Introduction
Trauma remains one of the leading causes of morbidity and mortality, and injuries are responsible for ~ 5.8 million deaths annually, accounting for ~ 10% of deaths worldwide [
1,
2]. Massive bleeding in traumatic injury represents a substantial problem, and is a major cause of potentially preventable deaths [
3‐
5].
Trauma-induced coagulopathy (TIC) is present in approximately 24–34% of hospitalised patients with trauma [
6,
7]. It comprises an endogenous impairment of haemostasis that occurs early after injury [
7]. Failure to form haemostatic clots leads to coagulopathic bleeding, with diffuse phenotypes involving uninjured sites, and is difficult to stop with mechanical interventions [
8]. The causes of TIC are multifactorial, with key drivers including shock, acidosis, endotheliopathy, and consumption/loss of coagulation factors (e.g. due to haemodilution) [
8‐
12]. TIC is associated with increased mortality, transfusion requirements and multiple-organ failure [
6,
9,
13]. While progress has been made on understanding the causes of TIC, it continues to present a significant clinical challenge, and a clinically relevant, uniformly accepted definition for TIC is lacking [
8,
9].
This review focuses on treatments for TIC, which require different treatment strategies to those for other bleeding situations such as during surgery, that may require mechanical interventions [
14]. Current TIC treatment options include tranexamic acid (TXA), fresh frozen plasma (FFP), cryoprecipitate and coagulation factor concentrates (CFCs) [
10]. CFCs, including prothrombin complex concentrates (PCCs) and human fibrinogen concentrate (FCH), have several benefits over FFP in that they deliver a standardised and higher concentration of coagulation proteins, and are associated with a low risk of virus transmission and transfusion-related side effects, such as acute respiratory distress syndrome, sepsis and multiple organ failure. Furthermore, they are immediately available without requiring blood group testing [
15,
16]. CFCs can be used for goal-directed therapy, an individualised point-of-care (POC) approach, using viscoelastic tests to elucidate potential haemostatic deficiencies [
17]. The use of CFCs for the management of TIC has recently shifted into research focus; for example, several studies have documented a benefit with FCH, including lower mortality and/or reduced transfusion requirements, versus FFP/no fibrinogen supplementation [
18‐
20]. However, a meta-analysis of seven RCTs found no beneficial effect on in-hospital mortality with FCH versus controls. Although data on FCH use in trauma are limited and of poor quality; most studies were retrospective, with varied endpoints [
21]. Therefore, the beneficial effects of FCH on mortality still need to be elucidated.
Clinical strategies for TIC management, including the use of CFCs, are heterogeneous [
22]. In Europe, four-factor PCCs are indicated for the reversal of vitamin K antagonists (VKAs), and in acquired deficiency of prothrombin complex coagulation factors, e.g. in trauma [
23]. FCH is indicated for the treatment of acquired hypofibrinogenaemia across Europe, though in many countries, the indication is restricted to acquired hypofibrinogenaemia during surgical intervention [
24,
25]. Guidelines for the management of bleeding have been published both Europe-wide [
10] and locally [
26‐
31]; however, national guideline recommendations for haemostatic management (for example, the use of CFCs and FFP) differ between countries, as do the availability and licensing of the products; therefore, there is a need to streamline clinical pathways to facilitate consistent and effective management.
The aims of this review are 1) to summarise recommendations from the available European trauma guidelines, with a focus on the use of CFCs (mainly FCH), highlighting the differences between the European versus local guidelines; 2) to provide a simple definition of TIC and the criteria for initiation of a massive trauma protocol (MTP), that can be easily interpreted in clinical practice; and 3) to identify gaps in the guidelines that impact on their application in daily clinical practice, as well as the barriers to effective CFC administration, while providing practical guidance and recommendations on how these challenges may be overcome.
Methods
An advisory board was held on 2 February 2019, titled ‘The role of coagulation factor concentrates in the management of major trauma bleeding across Europe: an EU advisory board.’ The advisors, all experts in the fields of trauma and critical care medicine, discussed their clinical experience with CFCs (mainly FCH) in the management of trauma-related bleeding. The clinical application of the current European and local guidelines on trauma management was discussed. Evidence to support the use of CFCs in TIC, along with barriers to CFC use were also highlighted, with suggestions on how these barriers may be overcome.
A comprehensive literature search was conducted for articles on, or prior to, 19 April 2018, to identify guidelines and recommendations for fibrinogen supplementation and POC testing in the trauma setting, to support expert discussions. Google and PubMed searches were conducted using the search terms: ‘trauma bleeding guidelines,’ ‘trauma guidelines coagulation’ and ‘trauma management guidelines;’ country-specific terms were also added to identify local publications. The searches focused on the latest European guidelines published in English, supplemented with local European guidelines (as suggested by the advisors).
Overview of published European guidelines for major bleeding and coagulopathy following trauma
The literature search identified the fifth edition of the European guidelines for major bleeding and coagulopathy following trauma (published in 2019) [
10], and several local trauma and bleeding management guidelines, including those from the Czech and Slovak Republic [
31], Sweden [
32], Germany [
26], Spain [
27,
28] and the United Kingdom [
30,
33] (Table
1).
Table 1
Summary of European guidelines for the treatment of trauma-induced coagulopathy
Europe: The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition [ 10] | Initial management of expected massive haemorrhage: FFP (or pathogen-inactivated FFP) (1C) or FCH (1C), with RBC FCH or cryoprecipitate for major bleeding with viscoelastic signs of fibrinogen deficit or a plasma fibrinogen level ≤ 1.5 g/L (1C) Initial FCH dose of 3–4 g is suggested; repeat doses guided by viscoelastic monitoring and fibrinogen laboratory tests (2C) Avoid FFP for hypofibrinogenaemia (1C) | PCC is recommended if fibrinogen levels are normal and viscoelastic monitoring indicates delayed coagulation initiation (2C) rFVIIa should be considered if major bleeding and coagulopathy continue despite all other attempts to control bleeding and best-practice use of conventional haemostatic measures (2C) | Yes |
Czech and Slovak Republic: Diagnosis and treatment of life-threatening bleeding in adult patients in intense and perioperative care (Czech-Slovak interdisciplinary recommended procedure) [ 31] | Initial treatment with FFP and ETP (1:2, 1B) or FCH and ETP (1C) at appropriate values/levels Initial dose of at least 50 mg/kg FCH (1C) FCH when fibrinogen level < 1.5–2 g/L or by equivalent by viscoelastic testing (1C) | To maintain fibrinogen level at 2 g/L PCC (25–50 U/kg) is recommended when coagulation factor deficit is assumed (2C); risk/benefit should be assessed rFVIIa (90–100 µg/kg) to be considered if all standard measures fail and there is still life-threatening bleeding | Yes |
Sweden: Hemostasis and severe bleeding: Care program prepared by The Swedish Society for Thrombosis and Hemostasis working group [ 32] | Early transfusion with plasma and erythrocytes (1:1) with platelet unit for every four units plasma/erythrocytes, if bleeding > 1–1.5 blood volume FCH (2–4 g) for > 1 blood volume | Subsequent fibrinogen supplementation based on viscoelastic testing; aim for fibrinogen level > 2 g/L and INR < 1.5 | Yes |
Germany: Level 3 guideline on the treatment of patients with severe/multiple injuries (Polytrauma Guideline Update Group) [ 26] | FFP is recommended for massive transfusion (4:4:1 FFP:pRBC:PLT ratio) FCH is recommended should a patient present with a fibrinogen level < 1.5 g/L (target fibrinogen level ≥ 1.5 g/L) PCC is recommended as a treatment option outside of VKA reversal if needed FXIII is also recommended if needed | N/A | Yes |
Spain: Spanish Consensus Statement on alternatives to allogeneic blood transfusion: the 2013 update of the "Seville Document" [ 27] | Early PCC administration is recommended in non-VKA-treated patients presenting with coagulopathy FCH should be given if plasma fibrinogen < 2 g/L rFVIIa is recommended for severe refractory haemorrhge | N/A | Yes |
Spain: Multidisciplinary consensus document on the management of massive haemorrhage (HEMOMAS document) [ 28] | FFP should be administered early for massive haemorrhage FCH should be given if plasma fibrinogen < 2 g/L rFVIIa is not recommended as a first-level option for massive haemorrhage | PCC is only recommended in non-VKA-treated patients if there is a risk of TACO or TRALI, or depending on the urgency of treatment and availability of FFP | Yes |
UK: A practical guideline for the haematological management of major haemorrhage (British Society of Haematology) [ 30] | Present or expected massive haemorrhage: 1:1 ratio of FFP:RBC (1B*) Further FFP should be guided by laboratory tests with a transfusion trigger of PT and/or aPTT > 1.5 times normal (2C) If laboratory results are unavailable and bleeding continues: FFP and RBC in at least 1:2 ratio, before switching to blood product use guided by laboratory results (2C) Use of FFP should not delay fibrinogen supplementation if it is required (2C) Fibrinogen levels < 1.5 g/L: cryoprecipitate (2 pools) (1C) | PCC and rFVIIa are not recommended for major haemorrhage unless as part of a clinical trial (1D) | No |
UK: Blood transfusion and the anaesthetist: management of massive haemorrhage (Association of Anaesthetists of Great Britain and Ireland | Early infusion of FFP (15 mL/kg) Established coagulopathy (widespread microvascular oozing or inadequate haemostasis) indicated by fibrinogen < 1 g/L or PT/aPTT > 1.5 × normal): FFP at doses likely to correct coagulation factor deficiencies (≥ 30 mL/kg) Hypofibrinogenaemia unresponsive to FFP: cryoprecipitate is often recommended, but FCH (30–60 mg/kg) can achieve fibrinogen replacement more rapidly and predictably PCC and intravenous vitamin K (5–10 mg) for warfarin reversal | Some centres use PCC in certain clinical situations, such as liver disease and post-CPB; local protocols must be agreed in advance rFVIIa has been used for massive haemorrhage unresponsive to conventional therapy, but there may be a risk of arterial thrombotic complications; local protocols must be agreed in advance | No |
For initial treatment of bleeding, the guidelines generally agree on the administration of TXA as soon as possible [
10,
26‐
32], followed by an initial ratio-driven approach of FFP:red blood cells (RBC) or FCH:RBC to prevent/treat massive haemorrhage [
10,
26,
30‐
32]. All European guidelines recommend fibrinogen supplementation with either FCH or cryoprecipitate when fibrinogen levels are low [
10,
26‐
32], though the threshold fibrinogen level varies. The use of PCC for treatment of TIC in non-VKA-treated patients also varies between guidelines [
10,
26‐
32], while activated recombinant factor VII (rFVIIa) is not recommended as a first-line therapy (Table
1).
Conclusions
The management of TIC remains challenging, with a high degree of variability in recommendations for the treatment of patients with major trauma bleeding in local and supranational guidelines. Indeed, the development and implementation of guidance can be challenging in some countries, and the lack of a clear definition of TIC may hinder the administration of effective treatment. Our suggestion for a simple definition of TIC may be helpful to both trigger and guide the initiation of haemostatic therapy.
CFCs, particularly FCH, play a major role in the early management of trauma, but the evidence base needs to be strengthened. A number of initiatives may improve TIC management. Better medical education is of major importance, as well as the generation of new and stronger data and improved access to viscoelastic testing. The key take-home messages are that TIC should be considered early in all major trauma bleeding patients, and when following protocols, the best practice is to be proactive and preventative; however, this can be difficult to justify from a cost perspective. Addressing these issues may help to contribute to the ultimate goal of improving patient care.
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