Temporal Transitions in Fibrinolysis after Trauma: Adverse Outcome Is Principally Related to Late Hypofibrinolysis.

BACKGROUND: The relationship between late clinical outcomes after injury and early dynamic changes between fibrinolytic states is not fully understood. The authors hypothesized that temporal transitions in fibrinolysis states using rotational thromboelastometry (ROTEM) would aid stratification of adverse late clinical outcomes and improve understanding of how tranexamic acid modulates the fibrinolytic response and impacts mortality. METHODS: The authors conducted a secondary analysis of previously collected data from trauma patients enrolled into an ongoing prospective cohort study (International Standard Randomised Controlled Trial Number [ISRCTN] 12962642) at a major trauma center in the United Kingdom. ROTEM was performed on admission and at 24 h with patients retrospectively grouped into three fibrinolysis categories: tissue factor-activated ROTEM maximum lysis of less than 5% (low); tissue factor-activated ROTEM maximum lysis of 5 to 15% (normal); or tissue factor-activated ROTEM maximum lysis of more than 15% (high). Primary outcomes were multiorgan dysfunction syndrome and 28-day mortality. RESULTS: Seven-hundred thirty-one patients were included: 299 (41%) were treated with tranexamic acid and 432 (59%) were untreated. Two different cohorts with low-maximum lysis at 24 h were identified: (1) severe brain injury and (2) admission shock and hemorrhage. Multiple organ dysfunction syndrome was greatest in those with low-maximum lysis on admission and at 24 h, and late mortality was four times higher than in patients who remained normal during the first 24 h (7 of 42 [17%] vs. 9 of 223 [4%]; P = 0.029). Patients that transitioned to or remained in low-maximum lysis had increased odds of organ dysfunction (5.43 [95% CI, 1.43 to 20.61] and 4.85 [95% CI, 1.83 to 12.83], respectively). Tranexamic acid abolished ROTEM hyperfibrinolysis (high) on admission, increased the frequency of persistent low-maximum lysis (67 of 195 [34%]) vs. 8 of 79 [10%]; P = 0.002), and was associated with reduced early mortality (28 of 195 [14%] vs. 23 of 79 [29%]; P = 0.015). No increase in late deaths, regardless of fibrinolysis transition patterns, was observed. CONCLUSIONS: Adverse late outcomes are more closely related to 24-h maximum lysis, irrespective of admission levels. Tranexamic acid alters early fibrinolysis transition patterns, but late mortality in patients with low-maximum lysis at 24 h is not increased.

Fibrinolytic Activation in Patients with Progressive Intracranial Hemorrhage after Traumatic Brain Injury.

Progression of intracranial hemorrhage (PICH) is a significant cause of secondary brain injury in patients with traumatic brain injury (TBI). Previous studies have implicated a variety of mediators that contribute to PICH. We hypothesized that patients with PICH would display either a hypocoagulable state, hyperfibrinolysis, or both. We conducted a prospective study of adult trauma patients with isolated TBI. Blood was obtained for routine coagulation assays, platelet count, fibrinogen, thrombelastography, markers of thrombin generation, and markers of fibrinolysis at admission and 6, 12, 24, and 48 h. Univariate analyses were performed to compare baseline characteristics between groups. Linear regression models were created, adjusting for baseline differences, to determine the relationship between individual assays and PICH. One hundred forty-one patients met entry criteria, of whom 71 had hemorrhage progression. Patients with PICH had a higher Injury Severity Score and Abbreviated Injury Scale score (head), a lower Glasgow Coma Scale score, and lower plasma sodium on admission. Patients with PICH had higher D-dimers on admission. After adjusting for baseline differences, elevated D-dimers remained significantly associated with PICH compared to patients without PICH at admission. Hypocoagulation was not significantly associated with PICH in these patients. The association between PICH and elevated D-dimers early after injury suggests that fibrinolytic activation may contribute to PICH in patients with TBI.

Influence of alcohol consumption on blood coagulation in rotational thromboelastometry (ROTEM): an in-vivo study.

BACKGROUND: Twenty-five to 85% of trauma patients are under the influence of alcohol in addition to experiencing injury-related coagulation impairment. Viscoelastic point-of-care tests (thrombelastography [TEG], rotational thromboelastometry [ROTEM]) are popular tools for rapid hemostasis assessment and therapeutic decision-making in this and other settings. While alcohol affects these tests in-vitro, their specific effects in-vivo are unclear. Therefore, we evaluated the effects of alcohol ingestion on ROTEM parameters. METHODS: Twenty volunteers provided informed consent to drinking red wine, whisk(e)y, or vodka to a target blood alcohol concentration of 1 ‰ within one hour, calculated with the Widmark formula. Blood samples were collected before drinking, at a breath alcohol concentration of 0.5 ‰, and at 1.0 ‰, but no later than one hour. After each blood collection, ExTEM and FibTEM tests were performed directly "at the bedside." RESULTS: All participants had a blood alcohol concentration (BAC) of 0.00 ‰ at the beginning. The mean BACs at the second and third collection were 0.48 and 0.76 ‰, respectively. There were no significant differences in the ExTEM parameters. FibTEM measurements showed a significant difference at the A10 value (13.0 vs. 14.0 mm, P = 0.014) and a trend at the maximum amplitude (maximum clot firmness [MCF] 13.7 vs. 16.2 mm, P = 0.075). We saw no significant differences in fibrinolysis parameters and no hyperfibrinolysis in our ROTEM measurements. CONCLUSIONS: Ethanol ingestion can impair early fibrin polymerization. These results might be of special relevance in trauma and support routine application of ROTEM/TEG in such cases.

Correlation of Thromboelastography with Apparent Rivaroxaban Concentration: Has Point-of-Care Testing Improved?

BACKGROUND: Concern remains over reliable point-of-care testing to guide reversal of rivaroxaban, a commonly used factor Xa inhibitor, in high-acuity settings. Thromboelastography (TEG), a point-of-care viscoelastic assay, may have the ability to detect the anticoagulant effect of rivaroxaban. The authors ascertained the association of apparent rivaroxaban concentration with thromboelastography reaction time, i.e., time elapsed from blood sample placement in analyzer until beginning of clot formation, as measured using TEG and TEG6S instruments (Haemonetics Corporation, USA), hypothesizing that reaction time would correlate to degree of functional factor Xa impairment. METHODS: The authors prospectively performed a diagnostic accuracy study comparing coagulation assays to apparent (i.e., indirectly assessed) rivaroxaban concentration in trauma patients with and without preinjury rivaroxaban presenting to a single center between April 2016 and July 2018. Blood samples at admission and after reversal or 24 h postadmission underwent TEG, TEG6S, thrombin generation assay, anti-factor Xa chromogenic assay, prothrombin time (PT), and ecarin chromogenic assay testing. The authors determined correlation of kaolin TEG, TEG6S, and prothrombin time to apparent rivaroxaban concentration. Receiver operating characteristic curve compared capacity to distinguish therapeutic rivaroxaban concentration (i.e., greater than or equal to 50 ng/ml) from nontherapeutic concentrations. RESULTS: Eighty rivaroxaban patients were compared to 20 controls. Significant strong correlations existed between rivaroxaban concentration and TEG reaction time (ρ = 0.67; P < 0.001), TEG6S reaction time (ρ = 0.68; P < 0.001), and prothrombin time (ρ = 0.73; P < 0.001), however reaction time remained within the defined normal range for the assay. Rivaroxaban concentration demonstrated strong but not significant association with coagulation assays postreversal (n = 9; TEG reaction time ρ = 0.62; P = 0.101; TEG6S reaction time ρ = 0.57; P = 0.112) and small nonsignificant association for controls (TEG reaction time: ρ = -0.04; P = 0.845; TEG6S reaction time: ρ = -0.09; P = 0.667; PT-neoplastine: ρ = 0.19; P = 0.301). Rivaroxaban concentration (area under the curve, 0.91) and TEG6S reaction time (area under the curve, 0.84) best predicted therapeutic rivaroxaban concentration and exhibited similar receiver operating characteristic curves (P = 0.180). CONCLUSIONS: Although TEG6S demonstrates significant strong correlation with rivaroxaban concentration, values within normal range limit clinical utility rendering rivaroxaban concentration the gold standard in measuring anticoagulant effect.

Point-of-care viscoelastic assay devices (rotational thromboelastometry and thromboelastography): a primer for surgeons.

BACKGROUND: Bleeding is a common occurrence in surgery. Point-of-care testing with viscoelastic (VE) assays such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM) has become more common place. TEG and ROTEM have the potential to guide management of coagulopathy. Many healthcare professionals still rely upon standard laboratory tests (SLTs) to manage a bleeding patient. It was our aim to investigate the literature surrounding management of the surgically bleeding patient via VE assays. METHODS: Literature review of Embase, MEDLINE, PubMed and the Cochrane Library using 'TEG, ROTEM and surgery' search terms was conducted. RESULTS: Through the literature search and reference lists reviewed by both authors, a total of 62 articles have been evaluated, 35 of these have been included in this review. CONCLUSION: VE assays are used most commonly during orthotopic liver transplantation, trauma, postpartum haemorrhage and cardiac surgery. Although the evidence is not overwhelming, we have identified recurrent themes where VE assays seem to be beneficial. VE assay use, especially when incorporated into an algorithm, appears to reduce blood product administration which in turn reduces cost and potential adverse events. They are quicker than SLTs and they can detect hyperfibrinolysis, the hallmark of coagulopathy, via in vivo clot analyses which SLTs are unable to do. Ultimately more randomized controlled trials are required.

Hemodilution on Cardiopulmonary Bypass: Thromboelastography Patterns and Coagulation-Related Outcomes.

OBJECTIVE: Hemodilution has been associated with both hypocoagulability and hypercoagulability in studies based on thromboelastography (TEG). Severe hemodilution during cardiopulmonary bypass (CPB) is a risk factor for morbidity in cardiac surgery. This study investigated the effects of different degrees of hemodilution with CPB on post-CPB TEG parameters and coagulation-related outcomes. DESIGN: Retrospective cohort study. SETTING: University research hospital. PARTICIPANTS: The study comprised 793 cardiac surgery patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The patient population was divided into low (LH), moderate (MH), and severe (SH) hemodilution groups based on the hemodilution degree on CPB. Differences in TEG parameters and coagulation-related outcomes were assessed. Patients with SH experienced significantly (p = 0.019) prolonged clotting times (median r-time 6.1 min, interquartile range 5.1-7.4 min) with respect to patients with MH (median r-time 5.8 min, interquartile range 4.8-7 min) and LH (median r-time 5.9 min, interquartile range 4.8-7.2 min). Clot firmness was significantly (p = 0.001) lower in patients with SH (median maximum amplitude 63 mm, interquartile range 57-68 mm) compared with patients with MH (median maximum amplitude 65 mm, interquartile range 61-71 mm) and LH (median maximum amplitude 67 mm, interquartile range 62-74 mm). Patients with SH had higher chest drain blood loss and required more fresh frozen plasma and platelet concentrate transfusions than did patients with MH or LH. Postoperative thromboembolic complications were significantly (p = 0.006) more common in patients with SH (2.6%) than in patients with MH (0%) or LH (0.4%). CONCLUSIONS: SH on CPB is associated with hypocoagulation, bleeding, and thrombosis-associated worse outcomes.

The role of thromboelastometry in the assessment and treatment of coagulopathy in liver transplant patients / O papel da tromboelastometria na avaliação e no tratamento da coagulopatia em pacientes submetidos ao transplante hepático

ABSTRACT Perioperative monitoring of coagulation is vital to assess bleeding risks, diagnose deficiencies associated with hemorrhage, and guide hemostatic therapy in major surgical procedures, such as liver transplantation. Routine static tests demand long turnaround time and do not assess platelet function; they are determined on plasma at a standard temperature of 37°C; hence these tests are ill-suited for intraoperative use. In contrast, methods which evaluate the viscoelastic properties of whole blood, such as thromboelastogram and rotational thromboelastometry, provide rapid qualitative coagulation assessment and appropriate guidance for transfusion therapy. These are promising tools for the assessment and treatment of hyper- and hypocoagulable states associated with bleeding in liver transplantation. When combined with traditional tests and objective assessment of the surgical field, this information provides ideal guidance for transfusion strategies, with potential improvement of patient outcomes.

RESUMO A monitorização perioperatória da coagulação é fundamental para estimar o risco de sangramento, diagnosticar deficiências causadoras de hemorragia e guiar terapias hemostáticas durante procedimentos cirúrgicos de grande porte, como o transplante hepático. Os testes estáticos, comumente usados na prática clínica, são insatisfatórios no intraoperatório, pois demandam tempo e não avaliam a função plaquetária; são determinados no plasma e realizados em temperatura padrão de 37°C. Os métodos que avaliam as propriedades viscoelásticas do sangue total, como o tromboelastograma e a tromboelastometria rotacional, podem suprir as deficiências dos testes estáticos tradicionais, uma vez que permitem avaliar a coagulação de forma rápida e qualitativa, guiando a terapia transfusional de forma adequada. A tromboelastometria rotacional mostrou-se promissora na avaliação e no tratamento de estados de hipercoagulação e hipocoagulação, associados a sangramento no transplante hepático. Estas informações, combinadas com os testes tradicionais e uma avaliação objetiva do campo cirúrgico, promovem um cenário ótimo para guiar as estratégias transfusionais e potencialmente melhorar o desfecho destes pacientes.

The role of thromboelastometry in the assessment and treatment of coagulopathy in liver transplant patients.

Perioperative monitoring of coagulation is vital to assess bleeding risks, diagnose deficiencies associated with hemorrhage, and guide hemostatic therapy in major surgical procedures, such as liver transplantation. Routine static tests demand long turnaround time and do not assess platelet function; they are determined on plasma at a standard temperature of 37°C; hence these tests are ill-suited for intraoperative use. In contrast, methods which evaluate the viscoelastic properties of whole blood, such as thromboelastogram and rotational thromboelastometry, provide rapid qualitative coagulation assessment and appropriate guidance for transfusion therapy. These are promising tools for the assessment and treatment of hyper- and hypocoagulable states associated with bleeding in liver transplantation. When combined with traditional tests and objective assessment of the surgical field, this information provides ideal guidance for transfusion strategies, with potential improvement of patient outcomes. RESUMO A monitorização perioperatória da coagulação é fundamental para estimar o risco de sangramento, diagnosticar deficiências causadoras de hemorragia e guiar terapias hemostáticas durante procedimentos cirúrgicos de grande porte, como o transplante hepático. Os testes estáticos, comumente usados na prática clínica, são insatisfatórios no intraoperatório, pois demandam tempo e não avaliam a função plaquetária; são determinados no plasma e realizados em temperatura padrão de 37°C. Os métodos que avaliam as propriedades viscoelásticas do sangue total, como o tromboelastograma e a tromboelastometria rotacional, podem suprir as deficiências dos testes estáticos tradicionais, uma vez que permitem avaliar a coagulação de forma rápida e qualitativa, guiando a terapia transfusional de forma adequada. A tromboelastometria rotacional mostrou-se promissora na avaliação e no tratamento de estados de hipercoagulação e hipocoagulação, associados a sangramento no transplante hepático. Estas informações, combinadas com os testes tradicionais e uma avaliação objetiva do campo cirúrgico, promovem um cenário ótimo para guiar as estratégias transfusionais e potencialmente melhorar o desfecho destes pacientes.

[Thromboelastography - useful in cases of bleeding?] / Tromboelastografi ­ nyttig når det blør?

Blood products are a limited resource. A number of studies have shown that the use of thromboelastography (TEG) may reduce the need for blood transfusions. The analysis can be used in acute situations in patients with massive haemorrhage as a guide to transfusion therapy. Use of TEG may play an important role in targeting transfusion therapy.

Comparison of Thrombelastography-Derived Fibrinogen Values at Rewarming and Following Cardiopulmonary Bypass in Cardiac Surgery Patients.

BACKGROUND: The inflated costs and documented deleterious effects of excess perioperative transfusion have led to the investigation of targeted coagulation factor replacement strategies. One particular coagulation factor of interest is factor I (fibrinogen). Hypofibrinogenemia is typically tested for using time-consuming standard laboratory assays. The thrombelastography (TEG)-based functional fibrinogen level (FLEV) provides an assessment of whole blood clot under platelet inhibition to report calculated fibrinogen levels in significantly less time. If FLEV values obtained on cardiopulmonary bypass (CPB) during rewarming are similar to values obtained immediately after the discontinuation of CPB, then rewarming values could be used for preemptive ordering of appropriate blood product therapy. METHODS: Fifty-one cardiac surgery patients were enrolled into this prospective nonrandomized study to compare rewarming fibrinogen values with postbypass values using TEG FLEV assays. Baseline, rewarming, and postbypass fibrinogen values were recorded for all patients using both standard laboratory assay (Clauss method) and FLEV. Mixed-effects regression models were used to examine the change in TEG FLEV values over time. Bland-Altman analysis was used to examine bias and the limits of agreement (LOA) between the standard laboratory assay and FLEVs. RESULTS: Forty-nine patients were included in the analysis. The mean FLEV value during rewarming was 333.9 mg/dL compared with 332.8 mg/dL after protamine, corresponding to an estimated difference of -1.1 mg/dL (95% confidence interval [CI], -25.8 to 23.6; P = 0.917). Rewarming values were available on average 47 minutes before postprotamine values. Bland-Altman analysis showed poor agreement between FLEV and standard assays: mean difference at baseline was 92.5 mg/dL (95% CI, 71.1 to 114.9), with a lower LOA of -56.5 mg/dL (95% CI, -94.4 to -18.6) and upper LOA of 242.4 mg/dL (95% CI, 204.5 to 280.3). The difference between assays increased after CPB and persisted after protamine administration. CONCLUSIONS: Our results revealed negligible change in FLEV values from the rewarming to postbypass periods, with a CI that does not include clinically meaningful differences. These findings suggest that rewarming samples could be utilized for ordering fibrinogen-specific therapies before discontinuation of CPB. Mean FLEV values were consistently higher than the reference standard at each time point. Moreover, bias was highly heterogeneous among samples, implying a large range of potential differences between assays for any 1 patient.

Rotational thromboelastometry-guided trauma resuscitation.

PURPOSE OF REVIEW: Haemorrhage from major trauma is a significant cause of death worldwide. The UK Defence Medical Service (UK-DMS) has had significant experience in managing severely injured and shocked trauma casualties over the last decade. This has led to the integration of rotational thromboelastometry (ROTEM) into damage control resuscitation delivered at Camp Bastion Field Hospital in Afghanistan. This review aims to describe the rationale for its use and how its use has evolved by UK-DMS. RECENT FINDINGS: Although there is reasonable evidence showing its benefit in cardiac and liver surgery, evidence for its use in trauma is limited. More recent studies and meta-analyses have demonstrated a reduced rate of transfusion and blood loss, but no benefit on mortality. Despite this, there is a growing body of opinion supporting ROTEM use in trauma with European guidelines supporting its use where available. Recent UK-DMS experience has shown that it is a fast, reliable and robust means of identifying transfusion requirements. SUMMARY: ROTEM provides a means to rapidly assess coagulation in trauma casualties, allowing targeted use of blood products. It provides information on clot initiation strength and breakdown. However, its use in trauma has still to be fully evaluated.

Prospective longitudinal study of thromboelastography and standard hemostatic laboratory tests in healthy women during normal pregnancy.

BACKGROUND: Hemostatic disorders are common in obstetric complications. Thromboelastography (TEG®) simultaneously measures coagulation and fibrinolysis within 10 to 20 minutes. Our primary aim in this prospective longitudinal study was to obtain knowledge about physiological changes in TEG® variables during normal pregnancy and 8 weeks postpartum. The secondary aims were to compare TEG® variables during pregnancy with TEG® variables 8 weeks postpartum and gestational weeks 10 to 15 and to correlate TEG® variables to standard laboratory analyses. METHODS: Blood samples were collected from 45 healthy pregnant women at gestational weeks 10 to 15, 20 to 22, 28 to 30, and 38 to 40, and at 8 weeks postpartum. The following TEG® analyses were performed: time until start of clotting (TEG®-R), time until 20-mm clot firmness (TEG®-K), angle of clotting (TEG®-Angle), maximum amplitude (TEG®-MA), and lysis after 30 minutes (TEG®-LY30). Activated partial thromboplastin time, prothrombin time, soluble fibrin, antithrombin, D-dimer, and platelet count were analyzed. RESULTS: Compared to 8 weeks postpartum TEG®-R was at least 0.9 minutes shorter (upper limit 99% confidence intervals) until gestational weeks 28 to 30 and the mean reduction varied between 23%-26%. TEG®-K was at least 0.1 minutes shorter throughout pregnancy and the mean reduction varied between 18%-35%. TEG®-Angle was at least 2.5 degrees greater during pregnancy and the mean increase varied between 12%-20%. TEG®-MA was also at least 0.4 mm greater during pregnancy and the mean increase varied between 6%-8%. TEG®-LY30 was at least 0.03% lower during gestational weeks 28 to 30 and 38 to 40 and the mean reduction varied between 67%-73%. The routine coagulation laboratory values were within normal pregnant limits. There were no or weak correlations between TEG® and the laboratory variables. CONCLUSIONS: TEG® demonstrates increased coagulability and decreased fibrinolysis during pregnancy. There was a faster initiation of hemostasis, with a minor increase in clot strength. Fibrinolysis decreased during late pregnancy. Alternative cutoff limits for TEG® variables may be required during pregnancy. Standard hemostatic laboratory tests were as expected during pregnancy. Future studies are needed to ascertain whether viscoelastic methods are preferable to standard hemostatic tests for the diagnosis of coagulopathy during obstetric hemorrhage.

Thrombelastography.

Thrombelastography is a 'near patient' test of coagulation. It is easy to perform and can provide information on a patient's coagulation status within 30 min. Despite more than 25 years of clinical experience, however, several basic questions relating thromboelastograph (TEG) parameters to standard coagulation tests remain unanswered, and the value of the TEG is established only in the setting of orthotopic liver transplantation and cardiopulmonary bypass surgery. This review will focus on the principles and practise of the TEG(R), and data supporting the current accepted uses. Potential future uses will also be discussed including evaluation of hypercoagulable states, and investigating the mechanism of coagulopathies due to drugs or disease that standard tests have failed to unravel.