Fibrinogen contribution to clot strength in patients with sepsis and hematologic malignancies and thrombocytopenia-a prospective, single-center, analytical, cross-sectional study.

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 specific 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 significantly higher (60.5 ± 12.8% vs 43.6 ± 9.7%; P < .001) and that of platelets was significantly 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.

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The role of thromboinflammation in acute kidney injury among patients with septic coagulopathy.

Inflammation and coagulation are critical self-defense mechanisms for mitigating infection that can nonetheless induce tissue injury and organ dysfunction. In severe cases, like sepsis, a dysregulated thromboinflammatory response may result in multiorgan dysfunction. Sepsis-associated acute kidney injury (AKI) is a significant contributor to patient morbidity and mortality. The connection between AKI and thromboinflammation is largely due to unique aspects of the renal vasculature. Specifically, the interaction between blood cells with the endothelial, glomerular, and peritubular capillary systems during thromboinflammation reduces oxygen supply to tubular epithelial cells. Previous studies have focused on tubular epithelial cell damage due to hypoxia, oxidative stress, and nephrotoxins. Although these factors are pivotal in acute tubular injury or necrosis, recent studies have demonstrated that AKI in sepsis encompasses a mixture of tubular and glomerular damage subtypes. In cases of sepsis-induced coagulopathy, thromboinflammation within the glomerulus and peritubular capillaries is an important pathogenic mechanism for AKI. Unfortunately, and despite the use of renal replacement therapy, the development of AKI in sepsis continues to be associated with high morbidity, mortality, and clinical challenges requiring alternative approaches. This review introduces the important role of thromboinflammation in AKI pathogenesis and details innovative vascular-targeting therapeutic strategies.

Treating periprocedural bleeding in patients with cirrhosis.

Patients with cirrhosis are known to have an abnormal coagulation status, which is a particular concern when planning invasive procedures in which blood loss is possible or predictable. Careful consideration must be given to the bleeding risk for each individual patient and coagulation management strategies should be established in advance of procedural interventions, where possible. Perioperative clinical decision-making should utilize viscoelastic testing in addition to usual assessments, where possible, and focus on the well-established three pillars of patient blood management: optimization of erythropoiesis, minimization of bleeding and blood loss, and management of anemia. Restrictive transfusion policies, careful hemostatic monitoring, and a proactive approach to predicting and preventing bleeding on an individual patient basis should be central to managing perioperative bleeding in the fragile patient population with cirrhosis. This review discusses coagulation assessments and bleeding management techniques necessary before, during, and after surgical interventions in patients with cirrhosis, and provides expert clinical opinion and physician experience on the perioperative management of these patients.

Validation of the time to attain maximal clot amplitude after reaching maximal clot formation velocity parameter as a measure of fibrinolysis using rotational thromboelastometry and its application in the assessment of fibrinolytic resistance in septic patients: a prospective observational study: communication from the ISTH SSC Subcommittee on Fibrinolysis.

BACKGROUND: In sepsis, fibrinolysis resistance correlates with worse outcomes. Practically, rotational thromboelastometry (ROTEM) is used to report residual clot amplitude relative to maximum amplitude at specified times after clot formation clot lysis indices (CLIs). However, healthy individuals can exhibit similar CLIs, thus making it challenging to solely diagnose the low fibrinolytic state. Furthermore, CLI does not include the kinetics of clot formation, which can affect overall fibrinolysis. Therefore, a more nuanced analysis, such as time to attain maximal clot amplitude after reaching maximal clot formation velocity (t-AUCi), is needed to better identify fibrinolysis resistance in sepsis. OBJECTIVES: To evaluate the correlation between the degree of fibrinolytic activation and t-AUCi in healthy or septic individuals. METHODS: Whole blood (n = 60) from septic or healthy donors was analyzed using tissue factor-activated (EXTEM) and nonactivated (NATEM) ROTEM assays. Lysis was initiated with tissue-type plasminogen activator, and CLI and t-AUCi were calculated. Standard coagulation tests and plasma fibrinolysis markers (D-dimer, plasmin-α2-antiplasmin complex, plasminogen activator inhibitor type 1, and plasminogen) were also measured. RESULTS: t-AUCi values decreased with increasing fibrinolytic activity and correlated positively with CLI for different degrees of clot lysis both in EXTEM and NATEM. t-AUCi cutoff value of 1962.0 seconds in EXTEM predicted low fibrinolytic activity with 81.8% sensitivity and 83.7% specificity. In addition, t-AUCi is not influenced by clot retraction. CONCLUSION: Whole-blood point-of-care ROTEM analyses with t-AUCi offers a more rapid and parametric evaluation of fibrinolytic potential compared with CLI, which can be used for a more rapid and accurate diagnosis of fibrinolysis resistance in sepsis.

The Yin and the Yang of Hemostasis in End-Stage Liver Disease.

Patients with end-stage liver disease (ESLD) undergoing liver transplantation (LT) are prone to thromboses both while on the waiting list and in the perioperative period. This hypercoagulability is associated with significant endothelial dysfunction (ED) due to nitric oxide dysregulation. ED and increased thrombin generation are the main factors responsible for this hypercoagulability. Sepsis alone can significantly alter a patient's coagulation profile. In combination with ESLD, however, sepsis or septic shock are responsible for very complex changes. This makes both the assessment and management of coagulation in septic patients with ESLD very challenging. Viscoelastic testing (VET) is the preferred method of coagulation management in patients with cirrhosis because, as with standard laboratory testing, VET can assess the entire coagulation system including the interaction between both pro- and anticoagulants and platelets.

Management of severe peri-operative bleeding: Guidelines from the European Society of Anaesthesiology and Intensive Care: Second update 2022.

BACKGROUND: Management of peri-operative bleeding is complex and involves multiple assessment tools and strategies to ensure optimal patient care with the goal of reducing morbidity and mortality. These updated guidelines from the European Society of Anaesthesiology and Intensive Care (ESAIC) aim to provide an evidence-based set of recommendations for healthcare professionals to help ensure improved clinical management. DESIGN: A systematic literature search from 2015 to 2021 of several electronic databases was performed without language restrictions. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used to assess the methodological quality of the included studies and to formulate recommendations. A Delphi methodology was used to prepare a clinical practice guideline. RESULTS: These searches identified 137 999 articles. All articles were assessed, and the existing 2017 guidelines were revised to incorporate new evidence. Sixteen recommendations derived from the systematic literature search, and four clinical guidances retained from previous ESAIC guidelines were formulated. Using the Delphi process on 253 sentences of guidance, strong consensus (>90% agreement) was achieved in 97% and consensus (75 to 90% agreement) in 3%. DISCUSSION: Peri-operative bleeding management encompasses the patient's journey from the pre-operative state through the postoperative period. Along this journey, many features of the patient's pre-operative coagulation status, underlying comorbidities, general health and the procedures that they are undergoing need to be taken into account. Due to the many important aspects in peri-operative nontrauma bleeding management, guidance as to how best approach and treat each individual patient are key. Understanding which therapeutic approaches are most valuable at each timepoint can only enhance patient care, ensuring the best outcomes by reducing blood loss and, therefore, overall morbidity and mortality. CONCLUSION: All healthcare professionals involved in the management of patients at risk for surgical bleeding should be aware of the current therapeutic options and approaches that are available to them. These guidelines aim to provide specific guidance for bleeding management in a variety of clinical situations.

Communication from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis on sepsis-induced coagulopathy in the management of sepsis.

Disseminated intravascular coagulation (DIC) is a life-threatening complication in sepsis and other critical conditions. The International Society on Thrombosis and Haemostasis (ISTH) released the diagnostic criteria for overt DIC in 2001. Since then, ISTH overt DIC has been used as the global standard criterion for a decompensated stage of DIC. Because detecting an earlier stage of DIC would be useful for therapeutic considerations, the scientific standardization committees of the ISTH introduced the sepsis-induced coagulopathy (SIC) scoring system in 2019. The SIC scoring system is specifically designed to detect the compensated phase of DIC in sepsis, which can lead to overt DIC with disease progression. Studies examining the performance of the SIC scoring system have reported its usefulness over the past 5 years. The reported incidence of SIC was approximately 60% in patients with sepsis, which was twice as much as that of overt DIC. Almost all patients with overt DIC were diagnosed with SIC earlier. The reported mortality of SIC was ≥30% and, thus, can be used for patient selection for anticoagulant therapy. Despite the limited data, some continue to suggest the potential efficacy of anticoagulant therapy in patients with SIC. Although heparin, antithrombin, and thrombomodulin are the candidates for anticoagulation, none of them have proven to be effective with robust evidence, and future trials are warranted.

Communication from the Scientific Standardization Committees of the International Society on Thrombosis and Haemostasis on vascular endothelium-related biomarkers in disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) is not a disease criterion but a pathomechanistic process that accompanies various underlying diseases. According to the International Society on Thrombosis and Haemostasis definition, endothelial injury is an essential component in addition to systemic coagulation activation. Despite this definition, current diagnostic criteria for DIC do not include biomarkers for vascular endothelial injury. Endothelial cells are critical for hemostatic regulation because they produce various antithrombotic substances and express anticoagulant factors at the same time as facilitating coagulation, inflammatory reactions, platelet aggregation, and fibrinolysis with acute injury. Endothelial cells also exhibit various receptors, adhesion molecules, and the critical role of glycocalyx that regulates cellular interactions in thromboinflammation. For clinicians, biomarkers suitable for assessing endothelial injury are not readily available. Although we still do not have ideal biomarkers, antithrombin activity and von Willebrand factor can be candidates for the endothelium-related markers because those reflect the severity and are available in most clinical settings. Further, the dysfunction of endothelial cell in DIC arising from various underlying diseases is likely highly variable. For example, the involvement of endothelial dysfunction is significant in sepsis-induced coagulopathy, while moderate in trauma-induced coagulopathy, and variable in hematologic malignancy-associated coagulopathy. Because of the complexity of disease status associated with DIC, further research searching clinically available endothelium-related biomarkers is expected to establish individualized diagnostic criteria and potential therapeutic approaches.

Cirrhotic Cardiomyopathy-A Veiled Threat.

Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction in patients with liver cirrhosis without preexisting cardiac disease. According to the definition established by the World Congress of Gasteroenterology in 2005, the diagnosis of CCM includes criteria reflecting systolic dysfunction, impaired diastolic relaxation, and electrophysiological disturbances. Because of minimal or even absent clinical symptoms and echocardiographic signs at rest according to the 2005 criteria, CCM diagnosis is often missed or delayed in most clinically stable cirrhotic patients. However, cardiac dysfunction progresses in time and contributes to the pathogenesis of hepatorenal syndrome and increased morbidity and mortality after liver transplantation, surgery, or other invasive procedures in cirrhotic patients. Therefore, a comprehensive cardiovascular assessment using newer techniques for echocardiographic evaluation of systolic and diastolic function, allowing the diagnosis of CCM in the early stage of subclinical cardiovascular dysfunction, should be included in the screening process of liver transplant candidates and patients with cirrhosis in general. The present review aims to summarize the most important pathophysiological aspects of CCM, the usefulness of contemporary cardiovascular imaging techniques and parameters in the diagnosis of CCM, the current therapeutic options, and the importance of early diagnosis of cardiovascular impairment in cirrhotic patients.

The effect of a viscoelastic-guided bleeding algorithm implementation on blood products use in adult liver transplant patients. A propensity score-matched before-after study.

BACKGROUND: Perioperative blood products transfusion is correlated with increased morbidity and mortality in liver transplantation (LTx). The objectives of our study are to assess the effect of a standardized viscoelastic test (VET)-guided bleeding management algorithm implementation on intraoperative bleeding, allogenic blood products and factor concentrates requirements and on early postoperative complications in LTx. METHODS: Retrospective before-after study comparing two matched cohorts of patients undergoing LTx before (control cohort) and after (intervention cohort) the implementation of a VET-based bleeding algorithm in a single center academic hospital. RESULTS: After propensity score matching, we included 94 patients in each cohort. Patients in intervention cohort received significantly less blood products, fresh frozen plasma (FFP), and cryoprecipitate (p < 0.001 for each), while the amount of fibrinogen concentrate used was significantly higher (p < 0.001). Postoperatively, intervention cohort patients had significantly lower postoperative hemoglobin and fibrinogen levels and longer prothrombin time compared to control cohort. There were no significant differences in red blood cells transfusions, intraoperative bleeding, early postoperative complications, and short term survival. CONCLUSIONS: The implementation of a VET-guided bleeding algorithm decreases allogenic blood products requirements, mainly FFP use and allows a more restrictive management of coagulopathy in patients with chronic liver disease undergoing LTx.

Intermittent High-Frequency Percussive Ventilation Therapy in 3 Patients with Severe COVID-19 Pneumonia.

BACKGROUND High-frequency percussive ventilation (HFPV) is a method that combines mechanical ventilation with high-frequency oscillatory ventilation. This report describes 3 cases of patients with severe COVID-19 pneumonia who received intermittent adjunctive treatment with HFPV at a single center without requiring admission to the Intensive Care Unit (ICU). CASE REPORT Case 1 was a 60-year-old woman admitted to the hospital 14 days after the onset of SARS-CoV-2 infection symptoms, and cases 2 and 3 were men aged 65 and 72 years who were admitted to the hospital 10 days after the onset of SARS-CoV-2 infection symptoms. All 3 patients presented with clinical deterioration accompanied by worsening lung lesions on computed tomography (CT) scans after 21 days from the onset of symptoms. SARS-CoV-2 infection was confirmed in all patients by real-time reverse transcription-polymerase chain reaction (RT-PCR) assay from nasal swabs. All 3 patients had impending respiratory failure when non-invasive intermittent HFPV therapy was initiated. After therapy, the patients had significant clinical improvement and visibly decreased lung lesions on followup CT scans performed 4-6 days later. CONCLUSIONS The 3 cases described in this report showed that the use of intermittent adjunctive treatment with HFPV in patients with severe pneumonia due to infection with SARS-CoV-2 improved lung function and may have prevented clinical deterioration. However, recommendations on the use of intermittent HFPV as an adjunctive treatment in COVID-19 pneumonia requires large-scale controlled clinical studies. In the pandemic context, with a shortage of ICU beds, avoiding ICU admission by using adjunctive therapies on the ward is a useful option.

Lidocaine effects on coagulation assessed by whole blood rotational thromboelastometry.

Lidocaine may be beneficial when added in solutions for the preservation of vascular grafts or solid organs as it has anti-inflammatory, endothelial protective, and antithrombotic effects. However, the mechanisms of lidocaine-induced changes in hemostasis were not elucidated until now. The aim of the study was to examine the effect of increasing concentrations of lidocaine on coagulation parameters and blood-clotting kinetics using velocity curves of clot formation assessed by rotational thromboelastometry. Ex-vivo blood coagulation using whole blood from healthy volunteers was studied with rotational thromboelastometry. For each volunteer, four assays were performed: saline control and samples with lidocaine end blood concentrations of 0.3, 0.6, and 0.9%. In this in-vitro study, whole blood from 15 healthy volunteers was used. Lidocaine concentration of 0.3% prolonged the initiation phase of clotting without significant differences in the propagation phase or clot stability and inhibited clot lysis compared with the control group. Higher lidocaine concentrations (0.6 and 0.9%) resulted in prolongation of both initiation and propagation phases and decreased clot firmness compared with the control group. Lysis was significantly increased only in the 0.6% lidocaine group compared with control. Although lidocaine concentration of 0.3% only delays coagulation initiation, the 0.6% concentration inhibits all phases of hemostasis and increases clot lysis compared with control. Higher lidocaine concentration results in very weak clot formation with very low lysis visible on thromboelastometry. More research is needed to explain the effects of lidocaine on clotting kinetics.

Continuous renal replacement therapy in cytokine release syndrome following immunotherapy or cellular therapies?

Recently, an increasing number of novel drugs were approved in oncology and hematology. Nevertheless, pharmacology progress comes with a variety of side effects, of which cytokine release syndrome (CRS) is a potential complication of some immunotherapies that can lead to multiorgan failure if not diagnosed and treated accordingly. CRS generally occurs with therapies that lead to highly activated T cells, like chimeric antigen receptor T cells or in the case of bispecific T-cell engaging antibodies. This, in turn, leads to a proinflammatory state with subsequent organ damage. To better manage CRS there is a need for specific therapies or to repurpose strategies that are already known to be useful in similar situations. Current management strategies for CRS are represented by anticytokine directed therapies and corticosteroids. Based on its pathophysiology and the resemblance of CRS to sepsis and septic shock, as well as based on the principles of initiation of continuous renal replacement therapy (CRRT) in sepsis, we propose the rationale of using CRRT therapy as an adjunct treatment in CRS where all the other approaches have failed in controlling the clinically significant manifestations.

Standard and derived rotational thromboelastometry parameters for prediction of disseminated intravascular coagulation in septic patients.

: Waiting for lab tests results for the calculation of disseminated intravascular coagulation (DIC) scores leads to unwanted delays in diagnosis. The use of rotational thromboelastometry (ROTEM) for this purpose would allow for a more rapid DIC diagnosis at the bedside. The aim of this study was to assess the ability of standard ROTEM parameters and calculated parameters from the ROTEM velocity curve to predict DIC. The retrospective observational study included 97 septic patients. Japanese Association for Acute Medicine score was used for DIC diagnosis and whole-blood ROTEM was performed at study inclusion. Univariate analysis revealed delayed coagulation initiation and propagation and reduced clot firmness and maximum elasticity in DIC patients compared with patients without DIC. To adjust for confounders, multivariable logistic regression models were created and fibrinogen levels, prothrombin time and ROTEM parameters such as maximum clot firmness, maximum clot elasticity (MCE) and total thrombus formation [area under the curve (AUC)] were identified as significant predictors of DIC. According to receiver operating characteristics analysis, MCE and total thrombus formation (AUC) were the most useful ROTEM parameters for DIC prediction. MCE less than 158 (73% sensitive, 80% specific) and AUC less than 6175 mm × 100 (73% sensitive, 76% specific) predicted DIC in septic patients. Both standard and derived ROTEM parameters are useful for rapid DIC prediction in septic patients, allowing the timely identification of patients with higher mortality risk which might benefit from additional therapies. Further studies are needed to assess the clinical relevance of these findings.

Can goal-directed fluid therapy decrease the use of blood and hemoderivates in surgical patients?

The purpose of goal-directed therapy (GDT) is to improve patient outcome by the optimization of hemodynamic status, as it is considered that many perioperative complications are related to microcirculatory disturbance due to an imbalance between oxygen delivery and consumption. The application of GDT protocols incorporating the assessment and optimization of patients' intravascular status should theoretically lead to a reduction in perioperative bleeding and transfusion requirements, as both hypervolemia and hypovolemia and their consequences such as dilutional coagulopathy, anemia and inadequate oxygen delivery to the tissues are avoided. However, the research reporting decreased usage of blood products in patients which received targeted fluid management is sparse; decreased blood loss and transfusion requirements were reported in spine surgery using GDT, while studies in abdominal or cardiac surgery did not consistently report significant decreases in blood products transfusion when GDT were applied. These heterogenous results reported can be explained by the differences between the GDT protocols used, as the differences in therapeutic goals can impact on blood transfusion requirements. In the future, the GDT protocols should include not only the prediction of fluid responsiveness and optimization of hemodynamic status, but also the assessment of microcirculation and measures to improve tissue oxygenation, parameters which can also guide the decision for blood product transfusion. A better standardization of GDT algorithms is also required in order to perform a more accurate assessment of the effects of applying GDT on the consumption of blood products.

Diagnosis and Treatment of Trauma-Induced Coagulopathy by Viscoelastography.

This article explores the application of viscoelastic tests (VETs) in trauma-induced coagulopathy and trauma resuscitation. We describe the advantages of VETs over conventional coagulation tests in the trauma setting and refer to previous disciplines in which VET use has reduced blood product utilization, guided prohemostatic agents, and improved clinical outcomes such as the mortality of critically bleeding patients. We describe different VETs and provide guidance for blood component therapy and prohemostatic therapy based on specific VET parameters. Because the two most commonly used VET systems, rotational thromboelastometry and thromboelastography, use different activators and have different terminologies, this practical narrative review will directly compare and contrast these two VETs to help the clinician easily interpret either and use the interpretation to determine hemostatic integrity in the bleeding trauma patient. Finally, we anticipate the future of new viscoelastic technologies that can be used in this setting.

The current status of viscoelastic testing in septic coagulopathy.

Sepsis can be associated with different degrees of coagulopathy, ranging from a mild activation of the coagulation system to disseminated intravascular coagulation (DIC). The evaluation of haemostasis in the context of sepsis is important since it has been shown that anticoagulant therapies were beneficial mainly in patients with sepsis-induced DIC, but not in the general population of septic patients. Sepsis-induced haemostatic disturbances are not adequately reflected by standard coagulation tests (SCTs) which only consider the plasmatic components of the haemostatic system and not the cellular components. In addition, SCTs only assess the initiation phase of coagulation and reflect the activity of pro-coagulant factors, but lack sensitivity for the anticoagulant drive and the fibrinolytic activity. Viscoelastic tests (VET) are whole-blood tests which can assess clot formation and dissociation, and the contribution of both plasmatic and cellular components with a shorter turnaround time compared to SCTs. The use of VET in septic patients has proved useful for the assessment of the fibrinolytic activity, detecting hypercoagulable status and for the diagnosis of DIC and mortality risk prediction. While having relevant advantages over SCTs, the VET also present some blind spots or limitations leaving space for future improvement by the development of new reagents or new viscoelastic parameters.