in development. This includes the specific reversal agent idarucizumab, which has been approved by the U.S. Food and Drug Administration and the European Medicines Agency for use in patients treated with dabigatran when urgent reversal of its anticoagulant effects is needed. Idarucizumab is a humanized monoclonal antibody fragment that binds with high affinity to free and thrombin-bound dabigatran, resulting in an almost irreversibly bound idarucizumab–dabigatran complex and thereby neutralizing dabigatran's anticoagulant activity. The reversal of the anticoagulant effects of dabigatran by idarucizumab has been demonstrated in animal bleeding models, in healthy volunteers with a range of ages and renal function, and in anticoagulated patients. In the phase 1 trials, at doses of 2 g or greater, idarucizumab resulted in immediate and complete reversal of the dabigatran anticoagulant effects and was well tolerated. In the absence of dabigatran, idarucizumab showed no effect on coagulation parameters or thrombin formation. These findings provide initial evidence that idarucizumab could provide a safe and effective means of reversing anticoagulant activity in patients treated with dabigatran in need of emergency surgery or in emergency bleeding situations.

Clinical and applied thrombosis, hemostasis 22(8), 749-759 (2016). doi:10.1177/1076029615584662, Published by Sage, Thousand Oaks, Calif.

The licensed anesthetic xenon, which exerts organ protective properties, was recently added by the World Anti-Doping Agency to the list of prohibited substances. Xenon is supposed to trigger the production of hypoxia-inducible factor 1α (HIF-1α) and subsequently erythropoietin, but data are limited to in vivo experimental work. Therefore we evaluated the effect of xenon on erythropoietin levels in healthy persons. Twenty-four healthy volunteers were randomly assigned either to a group spontaneously breathing xenon 30 % (Xe/O2 30 %/60 %) or a group breathing control gas (N2/O2 40 %/60 %) for 45 min. Primary outcome parameters were erythropoietin levels at several time-points after exposure. Secondary outcome parameters were serum levels of testosterone, cytokines, and growth factors as well as concentrations of xenon in blood and exhalation samples measured at several time-points after exposure. In addition, hemodynamic safety parameters were monitored during exposure. The administration of xenon significantly increased erythropoietin levels 8 h after exposure (1.34 [±0.368]; p = 0.008), peaking at 24 h compared to the baseline values (1.45 [±0.498]; p = 0.01) and remained traceable in blood and exhalation probes until 24 h after exposure. In contrast, no significant change was observed in the control group. Measurement of stromal cell-derived factor 1 (SDF-1) revealed a significant increase of SDF-1 levels (p = 0.005), whereas no differences were observed with respect to growth factors, cytokines, or androgens. In an in vitro chemotaxis assay, endothelial progenitor cells (EPCs) showed a trend towards increased migration in serum samples received from participants after xenon exposure (p = 0.080). The present study presents first evidence about a xenon-induced effect on increased erythropoietin levels in healthy volunteers. The study was registered at the European Medicines Agency (EudraCT-number: 2014-000973-38) and at ClinicalTrials.gov (NCT number: 02129400).

Clinical nutrition 38(6), 2756-2762 (2019). doi:10.1016/j.clnu.2018.11.033, Published by Elsevier, Amsterdam [u.a.]

Clinical and applied thrombosis, hemostasis 24(5), 724-733 (2018). doi:10.1177/1076029618755947, Published by Sage, Thousand Oaks, Calif.

There is increasing interest in prothrombin complex concentrates as therapy for perioperative and trauma-related bleeding. A suitable point-of-care test is needed to guide such therapy, and randomized controlled trials are needed for robust, evidence-based recommendations.

Purpose of review To provide an overview of acquired coagulopathies that can occur in various perioperative clinical settings. Also described are coagulation disturbances linked to antithrombotic medications and currently available strategies to reverse their antithrombotic effects in situations of severe hemorrhage. Recent findings Recent studies highlight the link between low fibrinogen and decreased fibrin polymerization in the development of acquired coagulopathy. Particularly, fibrin(ogen) deficits are observable after cardiopulmonary bypass in cardiac surgery, on arrival at the emergency room in trauma patients, and with ongoing bleeding after child birth. Regarding antithrombotic therapy, although new oral anticoagulants offer the possibility of efficacy and relative safety compared with vitamin K antagonists, reversal of their anticoagulant effect with nonspecific agents, including prothrombin complex concentrate, has provided conflicting results. Specific antidotes, currently being developed, are not yet licensed for clinical use, but initial results are promising. Summary Targeted hemostatic therapy aims to correct coagulopathies in specific clinical settings, and reduce the need for allogeneic transfusions, thus preventing massive transfusion and its deleterious outcomes. Although there are specific guidelines for reversing anticoagulation in patients treated with antiplatelet agents or warfarin, there is currently little evidence to advocate comprehensive recommendations to treat drug-induced coagulopathy associated with new oral anticoagulants.

Background Traumatic brain injury (TBI) is the leading cause of death among trauma patients. Patients under antithrombotic therapy (ATT) carry an increased risk for intracranial haematoma (ICH) formation. There is a paucity of data about the role of direct oral anticoagulants (DOACs) among TBI patients. Methods In this retrospective study, we investigated all TBI patients ≥60-years-old who were admitted to the intensive care unit (ICU) from January 2014 until May 2017. Patients were grouped into those receiving vitamin K antagonists (VKA), platelet inhibitors (PI), DOACs and no antithrombotic therapy (no-ATT). Results One-hundred-eighty-six, predominantly male (52.7%) TBI patients with a median age of 79 years (range: 70–85 years) were enrolled in the study. Glasgow Coma Scale and S-100β were not different among the groups. Patients on VKA and DOACs had a higher Charlson Comorbidity Index compared to the PI group and no-ATT group (p = 0.0021). The VKA group received reversal agents significantly more often than the other groups (p

Background Although idarucizumab is the preferred treatment for urgent dabigatran reversal, it is not always available. Prothrombin complex concentrate (PCC) may be an alternative and, with bleeding in trauma, additional hemostatic therapy may be required. The authors investigated multimodal treatment in a preclinical polytrauma model. Methods Dabigatran etexilate (30 mg/kg twice daily) was given orally to 45 male pigs for 3 days. On day 4, animals received a dabigatran infusion before blunt liver injury and bilateral femur fractures. After injury, animals were randomized 1:1:1:1:1 to receive placebo (control), tranexamic acid (TXA; 20 mg/kg) plus human fibrinogen concentrate (FCH; 80 mg/kg) (TXA–FCH group), PCC (25 U/kg or 50 U/kg) plus TXA plus FCH (PCC25 and PCC50 groups), or 60 mg/kg idarucizumab (IDA) plus TXA plus FCH (IDA group). Animals were monitored for 240 min after trauma, or until death. Results The degree of injury was similar in all animals before intervention. Control and TXA–FCH animals had the highest total postinjury blood loss (3,652 ± 601 and 3,497 ± 418 ml) and 100% mortality (mean survival time 96 and 109 min). Blood loss was significantly lower in the PCC50 (1,367 ± 273 ml) and IDA (986 ± 144 ml) groups, with 100% survival. Thrombin–antithrombin levels and thrombin generation were significantly elevated in the PCC50 group. Conclusions Idarucizumab may be considered the optimal treatment for emergency reversal of dabigatran anticoagulation. However, this study suggests that PCC may be similarly effective as idarucizumab and could therefore be valuable when idarucizumab is unavailable. (Anesthesiology 2017; 127:852-61)

Plasma products, including fresh frozen plasma, are administered extensively in a variety of settings from massive transfusion to vitamin K antagonist reversal. Despite the widespread use of plasma as a hemostatic agent in bleeding patients, its effect in comparison with other available choices of hemostatic therapies is unclear. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PubMed Central, and databases of ongoing trials for randomized controlled trials that assessed the efficacy and/or safety of therapeutic plasma as an intervention to treat bleeding patients compared with other interventions or placebo. Of 1243 unique publications retrieved in our initial search, no randomized controlled trials were identified. Four nonrandomized studies described the effect of therapeutic plasma in bleeding patients; however, data gathered from these studies did not allow for comparison with other therapeutic interventions primarily as a result of the low number of patients and the use of different (or lack of) comparators. We identified two ongoing trials investigating the efficacy and safety of therapeutic plasma, respectively; however, no data have been released as yet. Although plasma is used extensively in the treatment of bleeding patients, evidence from randomized controlled trials comparing its effect with those of other therapeutic interventions is currently lacking.

Supplemental Digital Content is available in the text. Published ahead of print August 24, 2017., Prothrombin complex concentrates (PCCs) have been associated with a possible risk of thromboembolic complications, potentially attributable to an increased ratio of the plasma concentration of factor II (FII) to antithrombin (AT). We developed a mathematical model to examine the relationship between amounts of PCC or therapeutic plasma administered, and plasma levels of FII and AT. The model showed that PCC produces substantial increases in plasma levels of FII but only small changes in AT, increasing the FII:AT ratio. Therapeutic plasma was shown to have only modest effects on levels of FII or AT, unless high doses are used.

Supplemental Digital Content is available in the text, Several direct oral anticoagulants (DOACs), including direct thrombin and factor Xa inhibitors, have been approved as alternatives to vitamin K antagonist anticoagulants. As with any anticoagulant, DOAC use carries a risk of bleeding. In patients with major bleeding or needing urgent surgery, reversal of DOAC anticoagulation may be required, presenting a clinical challenge. The optimal strategy for DOAC reversal is being refined, and may include use of hemostatic agents such as prothrombin complex concentrates (PCCs; a source of concentrated clotting factors), or DOAC-specific antidotes (which bind their target DOAC to abrogate its activity). Though promising, most specific antidotes are still in development. Preclinical animal research is the key to establishing the efficacy and safety of potential reversal agents. Here, we summarize published preclinical animal studies on reversal of DOAC anticoagulation. These studies (n = 26) were identified via a PubMed search, and used rodent, rabbit, pig, and non-human primate models. The larger of these animals have the advantages of similar blood volume/hemodynamics to humans, and can be used to model polytrauma. We find that in addition to varied species being used, there is variability in the models and assays used between studies; we suggest that blood loss (bleeding volume) is the most clinically relevant measure of DOAC anticoagulation-related bleeding and its reversal. The studies covered indicate that both PCCs and specific reversal agents have the potential to be used as part of a clinical strategy for DOAC reversal. For the future, we advocate the development and use of standardized, clinically, and pharmacologically relevant animal models to study novel DOAC reversal strategies.

Shear stress from left ventricular assist devices induces von Willebrand factor degradation and platelet dysfunction, leading to nonsurgical bleeding. We characterized the hemostatic changes induced by 2 centrifugal left ventricular assist devices, the HeartMate 3 (Abbott Inc, Chicago, Ill) and the EVAHEART (Evaheart Inc, Houston, Tex), for comparison.Whole blood from 8 healthy volunteers was used ex vivo. Blood from the same donor was used for 6 hours of circulation in a miniature mock-loop system consisting of 2 identical extracorporeal circuits to compare the following experimental settings: (1) optimal revolutions per minute (rpm) for the HeartMate 3 (n = 4; 5000 rpm) and the EVAHEART (n = 4; 2500 rpm) and (2) equal rpm (3000 rpm for the HeartMate 3 and EVAHEART, n = 4 vs n = 4). For both settings, blood flow was adjusted to 1 mock-loop filling volume per minute (HeartMate 3 = 82 mL/min, EVAHEART = 100 mL/min). A panel of coagulation markers was analyzed to investigate hemostatic changes.The free plasma hemoglobin concentration was significantly lower in the EVAHEART compared with the HeartMate 3 after 6 hours of mock-loop circulation under both settings (optimal: 37 ± 31 vs 503 ± 173 mg/dL, P .0001; equal: 27 ± 4 vs 139 ± 135 mg/dL, P = .024). Loss of von Willebrand factor high-molecular-weight multimers occurred in both left ventricular assist devices and settings, but the von Willebrand factor:activity/von Willebrand factor:antigen ratio after 6 hours was significantly lower in optimal settings for the HeartMate 3 (P = .009). The thrombin-antithrombin complex level was significantly lower with the EVAHEART for both settings (P .0001).The EVAHEART left ventricular assist device caused less hemolysis, resulted in lower coagulation activation, and provided better preservation of von Willebrand factor functional activity compared with the HeartMate 3 device. These findings prove that left ventricular assist device design plays a major role in minimizing blood damage during left ventricular assist device support.

Significant advancements in nonsurgical and surgical approaches to control bleeding in severely injured patients have also improved the treatment of critical trauma-related coagulopathy. Nonsurgical procedures such as angiographic embolization are progressively considered to terminate arterial bleeding from pelvic fractures. The disturbance of coagulation may aggravate bleeding and hamper surgical procedures. The administration of coagulation factors and factor concentrates may be useful for correcting systemic coagulopathy and reducing the need for fresh frozen plasma, platelet, and red blood cell transfusions, which are associated with various adverse outcomes. In this review, nonsurgical management of critical trauma bleeding is discussed.

Trauma-induced coagulopathy is a frequent complication in severely injured patients. To correct coagulopathy and restore haemostasis, these patients have traditionally been treated with fresh frozen plasma, but in the last decade, there has been a shift from empirical therapy to targeted therapy with coagulation factor concentrates and other haemostatic agents. This review highlights emerging therapeutic options and controversial topics.Early administration of the antifibrinolytic medication tranexamic acid was shown in the multicentre CRASH-2 trial to be an effective and inexpensive means of decreasing blood loss. Numerous retrospective and experimental studies have shown that the use of coagulation factor concentrates decreases blood loss and may be useful in reducing the need for transfusion of allogeneic blood products. In particular, early use of fibrinogen concentrate and thrombin generators has a positive impact on haemostasis. However, the use of prothrombin complex concentrate to correct trauma-induced coagulopathy has also been associated with a potential risk of serious adverse events.Current evidence in trauma resuscitation indicates a potential role for coagulation factor concentrates and other haemostatic agents in correcting trauma-induced coagulopathy. Despite a shift towards such transfusion strategy, there remains a shortage of data to support this approach.

Dabigatran is effective in decreasing the risk of ischaemic stroke in patients with atrial fibrillation. However, like all anticoagulants, it is associated with a risk of bleeding. In cases of trauma or emergency surgery, emergency reversal of dabigatran-induced anticoagulation may be required. A specific reversal agent for dabigatran, idarucizumab, has been approved by the US Food and Drug Administration. Alternative reversal agents are available, such as prothrombin complex concentrates (PCCs) and activated PCCs (aPCCs). In this review we evaluate the role of PCCs and aPCCs in the reversal of dabigatran anticoagulation and consider which tests are appropriate for monitoring coagulation in this setting. Pre-clinical studies, small clinical studies and case reports indicate that PCCs and aPCCs may be able to reverse dabigatran-induced anticoagulation in a dose-dependent manner. However, dosing based on coagulation parameters can be difficult because available assays may not provide adequate sensitivity and specificity for measuring anticoagulation induced by dabigatran or the countering effects of PCCs/aPCCs. In addition, PCCs or aPCCs can potentially provoke thromboembolic complications. Despite these limitations and the fact that PCCs and aPCCs are not yet licensed for dabigatran reversal, their use appears to be warranted in patients with life-threatening haemorrhage if idarucizumab is not available.

Veno-venous extracorporeal lung assist (ECLA) can provide sufficient gas exchange even in most severe cases of acute respiratory distress syndrome. Commercially available systems are manually controlled, although an automatically controlled ECLA could allow individualized and continuous adaption to clinical requirements. Therefore, we developed a demonstrator with an integrated control algorithm to keep continuously measured peripheral oxygen saturation and partial pressure of carbon dioxide constant by automatically adjusting extracorporeal blood and gas flow. The "SmartECLA" system was tested in six animal experiments with increasing pulmonary hypoventilation and hypoxic inspiratory gas mixture to simulate progressive acute respiratory failure. During a cumulative evaluation time of 32 h for all experiments, automatic ECLA control resulted in a peripheral oxygen saturation ≥90% for 98% of the time with the lowest value of 82% for 15 s. Partial pressure of venous carbon dioxide was between 40 and 49 mm Hg for 97% of the time with no value 35 mm Hg or 49 mm Hg. With decreasing inspiratory oxygen concentration, extracorporeal oxygen uptake increased from 68 ± 25 to 154 ± 34 mL/min (P 0.05), and reducing respiratory rate resulted in increasing extracorporeal carbon dioxide elimination from 71 ± 37 to 92 ± 37 mL/min (P 0.05). The "SmartECLA" demonstrator allowed reliable automatic control of the extracorporeal circuit. Proof of concept could be demonstrated for this novel automatically controlled veno-venous ECLA circuit.

SummaryAlthough prothrombin complex concentrate (PCC) is increasingly used for the treatment of trauma-induced coagulopathy, few studies have investigated the impact and safety of PCC for this indication. The present study was performed to assess PCC for treatment of coagulopathy after blunt liver injury under severe hypothermia. Coagulopathy in 14 anaesthetised pigs was induced by haemodilution. Subsequently, standardised blunt liver injury was induced under severe hypothermia (32.8–33.2°C). Animals were randomised to receive either PCC (35 IU kg-1) or saline (control). Coagulation was assessed over the following 2 hours by thromboelastometry and thrombin generation. Internal organs were examined to determine presence of emboli. The administration of PCC showed a significant reduction in blood loss (p=0.002 vs. controls) and a significant increase in the rate of survival (p=0.022 vs. controls). Plasma thrombin generation in the PCC group increased considerably above baseline levels, with significant increases in peak thrombin levels and endogenous thrombin potential versus controls throughout the follow-up period. In addition, PT decreased significantly in the PCC group versus the control group. However, only slight improvements in thromboelastometry variables were observed. Histology showed an equal degree of liver injury in both groups, and no thromboembolism. In severely hypothermic pigs, the application of PCC corrected trauma-induced coagulopathy and reduced blood loss. Thus, the infusion of PCC might be a reasonable approach to reduce the need for blood cell transfusion in trauma. Furthermore, the impact and safety of PCC application can be monitored through thrombin generation and thromboelastometry under hypothermia.Note: This study was performed at the RWTH Aachen University Hospital, Pauwelsstrasse 30, D-52074 Aachen, Germany.

Background and objective In the elderly, monitoring depth of anaesthesia seems to be of particular importance. We evaluated the bispectral index (BIS) for monitoring depth of anaesthesia during clinically guided balanced xenon or sevoflurane anaesthesia in aged patients. Methods In this randomized controlled clinical trial, 40 patients (65–75 years) undergoing elective noncardiac surgery were randomly assigned to balanced anaesthesia with either 53.2 ± 0.8% xenon (n = 19) or 1.6 ± 0.1% sevoflurane (n = 20) in minimum 30% oxygen and remifentanil titrated to clinical needs. Depth of anaesthesia was guided by end-tidal gas concentrations and clinical signs. The attending anaesthesiologist was blinded to the BIS values, which were recorded at 1 min rates during induction, at 5 min rates during maintenance and at 20 s rates during emergence. Emergence from anaesthesia was assessed by the times to open eyes, react on demand, extubation and orientation. Results During induction and maintenance of anaesthesia, BIS values in the xenon group were comparable to sevoflurane and at the lower limit of the recommended range for deep anaesthesia. Emergence to full orientation was significantly faster from xenon than from sevoflurane. BIS values were significantly lower during emergence from xenon anaesthesia. Conclusion During xenon and sevoflurane anaesthesia in the elderly, BIS-values show sufficient concordance with clinical signs of anaesthetic depth. Since during clinically guided anaesthesia values were at the lower recommended limit, additional BIS monitoring may help reduce anaesthetic consumption and costs.

BMC anesthesiology 15, 158 (2015). doi:10.1186/s12871-015-0140-7, Published by BioMed Central, [S.l.]

Objective Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine with chemokine-like functions that plays a role in several inflammatory diseases including atherosclerosis. We recently demonstrated that in addition to macrophages and endothelial cells, platelets are a source of MIF. However, the functional relevance of platelet-derived MIF and differences to other platelet chemokines are unclear. Here, we sought to define the secretion pattern of platelet MIF and to characterize its functional profile in comparison with known atherogenic platelet chemokines. Methods and results Applying ELISA, we show that MIF is released from thrombin-stimulated platelets after 2 h, whereas CXCL12 and CXCL4 are secreted within minutes. Applied to platelets, MIF, unlike CXCL12, did not enhance platelet activation as analyzed by platelet aggregation, CD62P exposure and chemokine secretion studies. In contrast, both MIF and CXCL12 attenuated ADP-induced calcium transients in platelets. Transmigration and monocyte flow adhesion assays toward conditioned platelet supernatants together with MIF antibody blockade or supernatants from Mif −/− mice suggested that platelet-derived MIF has a stronger chemotactic activity than CXCL12 at its respective optimal secretion interval, and showed that platelet MIF substantially contributes to monocyte adhesion on endothelial layers. Moreover, MIF was found to delay clot retraction. Conclusions We demonstrate that MIF differs from other platelet-derived chemokines by delayed secretion kinetics and by a distinct autocrine/paracrine modulation potential. Importantly, MIF was found to be a major platelet-derived chemotactic recruitment factor with clot-modulating properties and therefore might be relevant in inflammatory diseases such as atherosclerosis.

Background: Fibrinogen concentrate may reduce blood loss after trauma. However, its effect on endogenous fibrinogen synthesis is unknown. The authors investigated the effect of exogenous human fibrinogen on endogenous fibrinogen metabolism in a 24-h porcine trauma model. Methods: Coagulopathy was induced in 20 German Landrace pigs by hemodilution and blunt liver injury. Animals were randomized to receive fibrinogen concentrate (100 mg/kg; infusion beginning 20 min postinjury and lasting approximately 10 min) or saline. Fibrinogen concentration, thromboelastometry, and quantitative reverse transcriptase polymerase chain reaction of fibrinogen genes in liver tissue samples were recorded. Internal organs were examined histologically for emboli. Results: Coagulation parameters were impaired and plasma fibrinogen concentrations were reduced before starting infusion of fibrinogen concentrate/saline. Twenty minutes after starting infusion, exogenous fibrinogen supplementation had increased plasma fibrinogen concentration versus controls (171 ± 19 vs. 63 ± 10 mg/dl [mean ± SD for Multifibren U]; 185 ± 30 vs. 41 ± 4 mg/dl [Thrombin reagent]; P < 0.05 for both comparisons). The between-group difference in plasma fibrinogen concentration diminished thereafter, with maximum concentrations in both groups observed at approximately 24 h, that is, during the acute-phase reaction after trauma. Fibrinogen supplementation did not down-regulate endogenous fibrinogen synthesis (no between-group differences in fibrinogen messenger RNA). Total postinjury blood loss was significantly lower in the fibrinogen group (1,062 ± 216 vs. 1,643 ± 244 ml; P < 0.001). No signs of thromboembolism were observed. Conclusions: Administration of human fibrinogen concentrate did not down-regulate endogenous porcine fibrinogen synthesis. The effect on plasma fibrinogen concentration was most pronounced at 20 min but nonsignificant at approximately 24 h.

Idarucizumab is a humanized antibody fragment that specifically reverses dabigatran and provides immediate and sustained reversal of dabigatran anticoagulation [(1–3)][1]. However, its effect on life-threatening bleeding following major trauma has not been studied. Thus, we investigated whether

PLoS one 8(5), e64100 (2013). doi:10.1371/journal.pone.0064100, Published by PLoS ; [S.l.] : PubMed Central [u.a.], Lawrence, Kan.

Recombinant activated factor VII (rFVIIa) is a haemostatic agent, which was originally developed for the treatment of haemophilia patients with inhibitors against factor FVIII or FIX. The efficacy of rFVIIa in preventing or stopping life-threatening bleeding for these patients has been demonstrated in several studies. Since the first report about the successful use of rFVIIa in a bleeding soldier in 1999, rFVIIa has gained popularity as an adjunct for the treatment of coagulopathy in a wide array of clinical conditions with serious or life-threatening bleeding. The number of case reports and case series documenting the successful use of rFVIIa as last resort to terminate uncontrollable bleeding has steadily grown. Conflicting results have been reported from various studies. Considering the lack of data and potential publication bias associated with case reports, this review summarises the clinical evidence of the efficacy and safety of rFVIIa in the perioperative period.