Sisse R. Ostrowski

Exercise and IL-6 infusion inhibit endotoxin-induced TNF-α production in humans

During “nondamaging” exercise, skeletal muscle markedly releases interleukin (IL)‐6, and it has been suggested that one biological role of this phenomenon is to inhibit the production of tumor necrosis factor (TNF)‐α, which is known to cause pathogenesis such as insulin resistance and atherosclerosis. To test this hypothesis, we performed three experiments in which eight healthy males either rested (CON), rode a bicycle for 3 h (EX), or were infused with recombinant human IL‐6 (rhIL‐6) for 3 h while they rested. After 2.5 h, the volunteers received a bolus of Escherichia coli lipopolysaccharide endotoxin (0.06 ng/kg) i.v. to induce low‐grade inflammation. In CON, plasma TNF‐α increased significantly in response to endotoxin. In contrast, during EX, which resulted in elevated IL‐6, and rhIL‐6, the endotoxin‐induced increase in TNF‐α was totally attenuated. In conclusion, physical exercise and rhIL‐6 infusion at physiological concentrations inhibit endotoxin‐induced TNF‐α production in humans. Hence, these data provide the first experimental evidence that physical activity mediates antiinflammatory activity and suggest that the mechanism include IL‐6, which is produced by and released from exercising muscles.

Thrombelastography and tromboelastometry in assessing coagulopathy in trauma

Death due to trauma is the leading cause of lost life years worldwide, with haemorrhage being responsible for 30-40% of trauma mortality and accounting for almost 50% of the deaths the initial 24 h. On admission, 25-35% of trauma patients present with coagulopathy, which is associated with a several-fold increase in morbidity and mortality. The recent introduction of haemostatic control resuscitation along with emerging understanding of acute post-traumatic coagulability, are important means to improve therapy and outcome in exsanguinating trauma patients. This change in therapy has emphasized the urgent need for adequate haemostatic assays to monitor traumatic coagulopathy and guide therapy. Based on the cell-based model of haemostasis, there is emerging consensus that plasma-based routine coagulation tests (RCoT), like prothrombin time (PT) and activated partial thromboplastin time (APTT), are inappropriate for monitoring coagulopathy and guide therapy in trauma. The necessity to analyze whole blood to accurately identify relevant coagulopathies, has led to a revival of the interest in viscoelastic haemostatic assays (VHA) such as Thromboelastography (TEG®) and Rotation Thromboelastometry (ROTEM®). Clinical studies including about 5000 surgical and/or trauma patients have reported on the benefit of using the VHA as compared to plasma-based assays, to identify coagulopathy and guide therapy.This article reviews the basic principles of VHA, the correlation between the VHA whole blood clot formation in accordance with the cell-based model of haemostasis, the current use of VHA-guided therapy in trauma and massive transfusion (haemostatic control resuscitation), limitations of VHA and future perspectives of this assay in trauma.

Management of major blood loss: An update

Haemorrhage remains a major cause of potentially preventable deaths. Trauma and massive transfusion are associated with coagulopathy secondary to tissue injury, hypoperfusion, dilution and consumption of clotting factors and platelets. Concepts of damage control surgery have evolved, prioritizing the early control of the cause of bleeding by non‐definitive means, while haemostatic control resuscitation seeks early control of coagulopathy. Haemostatic resuscitation provides transfusions with plasma and platelets in addition to red blood cells (RBCs) in an immediate and sustained manner as part of the transfusion protocol for massively bleeding patients. Transfusion of RBCs, plasma and platelets in a similar proportion as in whole blood prevents both hypovolaemia and coagulopathy. Although an early and effective reversal of coagulopathy is documented, the most effective means of preventing coagulopathy of massive transfusion remains debated and randomized controlled studies are lacking. Results from recent before‐and‐after studies in massively bleeding patients indicate that trauma exsanguination protocols involving the early administration of plasma and platelets are associated with improved survival. Furthermore, viscoelastic whole blood assays, such as thrombelastography (TEG)/rotation thromboelastometry (ROTEM), appear advantageous for identifying coagulopathy in patients with severe haemorrhage, as opposed to conventional coagulation assays. In our view, patients with uncontrolled bleeding, regardless of its cause, should be treated with goal‐directed haemostatic control resuscitation involving the early administration of plasma and platelets and based on the results of the TEG/ROTEM analysis. The aim of the goal‐directed therapy should be to maintain a normal haemostatic competence until surgical haemostasis is achieved, as this appears to be associated with reduced mortality.

How I treat patients with massive hemorrhage.

Massive hemorrhage is associated with coagulopathy and high mortality. The transfusion guidelines up to 2006 recommended that resuscitation of massive hemorrhage should occur in successive steps using crystalloids, colloids, and red blood cells (RBCs) in the early phase and plasma and platelets in the late phase. With the introduction of the cell-based model of hemostasis in the mid-1990s, our understanding of the hemostatic process and of coagulopathy has improved. This has contributed to a change in resuscitation strategy and transfusion therapy of massive hemorrhage along with an acceptance of the adequacy of whole blood hemostatic tests to monitor these patients. Thus, in 2005, a strategy aiming at avoiding coagulopathy by proactive resuscitation with blood products in a balanced ratio of RBC:plasma:platelets was introduced, and this has been reported to be associated with reduced mortality in observational studies. Concurrently, whole blood viscoelastic hemostatic assays have gained acceptance by allowing a rapid and timely identification of coagulopathy along with enabling an individualized, goal-directed transfusion therapy. These strategies joined together seem beneficial for patient outcome, although final evidence on outcome from randomized controlled trials are lacking. We present how we in Copenhagen and Houston, today, manage patients with massive hemorrhage.

Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? An observational study

IntroductionIt is debated whether early trauma-induced coagulopathy (TIC) in severely injured patients reflects disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype, acute coagulopathy of trauma shock (ACoTS) or yet other entities. This study investigated the prevalence of overt DIC and ACoTS in trauma patients and characterized these conditions based on their biomarker profiles.MethodsAn observational study was carried out at a single Level I Trauma Center. Eighty adult trauma patients (≥18 years) who met criteria for full trauma team activation and had an arterial cannula inserted were included. Blood was sampled a median of 68 minutes (IQR 48 to 88) post-injury. Data on demography, biochemistry, injury severity score (ISS) and mortality were recorded. Plasma/serum was analyzed for biomarkers reflecting tissue/endothelial cell/glycocalyx damage (histone-complexed DNA fragments, Annexin V, thrombomodulin, syndecan-1), coagulation activation/inhibition (prothrombinfragment 1+2, thrombin/antithrombin-complexes, antithrombin, protein C, activated protein C, endothelial protein C receptor, protein S, tissue factor pathway inhibitor, vWF), factor consumption (fibrinogen, FXIII), fibrinolysis (D-dimer, tissue-type plasminogen activator, plasminogen activator inhibitor-1) and inflammation (interleukin (IL)-6, terminal complement complex (sC5b-9)). Comparison of patients stratified according to the presence or absence of overt DIC (International Society of Thrombosis and Hemostasis (ISTH) criteria) or ACoTS (activated partial thromboplastin time (APTT) and/or international normalized ratio (INR) above normal reference).ResultsNo patients had overt DIC whereas 15% had ACoTS. ACoTS patients had higher ISS, transfusion requirements and mortality (all P < 0.01) and a biomarker profile suggestive of enhanced tissue, endothelial cell and glycocalyx damage and consumption coagulopathy with low protein C, antithrombin, fibrinogen and FXIII levels, hyperfibrinolysis and inflammation (all P < 0.05). Importantly, in non-ACoTS patients, apart from APTT/INR, higher ISS correlated with biomarkers of enhanced tissue, endothelial cell and glycocalyx damage, protein C activation, coagulation factor consumption, hyperfibrinolysis and inflammation, that is, resembling that observed in patients with ACoTS.ConclusionsACoTS and non-ACoTS may represent a continuum of coagulopathy reflecting a progressive early evolutionarily adapted hemostatic response to the trauma hit and both are parts of TIC whereas DIC does not appear to be part of this early response.

Acute coagulopathy of trauma: Balancing progressive catecholamine induced endothelial activation and damage by fluid phase anticoagulation

Acute coagulopathy of trauma predicts a poor clinical outcome. Tissue trauma activates the sympathoadrenal system resulting in high circulating levels of catecholamines that influence hemostasis dose-dependently through immediate effects on the two major compartments of hemostasis, i.e., the circulating blood and the vascular endothelium. There appears to be a dose-dependency with regards to injury severity and the hemostatic response to trauma evaluated in whole blood by viscoelastic assays like thrombelastography (TEG), changing from normal to hypercoagulable, to hypocoagulable and finally hyperfibrinolytic in severely injured patients. Since high catecholamine levels may directly damage the endothelium and thereby promote systemic coagulation activation, we hypothesize that the progressive hypocoagulability and ultimate hyperfibrinolysis observed in whole blood with increasing injury severity, is an evolutionary developed response that counterbalances the injury and catecholamine induced endothelial activation and damage. Given this, the rise in circulating catecholamines in trauma patients may favor a switch from hyper- to hypocoagulability in the blood to keep the progressively more procoagulant microvasculature open. The hypothesis delineated in the present paper thus infers that the state of the fluid phase, including its cellular elements, is a consequence of the degree of the tissue injury and importantly, critically related to the degree of endothelial damage, with a progressively more procoagulant endothelium inducing a gradient of increasing anticoagulation towards the fluid phase. The implications of this hypothesis may include targeted treatment strategies according to the degree of sympathoadrenal response as evaluated by whole blood viscoelastical hemostatic assays in trauma patients.

High circulating adrenaline levels at admission predict increased mortality after trauma

Background: Trauma-induced acute coagulopathy predicts a poor outcome. Although its pathophysiology is unclear, severe injury and shock (hypoperfusion) are proposed drivers. This study investigated the association between sympathoadrenal activation (circulating catecholamines) and biomarkers of coagulopathy. Methods: Prospective study of 75 adult trauma patients admitted to a Level I trauma center directly from the scene of accident. Patients were selected blinded post hoc from three predefined Injury Severity Score groups (<16, 16–27, and >27) and had available blood samples on arrival. We measured activated partial thromboplastin time, international normalized ratio, hematology, biochemistry, circulating adrenaline and noradrenaline, 11 biomarkers of tissue and endothelial damage, glycocalyx degradation, natural anticoagulation and fibrinolysis (histone-complexed DNA fragments, high-mobility group box 1, syndecan-1, von Willebrand factor, soluble thrombomodulin, protein C, tissue factor pathway inhibitor, antithrombin, tissue-type plasminogen activator, plasminogen activator inhibitor-1, D-dimer) and registered 30-day mortality. Biomarkers were compared between survivors and nonsurvivors. Results: The adrenaline level was increased in nonsurvivors (p = 0.026), it was independently associated with increased activated partial thromboplastin time (p = 0.034) and syndecan-1 (p = 0.007), a marker of glycocalyx degradation, and it correlated with biomarkers of tissue and endothelial damage (histone-complexed DNA, high-mobility group box 1, soluble thrombomodulin) and hyperfibrinolysis (tissue-type plasminogen activator, D-dimer). Furthermore, nonsurvivors had higher syndecan-1, tissue factor pathway inhibitor, and D-dimer levels (all p < 0.05). Circulating adrenaline was independently associated with 30-day mortality (OR, 5.92 [95% CI, 1.48–23.73]; p = 0.012) together with age (p = 0.001) and severe head injury (Abbreviated Injury Scale head >3; p = 0.011). Conclusions: The trauma-induced catecholamine surge is closely associated with biomarkers of tissue and endothelial damage, glycocalyx degradation, coagulopathy including hyperfibrinolysis and independently predicts mortality.

Low hemorrhage‐related mortality in trauma patients in a Level I trauma center employing transfusion packages and early thromboelastography‐directed hemostatic resuscitation with plasma and platelets

Hemorrhage accounts for most preventable trauma deaths, but still the optimal strategy for hemostatic resuscitation remains debated.

Thrombelastography and biomarker profiles in acute coagulopathy of trauma: a prospective study

BackgroundSevere injury induces an acute coagulopathy associated with increased mortality. This study compared the Thrombelastography (TEG) and biomarker profiles upon admission in trauma patients.MethodsProspective observational study of 80 trauma patients admitted to a Level I Trauma Centre. Data on demography, biochemistry including standard coagulation tests, hematology, transfusions, Injury Severity Score (ISS) and TEG were recorded. Retrospective analysis of thawed plasma/serum for biomarkers reflecting tissue injury (histone-complexed DNA fragments), sympathoadrenal activation (adrenaline, noradrenaline), coagulation activation/inhibition and fibrinolysis (sCD40L, protein C, activated Protein C, tissue-type plasminogen activator, plasminogen activator inhibitor-1, D-dimer, prothrombinfragment 1+2, plasmin/α2-antiplasmin complex, thrombin/antithrombin complex, tissue factor pathway inhibitor, antithrombin, von willebrand factor, factor XIII). Comparison of patients stratified according to ISS/TEG maximum clot strength. Linear regression analysis of variables associated with clot strength.ResultsTrauma patients had normal (86%), hypercoagulable (11%) or hypocoagulable (1%) TEG clot strength; one had primary hyperfibrinolysis. Hypercoagulable patients had higher age, fibrinogen and platelet count (all p < 0.05), none had increased activated partial thromboplastin time (APTT) or international normalized ratio (INR) and none required massive transfusion (> 10 red blood cells the initial 24 h). Patients with normal or hypercoagulable TEG clot strength had comparable biomarker profiles, but the few patients with hypocoagulable TEG clot strength and/or hyperfibrinolysis had very different biomarker profiles.Increasing ISS was associated with higher levels of catecholamines, histone-complexed DNA fragments, sCD40L, activated protein C and D-dimer and reduced levels of non-activated protein C, antithrombin, fibrinogen and factor XIII (all p < 0.05). Fibrinogen and platelet count were associated independently with clot strength in patients with ISS ≤ 26 whereas only fibrinogen was associated independently with clot strength in patients with ISS > 26. In patients with ISS > 26, adrenaline and sCD40L were independently negatively associated with clot strength.ConclusionsTrauma patients displayed different coagulopathies by TEG and variables independently associated with clot strength changed with ISS. In the highest ISS group, adrenaline and sCD40L were independently negatively associated with clot strength indicating that these may contribute to acute coagulopathy.

The influence of platelets, plasma and red blood cells on functional haemostatic assays.

Functional whole blood haemostatic assays are used increasingly to guide transfusion therapy and monitor medical treatment and are also applied for in-vitro evaluations of the haemostatic potential of stored platelets. We investigated how the cellular and plasmatic elements, both isolated and combined, influenced the two methodologically different assays, thrombelastography (TEG) and impedance aggregometry (Multiplate). Platelet-rich plasma (200 × 109/l) or pure plasma (0 platelets), with and without added red blood cells (RBCs), hematocrit 0, 0.15 or 0.29, were produced in vitro from platelet concentrates, fresh frozen plasma and stored RBC. Pure platelets were investigated by removing plasma components from platelet concentrates by diafiltration against the platelet storage solution Intersol. Plasma was readded by diafiltration against plasma in Intersol. Haemostatic function was evaluated by TEG and Multiplate. In the TEG, increasing amounts of RBC reduced clot strength and clot kinetics (α-angle), most markedly in plasma/RBC without platelets. In contrast, RBC in a platelet concentrate matrix enhanced Multiplate aggregation in response to weak agonists (ADP and arachidonic acid). Furthermore, removing plasma from platelet concentrates eliminated the TEG response and diminished the Multiplate aggregation response, but readding plasma to the pure platelet concentrates restored the response. Each of the elements in whole blood, plasma, platelets and RBC, affected the Multiplate and TEG results differently. The results emphasize that the concentrations of all cellular and plasmatic components in whole blood should be taken into account when interpreting results obtained by TEG and multiplate.