Search

Bleeding is a potential complication after neuraxial and peripheral nerve blocks. The risk is increased in patients on antiplatelet and anticoagulant drugs. This joint guideline from the European Society of Anaesthesiology and Intensive Care and the European Society of Regional Anaesthesia aims to provide an evidence-based set of recommendations and suggestions on how to reduce the risk of antithrombotic drug-induced haematoma formation related to the practice of regional anaesthesia and analgesia.A systematic literature search was performed, examining seven drug comparators and 10 types of clinical intervention with the outcome being peripheral and neuraxial haematoma. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used for assessing the methodological quality of the included studies and for formulating recommendations. A Delphi process was used to prepare a clinical practice guideline.Clinical studies were limited in number and quality and the certainty of evidence was assessed to be GRADE C throughout. Forty clinical practice statements were formulated. Using the Delphi-process, strong consensus (90% agreement) was achieved in 57.5% of recommendations and consensus (75 to 90% agreement) in 42.5%.Specific time intervals should be observed concerning the adminstration of antithrombotic drugs both prior to, and after, neuraxial procedures or those peripheral nerve blocks with higher bleeding risk (deep, noncompressible). These time intervals vary according to the type and dose of anticoagulant drugs, renal function and whether a traumatic puncture has occured. Drug measurements may be used to guide certain time intervals, whilst specific reversal for vitamin K antagonists and dabigatran may also influence these. Ultrasound guidance, drug combinations and bleeding risk scores do not modify the time intervals. In peripheral nerve blocks with low bleeding risk (superficial, compressible), these time intervals do not apply.In patients taking antiplatelet or anticoagulant medications, practitioners must consider the bleeding risk both before and after nerve blockade and during insertion or removal of a catheter. Healthcare teams managing such patients must be aware of the risk and be competent in detecting and managing any possible haematomas.

Early recognition of coagulopathy is necessary for its prompt correction and successful management. Novel approaches, such as point-of-care testing (POC) and administration of coagulation factor concentrates (CFCs), aim to tailor the haemostatic therapy to each patient and thus reduce the risks of over- or under-transfusion. CFCs are an effective alternative to ratio-based transfusion therapies for the correction of different types of coagulopathies. In case of major bleeding or urgent surgery in patients treated with vitamin K antagonist anticoagulants, prothrombin complex concentrate (PCC) can effectively reverse the effects of the anticoagulant drug. Evidence for PCC effectiveness in the treatment of direct oral anticoagulants-associated bleeding is also increasing and PCC is recommended in guidelines as an alternative to specific reversal agents. In trauma-induced coagulopathy, fibrinogen concentrate is the preferred first-line treatment for hypofibrinogenaemia. Goal-directed coagulation management algorithms based on POC results provide guidance on how to adjust the treatment to the needs of the patient. When POC is not available, concentrate-based management can be guided by other parameters, such as blood gas analysis, thus providing an important alternative. Overall, tailored haemostatic therapies offer a more targeted approach to increase the concentration of coagulation factors in bleeding patients than traditional transfusion protocols.

BACKGROUND Heparan sulfate is an integral component of the glycocalyx that provides an anticoagulant layer close to the endothelium. Hypoperfusion, inflammation and sympathoadrenal activation following major trauma result in glycocalyx shedding and subsequent release of heparan sulfate into the bloodstream. The possible anticoagulant effect of this "auto-heparinization" has been suggested as a potential driver of trauma-induced coagulopathy. We investigated whether thromboelastometry can be used to detect trauma-induced auto-heparinization. METHODS This study comprised three parts. First, in a retrospective clinical study of 264 major trauma patients, the clotting time (CT) in the INTEM (intrinsic activation) and HEPTEM (intrinsic activation plus heparinase) assays were evaluated upon emergency room admission. Second, in an in-vivo experimental rat model of hemorrhagic-traumatic shock, the release of heparan sulfate was investigated with INTEM and HEPTEM analysis of whole blood. Third, in-vitro spiking of whole blood from healthy volunteers was undertaken to assess the effects of clinically relevant quantities of heparan sulfate and heparin on CT in the INTEM and HEPTEM assays. RESULTS In the first part, severe injury and hemorrhagic shock was not associated with any increases in INTEM CT versus HEPTEM CT. Part two showed that an approximate 3-fold increase in heparan sulfate resulting from hemorrhagic traumatic shock in rats did not prolong INTEM CT, and no significant differences between INTEM CT and HEPTEM CT were observed. Third, spiking of whole blood with heparan sulfate had no impact on INTEM CT, whereas heparin elicited significant prolongation of INTEM CT. CONCLUSIONS Despite structural similarity between heparan sulfate and heparin, the amounts of heparan sulfate shed in response to trauma did not exert an anticoagulant effect that was measurable by the intrinsically activated CT in thromboelastometry. The extent to which heparan sulfate contributes to trauma-induced coagulopathy is yet to be elucidated. LEVEL OF EVIDENCE III. Retrospective clinical analysis. Prospective preclinical study.

Trauma patients admitted to an intensive care unit (ICU) may potentially experience a deficiency of coagulation factor thirteen (FXIII). In this retrospective cohort study conducted at a specialized trauma center, ICU patients were studied to determine the dependency of FXIII activity levels on clinical course and substitution with blood and coagulation products. A total of 189 patients with a median injury severity score (ISS) of 25 (16–36, IQR) were included. Abbreviated injury scores for extremities (r = −0.38, p < 0.0001) but not ISS (r = −0.03, p = 0.45) showed a negative correlation with initial FXIII levels. Patients receiving FXIII concentrate presented with a median initial FXIII level of 54 (48–59)% vs. 88 (74–108)%, p < 0.0001 versus controls; they had fewer ICU-free days: 17 (0–22) vs. 22 (16–24), p = 0.0001; and received higher amounts of red blood cell units: 5 (2–9) vs. 4 (1–7), p < 0.03 before, and 4 (2–7) vs. 1 (0–2), p < 0.0001 after FXIII substitution. Matched-pair analyses based on similar initial FXIII levels did not reveal better outcome endpoints in the FXIII-substituted group. The study showed that a low initial FXIII level correlated with the clinical course in this trauma cohort, but a substitution of FXIII did not improve endpoints within the range of the studied FXIII levels. Future prospective studies should investigate the utility of FXIII measurement and lower threshold values of FXIII, which trigger substitution in trauma patients.

Platelet dysfunction is a suggested driver of trauma-induced coagulopathy. However, there is still a paucity of data regarding the impact of injury pattern on platelet function and the association of platelet dysfunction on transfusion requirements and mortality. In this retrospective cohort study, patients were grouped into those with isolated severe traumatic brain injury (TBI group), those with major trauma without TBI (MT group), and a combination of both major trauma and traumatic brain injury (MT + TBI group). Platelet function was assessed by whole blood impedance aggregometry (Multiplate®, MP). Three different platelet activators were used: adenosine-diphosphate (ADP test), arachidonic acid (ASPI test), and thrombin activated peptide-6 (TRAP test). Blood transfusion requirements within 6 h and 24 h and the association of platelet dysfunction on mortality was investigated. A total of 328 predominantly male patients (75.3%) with a median age of 53 (37–68) years and a median ISS of 29 (22–38) were included. No significant difference between the TBI group, the MT group, and the MT + TBI group was detected for any of the investigated platelet function tests. Unadjusted and adjusted for platelet count, the investigated MP assays revealed no significant group differences upon ER admission and were not able to sufficiently predict massive transfusion, neither within the first 6 h nor for the first 24 h after hospital admission. No association between platelet dysfunction measured by MP upon ER admission and mortality was observed. Conclusion: Injury pattern did not specifically impact platelet function measurable by MP. Platelet dysfunction upon ER admission measurable by MP was not associated with transfusion requirements and mortality. The clinical relevance of platelet function testing by MP in trauma patients not on platelet inhibitors is questionable.

There is an ever-increasing number of hip fracture (HF) patients on direct oral anticoagulants (DOAC). The impact of DOAC plasma level prior to HF surgery on perioperative blood loss and transfusion requirements has not been investigated so far.In this retrospective study of HF patients on DOACs admitted to the AUVA Trauma Center Salzburg between February 2015 and December 2021. DOAC plasma levels were analysed prior to surgery. Patients were categorized into four DOAC groups: Group A 30 ng/mL, Group B 30-49 ng/mL, Group C 50-79 ng/mL, and Group D ≥ 80 ng/mL. Haemoglobin concentration was measured upon admission, prior to surgery, after ICU/IMC admission, and on day 1 and 2 post-surgery. Difference in the blood loss via drains, transfusion requirements and time to surgery were compared.A total of 155 subjects fulfilled the predefined inclusion criteria. The median age of the predominantly female patients was 86 (80-90) years. Haemoglobin concentration in Group D was lower upon admissions but did not reach statistical significance. The decrease in haemoglobin concentration over the entire observation time was comparable between groups. Blood transfusion requirements were significantly higher in Group D compared to Group A and B (p = 0.0043). Time to surgery, intra- and postoperative blood loss via drains were not different among groups.No strong association between the DOAC plasma levels and perioperative blood loss was detected. Higher transfusion rates in patients with DOAC levels ≥ 80 ng/mL were primarily related to lower admission haemoglobin levels. DOAC concentration measurement is feasible and expedites time to surgery.

Hyperfibrinolysis (HF) frequently occurs after severe systemic hypoperfusion during major trauma and out-of-hospital cardiac arrest (OHCA). In trauma-induced HF, hypoperfusion, the activation of protein C (APC), and the release of tissue plasminogen activator (t-PA) have been identified as the driving elements of premature clot breakdown. The APC pathway also plays a role in inflammatory responses such as neutrophil extracellular trap formation (NETosis), which might contribute to lysis through cleavage of fibrin by neutrophil elastases. We investigated whether the APC and the plasminogen pathway were general drivers of HF, even in the absence of a traumatic incident. Additionally, we were interested in inflammatory activation such as the presence of NETs as potential contributing factors to HF. A total of 41 patients with OHCA were assigned to a HF and a non-HF group based on maximum lysis (ML) in thromboelastometry. Thrombin–antithrombin (TAT)-complex, soluble thrombomodulin (sTM), APC–PC inhibitor complex, t-PA, PAI-1, t-PA–PAI-1 complex, plasmin–antiplasmin (PAP), d-dimers, neutrophil elastase, histonylated DNA (hDNA) fragments, and interleukin-6 were assessed via immunoassays in the HF group vs. non-HF. APC–PC inhibitor complex is significantly higher in HF patients. Antigen levels of t-PA and PAI-1 do not differ between groups. However, t-PA activity is significantly higher and t-PA–PAI-1 complex significantly lower in the HF group. Consistent with these results, PAP and d-dimers are significantly elevated in HF. HDNA fragments and neutrophil elastase are not elevated in HF patients, but show a high level of correlation, suggesting NETosis occurs in OHCA as part of inflammatory activation and cellular decay. Just as in trauma, hypoperfusion, the activation of protein C, and the initiation of the plasminogen pathway of fibrinolysis manifest themselves in the HF of cardiac arrest. Despite features of NETosis being detectable in OHCA patients, early pro-inflammatory responses do not appear be associated with HF in cardiac arrest.

Specific antagonists have been developed for the reversal of direct oral anticoagulants (DOAC). We investigated the impact of these reversal agents on the plasma concentration and visco-elastic test results of dabigatran and factor Xa inhibitors. After baseline measurements of dabigatran, the plasma concentration, and the visco-elastic ClotPro® ecarin clotting time (ECA-CT), we added the reversal agent Idarucizumab in vitro and these two analyses were repeated. Likewise, the baseline plasma concentration of apixaban, edoxaban, and rivaroxaban as well as ClotPro® Russell’s viper venom test clotting time (RVV-CT) were measured and reanalyzed following Andexanet alfa spiking. We analyzed fifty blood samples from 37 patients and 10 healthy volunteers. Idarucizumab decreased the measured dabigatran plasma concentration from 323.9 ± 185.4 ng/mL to 5.9 ± 2.3 ng/mL and ECA-CT from 706.2 ± 344.6 s to 70.6 ± 20.2 s, (all, p &lt, 0.001). Andexanet alfa decreased the apixaban concentration from 165.1 ± 65.5 ng/mL to 9.8 ± 8.1 ng/mL, edoxaban from 152.4 ± 79.0 ng/mL to 36.4 ± 19.2 ng/mL, and rivaroxaban from 153.2 ± 111.8 ng/mL to 18.1 ± 9.1 ng/mL (all p &lt, 0.001). Andexanet alfa shortened the RVV-CT of patients with apixaban from 239.2 ± 71.7 s to 151.1 ± 30.2 s, edoxaban from 288.2 ± 65.0 s to 122.7 ± 37.1 s, and rivaroxaban from 225.9 ± 49.3 s to 103.7 ± 12.1 s (all p &lt, 0.001). In vitro spiking of dabigatran-containing blood with Idarucizumab substantially reduced the plasma concentration and ecarin-test clotting time. Andexanet alfa lowered the concentration of the investigated factor Xa-inhibitors but did not normalize the RVV-CT. In healthy volunteers’ blood, Idarucizumab spiking had no impact on ECA-CT. Andexanet alfa spiking of non-anticoagulated blood prolonged RVV-CT (p = 0.001), potentially as a consequence of a competitive antagonism with human factor Xa.

Severe bleeding remains a prominent cause of early in-hospital mortality in major trauma patients. Thus, prompt prediction of patients at risk of massive transfusion (MT) is crucial. We investigated the ability of the inflammatory marker interleukin (IL)-6 to forecast MT in severely injured trauma patients. IL-6 plasma levels were measured upon admission. Receiver operating characteristic curves (ROCs) were calculated, and sensitivity and specificity were determined. In this retrospective study, a total of 468 predominantly male (77.8%) patients, with a median injury severity score (ISS) of 25 (17–34), were included. The Youden index for the prediction of MT within 6 and 24 h was 351 pg/mL. Patients were dichotomized into two groups: (i) low-IL-6 &lt, 350 pg/mL and (ii) high-IL-6 ≥ 350 pg/mL. IL-6 ≥ 350 pg/mL was associated with a lower prothrombin time index, a higher activated partial thromboplastin time, and a lower fibrinogen concentration compared with IL-6 &lt, 350 pg/mL (p &lt, 0.0001 for all). Thromboelastometric parameters were significantly different between groups (p &lt, 0.03 in all). More patients in the high-IL-6 group received MT (p &lt, 0.0001). The ROCs revealed an area under the curve of 0.76 vs. 0.82 for the high-IL-6 group for receiving MT in the first 6 and 24 h. IL-6 ≥ 350 pg/mL predicted MT within 6 and 24 h with a sensitivity of 45% and 58%, respectively, and a specificity of 89%. IL-6 ≥ 350 pg/mL appears to be a reasonable early predictor for coagulopathy and MT within the first 6 and 24 h intervals. Large-scale prospective studies are warranted to confirm these findings.

Trauma and bleeding are associated with a high mortality, and most of these deaths occur early after injury. Viscoelastic haemostatic tests have gained increasing importance in goal-directed transfusion and bleeding management. A new generation of small-sized and thus portable ultrasound-based viscoelastic analysers have been introduced in clinical practice. We questioned whether a promising candidate can be used in emergency helicopters, with a focus on the susceptibility to vibration stress. We investigated whether the high vibration environment of an emergency helicopter would affect the operability of an ultrasound-based viscoelastic analyser and would yield reproducible results in flight and on the ground. We drew blood from 27 healthy volunteers and performed simultaneous analyses on two TEG 6s. Each measurement was performed in-flight on board an Airbus H135 emergency helicopter and was repeated on the ground, close to the flight area. Results from both measurements were compared, and the recorded tracings and numeric results were analysed for artifacts. Vibratometric measurements were performed throughout the flight in order to quantify changes in the magnitude and character of vibrations in different phases of helicopter operation. The high vibration environment was associated with the presence of artifacts in all recorded tracings. There were significant differences in citrated Kaolin + Heparinase measurements in-flight and on the ground. All other assays increased in variability but did not show significant differences between the two time points. We observed numerous artifacts in viscoelastic measurements that were performed in flight. Some parameters that were obtained from the same sample showed significant differences between in-flight and on-ground measurements. Performing resonance-based viscoelastic tests in helicopter medical service is prone to artifacts. However, a 10 min delay between initiation of measurement and take-off might produce more reliable results.

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

Endothelial cells (ECs) are major modulators of hemostasis by expressing and releasing pro- and anticoagulant mediators into the circulation. Previous studies showed that cultured ECs release procoagulant mediators into cell culture supernatants as evidenced by the reduction of viscoelastic clotting time. This effect was reversed with an anti-tissue factor antibody. Here, we aimed to investigate whether tissue factor (TF) was released by endothelial-derived extracellular vesicles (EVs) and which portion of the released vesicles displays the most prominent procoagulant properties. After stimulation of ECs with tumor-necrosis factor-α (TNF-α) the supernatants of EC cultures were subjected to differential centrifugation steps to collect larger and smaller EVs which were then characterised by nanoparticle tracking analysis (NTA) and flow cytometry. Mixed with fresh human blood and analysed by thromboelastometry EVs exerted a significant procoagulant stimulus, which could be partly reversed by addition of an anti-TF antibody. Moreover, TF activity was confirmed in the centrifuged fractions. In summary, our results provide evidence of the procoagulant potential of smaller and larger endothelial-derived EV fractions detected by thromboelastometry. The observed effect is most likely due to the release of TF-bearing EVs of different dimensions, which are released upon TNF-α stimulation of endothelial cell cultures.

Platelet dysfunction has been identified as an important contributor of trauma-induced coagulopathy, but the underlying mechanism still remains to be elucidated. Trauma-associated proinflammatory stimuli strongly activate leukocytes, which in turn bind activated platelets. Therefore, we investigated the role of platelet-leukocyte aggregation (PLA) as a potential feature of trauma-induced platelet dysfunction. Whole blood from 10 healthy donors was exposed to selective and collective platelet and leukocyte agonists in order to simulate differential states of activation. PLA formation and CD11b expression as a measure of leukocyte activation were determined by flow cytometry. Platelet-mediated hemostatic function was measured by thromboelastometry (ROTEM) and impedance aggregometry (Multiplate). Activation of platelets and leukocytes was associated with diminished platelet-mediated hemostatic potential. Aggregation of platelets with monocytes rather than granulocytes resulted in a reduction of hemostatic function, as indicated by an impaired responsiveness in platelet aggregometry and a reduction of thromboelastometric maximum clot firmness. This finding was irrespective of CD11b expression and was not paralleled by a reduction of measurable platelet counts. PLA formation occurs primarily between monocytes and activated platelets and is associated with impaired platelet-mediated hemostatic function. PLA formation was not paralleled by a reduction in platelet complete blood counts.

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.

The viscoelastic properties of blood clot have been studied most commonly using thrombelastography (TEG®) and thromboelastometry (ROTEM®). ROTEM®-based bleeding treatment algorithms recommend administering platelets to patients with low EXTEM clot strength (e.g., clot amplitude at 10 minutes [A10]

Viscoelastic tests such as thrombelastography (TEG, Haemoscope Inc., Niles, IL) and thromboelastometry (ROTEM, Tem International GmbH, Munich, Germany), performed in whole blood, are increasingly used at the point-of-care to characterize coagulopathic states and guide hemostatic therapy. An algorithm, based on a mono-analysis (kaolin-activated assay) approach, was proposed in the TEG patent (issued in 2004) where the α-angle and the maximum amplitude parameters are used to guide fibrinogen supplementation and platelet administration, respectively. Although multiple assays for both the TEG and ROTEM devices are now available, algorithms based on TEG mono-analysis are still used in many institutions. In light of more recent findings, we discuss here the limitations and inaccuracies of the mono-analysis approach. Research shows that both α-angle and maximum amplitude parameters reflect the combined contribution of fibrinogen and platelets to clot strength. Therefore, although TEG mono-analysis is useful for identifying a coagulopathic state, it cannot be used to discriminate between fibrin/fibrinogen and/or platelet deficits, respectively. Conversely, the use of viscoelastic methods where 2 assays can be run simultaneously, one with platelet inhibitors and one without, can effectively allow for the identification of specific coagulopathic states, such as insufficient fibrin formation or an insufficient contribution of platelets to clot strength. Such information is critical for making the appropriate choice of hemostatic therapy.

Perioperative fluid therapy is an important component of many medical procedures with animals. Buffered crystalloid solutions avoid inducing metabolic acidosis, but lactated solutions can elevate blood lactate concentrations and acetated solutions have not been thoroughly investigated using large animals. Here, the authors compare blood biochemical parameters in 20 juvenile pigs after perioperative fluid administration of an acetate-buffered solution (Elo-Mel isoton, EMI) or a lactate-buffered solution (lactated Ringer's solution, LRS). The authors measured blood lactate, glucose and electrolyte concentrations before and after administering the test fluid during surgery. Blood lactate concentration after administration was significantly higher in pigs that received LRS than in pigs that received EMI, but glucose and electrolyte concentrations did not differ significantly between treatment groups before or after administration. These findings suggest that EMI might be a preferable option for perioperative fluid therapy in pigs.

F adequate hemostasis, sufficient amounts of thrombin and coagulable substrate are fundamental prerequisites. In addition to platelets, on whose surfaces most of the thrombin is generated, fibrinogen can be considered as the substrate of the coagulation process. If sufficient thrombin is formed, it converts fibrinogen into stable fibrin, which determines the firmness of the developing clot in the presence of activated coagulation factor XIII (Fig. 1). Under physiologic conditions, fibrinogen availability is regulated through dynamic changes in synthesis and breakdown to preserve coagulation function. As a consequence of blood loss, consumption of coagulation factors, dilutional coagulopathy, hypothermia and acidosis, as well as profibrinolytic activation, fibrinogen may reach critical levels earlier than any other procoagulant factor and also platelets even before packed red blood cell concentrate administration becomes necessary. Floccard et al. have described even significant drops in fibrinogen levels to occur already during the ultra early prehospital phase of care when comparing blood samples obtained from bleeding trauma patients at the scene and at the time point of arrival to the trauma bay (fibrinogen median, 2.6 g/L; interquartile range [IQR], 2.3Y3.1; 95% confidence interval [CI], 2.4Y2.9 vs. 2.1 g/L; IQR, 1.4Y2.5; 95% CI, 1.7Y2.3) (changes, j0.6 g/L; IQR, j1.1 to j0.3; 95%CI,j0.9 toj0.3;pG 0.001). In this study, fibrinogen levels decreased substantially as a function of injury severity reflected by Injury Severity Scores (ISSs). Recently, Kimura et al. have reported similar results when searching retrospectively for predictors of hypofibrinogenemia in 290 blunt traumapatients upon admission to aLevel 1 trauma center during a 3-year period. Their multivariate regression analysis identified patient’s age (odds ratio [OR], 0.97; p G 0.001), Triage Revised Trauma Score (T-RTS including Glasgow Coma Scale [GCS] score, respiratory rate, and systolic blood pressure; OR, 0.81; p = 0.003), and prehospital volume therapy (OR, 2.54; p = 0.01) as independent predictors for early hypofibrinogenemia. In contrast todisseminated intravascular coagulopathy, there is no generalized intravascular microcoagulation with increased consumption in trauma-induced coagulopathy. Instead, there is hemorrhage-related loss of coagulation factors and platelets with subsequent dilution of procoagulant factors due to (uncritical) volume resuscitation with direct effect on fibrinogen polymerization. Dilution of fibrinogen by crystalloid fluids and additional reduced fibrin interlinkage by synthetic colloids has been discussed. Recently, experimental data confirmed significant fibrinogen breakdown by acidosis following hypoperfusion with no effect on fibrinogen synthesis, while hypothermia decreased fibrinogen synthesis with no effect on fibrinogen degradation. Furthermore, synthesis and degradation seem to be regulated through different mechanisms, and a potential deficit in fibrinogen availability during hypothermia has been suggested.

The concept of haemostatic resuscitation implies early and high-volume plasma transfusion. We investigated the haemostatic profile of reconstituted whole blood prepared in a 1:1:1 ratio of blood, platelets and plasma. This consisted of packed red blood cells, platelet concentrate and four different plasma variants: fresh frozen; solvent-detergent; lyophilised quarantine; and lyophilised methylene blue-inactivated plasma. Haematocrit, platelet count, endogenous thrombin potential and coagulation factor activity were significantly lower in reconstituted blood compared with citrated whole blood (p < 0.01). Except for lyophilised methylene blue-inactivated plasma, no substantial differences between plasma variants in coagulation factor activity, endogenous thrombin potential and standard coagulation tests were observed. After reconstitution, haematocrit and platelet counts were slightly above recommended transfusion triggers, most thromboelastometry (ROTEM(®)) parameters were within the normal range and fibrinogen concentrations were between 1.57 g.l(-1) and 1.91 g.l(-1). Reconstitution of whole blood in a 1:1:1 ratio resulted in significant dilution of haematocrit and platelet count, but values remained above limits recommended by transfusion guidelines. Fibrinogen concentrations of reconstituted whole blood were also significantly reduced, and these were below the threshold value for supplementation recommended by recent guidelines.

Supplemental digital content is available in the text., BACKGROUND Fibrinogen plays a key role in hemostasis and is the first coagulation factor to reach critical levels in bleeding patients. Current European guidelines on the management of traumatic or perioperative bleeding recommend fibrinogen supplementation at specific threshold levels. Whole blood viscoelastic tests provide fast evaluation of fibrin deficits. Fast measurement of plasma fibrinogen concentration is not yet available. We investigated a method to rapidly determine whole blood fibrinogen concentration using standard Clauss assays and a steel ball coagulometer and provide an estimate of the “plasma-equivalent” fibrinogen concentration within minutes by adjustment of the measured whole blood fibrinogen concentration with a quickly measureable hemoglobin-derived hematocrit. METHODS The feasibility of this approach was tested with a Clauss assay using multiple porcine fresh blood samples obtained during in vivo bleeding, hemodilution, and after treatment with hemostatic therapy. Two different Clauss assays were then tested using multiple human volunteers’ blood samples diluted in vitro and supplemented with fibrinogen concentrate. Comparative measurements with fibrin-based thromboelastometry tests were performed. RESULTS Regression and Bland-Altman analyses of derived “plasma-equivalent” fibrinogen and measured plasma fibrinogen concentration was excellent in porcine and human blood samples, especially in the ranges relevant to traumatic or perioperative bleeding. CONCLUSION Fast whole blood fibrinogen measurements could be considered as an alternative to plasma fibrinogen measurement for acute bleeding management in trauma and perioperative care settings. Further studies are needed to prove this concept and determine the turnaround times for its clinical application in emergency departments and operating theaters.

The early and aggressive high-volume administration of fresh frozen plasma, platelet concentrates, and red blood cells (RBCs), using ratio-driven massive transfusion protocols, has been adopted by many for the treatment of trauma-induced coagulopathy and hemorrhagic shock. However, the optimal ratio of RBC: fresh frozen plasma and RBC:platelet concentrate is still under investigation. In some European trauma centers, hemostatic agents such as fibrinogen concentrate, prothrombin complex concentrates, and antifibrinolytics are integral parts of goal-directed massive transfusion protocols. Both a ratio-driven coagulation therapy and a point-of-care-guided coagulation management based on coagulation factor concentrates aim for the same target-the rapid prevention and treatment of shock and coagulopathy to prevent death from traumatic hemorrhage. In this review, we compare the evidence relating to the effectiveness and safety of the ratio-driven and goal-directed approaches to trauma-induced coagulopathy to draw attention to the potential benefits and drawbacks associated with these management strategies.

BACKGROUND Fibrinogen concentrate is increasingly considered as a hemostatic agent for trauma patients experiencing bleeding. Placing a venous access is sometimes challenging during severe hemorrhage. Intraosseous access may be considered instead. Studies of intraosseous infusion of coagulation factor concentrates are limited. We investigated in vivo recovery following intraosseous administration of fibrinogen concentrate and compared the results with intravenous administration. METHODS This study was performed on 12 pigs (mean [SD] body weight, 34.1 [2.8] kg). Following controlled blood loss (35 mL/kg) and fluid replacement with balanced crystalloid solution, intraosseous (n = 6) administration of fibrinogen concentrate (80 mg per kilogram of bodyweight) in the proximal tibia was compared with intravenous (n = 6) administration of the same dose (fibrinogen infusion time approximately 5 minutes in both groups). The following laboratory parameters were assessed: blood cell count, prothrombin time index, activated partial thromboplastin time, and plasma fibrinogen concentration (Clauss assay). Coagulation status was also assessed by thromboelastometry. RESULTS All tested laboratory parameters were comparable between the intraosseous and intravenous groups at baseline, hemodilution, and 30 minutes after fibrinogen concentrate administration. In vivo recovery of fibrinogen was also similar in the two groups (89% [23%] and 91% [22%], respectively). There were no significant between-group differences in any of the thromboelastometric parameters. Histologic examination indicated no adverse effects on the tissue surrounding the intraosseous administration site. CONCLUSION This study suggests that intraosseous administration of fibrinogen concentrate results in a recovery of fibrinogen similar to that of intravenous administration. The intraosseous route of fibrinogen concentrate could be a valuable alternative in situations where intravenous access is not feasible or would be time consuming. LEVEL OF EVIDENCE Prospective, randomized, therapeutic feasibility study in an animal model, level V.

Background Efficiently performed basic life support (BLS) after cardiac arrest is proven to be effective. However, cardiopulmonary resuscitation (CPR) is strenuous and rescuers' performance declines rapidly over time. Audio-visual feedback devices reporting CPR quality may prevent this decline. We aimed to investigate the effect of various CPR feedback devices on CPR quality. Methods In this open, prospective, randomised, controlled trial we compared three CPR feedback devices (PocketCPR ® , CPRmeter ® , iPhone app PocketCPR ® ) with standard BLS without feedback in a simulated scenario. 240 trained medical students performed single rescuer BLS on a manikin for 8min. Effective compression (compressions with correct depth, pressure point and sufficient decompression) as well as compression rate, flow time fraction and ventilation parameters were compared between the four groups. Results Study participants using the PocketCPR ® performed 17±19% effective compressions compared to 32±28% with CPRmeter ® , 25±27% with the iPhone app PocketCPR ® , and 35±30% applying standard BLS (PocketCPR ® vs. CPRmeter ® p =0.007, PocketCPR ® vs. standard BLS p =0.001, others: ns). PocketCPR ® and CPRmeter ® prevented a decline in effective compression over time, but overall performance in the PocketCPR ® group was considerably inferior to standard BLS. Compression depth and rate were within the range recommended in the guidelines in all groups. Conclusion While we found differences between the investigated CPR feedback devices, overall BLS quality was suboptimal in all groups. Surprisingly, effective compression was not improved by any CPR feedback device compared to standard BLS. All feedback devices caused substantial delay in starting CPR, which may worsen outcome.

Viscoelastic tests such as functional fibrinogen polymerization assays (FFPAs) in thrombelastography (TEG(®)) or thromboelastometry (ROTEM(®)) measure the elasticity of extrinsically activated clotting under conditions of platelet inhibition. There are no reports on whether components of the FFPAs have any effects on fibrin polymerization, aside from the effects of platelet inhibition.Using various platelet-free plasma (PFP) preparations, we compared the extrinsically activated EXTEM thromboelastometric assay with 3 FFPAs: FIBTEM, FIBTEM PLUS, and the Functional Fibrinogen Test(®) (FFTEG). These FFPAs activate coagulation extrinsically but additionally inhibit platelet function. We used calibration plasma (Instrumentation Laboratory and Siemens), pooled fresh-frozen plasma (Octaplas) and freshly prepared PFP from a healthy volunteer. EXTEM and all FFPAs were run in parallel on a ROTEM device.Median (interquartile range) maximum clot firmness (MCF) values for all plasma preparations were: 20.5 mm (17.25-22.0 mm) in EXTEM, 23.0 mm (18.5-24.0 mm) in FIBTEM, 23.0 mm (18.25-24.75 mm) in FIBTEM PLUS, and 18.0 mm (16.0-19.0 mm) in FFTEG. Compared with EXTEM, FIBTEM and FIBTEM PLUS (P0.01) showed increased MCF values whereas FFTEG (P0.001) showed decreased MCF values. Further experiments in PFP showed that the platelet inhibitors used in the FFPAs (cytochalasin D or the glycoprotein-IIb/IIIa inhibitor abciximab) were not causing these alterations in MCF. However, reducing the activating tissue factor concentration (by diluting the extrinsic assay) decreased the MCF.We speculate that FIBTEM and FIBTEM PLUS may contain stabilizing agents that enhance fibrin polymerization whereas FFTEG might contain less tissue factor than the ROTEM assays.

Background Cardiocirculatory arrest (CCA) activates procoagulant pathways. It has also been reported to inhibit fibrinolysis, resulting in fibrin deposition and further impairment of blood flow. Until now, no studies have used whole-blood viscoelastic tests to characterize coagulation and the impact of fibrinolysis in out-of-hospital cardiac arrest (OHCA). Methods Patient with established OHCA who underwent cardiopulmonary resuscitation (CPR) were enrolled. Blood samples were obtained immediately after placement of an intravenous line at the scene, for full blood cell count, standard coagulation tests and rotational thromboelastometric (ROTEM®) analyses. Patients with return of spontaneous circulation (ROSC) were compared to non-ROSC patients. Results Fifty-three patients (median age 67 years, interquartile range: 56–73 years) were included in the study. ROSC was established in 25 patients. Prothrombin time index (PTI) was significantly lower and activated partial thromboplastin time (aPTT) was significantly prolonged in non-ROSC patients compared to ROSC patients. Clotting time (CT) in the extrinsically activated ROTEM test (EXTEM) was significantly longer in non-ROSC versus ROSC patients. For the remaining EXTEM parameters, there were no significant differences between ROSC and non-ROSC patients. Hyperfibrinolysis (maximum lysis > 15% according to ROTEM test results) was observed in 19 patients (35.8%). There was no difference between ROSC and non-ROSC patients in the incidence of hyperfibrinolysis. Conclusions PTI, aPTT and EXTEM CT revealed significant differences between ROSC and non-ROSC patients. Hyperfibrinolysis according to ROTEM test results was much more common than previously assumed. Routine use of fibrinolytic therapy in all patients with prolonged CPR cannot therefore be recommended.

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.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.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.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.

Non-vitamin K antagonist oral anticoagulants (NOACs) have a favorable benefit-risk profile compared with vitamin K antagonists. However, the lack of specific reversal agents has made the management of some patients receiving long-term treatment with NOACs problematic in emergency situations such as major bleeding events or urgent procedures. Idarucizumab, a fully humanized Fab antibody fragment that binds specifically and with high affinity to dabigatran, was recently approved for use in adult patients treated with dabigatran when rapid reversal of its anticoagulant effect is required. Clinical experience with idarucizumab is currently limited. We report 11 real-life clinical cases in which idarucizumab was used after multidisciplinary consultation in a variety of emergency situations including severe postoperative bleeding, emergency high-bleeding-risk surgery (hip/spine surgery and neurosurgery), invasive diagnostic testing (lumbar puncture), intracranial bleeding (pre-pontine subarachnoid hemorrhage and lobar intracerebral hemorrhage) and thrombolysis with recombinant tissue plasminogen activator for acute ischemic stroke. This case series illustrates the role of idarucizumab in improving patient safety in rare emergency situations requiring rapid reversal of the anticoagulant effect of dabigatran, while highlighting the importance of information and education about the availability and appropriate use of this recently approved specific reversal agent.

SummaryFollowing vascular injury or activation, endothelial cells (ECs) participate in the modulation of haemostasis and fibrinolysis. Viscoelastic tests (VETs) are a potent bedside monitoring tool that reports haemostatic parameters in real time. However, VETs neglect the influence of the surrounding endothelium. Our aim was therefore to establish an assay that incorporates ECs in a whole blood VET and to assess the impact of ECs on coagulation parameters. Outgrowth endothelial cells (OECs) and human umbilical vein endothelial cells (HUVECs) were seeded onto microbeads to create transferable EC-microcarriers. Microbeads were then added to citrated whole blood in the measurement cup of a thromboelastometry device (ROTEM). After the addition of CaCl2 (star-TEM®) to the blood sample (NATEM assay), standard ROTEM parameters were analysed. Scanning electron microscopy (SEM) was carried out to visualise the interactions of the beads, whole blood components and the ROTEM pin after clotting. SEM showed that the added microbeads were effectively incorporated into the final blood clot. In the presence of activated ECs, the clotting time (CT) of the blood was shortened fourfold compared to that in uncoated control beads. A significant reduction in CT was also observed in the presence of unstimulated ECs. Interestingly, CT was also reduced by the addition of purified EC culture supernatant. CT shortening was prevented by incubating the supernatant with an inhibiting antibody against tissue factor (TF). Our findings demonstrate that ECs can be incorporated into a ROTEM assay via coated microbeads, and whole blood clotting initiation is accelerated by non-activated and activated ECs.

BACKGROUND: Platelets play a pivotal role in coagulation, inflammation and wound healing. Suitable animal models that have the potential to mimic human platelet function are limited. The objective of the current study was to compare platelet aggregation response in the whole blood of baboons and humans using impedance aggregometry.METHODS: Blood was drawn from 24 anesthetised male baboons and 25 healthy volunteers. The platelet aggregation response was determined by impedance aggregometry (Multiplate®). Platelets in the hirudinised whole blood samples were stimulated with four different activators: adenosine diphosphate (ADP), collagen (COL), thrombin receptor activating peptide-6 (TR1AP), and activation of PAR-4 thrombin receptor subtype (TR4AP) at standard concentrations. Higher than standard concentrations were tested in a subgroup of the animals.RESULTS: The cell counts showed no differences between baboons and humans. The platelet aggregation response was significantly lower in baboons compared to humans when stimulated with the platelet agonists ADP (pCONCLUSION: The current study revealed that testing the platelet function in baboon blood by impedance aggregometry is feasible with ADP, COL and TR4AP, but not with TR1AP. Compared to humans, the aggregation response is lower in baboons. Considering the limitations in accordance to these results, baboons might represent a potential species for further platelet research.

Background Fibrinogen concentrate (FC) is increasingly used as first line therapy in bleeding trauma patients. It remains unproven whether FC application increases post-traumatic plasma fibrinogen concentration (FIB) in injured patients, possibly constituting a prothrombotic risk. Thus, we investigated the evolution of FIB following trauma in patients with or without FC therapy. Methods At the AUVA Trauma Centre, Salzburg, we performed a retrospective study of patients admitted to the emergency room and whose FIB levels were documented thereafter up to day 7 post-trauma. Patients were categorized into those with (treatment group) or without (control group) FC therapy during the first 24 h after hospital admission. A subgroup analysis was carried out to investigate the influence of the amount of FC given. Results The study enrolled 435 patients: treatment group, n = 242 (56 %); control group, n = 193 (44 %), with median Injury Severity Score of 34 vs. 22 (P

Trauma-induced coagulopathy (TIC) occurs early after severe injury. TIC is associated with a substantial increase in bleeding rate, transfusion requirements, and a 4-fold higher mortality. Rapid surgical control of blood loss and early aggressive hemostatic therapy are essential steps in improving survival. Since the publication of the CRASH-2 study, early administration of tranexamic acid is considered as an integral step in trauma resuscitation protocols of severely injured patients in many trauma centers. However, the advantage of en route administration of tranexamic acid is not proven in prospective studies. Fibrinogen depletes early after severe trauma; therefore, it seems to be reasonable to maintain plasma fibrinogen as early as possible. The effect of prehospital fibrinogen concentrate administration on outcome in major trauma patients is the subject of an ongoing prospective investigation. The use of prothrombin complex concentrate is potentially helpful in patients anticoagulated with vitamin K antagonists who experience substantial trauma or traumatic brain injury. Beyond emergency reversal of vitamin K antagonists, safety data on prothrombin complex concentrate use in trauma are lacking.

Coagulopathy after trauma has several causes including loss, consumption, dilution, and dysfunction of coagulation factors, as well as hyperfibrinolysis. Standard coagulation tests are not useful in guiding hemostatic therapy in the acute bleeding trauma patient. In contrast, viscoelastic tests appear to be appropriate in this setting. Recommended therapeutic options include antifibrinolytic agents and a concept of a fixed mixture of packed red blood cells, plasma, and platelets for transfusion for all bleeding patients or the goal-directed coagulation management using an algorithm to supplement individually only those coagulation components that are needed. This chapter gives a short overview together with relevant and recent literature on this topic.

A bench study was performed to investigate the potential of air bubbles entering a central vein via a central venous catheter to ascend retrograde to the brain. The results support the hypothesis that air bubbles may rise retrograde against the venous blood flow, depending on bubble size, central vein diameter and cardiac output. A review of radiological findings in published case reports indicates that the occurrence of retrograde cerebral air embolism is underestimated.

The patients who do not respond even to very high dosages of heparin are assumed to suffer from heparin resistance. The aim of this study was to investigate whether critically ill patients suffering from heparin resistance generally have low antithrombin III (AT) levels, and if the direct thrombin inhibitor argatroban in that case can be an effective option to achieve prophylactic anticoagulation. The study was conducted at the Department for General and Surgical Intensive Care Medicine at the University Hospital Innsbruck. We retrospectively included all patients between 2008 and 2012, who received argatroban because of poor response to high-dosage heparin prophylaxis. The period under observation lasted in total for 9 days, 2 days of anticoagulation with unfractionated heparin (UFH) and 7 days with argatroban. The primary objective was to investigate if after 7 (± 1) hours of switching to argatroban the activated partial thromboplastin time (aPTT) levels were in a prophylactic range of 45 to 55 seconds. Further objectives were to assess the AT level, side effects such as bleeding or thromboembolism, platelet count, correlation between organ function and argatroban dose as well as any need for allogeneic blood products. The study population, consisting of 5 women and 15 men with a mean (± standard deviation, SD) age of 54.6 ± 16.3 years, differed in many clinical aspects. A median (interquartile range) heparin dose of 1,000, 819 to 1,125 IU/h was administered for 2 days and failed in providing a prophylactic anticoagulation measured by the aPTT. The mean aPTT level with heparin treatment was 38.5 seconds (± 4.7) its change within that period was not significant. After switching to argatroban, the mean increase of the aPTT levels in all study patients amounted from 38.5 to 48.3 seconds (p

Colloids and crystalloids are frequently use to restore intravascular volume. Both solutions interfere with the coagulation process in different ways. Increasing amounts of fluids result in dilutional coagulopathy. Artificial colloids exert additive effects on fibrin polymerisation and platelet function. In vitro and in vivo studies revealed that starches and dextrans show the greatest negative impact on hemostasis.

Silkworm's silk is natural biopolymer with unique properties including mechanical robustness, all aqueous base processing and ease in fabrication into different multifunctional templates. Additionally, the nonmulberry silks have cell adhesion promoting tri-peptide (RGD) sequences, which make it an immensely potential platform for regenerative medicine. The compatibility of nonmulberry silk with human blood is still elusive; thereby, restricts its further application as implants. The present study, therefore, evaluate the haematocompatibility of silk biomaterials in terms of platelet interaction after exposure to nonmulberry silk of Antheraea mylitta using thromboelastometry (ROTEM). The mulberry silk of Bombyx mori and clinically used Uni-Graft W biomaterial serve as references. Shortened clotting time, clot formation times as well as enhanced clot strength indicate the platelet mediated activation of blood coagulation cascade by tested biomaterials; which is comparable to controls.

The likelihood of successful defibrillation in patients with sustained ventricular fibrillation (VF) is increased after administering thrombolytics during cardiopulmonary resuscitation (CPR). While dissolution of coronary artery thrombosis resolves the underlying cause of myocardial infarction in the majority of patients, improved microcirculatory reperfusion and alteration of the electrical activity of the fibrillation process may increase the likelihood of restoring spontaneous circulation in cardiac arrest patients. Electrocardiography is a sensitive means of displaying current myocardial perfusion in VF using changes in the frequency and amplitude of fibrillation. Our hypothesis postulates that thrombolytic therapy during CPR increases fibrillation frequency, fibrillation amplitude and amplitude spectrum area, thus improving ventricular fibrillation status and the chance of successful defibrillation.

Viscoelastic tests such as functional fibrinogen polymerization assays (FFPAs) in thrombelastography (TEG®) or thromboelastometry (ROTEM®) measure clot elasticity under platelet inhibition. Incomplete platelet inhibition influences maximum clot firmness (MCF) of FFPAs. We compared the ability of existing and newly developed FFPAs to eliminate the platelet contribution to clot strength.MCF of whole blood (WB), platelet-rich plasma (PRP), and platelet-poor plasma samples was recorded using a ROTEM device with different FFPAs, including the TEG functional fibrinogen test (FFTEG) and different ROTEM-based assays: the standard fib-tem reagent (FIBTEM), a lyophilized single-portion reagent fib-tem S (FIBTEM-S), a newly developed reagent FIBTEM PLUS, as well as FIBTEM or the standard extrinsic activation reagent ex-tem® (EXTEM) combined with 10-μg abciximab (FIBTEM-ABC/EXTEM-ABC).In WB (platelet count [mean ± SD], 183 ± 37 × 10/μL; plasma fibrinogen concentration, 2.49 ± 0.58 g/L), FFTEG and EXTEM-ABC showed higher MCF (15.7 ± 2.8 mm) than FIBTEM or FIBTEM-S (11.4 ± 3.3 mm, P0.001), whereas FIBTEM-ABC and FIBTEM PLUS resulted in lower MCF (9.3 ± 2.8 mm, P0.001). In 2 different PRP samples, with platelet counts of 407 ± 80 × 10/μL and 609 ± 127 × 10/μL, FIBTEM-ABC and FIBTEM PLUS reduced platelet contribution to clot strength within 95% confidence interval limits of -1.4 to 0.1 mm and -1.2 to 0.4 mm, respectively. Using all FFPAs it was observed that the Pearson correlation coefficient between plasma fibrinogen concentration and WB MCF was high (range, 0.75-0.93) and significant, regardless of the underlying platelet inhibiting component. Evaluating differences in the interception of regression lines by using analysis of covariance, we compared platelet-poor plasma and both PRP samples within the same assays and found that in contrast to the FIBTEM-ABC and FIBTEM PLUS assays, the FFTEG, EXTEM-ABC, FIBTEM, and FIBTEM-S methods still detected residual platelet activity and grossly overestimated fibrin clot strength in samples with high platelet counts.FFPAs based solely on glycoprotein-IIb/IIIa inhibition, such as FFTEG or EXTEM-ABC, are less effective than cytochalasin D-based assays, such as FIBTEM or FIBTEM-S, at inhibiting the platelet component of clot strength. The FIBTEM PLUS assay, and the combination of FIBTEM and abciximab, sufficiently inhibits platelet contribution to clot elasticity. The combination of a glycoprotein-IIb/IIIa receptor blocker and cytochalasin D allows evaluation of functional fibrinogen polymerization without platelet "noise." In a clinical setting, the significance of potent platelet inhibition ensures a more accurate assessment of MCF and therefore the need for fibrinogen supplementation therapy. Further studies are necessary to investigate the application and impact of these tests in a clinical situation.

SummaryPlasma fibrinogen concentration is important for coagulopathy assessment, and is most commonly measured using the Clauss method. Several factors, including device type and reagent, have been shown to affect results. The study objective was to evaluate performance and repeatability of the Clauss method and to assess differences between measurements performed during and after cardiopulmonary bypass (CPB), by testing plasma samples from patients undergoing cardiac surgery with CPB. Samples were collected from 30 patients before surgery, approximately 20 minutes before weaning from CPB, and 5 minutes after CPB and protamine. Fibrinogen concentration was determined using the Clauss method at six quality-controlled specialised laboratories, according to accredited standard operating procedures. Regarding within-centre agreement for Clauss measurement, mean differences between duplicate measurements were between 0.00 g/l and 0.15 g/l, with intervals for 95% limits of agreement for mean Bland-Altman differences up to 1.3 g/l. Regarding between-centre agreement, some mean differences between pairs of centres were above 0.5 g/l. Differences of up to ∼2 g/l were observed with individual samples. Increased variability was observed between centres, with inter-class correlation values below 0.5 suggesting only fair agreement. There were no significant differences in fibrinogen concentration before weaning from CPB and after CPB for most centres and methods. In conclusion, considerable differences exist between Clauss-based plasma fibrinogen measured using different detection methods. Nevertheless, the similarity between measurements shortly before weaning from CPB and after CPB within centres suggests that on-pump measurements could provide an early estimation of fibrinogen deficit after CPB and thus guidance for haemostatic therapy.

The viscoelastic functional fibrinogen (FF) and FIBTEM assays measure the contribution of fibrin to clot strength. Inhibition of platelet function is a necessary precondition for these tests to work. We investigated a novel test for measuring fibrin-based clotting, FIBTEM PLUS, in cardiac surgery and compared it with FF and FIBTEM.A prospective, observational study was performed which included 30 patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Blood samples were drawn at the beginning of surgery (pre-CPB), approximately 20 minutes before weaning from CPB and 5 minutes after heparin neutralization. FF, FIBTEM, and FIBTEM PLUS tests were performed in duplicate for all blood samples. Additional coagulation parameters, including platelet count, plasma fibrinogen levels, factor XIII activity, and heparin concentration, were also recorded for each sample.At all time points, the lowest mean maximum clot firmness (MCF) was observed with FIBTEM PLUS, although a statistically significant difference between FIBTEM and FIBTEM PLUS was observed only at baseline (mean values 22 vs 19 mm, P = 0.01; FF value for comparison: 27.7 mm). FF maximum amplitude (MA) values were significantly higher than FIBTEM MCF and FIBTEM PLUS MCF pre-CPB, during CPB and after heparin neutralization (P ≤ 0.001 for FF MA versus FIBTEM MCF and for FF MA versus FIBTEM PLUS MCF at all time points). The difference between FIBTEM MCF and FIBTEM PLUS MCF correlated with platelet count (r = 0.46;P0.001), whereas differences between FF MA and FIBTEM MCF, or FF MA and FIBTEM PLUS MCF did not (r = -0.07, P = 0.51; r = 0.16, P = 0.12, respectively). Differences between the assays were unrelated to heparin levels, which decreased considerably after protamine administration compared with heparin levels recorded before weaning from CPB (decrease from 2.1 to 0.1 U/mL and from 2.8 to 0.2 U/mL for anti-factor IIa and anti-factor Xa, respectively). Agreement between duplicate measurements was similar with FIBTEM and FIBTEM PLUS assays and lower with FF. Significant positive correlations were found between MCF or MA and fibrinogen concentration (all P0.001); the highest correlation was with FIBTEM PLUS MCF (r = 0.70).The FIBTEM PLUS assay produces precise results. At baseline, it provides greater inhibition of platelets than FIBTEM, but there is no meaningful difference between FIBTEM PLUS and FIBTEM in patients with low platelet counts.

Hemorrhage remains one of the leading causes of trauma-related deaths. Uncontrolled diffuse microvascular bleeding in the course of initial care is common, potentially resulting in exsanguination. Early and aggressive hemostatic intervention increases survival and reduces the incidence of massive transfusion. Thus, timely diagnosis of the underlying coagulation disorders is mandatory. It has been shown that standard coagulation tests do not sufficiently characterize trauma-induced coagulopathy (TIC). This has led to increasing interest in alternatives, such as the viscoelastic test, to diagnose TIC and to provide the basis for a goal-directed hemostatic therapy. The concept of damage control resuscitation (DCR) has been introduced widely in trauma patients with severe bleeding. This strategy addresses important confounders of the coagulation process such as hemodilution, hypothermia, and acidosis; DCR is based on a damage control surgical approach, permissive hypotension, and improvement of hemostatic competence. Many studies have shown benefit in mortality when using high ratios of fresh frozen plasma (FFP) to red blood cells (RBC) as early treatment. However, there is increased awareness that coagulation factor concentrate could be beneficial in the treatment of trauma-induced coagulopathy.

SummaryFibrinogen plays an essential role in clot formation and stability. Importantly it seems to be the most vulnerable coagulation factor, reaching critical levels earlier than the others during the course of severe injury. A variety of causes of fibrinogen depletion in major trauma have been identified, such as blood loss, dilution, consumption, hyperfibrinolysis, hypothermia and acidosis. Low concentrations of fibrinogen are associated with an increased risk of diffuse microvascular bleeding. Therefore, repeated measurements of plasma fibrinogen concentration are strongly recommended in trauma patients with major bleeding. Recent guidelines recommend maintaining plasma fibrinogen concentration at 1.5–2 g/l in coagulopathic patients. It has been shown that early fibrinogen substitution is associated with improved outcome.

Purpose of review Diagnosis and treatment of trauma-induced coagulopathy (TIC) presents a challenge for trauma care providers. Viscoelastic tests (VETs) including thromboelastometry and thrombelastography are increasingly used to diagnose TIC and guide hemostatic therapy. We summarize the concept of individualized, goal-directed coagulation management using coagulation factor concentrates. Recent findings Early and aggressive treatment is mandatory to improve the survival of severely bleeding trauma patients. High ratios of fresh frozen plasma to red blood cells are linked to improved outcome in coagulopathic patients; however, treatment is often delayed because most blood products must first be thawed. Lyophilized plasma potentially overcomes these problems. However, until now only limited data on the use of lyophilized plasma in major trauma are available. VETs provide a rapid and comprehensive overview of the coagulation process. Low maximum clot firmness is associated with increased transfusion requirements, and premature lysis of the clot is indicative of poor outcome. Improvement in clot firmness can be achieved by the administration of fibrinogen concentrate or platelet concentrate, depending on the cause of coagulopathy. Early administration of tranexamic acid improves clot stability and outcome in major trauma. Prothrombin complex concentrate increases thrombin generation, but is potentially associated with increased risk of thromboembolic complications. Summary VETs are useful in the diagnosis of TIC, allowing precise deficits in the coagulation process to be identified and specifically targeted with coagulation factor concentrates.