Hemostasis and Fibrinolysis following Aneurysmal Subarachnoid Hemorrhage: A Systematic Review on Additional Knowledge from Dynamic Assays and Potential Treatment Targets
Seminars in thrombosis and hemostasis. 2021
Mortality after aneurysmal subarachnoid hemorrhage (aSAH) is augmented by rebleeding and delayed cerebral ischemia (DCI). A range of assays evaluating the dynamic process of blood coagulation, from activation of clotting factors to fibrinolysis, has emerged and a comprehensive review of hemostasis and fibrinolysis following aSAH may reveal targets of treatment. We conducted a systematic review of existing literature assessing coagulation and fibrinolysis following aSAH, but prior to treatment. PubMed, Embase, and Web of Science were searched on November 18, 2020, without time boundaries. In total, 45 original studies were eventually incorporated into this systematic review, divided into studies presenting data only from conventional or quantitative assays (n = 22) and studies employing dynamic assays (n = 23). Data from conventional or quantitative assays indicated increased platelet activation, whereas dynamic assays detected platelet dysfunction possibly related to an increased risk of rebleeding. Secondary hemostasis was activated in conventional, quantitative, and dynamic assays and this was related to poor neurological outcome and mortality. Studies systematically investigating fibrinolysis were sparse. Measurements from conventional or quantitative assays, as well as dynamic fibrinolysis assays, revealed conflicting results with normal or increased lysis and changes were not associated with outcome. In conclusion, dynamic assays were able to detect reduced platelet function, not revealed by conventional or quantitative assays. Activation of secondary hemostasis was found in both dynamic and nondynamic assays, while changes in fibrinolysis were not convincingly demonstrable in either dynamic or conventional or quantitative assays. Hence, from a mechanistic point of view, desmopressin to prevent rebleeding and heparin to prevent DCI may hold potential as therapeutic options. As changes in fibrinolysis were not convincingly demonstrated and not related to outcome, the use of tranexamic acid prior to aneurysm closure is not supported by this review.
Use of Thromboelastography in the Evaluation and Management of Patients With Traumatic Brain Injury: A Systematic Review and Meta-Analysis
Critical care explorations. 2021;3(9):e0526
Traumatic brain injury is associated with coagulopathy that increases mortality risk. Viscoelastic hemostatic assays such as thromboelastography (Haemonetics SA, Signy, Switzerland) provide rapid coagulopathy assessment and may be particularly useful for goal-directed treatment of traumatic brain injury patients. We conducted a systematic review to assess thromboelastography in the evaluation and management of coagulopathy in traumatic brain injury patients. DATA SOURCES MEDLINE, PubMed Central, Embase, and CENTRAL. STUDY SELECTION Clinical studies of adult patients with traumatic brain injury (isolated or polytrauma) who were assessed by either standard thromboelastography or thromboelastography with platelet mapping plus either conventional coagulation assays or platelet function assays from January 1999 to June 2021. DATA EXTRACTION Demographics, injury mechanism and severity, diagnostic, laboratory data, therapies, and outcome data were extracted for analysis and comparison. DATA SYNTHESIS Database search revealed 1,169 sources; eight additional articles were identified by the authors. After review, 31 publications were used for qualitative analysis, and of these, 16 were used for quantitative analysis. Qualitative and quantitative analysis found unique patterns of thromboelastography and thromboelastography with platelet mapping parameters in traumatic brain injury patients. Patterns were distinct compared with healthy controls, nontraumatic brain injury trauma patients, and traumatic brain injury subpopulations including those with severe traumatic brain injury or penetrating traumatic brain injury. Abnormal thromboelastography K-time and adenosine diphosphate % inhibition on thromboelastography with platelet mapping are associated with decreased survival after traumatic brain injury. Subgroup meta-analysis of severe traumatic brain injury patients from two randomized controlled trials demonstrated improved survival when using a viscoelastic hemostatic assay-guided resuscitation strategy (odds ratio, 0.39; 95% CI, 0.17-0.91; p = 0.030). CONCLUSIONS Thromboelastography and thromboelastography with platelet mapping characterize coagulopathy patterns in traumatic brain injury patients. Abnormal thromboelastography profiles are associated with poor outcomes. Conversely, treatment protocols designed to normalize abnormal parameters may be associated with improved traumatic brain injury patient outcomes. Current quality of evidence in this population is low; so future efforts should evaluate viscoelastic hemostatic assay-guided hemostatic resuscitation in larger numbers of traumatic brain injury patients with specific focus on those with traumatic brain injury-associated coagulopathy.
Viscoelastic Hemostatic Assays and Outcomes in Traumatic Brain Injury: A Systematic Literature Review
World neurosurgery. 2021
BACKGROUND Coagulopathy in Traumatic brain injury (TBI) occurs frequently and is associated with poor outcomes. Conventional coagulation assays (CCA) traditionally used to diagnose coagulopathy are often not time sensitive and do not assess complete hemostatic function. Viscoelastic hemostatic assays (VHA) including thromboelastography (TEG) and rotational thromboelastography (ROTEM) provide a useful rapid and comprehensive point-of-care alternative for identifying coagulopathy, which is of significant consequence in TBI patients with intracranial hemorrhage. METHODS A systematic review was performed in accordance with guidelines for the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) to identify studies comparing VHA to CCA in adult TBI patients. The following differences in outcomes were assessed based on ability to diagnose coagulopathy: mortality, need for neurosurgical intervention, and progression of traumatic intracranial hemorrhage (tICH). RESULTS Abnormal R-time, MA, and K value were associated with increased mortality in certain studies but not all studies. This association was reflected across studies utilizing different statistical parameters with different outcome definitions. An abnormal R-time was the only VHA parameter found to be associated with the need for neurosurgical intervention in one study. An abnormal R time was also the only VHA parameter associated with progression of tICH. Overall, many studies also demonstrated abnormal CCAs, mainly activated partial thromboplastin time (aPPT) to be associated with poor outcomes. CONCLUSION Given the heterogenous nature of the available evidence including methodology and study outcomes, the comparative difference between VHA and CCA in predicting rates of neurosurgical intervention, tICH progression, or mortality in TBI patients remains inconclusive.
Thromboelastography and Rotational Thromboelastometry in Bleeding Patients with Coagulopathy: Practice Management Guideline from the Eastern Association for the Surgery of Trauma
The journal of trauma and acute care surgery. 2020
BACKGROUND Assessment of the immediate need for specific blood product transfusions in acutely bleeding patients is challenging. Clinical assessment and commonly used coagulation tests are inaccurate and time-consuming. The goal of this practice management guideline was to evaluate the role of the viscoelasticity tests: thromboelastography (TEG) and rotational thromboelastometry (ROTEM), in the management of acutely bleeding trauma, surgical and critically ill patients. METHODS Systematic review and meta-analyses of manuscripts comparing TEG/ROTEM to non-TEG/ROTEM-guided blood products transfusions strategies were performed. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was applied to assess the level of evidence and create recommendations for TEG/ROTEM-guided blood product transfusions in adult trauma, surgical, and critically ill patients. RESULTS Utilizing TEG/ROTEM-guided blood transfusions in acutely bleeding trauma, surgical, and critically ill patients was associated with a tendency to fewer blood product transfusions in all populations. TEG/ROTEM-guided transfusions were associated with a reduced number of additional invasive hemostatic interventions (angioembolic, endoscopic, or surgical) in surgical patients. TEG/ROTEM -guided transfusions were associated with a reduction in mortality in trauma patients. CONCLUSION In patients with ongoing hemorrhage and concern for coagulopathy, we conditionally recommend using TEG/ROTEM-guided transfusions, compared with traditional coagulation parameters, to guide blood component transfusions in each of the following three groups: adult trauma patients, adult surgical patients, and patients with critical illness. LEVEL OF EVIDENCE Level II TYPE OF STUDY Therapeutic.
Are thromboelastometric and thromboelastographic parameters associated with mortality in septic patients? A systematic review and meta-analysis
Journal of critical care. 2020;61:5-13
BACKGROUND Thromboelastometry/elastography (ROTEM/TEG) showed promising results for diagnosis of sepsis-induced coagulopathy, but their association with the outcome is unclear. Our aim was to assess any difference in ROTEM/TEG measurements between septic survivors and non-survivors. METHODS Pubmed, Web of Science, Embase and Cochrane Library databases were investigated. The research aimed to include any randomized or observational study: i) on septic adult patients admitted to Intensive Care Unit (ICU) or Emergency Department (ED); ii) including ROTEM/TEG; iii) assessing mortality. RESULTS Seven prospective and four retrospective observational studies (952 patients) were included. According to the INTEM/kaolin-assay, clotting time (CT)/R (standardized mean difference(SMD) -0.29, 95% CI -0.49 to -0.09, p = 0.004) and clot formation time (CFT)/K (SMD -0.42, 95% CI -0.78 to -0.06, p = 0.02) were shorter in survivors. According to the EXTEM-assay, CT was shorter (MD -11.66 s, 95% CI -22.59 to -0.73, p = 0.04), while MCF was higher (MD 3.49 mm, 95% CI 0.43 to 6.55, p = 0.03) in survivors. A hypocoagulable profile was more frequent in non-survivors (OR 0.31, 95%CI 0.18 to 0.55, p < 0.0001). Overall, the risk of bias of the included studies was moderate and the quality of evidence low. CONCLUSIONS Hypocoagulability and lower MCF in EXTEM may be associated with higher mortality in sepsis.
The use of viscoelastic haemostatic assays in non-cardiac surgical settings: a systematic review and meta-analysis
Blood Transfusion = Trasfusione Del Sangue. 2018;:1-9.
BACKGROUND Thrombelastography (TEG) and rotational thromboelastometry (ROTEM) are viscoelastic haemostatic assays (VHA) which exploit the elastic properties of clotting blood. The aim of this systematic review and meta-analysis was to evaluate the usefulness of these tests in bleeding patients outside the cardiac surgical setting. MATERIALS AND METHODS We searched the Cochrane Library, MEDLINE, EMBASE and SCOPUS. We also searched clinical trial registries for ongoing and unpublished studies, and checked reference lists to identify additional studies. RESULTS We found 4 randomised controlled trials (RCTs) that met our inclusion criteria with a total of 229 participants. The sample size was small (from 28 to 111 patients) and the follow-up periods very heterogenous (from 4 weeks to 3 years). Pooled data from the 3 trials reporting on mortality (199 participants) do not show any effect of the use of TEG on mortality as compared to standard monitoring (based on the average treatment effect from a fixed-effects model): Risk Ratio (RR) 0.71; 95% Confidence Interval (CI): 0.43 to 1.16. Likewise, the use of VHA does not reduce the need for red blood cells (mean difference -0.64; 95% CI: -1.51 to 0.23), platelet concentrates (mean difference -1.12; 95% CI: -3.25 to 1.02), and fresh frozen plasma (mean difference -0.91; 95% CI: -2.02 to 0.19) transfusion. The evidence on mortality and other outcomes was uncertain (very low-certainty evidence, down-graded due to risk of biases, imprecision, and inconsistency). CONCLUSIONS Overall, the certainty of the evidence provided by the trials was too low for us to be certain of the benefits and harms of viscoelastic haemostatic assay in non-cardiac surgical settings. More, larger, and better-designed RCTs should be carried out in this area.
Thromboelastography-based anticoagulation management during extracorporeal membrane oxygenation: a safety and feasibility pilot study
Annals of Intensive Care. 2018;8((1)):7.
BACKGROUND There is no consensus on the management of anticoagulation during extracorporeal membrane oxygenation (ECMO). ECMO is currently burdened by a high rate of hemostatic complications, possibly associated with inadequate monitoring of heparin anticoagulation. This study aims to assess the safety and feasibility of an anticoagulation protocol for patients undergoing ECMO based on thromboelastography (TEG) as opposed to an activated partial thromboplastin time (aPTT)-based protocol. METHODS We performed a multicenter, randomized, controlled trial in two academic tertiary care centers. Adult patients with acute respiratory failure treated with veno-venous ECMO were randomized to manage heparin anticoagulation using a TEG-based protocol (target 16-24 min of the R parameter, TEG group) or a standard of care aPTT-based protocol (target 1.5-2 of aPTT ratio, aPTT group). Primary outcomes were safety and feasibility of the study protocol. RESULTS Forty-two patients were enrolled: 21 were randomized to the TEG group and 21 to the aPTT group. Duration of ECMO was similar in the two groups (9 (7-16) days in the TEG group and 11 (4-17) days in the aPTT group, p = 0.74). Heparin dosing was lower in the TEG group compared to the aPTT group (11.7 (9.5-15.3) IU/kg/h vs. 15.7 (10.9-21.3) IU/kg/h, respectively, p = 0.03). Safety parameters, assessed as number of hemorrhagic or thrombotic events and transfusions given, were not different between the two study groups. As for the feasibility, the TEG-based protocol triggered heparin infusion rate adjustments more frequently (p < 0.01) and results were less frequently in the target range compared to the aPTT-based protocol (p < 0.001). Number of prescribed TEG or aPTT controls (according to study groups) and protocol violations were not different between the study groups. CONCLUSIONS TEG seems to be safely used to guide anticoagulation management during ECMO. Its use was associated with the administration of lower heparin doses compared to a standard of care aPTT-based protocol. Trial registration ClinicalTrials.gov, October 22,2014. Identifier: NCT02271126.
Measuring coagulation in burns: an evidence-based systematic review
Scars, Burns & Healing. 3:2059513117728201, 2017 Jan-Dec.. 2017;3:2059513117728201
Introduction: Dynamic monitoring of coagulation is important to predict both haemorrhagic and thrombotic complications and to guide blood product administration. Reducing blood loss and tailoring blood product administration may improve patient outcome and reduce mortality associated with transfusion. The current literature lacks a systematic, critical appraisal of current best evidence on which clinical decisions may be based. Objectives: Establishing the role of different coagulation markers in burn patients, diagnosing coagulopathy, tailoring blood product administration and indicating prognosis. Methods: Literature during 2004-2017 from the Cochrane Library, PubMed, Scopus, Medline and Embase was reviewed. Eligibility criteria included randomised controlled trials, systematic reviews, multi-/single-centre study and meta-analyses. Keywords searched were 'burns', 'blood coagulation disorders', 'rotem', 'blood coagulation' and 'thromboelastography'. The PRISMA flow system was used for stratification and the CASP framework for appraisal of the studies retrieved. Results: In total, 13 articles were included after inclusion/exclusion criteria had been applied to the initial 79 studies retrieved. Hypercoagulation increases in proportion to the severity of thermal injury. Whole blood testing, using thrombelastography (TEG) and rotation thromboelastometry (ROTEM), was superior to standard plasma based tests, including prothrombin time (PT) and activated partial thromboplastin time (APTT) at detecting burn-related coagulopathies. Conclusions: Routine laboratory markers such as PT/APTT are poor indicators of coagulation status in burns patients. Viscoelastic tests, such as TEG and ROTEM, are efficient, fast and have a potential use in the management of burn patients; however, strong evidence is lacking. This review highlights the need for more randomised controlled trials, to guide future practice.
The use of viscoelastic haemostatic assays in goal-directing treatment with allogeneic blood products - a systematic review and meta-analysis
Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. 2017;25((1)):39.
BACKGROUND Management of the critically bleeding patient can be encountered in many medical and surgical settings. Common for these patients is a high risk of dying from exsanguination secondary to developing coagulopathy. The purpose of this meta-analysis was to systematically review and assess randomised controlled trials (RCTs) performed on patients in acute need for blood transfusions due to bleeding to evaluate the effect of viscoelastic haemostatic assay (VHA) guidance on bleeding, transfusion requirements and mortality. METHODS PubMed and EMBASE were searched for RCTs that 1) randomised patients into receiving transfusions based on either a VHA-guided (thromboelastography [TEG] or rotational thromboelastometry [ROTEM]) algorithm (intervention group) or at the clinician's discretion and/or based on conventional coagulation tests (control group) and 2) adequately reported on the outcomes bleeding and/or transfusions and/or mortality. Data on bleeding, transfusions and mortality were extracted from each trial and included in a meta-analysis. RESULTS Fifteen RCTs (n = 1238 patients) were included. Nine trials referred to cardiothoracic patients, one to liver transplantation, one to surgical excision of burn wounds and one to trauma. One trial was conducted with cirrhotic patients, one with patients undergoing scoliosis surgery while one trial randomised treatment in post-partum females presenting with bleeding. The amount of transfused red blood cells (RBCs), fresh frozen plasma (FFP) and bleeding volume was found to be significantly reduced in the VHA-guided groups, whereas no significant difference was found for platelet transfusion requirements or mortality.
A pilot, randomised controlled trial of a rotational thromboelastometry-based algorithm to treat bleeding episodes in extracorporeal life support: the TEM Protocol in ECLS Study (TEMPEST)
Critical Care and Resuscitation : Journal of the Australasian Academy of Critical Care Medicine. 2017;19((Suppl 1)):29-36.
OBJECTIVES Minimal evidence to guide haemostatic therapy for bleeding in extracorporeal life support (ECLS) has resulted in wide variability in practice. We aimed to show that a goal-directed algorithm incorporating results from thromboelastometry (TEM) is feasible and safe for the timely management of bleeding episodes in adult patients receiving ECLS. DESIGN AND PARTICIPANTS A pilot randomised controlled trial involving 16 adult patients who underwent ECLS, randomised over 10 months. INTERVENTION The intervention group was treated according to a goal-directed algorithm based on TEM results during bleeding episodes. Apart from the intervention, both groups received standard care including conventional laboratory coagulation tests. OUTCOME MEASURES Need for blood product transfusion, haemorrhagic and thromboembolic complications and survival. RESULTS There was a statistically non-significant trend towards reduction in the amount of blood products transfused, occurrence of bleeding, and thrombotic complications, when comparing the intervention arm with the control arm. Survival to hospital discharge was 69%. A significant correlation was found between fibrinogen levels and FIBTEM clot firmness at 10 minutes (R = 0.812; P < 0.001); activated partial thromboplastin time and clotting time HEPTEM/INTEM ratio (R = -0.719; P < 0.001); and platelet count and EXTEM clot firmness at 10 minutes (R = 0.783; P < 0.001). CONCLUSION TEM allows assessment for coagulation status in a timely manner and its use for the treatment of bleeding episodes in adult patients receiving ECLS appears feasible and safe. Clinical benefit should be investigated in larger multicentre randomised trials.