Objectives of the new Austrian guidelines for trauma-related bleeding management include the restriction of allogeneic blood products, consideration of the cell-based model of haemostasis, the use of point-of-care coagulation monitoring and of effective coagulation factor concentrates. E.g., measurement and correction of fibrinogen concentration < 1,5-2 g/l and/or diminished fibrin polymerization in the thrombelastometric FIBTEM assay is recommended in bleeding trauma patients. If FFP is used in massive coagulopathic bleeding about 30 ml/kg BW is required.

The use of coagulation factors concentrate for haemostatic therapy is encouraged for several reasons: transfusion of allogeneic blood products is associated with a number of adverse events; allogeneic blood products such as FFP lack efficacy in the correction of coagulation abnormalities; in vivo haemodilution decreases the concentration of fibrinogen, FII, FVII, and FXIII more than predicted by the degree of haemodilution. Prothrombin complex concentrate represents the state of the art in the acute reversal of vitamin K antagonist therapy. Fibrinogen concentrate has been shown to correct reduced clot firmness induced by haemodilution and to reduce transfusion requirements. Intraoperative administration of FXIII has been shown to improve clot firmness and reduce blood loss.

Recombinant activated factor VII has a licensed indication in haemophilia with inhibiting antibodies and Glanzmann's disease. Despite controversial study results, national and international guidelines for trauma-related bleeding management recommend off-label administration of recombinant activated factor VII in persisting bleeding (grade 2C) only after preconditioning of the patient with adequate fibrinogen, platelet concentrates and acidosis correction. Thrombotic events are a potential complication of recombinant activated factor VII.

A large proportion of severely traumatized patients are coagulopathic on arrival in the emergency room. The ratio of FFP:RBC administered for the treatment of bleeding in trauma patients may have an impact on survival, but the optimal ratio is unknown. Fibrinogen plays an important role in the management of trauma coagulopathic bleeding, because severe tissue trauma leads to a substantial consumption of fibrinogen. It has been shown that a high ratio of fibrinogen:RBC improves the survival of trauma patients. Application of a ROTEM-based coagulation management concept using fibrinogen concentrate and prothrombin complex concentrate may reduce transfusion and may have a positive effect on survival.

The aim of guidelines is to ensure the appropriate use of blood and blood components in the management of the bleeding patient, to identify the most appropriate blood components to treat coagulopathy, and to provide an indication of when treatment is required. Transfusion triggers for red blood cells, platelet concentrates, fresh frozen plasma, coagulation factor concentrates, and antifibrinolytics vary between guidelines and there is large variation in their application. The long turnaround time of standard coagulation analyses may impair the application of guidelines. Much of current perioperative transfusion practice is empirical. Many transfusions are inappropriate and unnecessary. Failure to identify the nature of the coagulopathy leads to increased transfusion of blood products.

Guidelines for the application of thromboelastometry in the clinical context should be based on knowledge gained from evidence-based medicine. A strategy of coagulation management based on an array of specific thromboelastometric tests to identify and treat individual coagulation disturbances has shown a substantial reduction in the transfusion of allogeneic blood products, in contrast to a strategy based on a single thrombelastographic test, which resulted in an increase in transfusion. Application of any algorithm should aim at reducing mortality, reducing the unnecessary use of allogeneic blood products, supporting a rational haemostatic intervention, optimizing health economics, and improving medical practice. Specific algorithms for cardiac surgery, non-cardiac surgery, and trauma have been developed with these aims in mid.

The key molecule of fibrinolysis is plasmin, with plasminogen as the precursor. Plasmin has the following functions: it cleaves fibrin and fibrinogen, resulting in the release of their degradation products, and it reduces platelet adhesion and aggregation by degradation of GP Ib and GP IIbIIIa. The main fibrinolysis activators are t-PA (tissue plasminogen activator) and u-Pa (urokinase plasminogen activator). The main fibrinolysis inhibitors are TAFI (thrombin-activated fibrinolysis inhibitor), PAI-1, and alpha2-antiplasmin. The risk factors for hyperfibinolysis include: hypoxia, trauma or surgery of organs containing t-PA, liver transplantation, extracorporeal circulation, hypo/hyperthermia, and iatrogenic factors such as fibrinolytic therapy, and SD plasma.

In recent years, it has become evident that RBC, FFP, and platelet transfusions are associated with a major adverse outcome, including increased mortality, major morbidity, risk of infection, TRALI, TACO, and so on. These findings have been obtained in different settings, such as cardiac surgery, trauma, liver transplantation, intensive care medicine, and orthopaedic surgery. Also, the costs associated with transfusion are higher than expected, because there are hidden costs which can only be identified by means of thorough process cost analysis. Patient blood management is a concept that includes the correction of preoperative anaemia, reduction in perioperative blood loss, and the optimization of anaemia management.

Thromboelastometry is a whole-blood point of care method of coagulation assessment with proven usefulness in the perioperative setting. Quality management for thromboelastometry includes: operational integrity of the instrument, internal quality assurance and external quality assurance. The following features contribute to operational integrity: measurement principle, very low inter-channel imprecision, automatic pipetting, constant verification, solid state temperature control, etc. The internal quality assurance depends on pre-analytical factors, regular functional check of the pipette, and regular use of internal control samples. External quality assurance is challenged by a lack of a standardized control material identical to the material used in clinical application (e.g. whole blood).

In the periperative setting, platelet diagnostics has following indications: positive bleeding history (inherited or acquired platelet defect; antiplatelet medication); extracorporeal circulation; unclear intra-/postoperative bleeding (after normal first-level tests; in the presence of factors that affect platelet function, e.g. colloids). New POC methods for platelet function assessment are available: Multiplate® (sensitive to COX-1 inhibitors and ADP-receptor antagonists; predictive of bleeding in cardiac surgery); PFA-100TM and Ultegra (sensitive to COX-1 inhibitors and GPIIbIIIa inhibitors); PlateletMapping Assay® (sensitive to COX-1 inhibitors and ADP-receptor antagonists). Following perioperative haemostatic interventions may be considered for improving platelet function: platelet concentrates, DDAVP, rFVIIa, fibrinogen concentrate, and antifibrinolytics.

Transfusion of allogeneic blood products is associated with adverse effects, adverse outcome, questionable efficacy and high costs. The main adverse effects include: acute reactions, AB0 mistransfusions, transmission of infectious diseases, immunosuppression resulting in increased cancer recurrence and increased postoperative infections, transfusion-related acute lung injury TRALI and transfusion-related circulatory overload TACO. TRALI, defined as non-cardiogenic pulmonary edema, hypoxemia, onset within 6h or transfusion and symptoms that include dyspnea, fever, tachycardia and hypotension, represents the leading cause of transfusion-associated mortality. The adverse effect on outcome is represented by an increase in mortality and major morbidity, observed in various settings like intensive care unit, cardiology and cardiac surgery.

Perioperative bleeding is a feared complication of surgery. The golden standard of preoperative coagulation screening includes prothrombin time PT, activated partial thromboplastin time aPTT, and platelet count. As preoperative PT and aPTT do not provide additional information to the bleeding history, do not predict bleeding and do not appear cost-effective, for surgical interventions like tonsillectomy the bleeding history may be more relevant than the standard coagulation screening. A practical concept for the preoperative identification of patients with impaired primary haemostasis based mainly on a standardized questionnaire has been developed. The concept ensured the satisfactory detection of impaired haemostasis and was associated with a significant costs reduction.

For the therapy of major bleeding in cardiac surgery, following aspects are of importance: haemostatic therapy is performed at the end of cardio-pulmonary bypass (CPB); haemostasis needs to occur fast; thromboembolic complications need to be avoided. Efficacious haemostasis requires sufficient thrombin generation and sufficient coagulation substrate, while the avoidance of thrombotic complications requires sufficient antithrombin activity. The fibrinogen deficit observed after long CPB may be corrected by administration of fibrinogen concentrate. This therapeutic approach has been shown to reduce transfusion of allogeneic blood products in aortic surgery. Fibrin is known as antithrombin I because it acts by sequestering thrombin in the clot; therefore, sufficient fibrin formation may also help avoid thrombotic complications.

In the recent years, the traditional Y-shaped cascade coagulation model has been replaced by a cell-based (C-based) coagulation model. The C-based model emphasizes the roles played by tissue factor-bearing cells and by platelets. In this model, initial formation of a small amount of thrombin is generated by the binding of circulating activated FVII to tissue factor at the injury site/on the surface of tissue factor bearing cells (initiation phase). Thrombin activates FVIII, FV and circulating platelets (amplification phase). Finally, the formation of a high amount of thrombin occurs on the surface of the activated platelets (propagation phase), and transformation of fibrinogen into fibrin occurs.

Since whole blood clot formation is not quantified by the standard coagulation tests, methods like thrombelastography/thromboelastometry have been developed for the concomitant assessment of many aspects of coagulation, including the effects of platelets, fibrinogen and FXIII, coagulation factors and fibrinolysis. Thromboelastometry (ROTEM) measures coagulation by registering the viscoelastic changes of the blood pipetted into a fixed cup in which a rotating plastic pin is immersed. Use of thrombelastography/thromboelastometry in various settings like ICU, trauma surgery, and cardiac surgery has been associated with a reduction of allogeneic blood products transfusion and of the associated costs. For the adequate application of these methods, a quality management system appears necessary.

Thrombin generation may be considered to represent "the momentum" of the haemostatic system. Thrombin activates FVIII to FVIIIa (component of the "intrinsic tenase"), FV to FVa (component of the "prothrombinase") and circulating platelets. The lag time of thrombin generation is primarily defined by levels of free tissue factor, tissue factor pathway inhibitor, free protein S, FVII, FIX and fibrinogen. Prothrombin appears to be one of the most important determinants of the thrombin potential. Direct quantification of thrombin generation is possible through continuous fluorometry and through subsampling and measurement of TAT-complexes. Furthermore, thromboelastometry may constitute a surrogate measure of thrombin generation.

Fibrinolysis results into the destruction of the blood clot, but it also plays an important role in vessel wound repair and remodeling and in angiogenesis. The main fibrinolytic enzyme is represented by plasmin; its formation from the precursor plasminogen is induced by t-PA and pro-urokinase/urokinase. The fibrinolytic process is controlled by PAI1 (t-PA inhibitor) and by alpha2-antiplasmin (plasmin inhibitor). The presence of D-dimers in circulation reflects the formation of the fibrin network and its degradation by plasmin. For the diagnosis of hyperfibrinolisis, following main tests may be considered: Eugobulin Lysis Time, D-Dimers, and thromboelastometry ROTEM (APTEM test).

In the medical setting, surgery remains the most common cause of major bleeding. The pro-haemostatic interventions are aimed at correcting the coagulopathy while avoiding the risk of thrombosis. The pro-haemostatic drugs may intervene at different levels of the haemostatic system. Improvement of primary haemostasis may be achieved by administering DDAVP that causes release of von Willebrand factor multimers. Anti-fibrinolytic agents like lysine analogues act on the precursor of plasmin and may correct the hyperfibrinolytic tendency and consequently decrease bleeding and transfusion requirements. Stimulation of thrombin generation may be obtained with rFVIIa for congenital bleeding disorders like haemophilia.

TRALI was first described in 1950 as severe illness with immediate faintness, chills, fever, hypotension, severe tachypnoea and dyspnoea that followed the injection of 50ml of plasma. The mechanism of TRALI involves donor antibodies reacting with recipient leukocytes that aggregate in pulmonary capillaries, and secrete cytokines and chemokines damaging the endothelial cells. Alternative mechanism: anti-class I antibodies bind to endothelial cells, and neutrophils bind to the antibodies via Fc receptors. TRALI is an important cause of pulmonary injury or death in transfused patients. Possible solutions to avoid/decrease TRALI include: reduction of plasma, use of pooled viricidally-treated plasma, antibody screening of donors, and transfusion of FFP obtained only from male donors.

Although anticoagulant therapy has become very common, the management of anticoagulation is still problematic. Adherence to the management guidelines is limited and the therapy-related haemorrhagic events may be underestimated. Vitamin K antagonists decrease the risk of thrombotic events in patients with cardiac valves, auricular fibrillation, phlebitis and pulmonary embolism. Anticoagulation reversal is indicated in patients with life-threatening bleeding. Once the diagnosis is confirmed, administration of haemostatic agents that contain the four coagulation factors affected by the vitamin K antagonists (FII, FVII, FIX and FX) is necessary. Unlike fresh frozen plasma FFP, prothrombin complex concentrate PCC has shown ease of use, improved efficacy and promptness of anticoagulation reversal.

Administration of haemostatic medication in congenital and acquired bleeding disorders aims at preventing intra-operative and postoperative bleeding, and thus at promoting wound healing. In vivo recovery is defined as the relation between the increase in the concentration of individual coagulation factors after the administration of haemostatic therapy and the dose administered. Both FFP and PCC have been used to correct the coagulopathy of critical illness and liver disease, as well as prophylactically pre-procedures, and for treating bleeding in liver transplantation. The peripheral indices of coagulation (PT, aPTT, platelet count) may be unreliable for guiding bleeding therapy in this setting.

Prothrombin complex concentrates (PCC) are purified coagulation factor concentrates containing FII, FVII, FIX, FX, as well as proteins C, S and Z, antithrombin and heparin. PCC is effective in the rapid reversal of oral anticoagulation (Warfarin, Phenprocoumon, Marcoumar). PCC can be used for acute bleeding therapy in patients with severe liver damage or liver failure. In contrast to fresh frozen plasma (FFP), PCC may quickly increase coagulation factors concentration without the risk of volume overload (TACO), TRALI, viral transmission, or mistransfusion. Administration of PCC can be guided by coagulation measurements like ACT, PT, INR, Quick time, and thromboelastometry (ROTEM).

In cardiac surgery, platelets count is influenced by CPB duration, re-do, transfused cell-saver blood, etc. In other settings, haemodilution plays a major role, with fibrinogen concentration being the first to reach a critical level, while platelet count reaches a critical level much later on. Platelet concentrates transfusion should be avoided because of unpredictable efficacy, viral/bacterial infection, immunologic reactions. High fibrinogen concentration has proven protective of bleeding in obstetrics, cardiac/neurosurgery. In swine thrombocytopaenia model, fibrinogen concentrate showed significantly higher efficacy in improving clot quality that platelet concentrates. Fibrinogen concentrate may compensate low platelet count and help avoid platelet concentrates transfusion.

Haemodilution is part of a vicious circle initiated by blood loss that leads to hypovolemia requiring volume replacement. Correction of the volume leads to a decrease in haematocrit and to dilution coagulopathy. Haematocrit influences significantly platelets' adhesion and has an important impact on the bleeding time. Many in vitro studies showed that colloids (DEX>HES>GEL>Albumin) impair the thromboelastometry/graphy parameters more than crystalloids. Furthermore, with regard to HES, gelatin and crystalloids, fibrin polymerization appears to be the main problem. Clinical studies during blood loss have shown that the routine coagulation tests are poor predictors of bleeding and that the fibrinogen deficiency is the first to occur with ongoing bleeding.

The methods of assessment of coagulation need to address following aspects: primary haemostasis, thrombin generation, clot formation and clot lysis. Thromboelastometry ROTEM is a whole blood method used to obtain information on most of these aspects. It measures the changes in the amplitude of rotation of a pin immersed in a plastic cup containing the blood sample. The rotation is progressively impeded by the fibrin strands forming between the cup and the pin. The method assesses the rapidity of initiation of fibrin formation, the dynamic interaction between platelets and fibrinogen, as well as the stability of the blood clot.

Uncontrolled haemorrhage is the leading cause of death in trauma patients. Acute traumatic coagulopathy may be detected upon admission in the ER. It reflects the severity of the tissue damage, it is not related to fluid administration and it has a prognostic value for the patient's survival. Acute traumatic coagulopathy is the result of bleeding, dilution, consumption, (hyper)fibrinolysis, acidosis and hypothermia. Standard coagulation tests do not appear advantageous for coagulation monitoring in trauma patients because they are too time consuming and reflect too little of the trauma coagulopathy. In contrast, viscoelastic methods like thromboelastometry ROTEM provide fast clinically relevant information on this complex blood clotting disorder.

In the management of perioperative bleeding specific challenges are raised: identifying whether the source of bleeding is surgical or coagulopathic, using the correct coagulation tests to identify fast and correctly the coagulation disturbance, tailoring the optimal haemostatic intervention according to the patient's acute needs. The standard coagulation analyses include ACT, APTT, INR, fibrinogen, and platelet count. Continuous thrombin generation analyses include measurement of thrombin generation in plasma and in platelet-rich plasma, while thrombelastography is used for continuous whole blood coagulation measurement. For all these methods, the advantages and the disadvantages need to be weighed separately.