Comparative analysis of andexanet alfa and prothrombin complex concentrate in reversing anticoagulation by rivaroxaban ex vivo.

BACKGROUND: The comparative effectiveness of the specific antidote andexanet alfa vs the nonspecific therapy four-factor prothrombin complex concentrates (4F-PCCs) as reversal agents for direct factor Xa (FXa) inhibitors in severely bleeding patients is unclear. We hypothesised that specific reversal using andexanet alfa would be more effective than a high dose of PCC (50 IU kg-1) for reversing the FXa inhibitor rivaroxaban. METHODS: The reversal potential of andexanet alfa, various 4F-PCCs, and activated PCC was investigated ex vivo in human blood anticoagulated with rivaroxaban (37.5, 75, 150, and 300 ng ml-1) using a panel of coagulation parameters, including conventional coagulation assays, thrombin generation, and a newly developed viscoelastometric device. We simulated in vivo conditions of coagulation activation and fibrin formation using flow chamber experiments of thrombogenicity potential under arterial flow conditions. RESULTS: The 4F-PCCs normalised clotting profiles only at low rivaroxaban concentrations, whereas andexanet alfa and activated PCC significantly shortened clotting time at all rivaroxaban concentrations. Only andexanet alfa restored thrombin generation to baseline. Flow chamber results showed that various 4F-PCCs concentration-dependently restored clot formation. CONCLUSIONS: In contrast to thrombin generation measurements, haemostatic reversal of rivaroxaban using high-dose 4F-PCCs exhibited similar efficacy as andexanet alfa in flow chamber experiments. The haemostatic effects of 4F-PCCs and andexanet alfa in the context of bleeding patients taking FXa inhibitors requires further study.

Antidote vs. unspecific hemostatic agents for the management of direct oral anticoagulant-related bleeding in trauma.

PURPOSE OF REVIEW: The advent of direct oral anticoagulants (DOACs) marks a significant milestone in anticoagulant treatment. However, DOACs can exacerbate bleeding, which is challenging for the treating clinician, especially when combined with traumatic injury. RECENT FINDINGS: In major bleeding associated with DOACs, rapid reversal of the anticoagulant effects is crucial. Recent observational and nonrandomized interventional trials have demonstrated the effectiveness of the specific antidotes andexanet alfa and idarucizumab as well as the unspecific prothrombin complex concentrates (PCCs) to counteract the anticoagulant effects of DOACs. The European Society of Anaesthesiology and Intensive Care guideline for severe perioperative bleeding and the European trauma guideline propose divergent recommendations for the use of andexanet alfa and PCC to obtain hemostasis in Factor Xa inhibitor-related bleeding. The conflicting recommendations are due to limited evidence from clinical studies and the potential increased risk of thromboembolic complications after the administration of andexanet. Regarding dabigatran-associated major bleeding, both guidelines recommend the specific reversal agent idarucizumab as first-line therapy. SUMMARY: Current guidelines recommend specific antidots and PCCs in DOAC-related major bleeding. Prospective randomized trials comparing specific vs. nonspecific hemostatic agents in the perioperative setting are needed to evaluate the effectiveness and safety of the hemostatic agents.

Direct oral anticoagulants in trauma patients.

PURPOSE OF REVIEW: Direct oral anticoagulants (DOACs) are increasingly prescribed for prevention of thromboembolic events. Thus, trauma care providers are facing a steadily raising number of injured patients on DOACs. RECENT FINDINGS: Despite a predictable pharmacokinetic profile, the resulting plasma levels of trauma patients upon admission and bleeding risks remain uncertain. Therefore, recent guidelines recommend the measurement of DOAC plasma concentrations in injured patients. Alternatively, DOAC specific visco-elastic tests assays can be applied to identify DOAC patients at bleeding risk.Bleeding complications in trauma patients on DOACs are generally higher compared to nonanticoagulated subjects, but comparable to vitamin K antagonists (VKAs). In particular, a traumatic brain injury does not carry an increased risk of intracranial bleeding due to a DOAK intake compared to VKAs. Current studies demonstrated that up to 14% of patients with a hip fracture are on DOACs prior to surgery. However, the majority can be operated safely within a 24h time window without an increased bleeding rate.Specific antagonists facilitate rapid reversal of patients on DOACs. Idarucizumab for dabigatran, and andexanet alfa for apixaban and rivaroxaban have been approved for life threatening bleeding. Alternatively, prothrombin complex concentrate can be used. Dialysis is a potential treatment option for dabigatran and haemoabsorption with special filters can be applied in patients on FXa-inhibitors. SUMMARY: Current guidelines recommend the measurement of DOAC plasma levels in trauma patients. Compared to VKAs, DOACs do not carry a higher bleeding risk. DOAC specific antagonists facilitate the individual bleeding management.

Point-of-care, goal-directed management of bleeding in trauma patients.

PURPOSE OF REVIEW: The purpose of this review is to consider the clinical value of point-of-care (POC) testing in coagulopathic trauma patients with traumatic brain injury (TBI) and trauma-induced coagulopathy (TIC). RECENT FINDINGS: Patients suffering from severe TBI or TIC are at risk of developing pronounced haemostatic disorders. Standard coagulation tests (SCTs) are insufficient to reflect the complexity of these coagulopathies. Recent evidence has shown that viscoelastic tests (VETs) identify haemostatic disorders more rapidly and in more detail than SCTs. Moreover, VET results can guide coagulation therapy, allowing individualised treatment, which decreases transfusion requirements. However, the impact of VET on mortality remains uncertain. In contrast to VETs, the clinical impact of POC platelet function testing is still unproven. SUMMARY: POC SCTs are not able to characterise the complexity of trauma-associated coagulopathy. VETs provide a rapid estimation of underlying haemostatic disorders, thereby providing guidance for haemostatic therapy, which impacts allogenic blood transfusion requirements. The value of POC platelet function testing to identify platelet dysfunction and guide platelet transfusion is still uncertain.

The impact of acquired coagulation factor XIII deficiency in traumatic bleeding and wound healing.

Factor XIII (FXIII) is a protein involved in blood clot stabilisation which also plays an important role in processes including trauma, wound healing, tissue repair, pregnancy, and even bone metabolism. Following surgery, low FXIII levels have been observed in patients with peri-operative blood loss and FXIII administration in those patients was associated with reduced blood transfusions. Furthermore, in patients with low FXIII levels, FXIII supplementation reduced the incidence of post-operative complications including disturbed wound healing. Increasing awareness of potentially low FXIII levels in specific patient populations could help identify patients with acquired FXIII deficiency; although opinions and protocols vary, a cut-off for FXIII activity of ~ 60-70% may be appropriate to diagnose acquired FXIII deficiency and guide supplementation. This narrative review discusses altered FXIII levels in trauma, surgery and wound healing, diagnostic approaches to detect FXIII deficiency and clinical guidance for the treatment of acquired FXIII deficiency.

Extended Coagulation Profiling in Isolated Traumatic Brain Injury: A CENTER-TBI Analysis.

BACKGROUND: Trauma-induced coagulopathy in traumatic brain injury (TBI) remains associated with high rates of complications, unfavorable outcomes, and mortality. The underlying mechanisms are largely unknown. Embedded in the prospective multinational Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, coagulation profiles beyond standard conventional coagulation assays were assessed in patients with isolated TBI within the very early hours of injury. METHODS: Results from blood samples (citrate/EDTA) obtained on hospital admission were matched with clinical and routine laboratory data of patients with TBI captured in the CENTER-TBI central database. To minimize confounding factors, patients with strictly isolated TBI (iTBI) (n = 88) were selected and stratified for coagulopathy by routine international normalized ratio (INR): (1) INR < 1.2 and (2) INR ≥ 1.2. An INR > 1.2 has been well adopted over time as a threshold to define trauma-related coagulopathy in general trauma populations. The following parameters were evaluated: quick's value, activated partial thromboplastin time, fibrinogen, thrombin time, antithrombin, coagulation factor activity of factors V, VIII, IX, and XIII, protein C and S, plasminogen, D-dimer, fibrinolysis-regulating parameters (thrombin activatable fibrinolysis inhibitor, plasminogen activator inhibitor 1, antiplasmin), thrombin generation, and fibrin monomers. RESULTS: Patients with iTBI with INR ≥ 1.2 (n = 16) had a high incidence of progressive intracranial hemorrhage associated with increased mortality and unfavorable outcome compared with patients with INR < 1.2 (n = 72). Activity of coagulation factors V, VIII, IX, and XIII dropped on average by 15-20% between the groups whereas protein C and S levels dropped by 20%. With an elevated INR, thrombin generation decreased, as reflected by lower peak height and endogenous thrombin potential (ETP), whereas the amount of fibrin monomers increased. Plasminogen activity significantly decreased from 89% in patients with INR < 1.2 to 76% in patients with INR ≥ 1.2. Moreover, D-dimer levels significantly increased from a mean of 943 mg/L in patients with INR < 1.2 to 1,301 mg/L in patients with INR ≥ 1.2. CONCLUSIONS: This more in-depth analysis beyond routine conventional coagulation assays suggests a counterbalanced regulation of coagulation and fibrinolysis in patients with iTBI with hemostatic abnormalities. We observed distinct patterns involving key pathways of the highly complex and dynamic coagulation system that offer windows of opportunity for further research. Whether the changes observed on factor levels may be relevant and explain the worse outcome or the more severe brain injuries by themselves remains speculative.

Reversing Rivaroxaban Anticoagulation as Part of a Multimodal Hemostatic Intervention in a Polytrauma Animal Model.

BACKGROUND: Life-threatening bleeding requires prompt reversal of the anticoagulant effects of factor Xa inhibitors. This study investigated the effectiveness of four-factor prothrombin complex concentrate in treating trauma-related hemorrhage with rivaroxaban-anticoagulation in a pig polytrauma model. This study also tested the hypothesis that the combined use of a low dose of prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate could improve its subtherapeutic effects. METHODS: Trauma (blunt liver injury and bilateral femur fractures) was induced in 48 anesthetized male pigs after 30 min of rivaroxaban infusion (1 mg/kg). Animals in the first part of the study received prothrombin complex concentrate (12.5, 25, and 50 U/kg). In the second part, animals were treated with 12.5 U/kg prothrombin complex concentrate plus tranexamic acid or plus tranexamic acid and fibrinogen concentrate. The primary endpoint was total blood loss postinjury. The secondary endpoints (panel of coagulation parameters and thrombin generation) were monitored for 240 min posttrauma or until death. RESULTS: The first part of the study showed that blood loss was significantly lower in the 25 U/kg prothrombin complex concentrate (1,541 ± 269 ml) and 50 U/kg prothrombin complex concentrate (1,464 ± 108 ml) compared with control (3,313 ± 634 ml), and 12.5 U/kg prothrombin complex concentrate (2,671 ± 334 ml, all P < 0.0001). In the second part of the study, blood loss was significantly less in the 12.5 U/kg prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate (1,836 ± 556 ml, P < 0.001) compared with 12.5 U/kg prothrombin complex concentrate plus tranexamic acid (2,910 ± 856 ml), and there were no early deaths in the 25 U/kg prothrombin complex concentrate, 50 U/kg prothrombin complex concentrate, and 12.5 U/kg prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate groups. Histopathologic analyses postmortem showed no adverse events. CONCLUSIONS: Prothrombin complex concentrate effectively reduced blood loss, restored hemostasis, and balanced thrombin generation. A multimodal hemostatic approach using tranexamic acid plus fibrinogen concentrate enhanced the effect of low doses of prothrombin complex concentrate, potentially reducing the prothrombin complex concentrate doses required for effective bleeding control.

Global Characterisation of Coagulopathy in Isolated Traumatic Brain Injury (iTBI): A CENTER-TBI Analysis.

BACKGROUND: Trauma-induced coagulopathy in patients with traumatic brain injury (TBI) is associated with high rates of complications, unfavourable outcomes and mortality. The mechanism of the development of TBI-associated coagulopathy is poorly understood. METHODS: This analysis, embedded in the prospective, multi-centred, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, aimed to characterise the coagulopathy of TBI. Emphasis was placed on the acute phase following TBI, primary on subgroups of patients with abnormal coagulation profile within 4 h of admission, and the impact of pre-injury anticoagulant and/or antiplatelet therapy. In order to minimise confounding factors, patients with isolated TBI (iTBI) (n = 598) were selected for this analysis. RESULTS: Haemostatic disorders were observed in approximately 20% of iTBI patients. In a subgroup analysis, patients with pre-injury anticoagulant and/or antiplatelet therapy had a twice exacerbated coagulation profile as likely as those without premedication. This was in turn associated with increased rates of mortality and unfavourable outcome post-injury. A multivariate analysis of iTBI patients without pre-injury anticoagulant therapy identified several independent risk factors for coagulopathy which were present at hospital admission. Glasgow Coma Scale (GCS) less than or equal to 8, base excess (BE) less than or equal to - 6, hypothermia and hypotension increased risk significantly. CONCLUSION: Consideration of these factors enables early prediction and risk stratification of acute coagulopathy after TBI, thus guiding clinical management.

Efficacy of prehospital administration of fibrinogen concentrate in trauma patients bleeding or presumed to bleed (FIinTIC): A multicentre, double-blind, placebo-controlled, randomised pilot study.

BACKGROUND: Trauma-induced coagulopathy (TIC) substantially contributes to mortality in bleeding trauma patients. OBJECTIVE: The aim of the study was to administer fibrinogen concentrate in the prehospital setting to improve blood clot stability in trauma patients bleeding or presumed to bleed. DESIGN: A prospective, randomised, placebo-controlled, double-blinded, international clinical trial. SETTING: This emergency care trial was conducted in 12 Helicopter Emergency Medical Services (HEMS) and Emergency Doctors' vehicles (NEF or NAW) and four trauma centres in Austria, Germany and Czech Republic between 2011 and 2015. PATIENTS: A total of 53 evaluable trauma patients aged at least 18 years with major bleeding and in need of volume therapy were included, of whom 28 received fibrinogen concentrate and 25 received placebo. INTERVENTIONS: Patients were allocated to receive either fibrinogen concentrate or placebo prehospital at the scene or during transportation to the study centre. MAIN OUTCOME MEASURES: Primary outcome was the assessment of clot stability as reflected by maximum clot firmness in the FIBTEM assay (FIBTEM MCF) before and after administration of the study drug. RESULTS: Median FIBTEM MCF decreased in the placebo group between baseline (before administration of study treatment) and admission to the Emergency Department, from a median of 12.5 [IQR 10.5 to 14] mm to 11 [9.5 to 13] mm (P = 0.0226), but increased in the FC Group from 13 [11 to 15] mm to 15 [13.5 to 17] mm (P = 0.0062). The median between-group difference in the change in FIBTEM MCF was 5 [3 to 7] mm (P < 0.0001). Median fibrinogen plasma concentrations in the fibrinogen concentrate Group were kept above the recommended critical threshold of 2.0 g l-1 throughout the observation period. CONCLUSION: Early fibrinogen concentrate administration is feasible in the complex and time-sensitive environment of prehospital trauma care. It protects against early fibrinogen depletion, and promotes rapid blood clot initiation and clot stability. TRIAL REGISTRY NUMBERS: EudraCT: 2010-022923-31 and ClinicalTrials.gov: NCT01475344.

Getting hit by the bus around the world - a global perspective on goal directed treatment of massive hemorrhage in trauma.

PURPOSE OF REVIEW: Major trauma remains one of the leading causes of death worldwide with traumatic brain injury and uncontrolled traumatic bleeding as the main determinants of fatal outcome. Interestingly, the therapeutic approach to trauma-associated bleeding and coagulopathy shows differences between geographic regions, that are reflected in different guidelines and protocols. RECENT FINDINGS: This article summarizes main principles in coagulation diagnostics and compares different strategies for treatment of massive hemorrhage after trauma in different regions of the world. How would a bleeding trauma patient be managed if they got hit by the bus in the United States, United Kingdom, Germany, Switzerland, Austria, Denmark, Australia, or in Japan? SUMMARY: There are multiple coexistent treatment standards for trauma-induced coagulopathy in different countries and different trauma centers. Most of them initially follow a protocol-based approach and subsequently focus on predefined clinical and laboratory targets.

Pathophysiological Response to Trauma-Induced Coagulopathy: A Comprehensive Review.

Hypercoagulability can occur after severe tissue injury, that is likely related to tissue factor exposure and impaired endothelial release of tissue plasminogen activator (tPA). In contrast, when shock and hypoperfusion occur, activation of the protein C pathway and endothelial tPA release induce a shift from a procoagulant to a hypocoagulable and hyperfibrinolytic state with a high risk of bleeding. Both thrombotic and bleeding phenotypes are associated with increased mortality and are influenced by the extent and severity of tissue injury and degree of hemorrhagic shock. Response to trauma is a complex, dynamic process in which risk can shift from bleeding to thrombosis depending on the injury pattern, hemostatic treatment, individual responses, genetic predisposition, and comorbidities. Based on this body of knowledge, we will review and consider future directions for the management of severely injured trauma patients.

Comparison of fresh frozen plasma vs. coagulation factor concentrates for reconstitution of blood: An in vitro study.

BACKGROUND: Many trauma centres have adopted the administration of fixed ratios of packed red blood cells (PRBCs), platelet concentrates and fresh frozen plasma (FFP) for bleeding patients. However, the haemostatic efficacy of this concept is not well proven. OBJECTIVE: Our objective was to characterise the haemostatic profile of different ratios (2 : 1 : 1, 1 : 1 : 1 and 1 : 1 : 2) of PRBCs, platelet concentrates and FFP in comparison with coagulation factor concentrates (fibrinogen and/or prothrombin complex concentrate). DESIGN: An in vitro study. SETTING: Research laboratories of the department of transfusion medicine, Linz, Austria. MATERIALS: Whole blood donations from a total of 20 male volunteers. INTERVENTION: Reconstitution of blood at different ratios of PRBCs, platelet concentrates and FFP or coagulation factor concentrates. MAIN OUTCOME MEASURES: Cell count, conventional and thromboelastometric coagulation parameters, single coagulation factor activities as well as endogenous thrombin potential. RESULTS: Fibrinogen levels and haematocrit were lower in the FFP group at any ratio compared with the concentrate-based groups (P < 0.0001). Reconstitution of blood with FFP at different ratios resulted in haematocrit or fibrinogen levels that were borderline with regard to recommended substitution triggers (haematocrit 41 ±â€Š2% and fibrinogen 1.5 ±â€Š0.3 g l at the 2 : 1 : 1 ratio vs. 21 ±â€Š1% and 2.1 ±â€Š0.4 g l respectively at the 1 : 1 : 2 ratio). Compared with FFP at any ratio, maximum clot firmness showed higher values in the groups using fibrinogen concentrate (P < 0.0001), whereas endogenous thrombin potential revealed higher values in the groups using prothrombin complex concentrate (P < 0.0001). CONCLUSION: Use of coagulation factor concentrates for the reconstitution of blood allows for delivery of a higher haematocrit and a higher fibrinogen content compared with FFP. However, prothrombin complex concentrate might result in an unnecessary excess of thrombin generation. Clinical studies are warranted to further investigate these in vitro findings.

Evaluation of combined idarucizumab and prothrombin complex concentrate treatment for bleeding related to dabigatran in a lethal porcine model of double trauma.

BACKGROUND: Idarucizumab (IDA) is approved for emergency reversal of dabigatran; prothrombin complex concentrates (PCCs) are recommended in the absence of specific antidote. The combined effects of IDA and PCC in trauma-related bleeding are unknown. The efficacy and safety of combined IDA + PCC were assessed in a lethal porcine model of double trauma under dabigatran anticoagulation. STUDY DESIGN AND METHODS: Male pigs (n = 28) received oral dabigatran etexilate (30 mg/kg bid) for 3 days; a non-dabigatran control group (n = 7) received placebo. On Day 4, dabigatran-treated animals were randomized 1:1:1:1 to receive placebo + placebo (dabigatran-treated control), IDA + PCC (60 mg/kg + 50 IU/kg), PCC + IDA, or IDA + IDA. Trauma was induced at t = 0 (bilateral femur fractures and blunt liver injury) and t = 60 minutes (second blunt liver injury). Study treatment was administered 15 minutes after each trauma. Animals were monitored for 5 hours or until death. RESULTS: Total blood loss in IDA + PCC, PCC + IDA, and IDA + IDA was 1673 ± 370, 1981 ± 361, and 1417 ± 135 mL, respectively, with 100% survival at 5 hours. Blood loss in dabigatran-treated controls was 4427 ± 162 mL with 100% mortality. With IDA + IDA, plasma coagulation parameters and thrombin generation were similar to non-dabigatran control group levels after the second dose and remained stable over time. In the IDA + PCC and PCC + IDA groups, thrombin generation and d-dimer levels after the second dose were higher than with IDA + IDA. No thromboembolic complications were found. CONCLUSION: IDA and PCC are effective in treating trauma-related bleeding with dabigatran anticoagulation. IDA is preferable for emergency reversal of dabigatran, but PCC may be valuable when the anticoagulant is unknown.

Prothrombin Complex Concentrate-induced Disseminated Intravascular Coagulation Can Be Prevented by Coadministering Antithrombin in a Porcine Trauma Model.

BACKGROUND: The risk of thromboembolic complications with prothrombin complex concentrates (PCCs) appears low when used for reversal of vitamin K antagonists but might be different in other indications (e.g., trauma). A difference in risk could arise from the plasma ratio of pro- versus anticoagulant proteins. This study used a porcine trauma model to investigate combined treatment with PCC and antithrombin. The hypothesis was that antithrombin can modulate prothrombotic effects and prevent adverse events of PCC. METHODS: Nine treatment groups (n = 7 per group) were included: control (placebo), PCC (50 IU/kg), PCC plus antithrombin (three groups, with antithrombin doses of 12.5, 25, or 50 IU/kg), fibrinogen concentrate (100 mg/kg) plus PCC, fibrinogen concentrate plus PCC plus antithrombin dose of 50 IU/kg, tranexamic acid (15 mg/kg) plus fibrinogen concentrate plus PCC, and tranexamic acid plus fibrinogen concentrate plus PCC plus antithrombin dose of 50 IU/kg. In each group, bilateral femur fractures and thorax contusion were followed 60 min later by blunt liver injury. Study treatment was then administered, and animals were subsequently observed for 210 min. RESULTS: Total blood loss (mean ± SD) was statistically significantly lower in all three PCC plus antithrombin groups (PCC plus antithrombin dose of 50 IU/kg, 672 ± 63 ml; PCC plus antithrombin dose of 25 IU/kg, 535 ± 72 ml; and PCC plus antithrombin dose of 12.5 IU/kg, 538 ± 50 ml) than in the PCC group (907 ± 132 ml), which in turn had statistically significantly reduced bleeding versus the control group (1,671 ± 409 ml). Signs of disseminated intravascular coagulation were apparent with PCC monotherapy, and early deaths occurred with fibrinogen concentrate plus PCC, attributable to pulmonary emboli. Antithrombin was protective against both of these effects: signs of disseminated intravascular coagulation were absent from the PCC plus antithrombin groups, and there were no early deaths in the group with fibrinogen concentrate plus PCC plus antithrombin dose of 50 IU/kg. CONCLUSIONS: According to this trauma model, 50 IU/kg PCC increases the risk of disseminated intravascular coagulation and other thromboembolic complications, most notably when coadministered with fibrinogen concentrate. The addition of antithrombin appears to reduce this risk.

Diagnostic and therapeutic approach in adult patients with traumatic brain injury receiving oral anticoagulant therapy: an Austrian interdisciplinary consensus statement.

There is a high degree of uncertainty regarding optimum care of patients with potential or known intake of oral anticoagulants and traumatic brain injury (TBI). Anticoagulation therapy aggravates the risk of intracerebral hemorrhage but, on the other hand, patients take anticoagulants because of an underlying prothrombotic risk, and this could be increased following trauma. Treatment decisions must be taken with due consideration of both these risks. An interdisciplinary group of Austrian experts was convened to develop recommendations for best clinical practice. The aim was to provide pragmatic, clear, and easy-to-follow clinical guidance for coagulation management in adult patients with TBI and potential or known intake of platelet inhibitors, vitamin K antagonists, or non-vitamin K antagonist oral anticoagulants. Diagnosis, coagulation testing, and reversal of anticoagulation were considered as key steps upon presentation. Post-trauma management (prophylaxis for thromboembolism and resumption of long-term anticoagulation therapy) was also explored. The lack of robust evidence on which to base treatment recommendations highlights the need for randomized controlled trials in this setting.

Comparison between the new fully automated viscoelastic coagulation analysers TEG 6s and ROTEM Sigma in trauma patients: A prospective observational study.

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

Concentrated lyophilized plasma used for reconstitution of whole blood leads to higher coagulation factor activity but unchanged thrombin potential compared with fresh-frozen plasma.

BACKGROUND: During massive hemorrhage, it is recommended to transfuse red blood cells, platelet concentrate, and fresh-frozen plasma in a ratio close to 1:1:1. To avoid the thawing process of fresh frozen plasma, lyophilized plasma (LP) is increasingly used. Evidence is limited on the activity of coagulation factors in reconstituted blood using LP and concentrated LP versions. STUDY DESIGN AND METHODS: Whole blood from ten healthy volunteers was separated into red blood cell, fresh frozen plasma, and platelet concentrate units. Aliquots of red blood cells and plasma concentrate were mixed with either fresh frozen plasma (200 mL) or LP at reconstitution ratios of 2:1:1, 1:1:1, and 1:1:2. LP was used either at the recommended standard volume of 200 mL (LP200) or was more concentrated at volumes of 100 and 50 mL (LP100 and LP50, respectively). The hemostatic capacity of each reconstituted whole blood sample was tested with blood cell counts, standard coagulation tests, factor activity, thrombin generation, and viscoelastic assays. RESULTS: Hematocrit, platelet counts, and fibrinogen levels of the three ratios were similar between FFP200 and LP200 units but were lower compared with the corresponding ratios in LP100 and LP50 units. The activity of procoagulant and anticoagulant factors increased linearly with the increasing plasmatic fraction and, at 1:1:2 ratio, was significantly higher in LP50 units compared with FFP200 and LP200 units. Thrombin generation was similar throughout the four plasma groups at any ratio. CONCLUSIONS: Decreasing the dilution volume of LP facilitates reaching higher hematocrit and coagulation protein levels without a relevant increase in thrombin generation. This is due to preserved balance between procoagulant and anticoagulant factors in the concentrated LP preparations.

Dual inhibition of thrombin and activated factor X attenuates disseminated intravascular coagulation and protects organ function in a baboon model of severe Gram-negative sepsis.

BACKGROUND: Inhibition of procoagulant pathways may improve outcome in sepsis. We examined whether a dual short-acting thrombin (factor II) and factor X (FX)a inhibitor (SATI) ameliorates sepsis-induced disseminated intravascular coagulation (DIC) and is organ-protective. METHODS: Escherichia coli were infused for 2 h in 22 anesthetized baboons. The control (CO) group (n = 8) received sterile isotonic solution only. In the treatment groups, SATI was administered starting 15 minutes after the end of the bacterial exposure. In the low-dose group (LD-SATI, n = 8), SATI was infused with 75 µg/kg/h for the first hour, followed by 23 µg/kg/h until the end of the study. In the high-dose SATI group (HD-SATI, n = 6), 225 µg/kg/h was administered for the first hour followed by continuous infusion of 69 µg/kg/h until termination of the study. RESULTS: Sepsis-induced DIC was attenuated, as reflected by lower peak thrombin-antithrombin complexes (threefold) and D-dimer levels (twofold) in both SATI groups compared to the CO. This coincided with strongly improved cell/organ protection assessed by decreased levels of lactate dehydrogenase (threefold), creatinine (twofold), aspartate aminotransferase (threefold), and amylase (twofold) compared to the CO group. Anuria, which started at 8 h in the CO group, was prevented in both SATI groups. Peak interleukin-6 release at 12 h was prevented in the treatment groups. In both SATI groups, fewer catecholamines were necessary and no bleeding complications were observed. CONCLUSIONS: Dual inhibition of thrombin and FXa preserved activation of coagulation, protected organ function and ameliorated inflammation in severe Gram-negative sepsis in baboons. SATI could be a novel therapeutic agent against sepsis-induced DIC.