Abstract:Introduction: used.Methods: This systematic review reviews different upcoming

Abstract:Introduction:  Trauma-induced coagulopathy (TIC) is one of the most preventable causes of death in severe trauma patients.  Nowadays, TIC is mainly treated with allogeneic blood product transfusions but the optimal therapy is not known. However, new and promising interventions are more and more used.Methods: This systematic review reviews different upcoming strategies for trauma-induced coagulopathy management.  A formal systematic review of literature was performed in 3-4 weeks. Results: Two relevant studies about Freeze dried plasma, and nine relevant studies about fibrinogen concentrate and Prothrombin complex were identified. Only one Randomised controlled trial,  three case reports,  five retrospective observational cohort studies, and one observational prospective cohort in human patients were included. One randomized controlled study in New Zealand white rabbits was included. In the studies, patient populations were considered heterogeneous. But between studies, heterogeneity differs. Observations from the included studies suggest that the use of Fibrinogen, Prothrombin complex and Freeze dried plasma reduce transfusion with allogeneic blood products and also reduce mortality. Conclusion: Big randomised controlled trials, but also smaller studies about fibrinogen, PCC and FDF are rare. But as the results of the studies reviewed are favourable, these controlled trials seriously need to be considered to clarify the safety, effects and feasibility of the new approaches in treatment of TIC. IntroductionTrauma-induced coagulopathy (TIC) is a condition which occurs frequently in severe trauma patients. TIC results from massive haemorrhage, dilution and increased fibrinolytic activity. This coagulopathy  is one of the most preventable causes of death.  Therefore, immediate and effective correction of TIC (and the causes of TIC) is needed.  European guidelines for the treatment of TIC recommend restoration of circulating volume and intervention to control bleeding, followed by therapy with blood products and/ or Pharmacological agents to restore haemostasis. (Brenni, M et al. 2010).  Nowadays, Fresh frozen plasma (FFP) is recommended by most guidelines as first line treatment to restore lacking coagulation factors. However,  there are significant drawbacks of FFP and massive transfusion, as increased morbidity and mortality but also transfusion-related acute lung injury, transfusion-related immunosuppression and pathogen transmission. FFP transfusion is also associated with substantial time delays, for example,  because it has to be thawed. Therefore, minimising or avoiding exposure to allogeneic blood products is clearly desirable.Observational studies have suggested that the exclusive use of coagulation factors decreases transfusion requirements and might improve the outcome. (Innerhofer, P et al 2017)In this systematic review different upcoming options as Fibrinogen concentrate (FC), Prothrombin complex (PCC) and Freeze dried plasma (FDP) are discussed. In massive haemorrhage, Fibrinogen is the first coagulation factor to reach critical levels followed by a decrease in platelet count. (Brenni, M et al. 2010).  This results in diminished clot amplitude for example. Lately, different studies have shown that high levels of fibrinogen concentrate are not only effective at increasing clot strength, but also in compensating the reduced platelet levels and reducing the bleeding. An increase in fibrinogen levels also minimises requirements for transfusion of allogeneic blood products. Prothrombin complex  also fulfills an important role in this mechanism.  (Schöchl, H et al 2010). Where Fibrinogen can increase the maximum clot firmness, Prothrombin complex is able to reduce clotting time. (Schöchl, H et al. 2011).  In comparison with FFP, Fibrinogen can be administered in a few minutes. For these reasons, it is thought that administration of fibrinogen concentrates, whether or not in combination with Prothrombin complex concentrates, is a new, promising approach in the treatment of Trauma-induced coagulopathy. Another intervention with promising results which is increasingly studied, is Freeze dried plasma (FDP). It is used on the battlefield, where the use of blood products is limited, and recently FDP is also being used in a few civilian emergency care units in Sweden and norwegian. Freeze dried plasma is a powder. To prepare the powder for transfusion, one only has to dissolve the powder in 200 mL of sterile water.  This intervention too, is way faster than transfusion with FFP. Preparing the freeze dried plasma for transfusion will only take 3 till 6 minutes. (Sunde, G.A. et al 2015). FDP has a lot of advantages, but big randomised controlled studies lack and therefore little is known about the effects and feasibility of FDP in civilian emergency care units. This systematic review is written to clarify different, new and promising options in the treatment for TIC in civilian emergency care units. The main questions are whether the treatments are safe, feasible and affordable.  MethodsStudy question and inclusion criteriaThis systematic review was designed to summarize available information addressing the following research question: ”What is the effect of providing procoagulant factors in severe trauma patients, prehospitally” The Population of interest was trauma patients with severe haemorrhage and traumatic coagulopathy. The interventions of interest were treatment with Fibrinogen (factor I), prothrombin complex (cofact) and freeze dried plasma,  while the comparator was  fresh frozen plasma, the nowadays most used treatment. Primary outcomes of interest included positive findings with the interventions of interest as well as negative findings or no significant effect. It is also important that the interventions of interest are safe for the patient and that these interventions are possible to set in the emergency medical services. Pre-specified criteria were used to include and identify studiesInclusion criteriaResearch on fibrinogen, prothrombin complex or freeze dried plasmaStudies from different countriesArticles published in the last five  to ten yearsStudies with prehospital administration of procoagulant factorsStudies with severe trauma patients as patient populationIn vitro research Exclusion criteriaSystematic reviewsStudies published more than ten years ago Studies not published in the English languageLiterature searchIn this systematic review of literature, electronic database Pubmed was used to seek relevant published studies between 2007 and 2017.  the full literature search in Pubmed: Figure 1. The full literature search in database Pubmed. Study screening and selectionIn stage one the different searches were screened for duplicates. In the second stage, the studies were screened based on the title and the abstract and so on the inclusion and exclusion criteria. After the screening,  11 relevant studies were chosen for this systematic review. The results from this screening Process are presented in a PRISMA flow diagram in the Results section. ResultsThe literature search analysed 265 potentially relevant studies from the online databases. Because the searches were very similar, the stage one screening removed a lot of duplicates.  After the second screening only 17 articles were left out of the searches. After reading the full 17 articles, more articles were identified as not relevant and in the end only 11 articles fitted the in- and exclusion criteria. The remaining relevant studies are represented in Table 1. The flow chart of the search is represented in figure 1.  Fig. 2. Systematic review supplement: Prisma flow diagramThe selected studies were all published between 2007 and 2017. The majority of the studies, six in total, were performed in Austria. One study is a Case report from Afghanistan. The other studies were performed in the USA (2), Norway (1) and Switzerland (1). The Studies included are randomized-controlled trials, as observational retrospective studies as case reports. In most of the studies, the inclusion criteria were severe trauma patients with an Injury Severity Score (ISS) greater than 15. The Sample sizes of the studies were quit small also in the one randomised controlled trial where only 100, out of 292 screened patients were included. Article results Author (year)StudyStudy Population(s)MethodOutcomesInnerhofer, Petra et al. 2013(Innsbruck, austria)The exclusive use of coagulation factor concentrates enables reversal of coagulopathy and decreases transfusion rates in patients with major blunt trauma 144 patients with major blunt traumaObservational Prospective cohort study, investigating characteristics and treatment of TIC66 patients exclusively received CF78 patients received CF and additionally FFPThe CF-alone group showed sufficient haemostasis and received significantly fewer units of red blood cells (RBC) and platelets than did those in the CF with FFP group. Innerhofer, Petra et al. 2017(innsbruck, austria)Reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group, open label, randomised trial94 Trauma patients aged 18-80, with an Injury Severity Score (ISS) greater than 15 and with trauma-induced coagulopathyA single-centre, parallel-group, open-label, randomised trial to compare first-line use of FFP and CFC for treatment of coagulopathy and associated bleeding in major blunt trauma. 44 patients  treated with Fresh Frozen Plasma (FFP)50 patients treated with primarily Fibrinogen concentrates (CFC)P < 0,001The results show the importance of early and effective fibrinogen supplementation in severe trauma patients with TIC.Gellerfors, Mikael et al. 2015(Afghanistan/ sweden)Helicopter in-flight resuscitation with Freeze-dried plasma of a patient with a high-velocity gunshot wound to the neck in afghanistan - A case reportOne patient with a high velocity gunshot wound to the neck.A case report of Prehospital use of FDP in a patient with carotid artery injury.The patient became hemodynamically stable after administration of FDP. Hannon, Matthew et al. 2015(San diego, California)Fibrinogen and prothrombin complex concentratie in trauma coagulopathyNew zealand white rabbitsRandomised trial8  in fibrinogen group8 control group8 in  PCC group Median blood loss was highest in the fibrinogen group, at 122 mL, intermediate in the control group, at 35 mL and lowest in the PCC group, at 26 mL.Joseph, Bellal et al 2012(Tucson, Arizona)Factor IX complex for the correction of traumatic coagulopathy45  patients receiving  doses of PCCTherapeutic study, IIIA retrospective observational cohort analysis.Mean international normalized ratio (INR) was decreased after PCC administration in both nonwarfarin and warfarin subgroups (p= 0,001) Packed red blood cell transfusion was also reduced after PCC. Ponschab, Martin et al. 2015(Austria)Effect of coagulation factor concentrate administration on ROTEM parameters in major trauma96 patients in totalpatients receiving only FCpatients receiving FC and PCCpatients treated with PCC onlyRetrospective observational studyAdministration of FC alone of in combination with PCC resulted in a significant improvement of fibrin polymerisation. Meaning reducing clotting time and increasing clot amplitude. Schochl, Herbert et al. 20(austria)Goal-directed management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate131 trauma  patients who received > 5 units of red blood cell concentrate within 24 hours. 98 received fibrinogen concentrate and additionally PCC.3 only PCC12 received FFP29 received platelet concentrateRetrospective analysisThe observed mortality was 24,4%, that is  lower than the mortality predicted bt the trauma injury severity score TRISS mortality of 33,7%  (P= 0,032) and the revised injury severity classification. RISC mortality of 28,7 (P> 0,05)Sunde, G. A. et al. 2015(bergen, Norway)Freeze dried plasma and fresh red blood cells for civilian prehospital hemorrhagic shock resuscitation16 trauma patients A retrospective observational study.Use of FDP (LyoPlas N-w) in 16 (14) patients  during a 12 month period.The results show that FDP seems feasible and also may be safe and that logistical and safety issues for the implementation of RBC’s are solvable.  Schochl, Herbert et al. (salzburg, Austria)Transfusion in trauma: Thromboelastometry-guided coagulation factor concentrate-bases therapy versus standard fresh frozen plasma-based therapyTrauma patients aged 18-70 with ISS > 16A retrospective analysis80 patients received fibrinogen concentrate and/ or PCC.601 patients received only FFP (> 2 units).In the fibrinogen and / or PCC group 29% avoidance of RBC transfusion was observed. Platelet concentrate was administered in only 9%.In the FFP group  only 3% RBC transfusion avoidance was observed. Administration of platelet concentrate was 44%. Brenni, M et al. 2010(Zurisch, Switserland)Succesfull rotational thromboelastometry-guided treatment of traumatic haemorrhage, hyperfibrinolysis and coagulopathyOne patient with severe blunt abdominal trauma.Case reportThe use of ROTEM for detection of hyperfibrinolysis and guidance of treatment with antifibrinolytics and fibrinogen concentrate in severe blunt abdominal trauma was succesfull in this case. Schöchl, Herbert et al. 2010(austria)Use of rotation thromboelastometry (ROTEM) to achieve successful treatment of polytrauma with fibrinogen concentrate and prothrombin complex concentrateA trauma patient with a glascow coma scale of 13. after 12 units of red blood cells, two doses (4 and 5 g) of fibrinogen concentrate was performed to increase FIBTEM MCF to > 10 mmCase reportSuccessful treatment using both fibrinogen concentrate and prothrombin complex concentrate. The overall outcome was to show the potential success of the treatments. This implies whether these treatments can reduce transfusion with allogeneic blood products and if  they are able to restore haemostasis. Fibrinogen concentrate and Prothrombin complex concentrateThe RETIC study compared the efficacy of first-line therapy using fresh frozen plasma (FFP) to coagulation factor concentrates (CFC). This study, the only randomised controlled trial in human patients included,  was terminated early. This was because of the high proportions of patients,  23 patients (52%), in the FFP group, who required rescue therapy compared with 2 patients(4%) in the CF group. Also 13 (30%) in the FFP group needed massive transfusion compared with 6 (12%) in the CF group.  Multiple organ failure (MOF) occured in 29 (66%) in FFP group and in 25 (50%) in the CFC group. The study showed that first-line coagulation factor concentrates (CFC) is superior to Fresh frozen plasma.  This conclusion can be made because the sample size in this study is big enough. The other randomised controlled trial, used New Zealand white rabbits. This study showed that blood loss was significantly higher in the fibrinogen group compared with the control group and the PCC group, unlike the RETIC study. In this rabbit model, Fibrinogen increased blood loss and fluid requirements and PCC did not have a significant effect on blood loss. However, resuscitation fluid requirement was not significantly different among the three groups. The other six studies about Fibrinogen concentrate whether or not in combination with Prothrombin complex concentrate all show positive potential success of treatment with these factors. Not only can these factors restore haemostasis, it is also thought they can minimise requirements for transfusion of allogeneic blood products. The one study about Factor IX complex alone shows that PCC alone, also rapidly and effectively treats TIC after traumatic injury. Using factor IX leads to significant correction in international normalized ratio (INR) in all trauma patients and it minimizes transfusion with allogeneic blood products. Feasible and affordableThe costs of fibrinogen concentrate and Prothrombin complex will concern several hundreds of euro’s. These factors can be stored in room temperature, meaning no cooling system is required. These aspects make that fibrinogen and prothrombin complex seem to be feasible and affordable for civilian emergency department. However, the costs of these factors will depend on a number of factors, such as the tax and healthcare systems of the concerning country. Freeze dried Plasma (Lyoplas N-w)Two studies using Freeze dried plasma (FDF) were included. The type of FDF was Lyoplas N-w. Both studies on Freeze dried plasma showed promising outcomes.  Besides the contribution of FDP in stabilizing haemostasis, it may have several other potential advantages, these include easy reconstitution, good intravascular volume effect and coagulation factor content. Therefore these studies conclude that FDP seems feasible and may be safe for the use in prehospital resuscitation of major haemorrhage in civilian emergency units too.  Also, early administration of FDP may contribute to reduce TIC and acidosis, especially when administration of FDF is followed by a balanced transfusion of Red Blood cells (RBC), plasma and platelets.  As a result of the promising outcomes, FDP is carried in swedish civilian helicopter emergency medical systems since 2015. Feasible and affordableBesides the main question whether these treatments are safe in patients, two other important questions are taken into account. Whether the options are feasible and affordable. The Freeze dried Plasma used in the studies reviewed, is Lyoplas N-w. The Freeze-dried human blood plasma Lyoplas N-w is derived from a single donation. According to the German license, the shelf life is 15 months at  +2°C to +25°C.  Therefore, Lyoplas N-w can be stored in a refrigerator at room temperature. Wherefore no cooling systems or cooling bags have to be purchased. Lyoplas N-w is used in the same indications as Fresh frozen plasma is. An advantage of Lyoplas N-w compared to FFP is that it only takes a few minutes (3-6) to dissolve the Freeze-dried plasma in the supplied water, therefore saving timePreparing the Freeze-dried plasma for transfusion is also easy and instructions can be found in Appendix 1. Prices depend on the blood type and quantity one would like to order.  The prices can be found in Appendix 2.The costs of Lyoplas N-w and Lyoplas P were requested at the DRK-Blutspende Dienst west. Freeze dried plasma (Lyoplas N-w) is only licensed in Germany by the national authority for blood products (Paul Ehrlich institute).  Therefore, Prerequisites have to be considered in order to receive and use Lyoplas N-w in the VUmc, Amsterdam.  Import of Lyoplas N-w is probably depending on an import authorization. (DRK_Blutspende dienst west). DiscussionIn this systematic review, a systematic search of literature was performed to identify new interventions for TIC.  A total of eleven relevant studies was selected, and a total of 1210 patients participated in these studies. In the Rabbit study, 24 rabbits were included.  The sample sizes varied from one patient in a case report to 681 in a retrospective analysis. The studies reported several different outcomes, as a decrease in mortality, reduced number of allogeneic blood product transfusions and significant improvement of fibrin polymerisation for example. The patient populations in the studies were assumed to be heterogeneous. But the heterogeneity between the studies may differ.  It is clear that larger definitive studies need to be performed to confirm the positive results of all these small studies. All studies reviewed showed very positive and promising outcomes with in the treatment with fibrinogen, prothrombin concentrate or Freeze dried plasma.  The most important questions in this systematic review are: is the intervention safe? Does the intervention work and is it feasible? And last: Is it affordable for civilian hospital emergency departments.  Looking closely at the studies, few limitations are present. A few limitations on the studies reviewed in this systematic review arestudies are unicentrereddifferent evidence levelsdifferent study populationssmall sample sizesdifferent methods in using the interventiontherefore, the question also, is whether these studies are comparable.Advantages and disadvantages will now be discussed taking a closer look at all the aspects. Lyoplas N-w and Lyoplas PLyoplas N-w is at this moment in use for military and a few civilian purposes and shows promising results in the few available studies.  The lack of studies on Freeze dried plasma is one concern.  But the fact that freeze dried plasma is already being used in civilian hospital settings since 2015 makes it plausible that it actually is safe and feasible. Lyoplas has some contra-indications:Plasma protein intolerance Cardiac  decompensation, hypervolaemia, hyperhydration, pulmonary oedemaProven IgA insufficiency(DRK Blutspendedienst West)However, these contra-indications also apply in other transfusions, so this is not an actual problem. AdvantagesDisadvantagesfast and easy preparationExpensivecan be stored in room temperatureThere are only a few studies about FDP and no randomised controlled trialsShelf life of 15 monthsOnly licensed in Germany already being used in civilian hospitals Import opportunities depend on import authorizationGiven these aspects, Freeze dried plasma for the Emergency department in the Vumc Amsterdam has to be seriously considered. Fibrinogen concentrate and Prothrombin complex A lot of of research is done on Fibrinogen concentrate and prothrombin complex. This systematic review included 9 studies investigating the use of fibrinogen and PCC compared to only 2 studies about Freeze dried plasma.  However, Fibrinogen concentrate and Prothrombin complex do not necessarily have better outcomes. Despite the lack of big randomised controlled trials and not knowing the optimal dosage and timing of fibrinogen administration, several recent studies now point towards the true effectiveness of ealy fibrinogen administration in reversing requirement for post-operative transfusions.  (Brenni, M et al. 2009)Besides the positive outcomes, fibrinogen and PCC seem also feasible and affordable. These factors are expensive on it’s own, but can be stored at room temperature. Meaning advanced cooling systems are not required. Also the preparation and time to administer are much shorter than in Fresh frozen plasma because these factors do not need to be thawed. (Schochl, H et al 2011) showed that typical doses of fibrinogen concentrate and prothrombin complex can be administered in less than 10 minutes, and plasma levels of the coagulation factors administered rise rapidly after infusion.Tabel X. An overview of the advantages and disadvantages of FC and PCC compared to FFPAdvantagesDisadvantages Minimal risk of pathogen transmissionexpensive Faster administration because the factors are immediately availablenot demonstrated in randomised controlled trials Faster infusion because of high concentrates Can be stored in room temperatureno volume expansion the factors are already registeredStudy limitations There are few limitations regarding this systematic review. First, only Pubmed was used for the performed search. Finally, EMBASE and Google scholar were not used.  The interventions investigated in the studies are relatively new, especially Freeze dried plasma.  Besides, not every study was accessible for me as a student. ConclusionThe positive effects of Fibrinogen concentrate, Prothrombin complex and Freeze dried plasma are clear in small studies.  The interventions all seem to be feasible and affordable for the emergency department in Vumc Amsterdam. However, we do need randomised controlled trials big with sample sizes in multi centres to confirm these preliminary data of the interventions. If these bigger studies can prove  the safety and efficacy , this could mean important changes in the field.  Although, it is possible to conclude that the interventions are feasible and affordable at this moment. And after all, we must acknowledge that our current treatments on TIC seem questionable. That is another aspect why we seriously need to consider these new treatments in TIC