Search

Importance: Early administration of supplemental oxygen for all severely injured trauma patients is recommended, but liberal oxygen treatment has been associated with increased risk of death and respiratory complications., Objective: To determine whether an early 8-hour restrictive oxygen strategy compared with a liberal oxygen strategy in adult trauma patients would reduce death and/or major respiratory complications., Design, Setting, and Participants: This randomized controlled trial enrolled adult trauma patients transferred directly to hospitals, triggering a full trauma team activation with an anticipated hospital stay of a minimum of 24 hours from December 7, 2021, to September 12, 2023. This multicenter trial was conducted at 15 prehospital bases and 5 major trauma centers in Denmark, the Netherlands, and Switzerland. The 30-day follow-up period ended on October 12, 2023. The primary outcome was assessed by medical specialists in anesthesia and intensive care medicine blinded to the randomization., Interventions: In the prehospital setting or on trauma center admission, patients were randomly assigned 1:1 to a restrictive oxygen strategy (arterial oxygen saturation target of 94%) (n = 733) or liberal oxygen strategy (12-15 L of oxygen per minute or fraction of inspired oxygen of 0.6-1.0) (n = 724) for 8 hours., Main Outcomes and Measures: The primary outcome was a composite of death and/or major respiratory complications within 30 days. The 2 key secondary outcomes, death and major respiratory complications within 30 days, were assessed individually., Results: Among 1979 randomized patients, 1508 completed the trial (median [IQR] age, 50 [31-65] years; 73% male; and median Injury Severity Score was 14 [9-22]). Death and/or major respiratory complications within 30 days occurred in 118 of 733 patients (16.1%) in the restrictive oxygen group and 121 of 724 patients (16.7%) in the liberal oxygen group (odds ratio, 1.01 [95% CI, 0.75 to 1.37]; P = .94; absolute difference, 0.56 percentage points [95% CI, -2.70 to 3.82]). No significant differences were found between groups for each component of the composite outcome. Adverse and serious adverse events were similar across groups, with the exception of atelectasis, which was less common in the restrictive oxygen group compared with the liberal oxygen group (27.6% vs 34.7%, respectively)., Conclusions and Relevance: In adult trauma patients, an early restrictive oxygen strategy compared with a liberal oxygen strategy initiated in the prehospital setting or on trauma center admission for 8 hours did not significantly reduce death and/or major respiratory complications within 30 days., Trial Registration: ClinicalTrials.gov Identifier: NCT05146700.

Background: Anticoagulation is essential for the treatment and prevention of thromboembolic events. Current guidelines recommend direct oral anticoagulants (DOACs) over vitamin K antagonists in DOAC-eligible patients. The major complication of anticoagulation is serious or life-threatening haemorrhage, which may necessitate prompt haemostatic intervention. Reversal of DOACs may also be required for patients in need of urgent invasive procedures. This guideline from the European Society of Anaesthesiology and Intensive Care (ESAIC) aims to provide evidence-based recommendations and suggestions on how to manage patients on DOACs undergoing urgent or emergency procedures including the treatment of DOAC-induced bleeding., Design: A systematic literature search was performed, examining four drug comparators (dabigatran, rivaroxaban, apixaban, edoxaban) and clinical scenarios ranging from planned to emergency surgery with the outcomes of mortality, haematoma growth and thromboembolic complications. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology was used to assess the methodological quality of the included studies. Consensus on the wording of the recommendations was achieved by a Delphi process., Results: So far, no results from prospective randomised trials comparing two active comparators (e.g. a direct reversal agent and an unspecific haemostatic agent such as prothrombin complex concentrate: PCC) have been published yet and the majority of publications were uncontrolled and observational studies. Thus, the certainty of evidence was assessed to be either low or very low (GRADE C). Thirty-five recommendations and clinical practice statements were developed. During the Delphi process, strong consensus (>90% agreement) was achieved in 97.1% of recommendations and consensus (75 to 90% agreement) in 2.9%., Discussion: DOAC-specific coagulation monitoring may help in patients at risk for elevated DOAC levels, whereas global coagulation tests are not recommended to exclude clinically relevant DOAC levels. In urgent clinical situations, haemostatic treatment using either the direct reversal or nonspecific haemostatic agents should be started without waiting for DOAC level monitoring. DOAC levels above 50 ng ml-1 may be considered clinically relevant necessitating haemostatic treatment before urgent or emergency procedures. Before cardiac surgery under activated factor Xa (FXa) inhibitors, the use of andexanet alfa is not recommended because of inhibition of unfractionated heparin, which is needed for extracorporeal circulation. In the situation of DOAC overdose without bleeding, no haemostatic intervention is suggested, instead measures to eliminate the DOACs should be taken. Due to the lack of published results from comparative prospective, randomised studies, the superiority of reversal treatment strategy vs. a nonspecific haemostatic treatment is unclear for most urgent and emergency procedures and bleeding. Due to the paucity of clinical data, no recommendations for the use of recombinant activated factor VII as a nonspecific haemostatic agent can be given., Conclusion: In the clinical scenarios of DOAC intake before urgent procedures and DOAC-induced bleeding, practitioners should evaluate the risk of bleeding of the procedure and the severity of the DOAC-induced bleeding before initiating treatment. Optimal reversal strategy remains to be determined in future trials for most clinical settings., (Copyright © 2024 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Purpose of Review: Tranexamic acid is routinely used as part of the management of traumatic bleeding. The dose recommendation in trauma was extrapolated from other clinical settings and the results of pragmatic randomized trials rather than pharmaco-kinetic and -dynamic evaluations. The review addresses current evidence on dosing of tranexamic acid in traumatized patients with a focus on efficacy, safety and risk-benefit profile., Recent Findings: A majority, but not all, of existing randomized clinical trials reports a reduction in mortality and/or blood loss with tranexamic acid administration. Increasing dose above the general recommendation (1 g bolus + 1 g infusion/8 h intravenously) has not been shown to further increase efficacy and could potentially increase side effects., Summary: The benefit of tranexamic acid as adjuvant therapy in the management of bleeding trauma patients on mortality and transfusion requirements is clear and well documented, being most effective if given early and to patients with clinical signs of hemorrhagic shock. Recent reports suggest that in some patients presenting with a shutdown of their fibrinolytic pathway the administration of tranexamic acid could be associated with an increased risk of thromboembolic events and poor outcomes. A more personalized approach based on bedside assessment of fibrinolytic activation and pharmacokinetic-based dose regimen should be developed moving forward., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: A main cause of trauma morbidity and mortality is multiple-organ failure, and endotheliopathy has been implicated. Pilot studies indicate that low-dose prostacyclin improves endothelial functionality in critically ill patients, suggesting that this intervention may improve trauma patient outcome., Methods: We conducted a multicenter, randomized, blinded, clinical investigator-initiated trial in 229 trauma patients with hemorrhagic shock who were randomized 1:1 to 72 hours infusion of the prostacyclin analog iloprost (1 ng/kg/min) or placebo. The primary outcome was the number of intensive care unit (ICU)-free days alive within 28 days of admission. Secondary outcomes included 28-day all-cause mortality and hospital length of stay., Results: The mean number of ICU-free days alive within 28 days was 15.64 days in the iloprost group versus 13.99 days in the placebo group (adjusted mean difference, -1.63 days [95% confidence interval (CI), -4.64 to 1.38 days]; p = 0.28). The 28-day mortality was 18.8% in the iloprost group versus 19.6% in the placebo group (odds ratio, 1.01 [95% CI, 0.51-2.0]; p = 0.97). The mean hospital length of stay was 19.96 days in the iloprost group versus 27.32 days in the placebo group (adjusted mean difference, 7.84 days [95% CI, 1.66-14.02 days], p = 0.01)., Conclusion: Iloprost did not result in a statistically significant increase in the number of ICU-free days alive within 28 days of admission, whereas it was safe and a statistically significant reduction in hospital length of stay was observed. Further research on prostacyclin in shocked trauma patients is warranted., Level of Evidence: Therapeutic/Care Management; Level II., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Surgery of Trauma.)

Thrombosis and bleeding are significant contributors to morbidity and mortality in patients with hematological cancer, and the impact of altered fibrinolysis on bleeding and thrombosis risk is poorly understood. In this prospective cohort study, we investigated the dynamics of fibrinolysis in patients with hematological cancer. Fibrinolysis was investigated before treatment and 3 months after treatment initiation. A dynamic clot formation and lysis assay was performed beyond the measurement of plasminogen activator inhibitor 1, tissue- and urokinase-type plasminogen activators (tPA and uPA), plasmin-antiplasmin complexes (PAP), α-2-antiplasmin activity, and plasminogen activity. Clot initiation, clot propagation, and clot strength were assessed using rotational thromboelastometry. A total of 79 patients were enrolled. Patients with lymphoma displayed impaired fibrinolysis with prolonged 50% clot lysis time compared with healthy controls (P = .048). They also displayed decreased clot strength at follow-up compared with at diagnosis (P = .001). A patient with amyloid light-chain amyloidosis having overt bleeding at diagnosis displayed hyperfibrinolysis, indicated by a reduced 50% clot lysis time, α-2-antiplasmin activity, and plasminogen activity, and elevated tPA and uPA. A patient with acute promyelocytic leukemia also displayed marked hyperfibrinolysis with very high PAP, indicating extreme plasmin generation, and clot formation was not measurable, probably because of the extremely fast fibrinolysis. Fibrinolysis returned to normal after treatment in both patients. In conclusion, patients with lymphoma showed signs of impaired fibrinolysis and increased clot strength, whereas hyperfibrinolysis was seen in patients with acute promyelocytic leukemia and light-chain amyloidosis. Thus, investigating fibrinolysis in patients with hematological cancer could have diagnostic value., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: Supplemental oxygen is commonly used in trauma patients, although it may lead to hyperoxaemia that has been associated with pulmonary complications and increased mortality. The primary objective of this trial, TRAUMOX2, is to compare a restrictive versus liberal oxygen strategy the first 8 hours following trauma., Methods and Analysis: TRAUMOX2 is an investigator-initiated, international, parallel-grouped, superiority, outcome assessor-blinded and analyst-blinded, randomised, controlled, clinical trial.Adult patients with suspected major trauma are randomised to eight hours of a restrictive or liberal oxygen strategy. The restrictive group receives the lowest dosage of oxygen ( > 21%) that ensures an SpO 2 of 94%. The liberal group receives 12-15 L O 2 /min or FiO 2 =0.6-1.0.The primary outcome is a composite of 30-day mortality and/or development of major respiratory complications (pneumonia and/or acute respiratory distress syndrome).With 710 participants in each arm, we will be able to detect a 33% risk reduction with a restrictive oxygen strategy if the incidence of our primary outcome is 15% in the liberal group., Ethics and Dissemination: TRAUMOX2 is carried out in accordance with the Helsinki II Declaration. It has been approved by the Danish Committee on Health Research Ethics for the Capital Region (H-21018062) and The Danish Medicines Agency, as well as the Dutch Medical Research Ethics Committee Erasmus MS (NL79921.078.21 and MEC-2021-0932). A website (www.traumox2.org) is available for updates and study results will be published in an international peer-reviewed scientific journal., Trial Registration Numbers: EudraCT 2021-000556-19; NCT05146700., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The main goal of perioperative coagulation monitoring is to improve safety of patients undergoing surgical procedures. Various conditions can affect the coagulation system during surgery and bleeding. The value of traditional standard coagulation tests is limited in detecting hemostatic dysfunctions and they are particularly ineffective in diagnosing hyperfibrinolysis. This article reports on key issues and pathophysiologic changes that affect the hemostatic system in the perioperative setting. Values of preoperative coagulation tests are discussed and the basic principles for point-of-care coagulation devices, including platelet analyzers and their clinical use, are evaluated., Competing Interests: Disclosure Author received unrestricted grants/travel support from Instrumentation Laboratory, Tem Innovations, CSL Behring, and Portola., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Antifibrinolytic drugs are used to reduce blood loss and subsequent transfusions during surgery and following trauma, but the optimal dosing regimen in the pediatric population is still unresolved. The aim of this systematic review was to evaluate efficacy and safety of antifibrinolytic drugs in pediatric surgery and trauma to determine the optimal dosing regimen. A literature search was performed in PubMed, Embase, Cochrane, and Web of Science on May 3, 2020. We included randomized controlled studies investigating the effect of tranexamic acid (TXA), aprotinin, and epsilon-aminocaproic acid, in terms of reducing blood loss, blood transfusions, reoperations, and rebleeds in pediatric patients aged 0 to 18 years undergoing cardiac surgery, noncardiac surgery, or trauma. Fifty randomized controlled trials (RCTs) were included; 28 RCTs investigated cardiac surgery and 22 investigated noncardiac surgery. No RCTs regarding trauma met the inclusion criteria. All antifibrinolytic drugs reduced postoperative blood loss and transfusions when used in pediatric surgery. The dosing regimen varied between studies, but similar effect sizes were found in terms of reduced blood loss regardless of the cumulative dose used. Few studies found adverse events, and no difference in incidence or type of adverse events was seen between the antifibrinolytic and the placebo group. In conclusion, use of antifibrinolytics is efficient and safe in children undergoing surgery. We propose TXA as the drug of choice based on its level of evidence and safety profile; we recommend a dosing regimen composed of a loading dose of 10 to 15 mg/kg prior to surgery followed by 1 to 5 mg/kg/h as continuous infusion throughout surgery., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction: Prehospital blood component therapy poses a possible treatment option among patients with severe bleeding. The aim of this paper was to characterize patients receiving prehospital blood component therapy by a paramedic-doctor-staffed, ground-based prehospital critical care (PHCC) service., Methods: Bleeding patients with a clinical need for prehospital blood transfusion were included prospectively. The following data were collected: indication for transfusion, mechanism of injury, vital parameters, units of red blood cells (RBCs)/plasma transfused, degree of shock, demographics, and mortality., Results: Twenty-one patients received blood products: 12 (57%) traumatic injuries and nine (43%) non-traumatic bleeds, with a median of 1.5 (range 1.0-2.0) units of RBCs and 1.0 (range 0.0-2.0) unit of plasma. The most frequent trigger to initiate transfusion was on-going excessive bleeding and hypotension. Improved systolic blood pressure (SBP) and milder degrees of shock were observed after transfusion. Mean time from initiation of transfusion to hospital arrival was 24 minutes. In-hospital, 11 patients (61%) received further transfusion and 13 (72%) had urgent surgery within 24 hours. Overall, 28-day mortality was 29% at 24-hours and 33% at 28-days., Conclusion: Prehospital blood component therapy is feasible in a ground-based prehospital service in a medium-sized Scandinavian city. Following transfusion, patient physiology and degree of shock were significantly improved.

Background: Tranexamic acid (TXA) reduces blood loss and transfusion requirements during craniosynostosis surgery in small children. Possible interaction from TXA on the inflammatory system is unknown., Objective: To evaluate the effect of TXA on a wide range of inflammatory markers in children receiving TXA in a randomized, blinded, and placebo controlled study design., Methods: Thirty children undergoing craniosynostosis surgery with significant blood loss received TXA (bolus dose of 10 mg kg -1 followed by 8 hours continuous infusion of 3 mg kg -1  h -1 ) or placebo in a randomized, double-blinded study design. Using a new proximity extension assays employing a panel of inflammatory biomarkers samples was used for analysis of blood samples obtained pre-operatively, 4 and 24 hours after operation., Results: Ninety-two inflammatory parameters were measured. TXA did not affect any of the measured parameters as compared with placebo. Among 34 of the 92 pro- and antiinflammatory parameters investigated changes were observed between pre-operative, 4 or 24 hours, respectively, reflecting immune activation during surgical stress., Conclusion: TXA administration in a low-dose regimen including bolus followed by 8 hours infusion during craniosynostosis surgery did not change any of 92 inflammatory markers as compared with placebo., (© 2020 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Objective:  Craniosynostosis surgery in small children is very often associated with a high blood loss. Tranexamic acid (TXA) reduces blood loss during this procedure, although the potential underlying coagulopathy in these children is not known in detail. Objective was to determine the nature of any coagulopathy found during and after craniosynostosis surgery and to characterize the effect of TXA on fibrin clot formation, clot strength, and fibrinolysis., Materials and Methods:  Thirty children received either TXA (bolus dose of 10 mg/kg followed by 8 hours continuous infusion of 3 mg/kg/h) or placebo. Dynamic whole blood clot formation assessed by thromboelastometry, platelet count, dynamic thrombin generation/thrombin-antithrombin, clot lysis assay, and fibrinogen/factor XIII (FXIII) levels were measured. Additionally, clot structure was investigated by real-time live confocal microscopy and topical data analysis., Results:  Increased ability of thrombin generation was observed together with a tendency toward shortened activated partial thromboplastin time and clotting time. Postoperative maximum clot firmness was higher among children receiving TXA. FXIII decreased significantly during surgery in both groups.Resistance toward tissue plasminogen activator-induced fibrinolysis was higher in children that received TXA, as evidenced by topical data analysis and by a significant longer lysis time. Fibrinogen levels were higher in the TXA group at 24 hours., Conclusion:  A significant coagulopathy mainly characterized by changes in clot stability and not parameters of thrombin generation was reported. Tranexamic acid improved clot strength and reduced fibrinolysis, thereby avoiding reduction in fibrinogen levels., Competing Interests: The authors declare no conflicts of interest with regard to the present manuscript. Dr. Hvas reports other from CSL Behring, other from Astellas, and other from Bayer A/S, outside the submitted work. Dr. Rasmussen reports grants from Health Research Foundation of Central Denmark Region, during the conduct of the study., (Georg Thieme Verlag KG Stuttgart · New York.)

Pediatric craniosynostosis (CS) surgery is frequently associated with extensive blood loss and transfusion requirements. The aim of the study was to evaluate the authors' institutional procedure with 2-surgeon approach and early transfusion strategy on blood loss and blood product transfusions in children undergoing craniofacial surgery. A retrospective analysis of medical records was performed of pediatric CS corrections during a 15-year period. Primary endpoint was blood loss and transfusion requirement during and the following 24 hours postoperatively. Linear regression analyses were performed of associations between intra and- postoperative blood loss and blood loss and weight. A total of 276 children (median 9 months) were included. Intraoperative blood loss was 22 mL/kg (14-33 mL/kg) and postoperatively 27 mL/kg (18-37 mL/kg), with no change during the study period. Intraoperative transfusions of red blood cell and plasma were 16 mL/kg (10-24 mL/kg) and postoperative 14 mL/kg (9-21 mL/kg). Postoperative red blood cell and plasma transfusions were 2 mL/kg (0-6 mL/kg) and of 0 mL/kg, respectively. Craniosynostosis type was related to blood loss (P < 0.001). There was an association between intraoperative and postoperative blood loss (P = 0.012) and intra- and postoperative blood loss and weight (P = 0.002, P = < 0.001). Duration of surgery was 110 minutes (range 60-300 minutes).Pediatric CS surgery is associated with substantial intra- and postoperative blood loss and transfusion requirements, which did not change over a 15-year period. Blood loss was associated with type of CS. Intraoperative blood loss was correlated to postoperative blood loss and body weight.

Background: Tranexamic acid (TXA) reduces intraoperative blood loss and transfusion during paediatric craniosynostosis surgery. Additional reduction of postoperative blood loss may further reduce exposure to allogeneic blood products. We studied the effect of combined intra- and postoperative TXA treatment on postoperative blood loss in children., Methods: Thirty children admitted for craniosynostosis surgery were randomised to combined intra- and postoperative TXA treatment or placebo. The primary endpoint was postoperative blood loss. Secondary endpoints included total blood loss, transfusion requirements, and clot stability evaluated by tissue plasminogen activator-stimulated clot lysis assay., Results: TXA reduced postoperative blood loss by 18 ml kg -1 (95% confidence interval 8.9) and total blood loss from a mean of 52 ml kg -1 (standard deviation [SD]; 20) ml kg -1 to 28 (14) ml kg -1 (P<0.001). Intraoperative red blood cell (RBC) and fresh frozen plasma (FFP) transfusions were reduced in the treatment group from RBC 14.0 (5.2) ml kg -1 to 8.2 (5.1) ml kg -1 (P=0.01) and from FFP 13.0 (6.3) ml kg -1 to 7.8 (5.9) ml kg -1 (P=0.03). Postoperative RBC transfusion median was 5 (inter-quartile range [IQR] 0-6) ml kg -1 in the placebo group and 0 (0-5.7) ml kg -1 in the TXA group. Resistance to lysis was higher in the treatment group (P<0.001)., Conclusions: Combined intra- and postoperative tranexamic acid treatment reduced postoperative and overall blood loss and transfusion requirements. Improved clot stability represents a possible mechanism for blood loss reduction., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: Central neuraxial blocks (CNB: epidural, spinal and their combinations) and other spinal pain procedures can cause serious harm to the spinal cord in patients on antihaemostatic drugs or who have other risk-factors for bleeding in the spinal canal. The purpose of this narrative review is to provide a practise advisory on how to reduce risk of spinal cord injury from spinal haematoma (SH) during CNBs and other spinal pain procedures. Scandinavian guidelines from 2010 are part of the background for this practise advisory., Methods: We searched recent guidelines, PubMed (MEDLINE), SCOPUS and EMBASE for new and relevant randomised controlled trials (RCT), case-reports and original articles concerning benefits of neuraxial blocks, risks of SH due to anti-haemostatic drugs, patient-related risk factors, especially renal impairment with delayed excretion of antihaemostatic drugs, and specific risk factors related to the neuraxial pain procedures., Results and Recommendations: Epidural and spinal analgesic techniques, as well as their combination provide superior analgesia and reduce the risk of postoperative and obstetric morbidity and mortality. Spinal pain procedure can be highly effective for cancer patients, less so for chronic non-cancer patients. We did not identify any RCT with SH as outcome. We evaluated risks and recommend precautions for SH when patients are treated with antiplatelet, anticoagulant, or fibrinolytic drugs, when patients' comorbidities may increase risks, and when procedure-specific risk factors are present. Inserting and withdrawing epidural catheters appear to have similar risks for initiating a SH. Invasive neuraxial pain procedures, e.g. spinal cord stimulation, have higher risks of bleeding than traditional neuraxial blocks. We recommend robust monitoring routines and treatment protocol to ensure early diagnosis and effective treatment of SH should this rare but potentially serious complication occur., Conclusions: When neuraxial analgesia is considered for a patient on anti-haemostatic medication, with patient-related, or procedure-related risk factors, the balance of benefits against risks of bleeding is decisive; when CNB are offered exclusively to patients who will have a reduction of postoperative morbidity and mortality, then a higher risk of bleeding may be accepted. Robust routines should ensure appropriate discontinuation of anti-haemostatic drugs and early detection and treatment of SH., Implications: There is an on-going development of drugs for prevention of thromboembolic events following surgery and childbirth. The present practise advisory provides up-to-date knowledge and experts' experiences so that patients who will greatly benefit from neuraxial pain procedures and have increased risk of bleeding can safely benefit from these procedures. There are always individual factors for the clinician to evaluate and consider. Increasingly it is necessary for the anaesthesia and analgesia provider to collaborate with specialists in haemostasis. Surgeons and obstetricians must be equally well prepared to collaborate for the best outcome for their patients suffering from acute or chronic pain. Optimal pain management is a prerequisite for enhanced recovery after surgery, but there is a multitude of additional concerns, such as early mobilisation, early oral feeding and ileus prevention that surgeons and anaesthesia providers need to optimise for the best outcome and least risk of complications.

: Institutional protocols need to address the indications for pharmacological and mechanical thromboprophylaxis. The use of graduated compression stockings (GCS) and intermittent pneumatic compression (IPC) strongly differs between institutions. As a consequence, no strong recommendations can be made based on the contemporary high-level evidence. Although different clinical practices can be supported, such approaches should be part of an institutional strategy to reduce the burden of venous thromboembolism (VTE). We recommend against the use of GCS alone without pharmacological thromboprophylaxis for prevention of VTE in patients at intermediate and high risk. For patients at high risk of VTE with contraindications for pharmacological thromboprophylaxis, we recommend the use of mechanical prophylaxis and suggest the use of IPC over GCS. However, for those patients receiving pharmacological thromboprophylaxis who are without a very high risk of VTE prophylaxis, we recommend against the routine use of mechanical thromboprophylaxis either with GCS or IPC. We suggest combined mechanical and pharmacological prophylaxis in selected patients at very high risk of VTE prophylaxis and suggest IPC rather than GCS in these selected patients.

: The risk for postoperative venous thromboembolism (VTE) is increased in patients aged more than 70 years and in elderly patients presenting with co-morbidities, for example cardiovascular disorders, malignancy or renal insufficiency. Therefore, risk stratification, correction of modifiable risks and sustained perioperative thromboprophylaxis are essential in this patient population. Timing and dosing of pharmacoprophylaxis may be adopted from the non-aged population. Direct oral anti-coagulants are effective and well tolerated in the elderly; statins may not replace pharmacological thromboprophylaxis. Early mobilisation and use of non-pharmacological means of thromboprophylaxis should be exploited. In elderly patients, we suggest identification of co-morbidities increasing the risk for VTE (e.g. congestive heart failure, pulmonary circulation disorder, renal failure, lymphoma, metastatic cancer, obesity, arthritis, post-menopausal oestrogen therapy) and correction if present (e.g. anaemia, coagulopathy) (Grade 2C). We suggest against bilateral knee replacement in elderly and frail patients (Grade 2C). We suggest timing and dosing of pharmacological VTE prophylaxis as in the non-aged population (Grade 2C). In elderly patients with renal failure, low-dose unfractionated heparin (UFH) may be used or weight-adjusted dosing of low molecular weight heparin (Grade 2C). In the elderly, we recommend careful prescription of postoperative VTE prophylaxis and early postoperative mobilisation (Grade 1C). We recommend multi-faceted interventions for VTE prophylaxis in elderly and frail patients, including pneumatic compression devices, low molecular weight heparin (and/or direct oral anti-coagulants after knee or hip replacement) (Grade 1C). : This article is part of the European guidelines on perioperative venous thromboembolism prophylaxis. For details concerning background, methods, and members of the ESA VTE Guidelines Task Force, please, refer to:Samama CM, Afshari A, for the ESA VTE Guidelines Task Force. European guidelines on perioperative venous thromboembolism prophylaxis. Eur J Anaesthesiol 2018; 35:73-76.A synopsis of all recommendations can be found in the following accompanying article: Afshari A, Ageno W, Ahmed A, et al., for the ESA VTE Guidelines Task Force. European Guidelines on perioperative venous thromboembolism prophylaxis. Executive summary. Eur J Anaesthesiol 2018; 35:77-83.

Background: Cardiac surgery may cause a serious coagulopathy leading to increased risk of bleeding and transfusion demands. Blood bank products are commonly first line haemostatic intervention, but has been associated with hazardous side effect. Coagulation factor concentrates may be a more efficient, predictable, and potentially a safer treatment, although prospective clinical trials are needed to further explore these hypotheses. This study investigated the haemostatic potential of ex vivo supplementation of coagulation factor concentrates versus blood bank products on blood samples drawn from patients undergoing cardiac surgery., Methods: 30 adults were prospectively enrolled (mean age=63.9, females=27%). Ex vivo haemostatic interventions (monotherapy or combinations) were performed in whole blood taken immediately after surgery and two hours postoperatively. Fresh-frozen plasma, platelets, cryoprecipitate, fibrinogen concentrate, prothrombin complex concentrate (PCC), and recombinant FVIIa (rFVIIa) were investigated. The haemostatic effect was evaluated using whole blood thromboelastometry parameters, as well as by thrombin generation., Results: Immediately after surgery the compromised maximum clot firmness was corrected by monotherapy with fibrinogen or platelets or combination therapy with fibrinogen. At two hours postoperatively the coagulation profile was further deranged as illustrated by a prolonged clotting time, a reduced maximum velocity and further diminished maximum clot firmness. The thrombin lagtime was progressively prolonged and both peak thrombin and endogenous thrombin potential were compromised. No monotherapy effectively corrected all haemostatic abnormalities. The most effective combinations were: fibrinogen+rFVIIa or fibrinogen+PCC. Blood bank products were not as effective in the correction of the coagulopathy., Conclusion: Coagulation factor concentrates appear to provide a more optimal haemostasis profile following cardiac surgery compared to blood bank products., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Fibrinogen concentrate can improve clot firmness and offers a better safety profile than platelet concentrates. Reduction or avoidance of blood transfusions represents a strategy to reduce associated risks. We investigated whether supplementation of fibrinogen concentrate ex vivo can compensate for clot strength as compared with platelet transfusion in vivo METHODS: One hundred patients in need of platelet transfusion (PT) were enrolled. Blood samples were collected immediately before PT and at 1 h and 24 h after PT. Fibrinogen concentrate was added to these citrated whole blood samples at concentrations of 50, 100, 200 and 400 mg kg -1 and the maximum clot firmness (MCF) was analysed using ROTEM thromboelastometry., Results: Fibrinogen supplementation increased MCF significantly and dose-dependently before and after PT. The effect of fibrinogen concentrate (equivalent to doses of 100 and 200 mg kg -1 ) ex vivo was comparable to that of PT in vivo, whereas 400 mg kg -1 fibrinogen significantly improved MCF compared with PT (P < 0.001)., Conclusions: Fibrinogen concentrate can match the effect of PT on MCF in thrombocytopenia. This potential alternative haemostatic intervention should be evaluated in clinical trials., (© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Patients with bone marrow failure secondary to chemotherapy often develop thrombocytopenia and require platelet transfusion. Fibrinogen plays an important role in platelet aggregation and the establishment of the primary haemostatic plug., Objectives: To compare the effects of in vivo platelet transfusion on clot firmness in thrombocytopenic patients with in vitro-performed fibrinogen concentrate substitution., Materials and Methods: Thirty patients with haematological malignancy admitted for platelet transfusion were included. Haemostatic effects from platelet transfusion and ex vivo addition of fibrinogen concentrate at three different doses were evaluated by thromboelastometry, with clot firmness as the primary endpoint (A30 ExTEM assay). Secondary endpoints were other thromboelastometry parameters, thrombin generation parameters, activated partial thromboplastin time (APTT), prothrombin time PT, fibrinogen and factor XIII levels and a clinical bleeding score., Results: Twenty patients (66%) had clinical bleeding signs by prior to transfusion. Platelets increased from 17 (range, 1-109) to 40 (range 2-139) × 10(9)  L(-1) following transfusion, with a median corrected count increment of 16·7 (range, 0·8-43·5). The A30 value increased significantly by platelet transfusion from 35 ± 11 to 47 ± 10 mm, with no changes in thrombin generation. Fibrinogen concentrate dose-dependently increased A 30 (to 43 ± 10, 49 ± 9 and 50 ± 9 mm, respectively) and reduced parameters of thrombin generation at high doses. Platelet transfusion, together with fibrinogen concentrate, further increased clot firmness. APTT and PT were within normal range, whereas fibrinogen levels were slightly elevated., Conclusion: Fibrinogen concentrate increased clot firmness to the same degree as platelet transfusion in patients with low platelet count requiring platelet transfusion., (© 2016 British Blood Transfusion Society.)

Tranexamic acid inhibits the degradation of a newly formed fibrin clot. The drug reduces blood loss and transfusion requirements in a wide range of different clinical scenarios and patient settings. So far, tranexamic acid is not part of standard treatment among patients with gastrointestinal bleeding. This article evaluates the available literature on this topic. Tranexamic acid seems appropriate as adjuvant treatment during upper gastrointestinal bleeding. However, these patients are often old and have several co-morbidities. Therefore, thromboembolic risk and tranexamic acid dosage should be carefully evaluated.

Background: Total thrombus formation velocity calculated using amplitude parameters obtained at different times could be used to estimate the amplification and the propagation phases observed during coagulation processes, and therefore might be useful to predict postoperative hemostatic products administration in pediatric patients., Methods: We retrospectively analyzed data from 49 children <3 months of age who underwent cardiac surgery. Children ≤1 month of age routinely received fresh frozen plasma during bypass while children >1 month of age did not. The EXTEM parameters were used to calculate velocity curves using amplitudes obtained at different times, the area under the curve called total thrombus formation and the maximum rate of thrombus formation. These parameters were compared between children who received fresh frozen plasma and those who did not. Receiver operating characteristics curves were used to define variables that could be used to predict postoperative fresh frozen plasma transfusion., Results: Total thrombus formation and maximum rate of thrombus formation significantly increased in children who received fresh frozen plasma compared to those who did not. Both total thrombus formation and maximum rate of thrombus formation have a better specificity to predict postoperative fresh frozen plasma transfusion compared to clotting time or maximal clot firmness., Conclusion: Based on this descriptive study, dynamic ROTEM(®) parameters of total thrombus formation could be used to estimate the amplification and the propagation phases of coagulation in children. These parameters might be used in further well-designed study to predict the need for hemostatic products in children undergoing cardiac surgery with cardiopulmonary bypass., (© 2015 John Wiley & Sons Ltd.)

We describe two cases of acute liver failure following heat stroke after participation in a running event. At admission both patients had a severely affected circulation, altered consciousness and hyperthermia, with a core temperature of > 40 degrees Celsius. Within the first 24 hours both patients suffered from acute liver failure, kidney failure and coagulopathy. No other causes but dehydration and hyperthermia could explain the liver failure. The treatment of heat stroke is symptomatic, but liver transplantation may be an option in case of fulminant liver failure.

New oral anticoagulants like the direct thrombin inhibitor, dabigatran (Pradaxa®), and factor Xa-inhibitors, rivaroxaban (Xarelto®) and apixaban (Eliquis®) are available for prophylaxis and treatment of thromboembolic disease. They are emerging alternatives to warfarin and provide equal or better clinical outcome together with reduced need for routine monitoring. Methods for measuring drug concentrations are available, although a correlation between plasma drug concentrations and the risk of bleeding has not been firmly established. Standard laboratory measures like prothrombin time and activated partial thromboplastin time are not sensitive enough to detect thrombin or factor Xa inhibition provided by new oral anticoagulants. Thus, these standard tests may only be used as a crude estimation of the actual anticoagulation status. Further challenges regarding patients receiving new oral anticoagulants who presents with major bleeding or need for emergency surgery pose a unique problem. No established agents are clinically available to reverse the anticoagulant effect, although preclinical data report prothrombin complex concentrate as more efficient than fresh frozen plasma or other prohaemostatic agents. This review summaries current knowledge on approved new oral anticoagulants and discusses clinical aspects of monitoring, with particular focus on the management of the bleeding patient., (© 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Cerebral injury and brain death is associated with apparent hypercoagulation and poor organ outcome. This experimental study challenges the hypotheses that i) brain death causes hypercoagulation and microvascular thrombosis and that ii) neutralizing systemic tissue factor (TF) by in vitro addition of a TF inhibitor (recombinant active site-inhibited factor VIIa (ASIS)) can reverse the hypercoagulable profile., Methods: Using a validated pig model of intracranial hemorrhage and brain death, 20 pigs were randomized to either control or brain death. The primary endpoints were coagulation parameters measured with whole blood thromboelastometry (ROTEM), thrombin generation and a porcine TF-sensitive plasma clotting time assay. In vitro spiking experiments with ASIS were performed in parallel with the latter two assessments. The kidneys were examined histologically for microvascular thromboses., Results: Brain death induced hypercoagulation, as demonstrated with ROTEM, thrombin generation, and reduced TF-sensitive plasma clotting time. In vitro inhibition of TF with ASIS did not reverse the hypercoagulation. No microvascular thromboses were found in the kidneys., Conclusion: Brain death causes hypercoagulation; however, inhibition of TF does not reverse the coagulopathy. Thus, TF release does not seem to be the primary cause of this hypercoagulation. Minor changes in the levels of protein C suggest that the protein C pathway may be linked to the observed coagulopathy., (© 2013.)

Introduction: Fibrinogen deficiency often develops during massive bleeding due to e.g. fluid resuscitation with colloid plasma expanders like hydroxyethyl starch. This study investigates the haemostatic effect of various sources of fibrinogen: fibrinogen concentrates (Haemocomplettan® (FC 1), CSL Behring and Clottagen® (FC 2), LFB Biomedicaments), fresh frozen plasma (FFP), and Cryoprecipitate (CP)., Methods: Whole blood samples provided by healthy individuals (n=8) were diluted 1:1 with HES or 0.9% isotonic saline as control. Various sources of fibrinogen was added to the HES diluted samples in concentrations equivalent to giving a 70 kg male either no correction, 2 grams of FC 1 or FC 2, 4 grams of FC 1 or FC 2, 15 ml/kg of FFP, 2 packs of CP or 4 packs of CP. Haemostatic effect was assessed by thromboelastometry initiated by tissue factor, with maximum clot firmness (MCF) as the primary endpoint. In addition thrombin generation was assessed for each intervention, Results: HES dilution reduced MCF significantly more than isotonic saline. High dose FC 1, 2 and CP corrected the MCF so that it did not differ significantly from the isotonic saline dilution group. Thrombin generation following isotonic saline and HES dilution was comparable and not decreased compared to whole blood. Fibrinogen concentrates supplementation did not increase thrombin generation whereas CP and FFP both increased thrombin generation, Conclusion: Fibrinogen concentrates investigated dose dependently and equally corrected the MCF and caused no increase in thrombin generation. Cryoprecipitate also corrected the MCF, but also increased thrombin generation. FFP failed to improve MCF, but increased thrombin generation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

This study introduces a new laboratory model of whole blood platelet aggregation stimulated by endogenously generated thrombin, and explores this aspect in haemophilia A in which impaired thrombin generation is a major hallmark. The method was established to measure platelet aggregation initiated by tissue factor evaluated by means of impedance aggregometry. Citrated whole blood from healthy volunteers and haemophilia A patients with the addition of inhibitors of the contact pathway and fibrin polymerization was evaluated. In healthy persons, a second wave of platelet aggregation was found to coincide with the thrombin burst and to be abolished by thrombin inhibitors. In this system, platelet aggregation in severe haemophilia A (n = 10) was found to be significantly decreased as compared with healthy individuals (912 ± 294 vs. 1917 ± 793 AU × min, P = 0.003), most probably due to the weak level of thrombin generation. For the first time, analysis of platelet aggregation as induced by endogenously generated thrombin was demonstrated. The new method makes it possible to explore the influence of the coagulation system on platelet function. In contrast to the general understanding, the data suggest that the impaired thrombin generation in haemophilia may affect platelet activation. Future studies will address whether our results may contribute to understanding differences in bleeding phenotypes and response to haemostatic substitution observed among patients., (© 2013 Blackwell Publishing Ltd.)

Context: The effectiveness of postoperative analgesia through a wound catheter is subject to considerable debate., Objective: To test the hypothesis that local wound infusion with bupivacaine followed by continuous infusion could reduce postoperative need for opioids in patients undergoing retropubic prostatectomy., Design: Single-centre prospective, double-blinded, placebo-controlled trial., Setting: A major university hospital in Denmark., Patients: Following written informed consent, 60 patients scheduled for prostatectomy were recruited to the study and 50 completed the protocol to reach data analysis., Interventions: Thirty millilitre bolus of bupivacaine (2.5 mg ml) or isotonic saline was injected through a subfascially placed wound catheter followed by continuous infusion at 5 ml h during the following 48 h. All patients were prescribed paracetamol, non-steroidal anti-inflammatory drugs, morphine and oxycodone if needed., Outcome Measures: Primary outcome was the opioid requirement. Secondary outcomes included pain scores at rest and with activity, and nausea and vomiting scores., Results: The total amount of morphine required during the postoperative period was not significantly higher (P=0.49) in the placebo group (12 mg, 25 to 75% percentile 5 to 18) than the bupivacaine group (10 mg, 25 to 75% percentile 0 to 16). Similarly, the total amount of oxycodone required was not significantly different (P=0.99) and was equal among the groups (5 mg, 25 to 75% percentile 5 to 10). At 2 h postoperatively, a significantly (P=0.0488) higher number of patients required additional morphine in the placebo group. No differences between the groups were detected at any time point regarding pain scores or the presence of nausea and vomiting., Conclusion: Additional use of a wound catheter in patients undergoing prostatectomy in the present perioperative setting appears superfluous.

Coagulation factor I (fibrinogen) plays an essential role in the hemostatic system by bridging activated platelets and being the key substrate for thrombin in establishing a consolidating fibrin network. Fibrinogen is synthesized in the liver and the plasma concentration is 1 to 5-4.0 g/L. During recent 10 years, fibrinogen has been recognized to play an important role in controlling hemorrhage. Dilutional coagulopathy induced by colloid plasma expanders is characterized by fibrinogen deficiency and dysfunctional fibrin polymerization. Trauma and use of extracorporeal circulation is also known to reduce levels of fibrinogen. A series of laboratory experiments and experimental animal studies have suggested fibrinogen as a potent hemostatic agent. These data are supported by retrospective surveys as well as a series of prospective proof of principal clinical trials. This article provides a description of the biochemistry and mechanisms of fibrinogen as well as the etiology for developing fibrinogen deficiency. Furthermore, it summarizes laboratory and experimental data on the role of fibrinogen in dilutional coagulopathy and addresses laboratory monitoring issues. Finally, it lists retrospective and prospective studies, which have been designed to assess the clinical efficacy and safety of hemostatic intervention with fibrinogen concentrate., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Thromboelastography/metry (TEG®; Haemoscope, Niles, IL/ROTEM®; Tem International GmbH, Munich, Germany) is increasingly used to guide transfusion therapy. This study investigated the diagnostic performance and therapeutic consequence of using kaolin-activated whole blood compared with a panel of specific TEM®-reagents to distinguish: dilutional coagulopathy, thrombocytopenia, hyperfibrinolysis, and heparinization., Methods: Blood was drawn from 11 healthy volunteers. Dilutional coagulopathy was generated by 50% dilution with hydroxyethyl starch 130/0.4 whereas thrombocytopenia (mean platelet count 20 ×10⁹/l) was induced using a validated model. Hyperfibrinolysis and heparin contamination were generated by tissue plasminogen activator 2 nM and unfractionated heparin 0.1U/ml, respectively. Coagulation tests were run on ROTEM® delta., Results: Kaolin-activated whole blood showed no differences between dilutional coagulopathy and thrombocytopenia (mean clotting time 450 s vs. 516 s, α-angle 47.1° vs. 41.5°, maximum clot firmness 35.0 mm vs. 34.2 mm, all P values ≥0.14). Hyperfibrinolysis specifically disclosed an increased maximum lysis (median: 100%, all P values less than 0.001), and heparin induced a distinctly prolonged clotting time (2283 s, all P values less than 0.02). The coagulopathies were readily distinguishable using a panel of TEM-reagents. In particular, dilutional coagulopathy was separated from thrombocytopenia using FIBTEM (maximum clot firmness 1.9 mm vs. 11.2 mm, P < 0.001). The run time of analysis to achieve diagnostic data was shorter applying a panel of TEM-reagents. A transfusion algorithm based on kaolin suggested platelets in case of dilutional coagulopathy, whereas an algorithm applying TEM-reagents suggested fibrinogen., Conclusion: Monoanalysis with kaolin was unable to distinguish coagulopathies caused by dilution from that of thrombocytopenia. Algorithms based on the use of kaolin may lead to unnecessary transfusion with platelets, whereas the application of TEM-reagents may result in goal-directed fibrinogen substitution.

Objectives: Acquired type 2A von Willebrand disease may develop as a consequence of aortic valve stenosis and is associated with varying degrees of bleeding tendency. It remains unknown, whether it portends excess blood loss during aortic valve replacement., Design: We consecutively enrolled 45 patients with severe aortic valve stenosis undergoing aortic valve replacement. Patients with acquired type 2A von Willebrand disease were identified measuring the von Willebrand factor high molecular weight multimer. Data on the intraoperative, early postoperative, and the total blood loss within 24 hours of surgery was obtained and compared between groups., Results: Acquired type 2A von Willebrand disease was found in 33% (n = 15/45) of the patients. Baseline characteristics were similar between groups. Patients with acquired type 2A von Willebrand disease neither had excess median intraoperative blood loss (375 ml (interquartile range 100-450 ml) vs. 350 ml (interquartile range 250-500 ml), p = 0.59) nor increased median total blood loss (695 ml (interquartile range 450-850 ml) vs. 752 ml (interquartile range 575-1035 ml), p = 0.41) as compared to patients without acquired type 2A von Willebrand disease., Conclusion: Acquired type 2A von Willebrand disease was not associated with increased blood loss during aortic valve replacement in patients with severe aortic valve stenosis.

Fibrinogen is involved in both primary and secondary hemostasis, playing an important role in platelet aggregation and the establishment of a fibrin network. Recent evidence suggests that very high levels of fibrinogen act as antithrombin and can reduce endogenous thrombin potential and compromise clot stability, particularly following a low tissue factor stimulus. Several laboratory methods for measuring plasma fibrinogen concentrations are available, but results vary depending on the type of method and the use of artificial colloid plasma expanders. Adopting only the Clauss method can provide erroneously high levels when used in patients who have received colloid plasma expanders. This may contribute to a hazardous delay or complete lack of treatment. Multiple in vitro experiments, animal studies, and proof-of-principle randomized, clinical studies have recently suggested that hemostatic intervention with a fibrinogen concentrate may be efficient and safe in controling perioperative bleeding. In particular, fibrinogen concentrate has a key role in improving clotting function and reducing blood loss in settings such as trauma and cardiothoracic surgery. However, prospective studies are needed to determine the clinical efficacy and safety of fibrinogen concentrate when used as a hemostatic intervention for patients with massive bleeding due to trauma or surgery., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Measurement of plasma fibrinogen is often required in critically ill patients or massively bleeding patients being resuscitated with colloid plasma expander. This study aimed at evaluating different assays of plasma fibrinogen after in vitro dilution with commonly used plasma expanders and challenged the hypothesis that levels of fibrinogen are estimated significantly higher in plasma diluted with colloid plasma expander compared with isotonic saline., Study Design and Methods: Fibrinogen measurements were established in plasma samples each diluted in vitro to 30 or 50% with isotonic saline, hydroxyethyl starch (HES) 130/0.4, and human albumin. Fibrinogen levels were assessed using an antigen determination, three photo-optical Clauss methods, one mechanical Clauss method, a prothrombin-derived method, and viscoelastic measurement through thromboelastometry., Results: Measurement of fibrinogen levels was significantly different when performed on alternate analytical platforms. By 30 and 50% dilution with HES 130/0.4 coagulation analyzers using the photo-optical Clauss methods significantly overestimated levels of fibrinogen. Dilution with human albumin did not affect fibrinogen levels except from one analyzer by 50% dilution level. Viscoelastic measurement of fibrin polymerization was reduced at both dilution levels and appeared to reflect the impairment of fibrin polymerization induced by HES 130/0.4 and to a lesser extent human albumin., Conclusion: This study demonstrated that different automated coagulation analyzers revealed significantly different levels of fibrinogen. The presence of colloid plasma expander gave rise to erroneous high levels of fibrinogen returned from some coagulation analyzers employing the method of Clauss., (© 2010 American Association of Blood Banks.)

Renewed interest has arisen in the use of thromboelastography/thromboelastometry in evaluating coagulation kinetics. The test medium, type of activator, and its concentration may influence the interpretation of coagulation kinetics. This study aimed to investigate methodologic influences of activator and test medium on thromboelastometric parameters of coagulation kinetics. Dynamic clot formation was evaluated by thromboelastometry using whole blood (WB), platelet-rich plasma, or platelet-poor plasma employing different concentrations of extrinsic (tissue factor) and contact activator (synthasil) and with variable concentrations of phospholipids. Plasma samples displayed prolonged clot initiation and enhanced clot propagation compared with WB. Clot firmness was markedly reduced in platelet-poor plasma as compared with platelet-rich plasma and WB. Increasing concentration of activator shortened the clot initiation and increased the velocity of clot propagation, whereas terminal clot firmness remained unaffected. Platelets accelerated clot propagation and raised clot firmness. Phospholipids shortened the time of clot initiation and increased velocity of propagation, while clot firmness remained unchanged. Our results demonstrate that evaluation of coagulation kinetics using thromboelastometry varies according to the composition of the test medium, type, and concentration of activator, as well as the presence and concentration of phospholipids in the test reagent.

Background: Human fibrinogen concentrates have been commercially available for decades for substitution therapy in hypofibrinogenemia, dysfibrinogenemia and afibrinogenemia. Accumulating new data suggest that fibrinogen plays a critical role in achieving and maintaining hemostasis, particularly in patients suffering from acquired fibrinogen deficiency during massive bleeding, where benefit from early intervention with fibrinogen concentrate appears to be important., Objective/methods: This work focuses on pasteurized fibrinogen concentrate, with special emphases on product characteristics, pharmacodynamics, pharmacokinetics, laboratory monitoring, dosing, clinical efficacy, safety and tolerability. Future clinical and laboratory perspectives on fibrinogen are discussed and outlined., Results/conclusion: Pasteurized fibrinogen concentrate is derived from human plasma. Its half life is 2.7 days in patients with congenital fibrinogen deficiency. For congenital and acquired deficiency in vivo recovery rates vary from 60% to 109%. Reportedly, administration of pasteurized fibrinogen in patients with congenital deficiency is efficacious. Acquired deficiency of fibrinogen appears to be an early event in seriously bleeding patients, preceding critical levels of platelets or other coagulation factors. Experimental animal studies, as well as clinical observations suggest a beneficial role of early substitution with fibrinogen in management of critical traumatic and surgical bleeds. Pasteurized fibrinogen concentrate is well tolerated and associated with a low incidence of adverse thrombo-embolic events.

Background: The biochemical mechanisms causing dilutional coagulopathy following infusion of hydroxyethyl starch 130/0.4 (HES) are not known in detail., Objectives: To give a detailed biochemical description of the mechanism of coagulopathy following 30%in vivo dilution with HES, to present a systematic ex vivo test of various hemostatic agents, and to investigate the hypothesis that acquired fibrinogen deficiency constitutes the most important determinant of the coagulopathy., Methods: Dynamic whole blood clot formation assessed by thromboelastometry, platelet count, thrombin generation, and the activities of von Willebrand factor, coagulation factor II, FVII, FVIII, FIX, FX and FXIII were measured in 20 bleeding patients enrolled in a prospective clinical study investigating in vivo substitution of blood loss with HES up to a target level of 30%. Thromboelastometry parameters were further evaluated after ex vivo spiking experiments with fibrinogen, prothrombin complex concentrate (PCC), FXIII, activated recombinant FVIIa (rFVIIa), fresh frozen plasma, and platelets., Results: Hemodilution reduced maximum clot firmness (MCF), whereas whole blood clotting time (CT) and maximum velocity remained unaffected. All coagulation factor activities were reduced. Fibrinogen, FII, FXIII and FX activities decreased significantly below the levels expected from dilution. The endogenous thrombin potential was unchanged. Ex vivo addition of fibrinogen normalized the reduced MCF and increased the maximum velocity, whereas PCC, rFVIIa and platelets shortened the CT but showed no effect on the reduced MCF., Conclusions: Acquired fibrinogen deficiency seems to be the leading determinant in dilutional coagulopathy, and ex vivo addition corrected the coagulopathy completely.

Background: Development of coagulopathy is a serious complication arising from isolated traumatic brain injury, and it predicts poor outcome. The underlying mechanism has not yet been established, although coagulopathy arising from brain tissue injury and the release of tissue factor may represent the pathophysiology. The authors investigated dynamic whole-blood clot formation (ROTEM) in a recently developed porcine model of induced severe intracranial hypertension., Methods: In this prospective, randomized experimental study, 17 pigs were designated for severe intracranial hypertension or sham operation. Intracranial hypertension was induced by inflation of an intracranial balloon. Whole-blood clot formation was assessed by clot initiation, and clot propagation and clot strength through thrombelastometry. The authors also assessed thrombin generation and prothrombin time, which were obtained at baseline, immediately after intervention, and 5 h after intervention., Results: A dramatic shortening in time to clot initiation and an increase in clot propagation were observed after induction of intracranial hypertension as compared to the control group. These results were further substantiated by a pronounced increase in thrombin generation and a significantly shortened prothrombin time in the intervention group. No difference in clot strength was detected between the groups., Conclusions: In a porcine model, induction of increased intracranial pressure causing severe intracranial hypertension was associated with a pronounced activation of the coagulation system. Taken together, the various results indicate that tissue factor probably represents the main trigger of hypercoagulopathy found in these pigs.

Summary Background: Infusion of artificial colloids such as hydroxyethyl starch (HES) induces coagulopathy to a greater extent than simple dilution. Several studies have suggested that the coagulopathy could be corrected by substitution with a fibrinogen concentrate., Objectives: The aims of the present prospective, randomized, placebo-controlled trial were to investigate the hemostatic effect of a fibrinogen concentrate after coagulopathy induced by hydroxyethyl starch in patients experiencing sudden excessive bleeding during elective cystectomy., Methods: Twenty patients were included. Blood loss was substituted 1:1 with HES 130/0.4. At a dilution level of 30%, patients were randomly selected for intra-operative administration of a fibrinogen concentrate or placebo. The primary endpoint was maximum clot firmness (MCF), as assessed by thromboelastometry. Secondary endpoints were blood loss and transfusion requirements, other thromboelastometry parameters, thrombin generation and platelet function., Results: Whole-blood MCF was significantly reduced after 30% dilution in vivo with HES. The placebo resulted in a further decline of the MCF, whereas randomized administration of fibrinogen significantly increased the MCF. Furthermore, only 2 out of 10 patients randomly chosen to receive fibrinogen substitution required postoperative red blood cell transfusions, compared with 8 out of 10 in the placebo group (P = 0.023). Platelet function and thrombin generation were reduced after 30% hemodilution in vivo, and fibrinogen administration caused no significant changes., Conclusions: During cystectomy, fluid resuscitation with HES 130/0.4 during sudden excessive bleeding induces coagulopathy that shows reduced whole-blood maximum clot firmness. Randomized administration of fibrinogen concentrate significantly improved maximum clot firmness and reduced the requirement for postoperative transfusion.

Background: Major blood loss requires fluid resuscitation for maintaining hemodynamic stability. Excessive volume infusions predispose to dilutional coagulopathy through loss, consumption and dilution of cells and proteins involved in haemostasis. Further treatment with fibrinogen concentrate and/or recombinant activated factor VII (rFVIIa) may be initiated, although the haemostatic effects in a situation with haemodilution are not fully detailed. The present study evaluates haemostatic effect of fibrinogen and rFVIIa and their combination in an in vitro model of haemodiluted whole blood with two commonly used crystalloids., Methods: Eight healthy, male volunteers were enrolled. Outcome variables were clot initiation, propagation and strength assessed by thrombelastographic parameters: clotting time, clot formation time, maximum velocity, time until maximum velocity, maximum clot firmness evaluated at dilution levels of 0% (control), 10%, 30% and 50% with isotonic saline and Ringer's lactate in a model of tissue factor-activated whole blood. Fibrinogen and rFVIIa were additional final reaction concentrations, reflecting commonly used clinically therapeutic dosages., Results: Dose-dependent coagulopathy developed following haemodilution with isotonic saline and Ringer's lactate, characterised by a prolonged clot initiation, reduced clot propagation and reduced clot strength. Fibrinogen improved clot strength and propagation phase while rFVIIa shortened clot initiation, both with a positive dose dependency., Conclusions: The combination of fibrinogen and rFVIIa displays an additive effect and improves overall in vitro whole blood clot formation in a model of in vitro crystalloid-induced haemodilution.

Most often, thrombelastographic analyses are carried out using citrated blood and re-calcification. However, calcium chelation may affect dynamics of tissue-factor-initiated thrombin generation. The present study investigates the effect of sample anticoagulant on the response of a colloid induced dilutional coagulopathy model to recombinant activated factor VII (rFVIIa) as measured by thrombelastography. Thrombelastographic evaluation of whole blood coagulation activated with minute amounts of tissue factor in a model of in vitro haemodilution with hydroxyethyl starch (HES) 130/0.4 in a prospective laboratory study. Whole blood coagulation was evaluated before and after 30% dilution with HES 130/0.4, and following in vitro addition of rFVIIa to whole blood collected into tubes containing citrate, corn trypsin inhibitor (CTI), and no stabilizers. Haemodilution with HES 130/0.4 induces a coagulopathy characterised by a reduced maximum rate of clot formation and a pronounced reduction in the final clot firmness. With all test mediums investigated, rFVIIa significantly shortened clot initiation phase. In cases of native whole blood and CTI-stabilised whole blood, rFVIIa shortens the clotting time but also demonstrated an acceleration of the maximum velocity of clot formation. When citrate is used as anticoagulants in thrombelastographic clotting assays, these may artificially mask the haemostatic effect of rFVIIa in colloid haemodilution. The effect in vitro of rFVIIa in citrated blood samples may underestimate the haemostatic potential of rFVIIa.

Background: Patients experiencing massive haemorrhage are at high risk of developing coagulopathy through loss, consumption, and dilution of coagulation factors and platelets. It has been reported that plasma fibrinogen concentrations may reach a critical low level relatively early during bleeding, calling for replacement fibrinogen therapy. Cryoprecipitate has been widely used in the past, but more recently, a pasteurized fibrinogen concentrate has become available. We audited the effects of fibrinogen concentrate therapy on laboratory and clinical outcome in patients with massive haemorrhage., Methods: We identified 43 patients over the previous 2 yr to whom a fibrinogen concentrate had been administered as treatment for hypofibrinogenaemia during serious haemorrhage. Platelet count, P-fibrinogen, activated partial thromboplastin time (APTT), prothrombin time (PT), D-dimer, and volume of blood lost were obtained from medical and laboratory records. Numbers of units of red blood cells (RBC), fresh frozen plasma (FFP), and pooled platelet concentrates were recorded before and after fibrinogen substitution., Results: A significant increase in plasma fibrinogen concentration was observed after fibrinogen concentrate therapy. Platelet counts and fibrin D-dimer values remained unchanged, whereas the APTT and PT improved significantly. Requirements for RBC, FFP, and platelets were significantly reduced. Blood loss decreased significantly., Conclusions: Off-label substitution therapy with a fibrinogen concentrate generally improved global laboratory coagulation results and as supplementary intervention, appeared to diminish the requirements for RBC, FFP, and platelet substitution in this patient cohort.