There are two different approaches to hemostatic resuscitation used in major hemorrhage protocols for critically bleeding trauma patients: A formulaic approach using fixed ratios of blood components and a targeted therapy approach guided by viscoelastic hemostatic assays. There is ongoing debate with differing opinions on what constitutes the most appropriate approach. There is also widespread variation in management approaches and options used. The aim of a major hemorrhage protocol is to guide a multidisciplinary multiple strategy approach to identify the source and cause of bleeding and control it expeditiously, correct coagulopathy, and normalize physiological derangement. Proponents of a fixed-ratio blood component approach to hemostatic resuscitation in traumatic hemorrhage argue that it provides the necessary blood components, reduces cognitive load on the trauma team and standardizes clinical practice. They also argue that the alternative of target-driven therapy is currently a utopian concept, delays care, and, if instituted, may result in harm to patients, carers, and the health system. Proponents of targeted therapy hold that a formulaic fixed-ratio approach does not treat specific deficits and may result in over-transfusion of components, exposing patients to the inherent risks of blood component transfusions. They propose that a targeted approach using viscoelastic hemostatic assays reduces exposure to blood components and reduces mortality. Both proposed strategies assume ready access to blood components and/or products, investigational tools, appropriately trained multidisciplinary staff and as such are targeted toward resuscitation of critical bleeding in advanced trauma systems.

During bleeding, the decrease A10EXTEM and A10FIBTEM (the clot firmness at 10 min) measured by rotational thromboelastometry (Rotem) can detect alterations in the fibrin contribution to clot firmness (FIBTEM) and in the extrinsic pathway (EXTEM). However, the significance of a decrease of A10FIBTEM and A10EXTEM for risk stratification in patients with bleeding remains unclear. 1942 consecutive patients were retrospectively examined between 2014 and 2020. All patients were tested with Rotem during a hemorrhage at Saarland University Hospital. A10EXTEM and A10FIBTEM and their association with mortality at 30 days were tested using C statistic. A threshold value for A10EXTEM reaching a specificity > 90

Allogeneic blood transfusion is frequently performed in critically ill patients, but accumulating evidence demonstrates that it is not a biologically neutral intervention. Transfusion-associated immunomodulation (TRIM) encompasses the immunological effects of transfusion, ranging from immune suppression to proinflammatory activation and cancer recurrence, with potential impact on morbidity and mortality in the intensive care unit. We conducted a narrative review of recent experimental and clinical evidence on TRIM to describe the molecular pathways involved. We reviewed, randomized trials, metaanalyses, and large observational cohorts to evaluate the clinical relevance of TRIM in critically ill populations. TRIM arises from multiple converging mechanisms. These pathways alter innate and adaptive immunity, leading to increased risk of healthcare-associated infections, transfusion-related acute lung injury, acute kidney injury, multiorgan dysfunction, prolonged length of stay, and cancer recurrence in surgical patients. Blood-sparing strategies, including patient blood management (PBM), mitigate exposure. The impact of storage duration and novel processing technologies remains unclear. There is still a gap in research that needs to be addressed. Transfusion-associated immunomodulation (TRIM) is a phenomenon in which donor leukocytes, extracellular vesicles, microparticles, bioactive lipids, and cytokines interact with the host immune system to produce a spectrum of immunological effects. In critically ill patients, the immune system is already fragile, and these mechanisms predispose patients to infections, pulmonary complications, organ dysfunction, prolonged recovery, and even cancer recurrence. Although TRIM cannot currently be diagnosed through a single biomarker or clinical test, its existence is strongly supported by mechanistic studies and consistent clinical associations between transfusion exposure and adverse outcomes.

The recommended treatment options for coagulation management during cardiac surgery include fibrinogen concentrate, packed red blood cells, fresh frozen plasma, platelet concentrate (pooled donors or single donor), cryoprecipitate, recombinant factor VIIa, tranexamic acid, epsilon aminocaproic acid, prothrombin complex concentrate, as well as antidotes such as protamine and desmopressin. At present, only the top institutes in the world have TEG and ROTEM testing facilities available for bleeding patients or selected patient populations undergoing major cardiovascular surgery or liver transplantation. TEG and ROTEM should be made available more widely (for all bleeding patients and patients at high risk of bleeding in tertiary hospitals) across India. Inconvenience caused by planning and requesting of blood components and multiple institute-specific hindrances delaying the availability of blood components can be resolved by having factor concentrates available and stored in the operation theater. This approach may reduce transfusion requirements, morbidity, mortality, and healthcare costs.

Background and objective During bleeding the prolongation of the clotting time (CT INTEM ) measured by rotational thromboelastometry (ROTEM) can detect alterations in the intrinsic pathway; however, the significance of a prolonged CT INTEM for risk stratification in patients with bleeding and the treatment with fresh frozen plasma remains unclear. Material and methods A total of 2197 consecutive patients between 2014 and 2020 were retrospectively investigated. All patients were tested by ROTEM during bleeding at the Saarland University Hospital. The CT INTEM values were compared to mortality at 30 days. Discrimination was assessed with C statistic. Adjusted hazard ratios (adjHR, 95% confidence interval, CI) were calculated with multivariable Cox models. Results The results of the C‑statistic showed that CT INTEM (C statistic 0.62, optimal threshold > 226 s) had a predictive power for 30-day mortality. The determined threshold value of CT INTEM > 226 s remained an independent risk predictor for 30-day mortality even after adjustment for confounding factors (adjHR 2.6, 95% CI 2.1–3.2, p < 0.001). The 30-day mortality rate was significantly increased in the group with CT INTEM > 226 s (29% versus 15%, p < 0.001). A multivariable analysis showed that treatment with fresh frozen plasma was not associated with increased 30-day mortality in patients with CT INTEM > 226 s, in contrast to all patients. Conclusion Our results indicate that CT INTEM > 226s detected alterations in the intrinsic pathway might be an independent predictor for 30-day mortality in patients with bleeding and could be useful for decision making regarding treatment with fresh frozen plasma.

Background: Patients with hematological malignancies (HM) frequently present thrombocytopenia and higher risk of bleeding. Although transfusion is associated with higher risk of adverse events and poor outcomes, prophylactic transfusion of platelets is a common practice to prevent hemorrhagic complications. Thromboelastometry has been considered a better predictor for bleeding than isolated platelet counts in different settings. In early stages of sepsis, hypercoagulability may occur due to higher fibrinogen levels. Objectives: To evaluate the behavior of coagulation in patients with HM who develop sepsis and to verify whether a higher concentration of fibrinogen is associated with a proportional increase in maximum clot firmness (MCF) even in the presence of severe thrombocytopenia. Methods: We performed a unicentric analytical cross-sectional study with 60 adult patients with HM and severe thrombocytopenia, of whom 30 had sepsis (sepsis group) and 30 had no infections (control group). Coagulation conventional tests and speci fic coagulation tests, including thromboelastometry, were performed. The main outcome evaluated was MCF. Results: Higher levels of fibrinogen and MCF were found in sepsis group. Both fibrinogen and platelets contributed to MCF. The relative contribution of fibrin was signi ficantly higher (60.5 +/- 12.8% vs 43.6 +/- 9.7%; P < .001) and that of platelets was signi ficantly lower (39.5 +/- 12.8% vs 56.4 +/- 9.7%; P < .001) in the sepsis group compared with the control group. Conclusion: Patients with sepsis and HM presented higher concentrations of fibrinogen than uninfected patients, resulting in greater MCF amplitudes even in the presence of thrombocytopenia.

This is a narrative review of the published evidence for bleeding management in critically ill patients in different clinical settings in the intensive care unit (ICU). We aimed to describe "The Ten Steps" approach to early goal-directed hemostatic therapy (EGDHT) using point-of-care testing (POCT), coagulation factor concentrates, and hemostatic drugs, according to the individual needs of each patient. We searched National Library of Medicine, MEDLINE for publications relevant to management of critical ill bleeding patients in different settings in the ICU. Bibliographies of included articles were also searched to identify additional relevant studies. English-language systematic reviews, meta-analyses, randomized trials, observational studies, and case reports were reviewed. Data related to study methodology, patient population, bleeding management strategy, and clinical outcomes were qualitatively evaluated. According to systematic reviews and meta-analyses, EGDHT guided by viscoelastic testing (VET) has been associated with a reduction in transfusion utilization, improved morbidity and outcome in patients with active bleeding. Furthermore, literature data showed an increased risk of severe adverse events and poor clinical outcomes with inappropriate prophylactic uses of blood components to correct altered conventional coagulation tests (CCTs). Finally, prospective, randomized, controlled trials point to the role of goal-directed fibrinogen substitution to reduce bleeding and the amount of red blood cell (RBC) transfusion with the potential to decrease mortality. In conclusion, severe acute bleeding management in the ICU is still a major challenge for intensive care physicians. The organized and sequential approach to the bleeding patient, guided by POCT allows for rapid and effective bleeding control, through the rational use of blood components and hemostatic drugs, since VET can identify specific coagulation disorders in real time, guiding hemostatic therapy with coagulation factor concentrates and hemostatic drugs with individual goals.

Key questions in bleeding management are “Why does my patient bleed?” and “How to fix it?” To answer the first question, the high negative predictive value of viscoelastic testing can be used to identify coagulopathic bleeding. Accordingly, goal-directed bleeding management (GDBM) guided by viscoelastic testing has been shown to be an effective and essential part of the second pillar of patient blood management (PBM) with the aim to improve patients’ outcomes and safety. Patient’s medical and drug history – with a focus on medication with oral anticoagulants and antiplatelet drugs – are important in emergency, urgent, and elective surgery. Furthermore, risk scores have been developed and validated for traumatic and obstetric hemorrhage and can be helpful tools to predict severe hemorrhage and the need for massive transfusion. Acidosis, hypocalcemia, anemia, and hypothermia (“diamond of death in trauma”) are important basic conditions for hemostasis and good predictors of coagulopathy and should be closely monitored by blood gas analysis and corrected in bleeding patients. Earlier time to hemostasis was associated with decreased mortality in trauma studies. Therefore, GDBM aims to stop the bleeding as soon as possible and avoid the main killers in blood transfusion: Transfusion-associated circulatory overload, transfusion-related acute lung injury, transfusion-related immune modulation, and thrombosis. Thromboelastometry-guided bleeding management follows the concepts of Good Medical Practice and Precision Medicine. Here, rotational thromboelastometry (ROTEM)-guided bleeding management algorithms are using a stepwise approach based on the sequence “Treat first what kills first:” (1) Fibrinolysis management, (2) clot firmness management, (3) thrombin generation management, and (4) avoidance of hypercoagulability and thrombosis. Here, thromboelastometry can not only identify patients with hypercoagulability and increased risk of thrombosis but also ROTEM-guided bleeding management can avoid thromboembolic complications, too. This may support the idea of personalized antithrombotic therapy guided by viscoelastic testing in the postoperative period. Finally, PBM is not about blood transfusion: It is about patients’ outcomes. Accordingly, several meta-analyses based on more than 20 randomized controlled trials on the effect of viscoelastic testing-guided perioperative bleeding management did not only demonstrate a significant reduction in transfusion requirements but also a significant reduction in mortality and postoperative acute kidney injury. The reduction in postoperative acute kidney injury again has a significant impact on long-term survival. Accordingly, recent PBM guidelines recommend the implementation of viscoelastic testing-guided bleeding management algorithms with a 1B or 1A recommendation. This is also addressed in the World Health Organization policy brief about the urgent need to implement PBM in all member states in a timely manner. However, even if the number of national activities is increasing, there is still a long way to go.

Liver transplantation is a complex surgical procedure in which various forms of coagulation dysfunction can occur, including perioperative hypercoagulability. The hemostasis balance in liver graft recipients with end-stage liver disease can shift to thrombosis or haemorrhage, depending on the associated risk factors and clinical conditions. Hypercoagulability can result in serious complications such as thromboembolism, which can affect the vessels of the newly transplanted liver graft. Standard coagulation tests (SCTs), such as prothrombin time and activated partial thromboplastin time (aPTT), have a poor ability to diagnose and monitor an early stage of hypercoagulability. Recent studies demonstrated that viscoelastic hemostatic elastic tests (VETs), such as rotational thromboelastometry (ROTEM) and thromboelastography (TEG), are promising alternative tools for diagnosing hypercoagulability disorders. VETs measure clotting and clot formation time, clot strength (maximum clot firmness), fibrin and platelet contribution to clot firmness, and fibrinolysis, which makes them more sensitive in identifying liver graft recipients at risk for thrombosis as compared with SCTs. However, developing evidence-based guidelines for the prophylaxis and treatment of hypercoagulability based on VET results is still needed.

1 Organ Transplant Center of Excellence, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 2 Department for General, Visceral, and Transplant Surgery, Medical Center University Duisburg-Essen, Essen, Germany. 3 Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 4 Medical Department, Tem Innovations, Munich, Germany. All authors contributed to the writing of the article. Prof. Dr. Saner received honoraria from CSL Behring and Werfen. Dr. Gorlinger received funding from TEM Innovations/Werfen patient blood management (PBM) and is the medical director of TEM Innovations/Werfen PBM. Dr. Stüben has disclosed that he does not have any potential conflicts of interest.

Thromboelastometry is considered the best method to assesses hemostasis in liver disease. Diagnostic performance could be improved by adding protein C activators such as thrombomodulin or Protac®. We assessed changes in ROTEM parameters after the addition of Protac® in patients with acute-on-chronic liver failure (ACLF), acute decompensation (AD), and healthy individuals (HI) to define different hemostasis patterns, considering standard and velocity ROTEM parameters, and assess whether Protac® can improve the definition of the pattern. Pre-test, we investigated whether diluted EXTEM reagent improved the effect of Protac® on the clotting time (CT)-ratio with and without Protac®. Ten ACLF and 20 AD patients and 21 HI were included in the main study. Standard EXTEM was used in the main study. INTEM CFT, INTEM A5 (inverse), and INTEM TPI (inverse) were the parameters that best differentiated liver disease from HI (ROC AUC, 0.921, 0.906, and 0.928, respectively; all P-values < 0.001). Combining INTEM CFT with EXTEM LI60-ratio only slightly improved the diagnostic performance (ROC AUC, 0.948; P < 0.001). EXTEM LI60 and INTEM maxV-t were the parameters that best differentiated between ACLF and AD patients (ROC AUC, 0.743, P = 0.033; and 0.723, P = 0.050; respectively). Combining EXTEM LI60 + INTEM maxV-t moderately improved the diagnostic performance (ROC AUC, 0.81, P < 0.001). ROTEM velocity, fibrinolysis parameters and the indices calculated improve the diagnosis in combination with standard parameters (e.g., CFT and A5). Ratios calculated with and without Protac® (e.g., EXTEM LI60-ratio) only slightly increased the diagnostic performance in discriminating hemostasis patterns.

Background The detection of direct oral anticoagulants (DOACs) is still challenging but important in emergency patients. We recently demonstrated that modified thromboelastometry can detect rivaroxaban and dabigatran. Data on the detection rates of modified compared to standard thromboelastometric tests of apixaban and edoxaban, are missing. The aim of this in-vitro dose-effect-study was to add data on these DOACs and to evaluate thromboelastometric tests in-vitro using data of both studies. Methods The study was approved by the Ludwig-Maximilians-University ethics committee (No 17-525-2). Written informed consent was obtained from all individuals. Blood samples of healthy volunteers and samples of 10 volunteers for each DOAC were used. Blood samples were spiked with six different concentrations of edoxaban and apixaban (0ng/ml; 31.25ng/ml; 62.5ng/ml; 125ng/ml; 250 ng/ml; 500ng/ml). Modified tests (low-tissue-factor test TFTEM and ecarin-based test ECATEM) as well as standard tests (e.g. FIBTEM) analyzing extrinsic pathway of coagulation were used. Receiver operating characteristics analyzes were performed as well as regression analyzes. Results TFTEM CT correlated well with anti-Xa levels of apixaban and edoxaban (apixaban: r(2) = 0.8064 p < 0.0001; edoxaban: r(2) = 0.8603; p < 0.0001). The detection of direct FXa inhibitors (> 30 ng/mL) was successful with FIBTEM CT with a sensitivity and specificity of 81% and 90%, respectively. As expected, ECATEM CT was not prolonged by direct FXa-inhibitors due to its specificity for direct thrombin inhibitors. Again, TFTEM CT provided the highest sensitivity and specificity for the detection of direct FXa inhibitors with 96% and 95%, respectively. ECATEM test showed 100% sensitivity and 100% specificity for the detection of dabigatran. Conclusions Our study presents modified thromboelastometric tests with improved detection of even low DOAC concentrations > 30 ng/mL, including apixaban in-vitro. The study thus complements the previously published data on dabigatran and rivaroxaban. Validation studies must confirm the results due to the explanatory design of this study.

Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) have become increasingly popular for urgent assessment of the hemostasis system. Accordingly, TEG and ROTEM algorithms and their corresponding cut-off values are not interchangeable. ROTEM provides fast results (including validated early clot firmness parameters [A5 and A10]), that are easy to use, and the graphical display of the results is easy to interpret. ROTEM manufacturer, Tem Innovations GmbH (Munich, Germany), mentions in the user manual that the manufacturer has not set any strict reference values for INTEM, EXTEM, FIBTEM, APTEM, and NATEM in any patient population (including pregnant women) and that these values are highly variable in healthy subjects. To date, no systematic review assessing ROTEM parameters in pregnant, parturient, and postpartum women is available. With the increasing usage of ROTEM, we conducted this systematic review and meta-analysis to determine the reference values of ROTEM parameters in pregnant, parturient, and postpartum women compared with non-pregnant population.

In this issue of the Journal of Cardiac Critical Care, Sharan et al and Datta et al are reporting on perioperative and peri-interventional platelet function testing in an attempt to implement personalized antiplatelet therapy in India.[1] [2]

In a developing country like India, with limited resources and access to healthcare facilities, dealing with massive hemorrhage is a major challenge. This challenge gets compounded by pre-existing anemia, hemostatic disorders, and logistic issues of timely transfer of such patients from peripheral hospitals to centers with adequate resources and management expertise. Despite the awareness amongst healthcare providers regarding management modalities of bleeding patients, no uniform Patient Blood Management (PBM) or perioperative bleeding management protocols have been implemented in India, yet. In light of this, an interdisciplinary expert group came together, comprising of experts working in transfusion medicine, hematology, obstetrics, anesthesiology and intensive care, to review current practices in management of bleeding in Indian healthcare institutions and evaluating the feasibility of implementing uniform PBM guidelines. The specific intent was to perform a gap analysis between the ideal and the current status in terms of practices and resources. The expert group identified interdisciplinary education in PBM and bleeding management, bleeding history, viscoelastic and platelet function testing, and the implementation of validated, setting-specific bleeding management protocols (algorithms) as important tools in PBM and perioperative bleeding management. Here, trauma, major surgery, postpartum hemorrhage, cardiac and liver surgery are the most common clinical settings associated with massive blood loss. Accordingly, PBM should be implemented as a multidisciplinary and practically applicable concept in India in a timely manner in order to optimize the use the precious resource blood and to increase patients' safety.