Update on the pathophysiology and management of acute trauma hemorrhage and trauma-induced coagulopathy based upon viscoelastic testing

Article information

Clin Exp Emerg Med. 2024;11(3):259-267

Publication date (electronic) : 2024 March 15

doi : https://doi.org/10.15441/ceem.24.202

Marc Maegele^,1,2

¹Department of Trauma and Orthopedic Surgery, Cologne-Merheim Medical Center (CMMC), Witten/Herdecke University, Cologne, Germany

²Institute for Research in Operative Medicine (IFOM), Witten/Herdecke University, Cologne, Germany

Correspondence to: Marc Maegele Department of Trauma and Orthopedic Surgery, Cologne-Merheim Medical Center (CMMC), University Witten/Herdecke (UW/H), Campus Cologne-Merheim, Ostmerheimer St 200, Cologne D-51109, Germany Email: Marc.Maegele@t-online.de

Received 2024 February 7; Accepted 2024 February 20.

Abstract

INTRODUCTION

Uncontrolled hemorrhage and trauma-induced coagulopathy (TIC) are the two predominant causes of preventable death after trauma [1–3]. One of four severely injured patients admitted to the trauma bay is bleeding and has a variable degree of laboratory coagulopathy; early detection, characterization, and management of this condition are associated with improved outcomes [4,5]. Dysfunctional hemostasis in trauma is multifactorial; and the pathophysiology of TIC can be separated into two main categories, acute traumatic coagulopathy and the coagulopathy associated with the lethal triad (resuscitation-associated coagulopathy). These two often exist in varying degrees either independently or together with the potential to become aggravated in a multifactorial sequalae [6]. Also, shock/trauma-induced damage to the endothelium (endotheliopathy) plays a central role in the initiation of TIC. However, much of the data that drive our current concepts continue to be more correlative than causative; robust links are still lacking (Fig. 1) [7].

Fig. 1.

Current concept of the pathophysiology underlying trauma-induced coagulopathy. Although several hypotheses have been proposed, there is agreement that trauma/tissue injury and shock (hypoperfusion) synergistically trigger the activation of the endothelium with several downstream cascades. Iatrogenic resuscitation may initiate the lethal triad resulting in resuscitation-associated coagulopathy. SHINE, shock-induced endotheliopathy.

EMPIRIC THERAPIES

Recent surveys confirm vast heterogeneity in the clinical diagnosis and management of acute trauma hemorrhage and TIC, even in advanced trauma centers [8–10]. In the acute phase, the clinical strategies follow the damage control resuscitation (DCR) concept. This concept advocates the empirical administration of blood products in predefined ratios [11]. However, optimum ratios are still under debate; no universal standard for the composition of these transfusion packages has yet been established, and storage time may affect the hemostatic competence of these products considerably [12]. Interestingly, the administration of blood products may also lead to coagulopathy in the context of massive bleeding due to anticoagulative factors and the fluid content of blood products [13]. Experimental studies have shown that administration of pRBCs, plasma and platelets in a predefined ratio of 1:1:1 as suggested by the DCR concept [11] results in a hematocrit of approximately 30%, a coagulation factor concentration of approximately 60% and a platelet count of 80×10⁹/L. These are far distant from normal or optimum values [13]. Also, this approach may not be adequate to correct hypoperfusion or coagulopathy during the acute phase of trauma hemorrhage [14]. Additionally, the results from three large-scale randomized controlled clinical trials have recently questioned the empirical and unguided administration of hemostatic agents, e.g., lyopholized plasma, prothrombin complex concentrate and cryoprecipitate, to correct early TIC in bleeding trauma patients [15–17]. As a consequence, several European and a few US trauma centers have instituted the concept of goal-directed coagulation therapy (GDCT) based upon results from early point-of-care (POC) viscoelastic testing (VET) [18–20].

LIMITATIONS OF CCAs

The coagulation status in severely injured patients is still largely assessed by conventional coagulation assays (CCAs) that have limitations, e.g., prothrombin time ratio (PTr), international normalized ratio (INR), activated partial thromboplastin time (aPTT), and functional fibrinogen level [21–24]. These standard tests only capture procoagulant pathways and focus only on the initial phase of the coagulation process until the maximum 5% to 7% of thrombin generation is achieved [22]. Amplification and propagation phases, the phases promoted by the more updated cell-based model of coagulation, are being ignored; and cellular components, especially platelets, are being removed from the samples through preanalytical centrifugation [25].

VISCOELASTIC TESTING

VET enables rapid and comprehensive assessment of the different steps of the coagulation process from initiation to clot formation including dynamics, stability, and sustainability of the evolving blood clot. The technology was first described by Hartert [26], a German physician, in 1948 and is now experiencing a revival for various indications that include trauma [27]. Different VET methods have been developed in which the blood sample is added into a heated cup with a suspended pin connected to a detector system. Either the cup (TEG 5000, Hamonetics Corp; ClotPro, Hamonetics Corp) or the pin (ROTEM, Werfen) rotates at a specific angle to the left and right. Fibrin strands form between the pin and the cup and diminish the rotation angle according to increasing clot strength to produce the typical trace. The technology used in TEG 6s (HemoSonics LLC) and Quantra (HemoSonics LLC) is slightly different; the TEG 6s exposes the blood sample to vibration and measures the resonance frequency induced by the motion of the blood meniscus, and Quantra is based upon ultrasonic estimation of elasticity through resonance to assess the evolution of the viscoelastic properties of the blood clot. Increasing clot stiffness lowers induced vibration and can be displayed as a graph over time. Fully automated and cartridge-based systems, such as ROTEM sigma, TEG 6s, and Quantra, in which blood samples are automatically processed with different activators, as well as the introduction of handling and pipetting aids, have largely eliminated preanalytical operational errors and have facilitated the acceptance and use of VET in daily clinical practice.

REAGENTS FOR VET

A range of different activators and/or inhibitors have been introduced for differential diagnosis of underlying hemostatic disorders in trauma. Like the technological spectrum integrated into the different devices, existing reagents are quite specific and vary considerably in terms of composition, concentration, and activation pathways [28]. Consequently, suggested treatment algorithms may not be transferred between devices without adjustment [29]. Focus is given to the most widespread systems, e.g., rotational thromboelastometry (ROTEM) and thromboelastography (TEG), which provide real-time, POC global information on the dynamics of clot development, stabilization and dissolution that reflect in vivo hemostasis. The most used assays for the two systems in relation to their respective activation pathways and the information derived from these assays are summarized in Table 1; the parameters delivered by the two systems are shown in Fig. 2.

Table 1.

ROTEM/TEG assay nomenclature, activation agents, and assay information

Fig. 2.

Viscoelastic test parameters for rotational thromboelastometry (ROTEM; Werfen) and thromboelastography (TEG; Hamonetics Corp). Both devices deliver comparable parameter results in seconds and millimeters but are labelled differently. For ROTEM: clot amplitude (CA) after 5 and 10 minutes, clotting time (CT), clot formation time (CFT), lysis index (LY) 30, 45, and 60 minutes after CT, maximum clot firmness (MCF), and maximum lysis (ML). For TEG: CA after 10 minutes, kinetic time (k), LY 30 and 60 minutes after maximum amplitude (MA), MA, and reaction time (r). Viscoelastic testing monitors whole blood hemostasis from clot formation to clot lysis (CL) in a temporal sequence.

CLINICAL APPLICATION OF VET-BASED GDCT

The concept of GDCT based upon results from early POC VET is intriguing, primarily driven by physiological understanding and promoting individualized care for bleeding trauma patients [19,30,31]. The concept has been shown to reduce bleeding, transfusion of packed RBC (pRBC), plasma, and platelet concentrates, and mortality in mixed surgical populations [32]. Early viscoelastic variables of clot firmness are good predictors of mortality and the need of massive transfusion [33,34]. A recent Cochrane review [32] and a recent meta-analysis [35] demonstrated the effects on the transfusion requirement and the survival benefit with the early use of VET in bleeding patients.

VET is increasingly being recognized for its potential to not only diagnose TIC but also to guide treatment [36–39] that augments DCR during the acute care of bleeding trauma patients. The updated European trauma guideline 2023 advocates that monitoring and measures to support coagulation should be initiated immediately upon arrival of the patient to the trauma bay and that routine practice should include the early and repeated monitoring of coagulation using VET. This is a strong grade 1B recommendation [38]. Further resuscitation measures should be continued using a goal-directed approach guided either by standard laboratory coagulation assays and/or POC VET, such as ROTEM (grade 1C recommendation) [38]. A recent survey among surgeons and anesthetists in Germany revealed that more than half already used extended VET, such as ROTEM or TEG, in advanced trauma centers [40].

EMERGING EVIDENCE

Recent evidence has confirmed that VET is highly specific for hyperfibrinolysis, the most lethal and resource-intense phenotype of fibrinolysis in trauma [41], and is more sensitive to detect coagulopathy as compared to CCAs [42]. The introduction of POC ROTEM has altered blood product transfusion practices for major trauma patients [43], leading to faster decision-making and initiation of therapy to correct coagulopathy [42,44], improved functional blood clotting parameters [45,46], and potentially improved safety of transfusion strategies [47,48], to meet the goal of reduced mortality [47,49]. Early goal-directed hemostatic resuscitation of TIC guided by TEG was prospectively explored in a single-center, pragmatic randomized controlled trial in 111 patients, and survival in the TEG group was significantly higher than in the CCA group with less use of plasma and platelets [50].

ECONOMIC ASPECTS

Two Italian trauma centers have replaced a former ratio-based transfusion strategy by an early coagulation support (ECS) protocol that includes POC VET and reported a reduction in blood product consumption. The results were statistically significant for plasma (65%) and platelets (52%), and there was a strong but nonsignificant trend toward a reduction in early and 28-day mortality [55]. The overall cost for transfusion and coagulation support including POC VET decreased by 23% after the ECS protocol was implemented in 2013. The clinical and cost-effectiveness of VET devices to assist with diagnosis, management, and monitoring of hemostasis was further assessed across different clinical settings, including TIC cases [56]. Apart from reductions in pRBC, platelet and FFP transfusion in the groups that had used VET devices and in the absence of any differences in clinical outcomes, the use of VET was cost-saving and more effective as compared to CCAs. For the trauma population, the cost-savings owing to VET devices were more substantial, amounting to per-patient savings of 688 GBP for ROTEM and 721 GBP for TEG compared to CCAs. This finding was entirely dependent on material costs, which were slightly higher for ROTEM [56]. Health economic aspects of VET use have also been the focus of other studies, and results have essentially been consistent [47,48,54].

CLINICAL ALGORITHMS

POC VET-based treatment algorithms, including thresholds to initiate GDCT with blood products, coagulation factors and hemostatic agents, have been introduced [27,30,31,36,55,57,58]. Their successful implementation was demonstrated even in initially naïve settings that were unexperienced with the technology [42]. Current and updated national [59] and international trauma and bleeding guidelines [38,39] recommend the local implementation of algorithms and clinical pathways for the management of bleeding trauma patients. These include measures for adherence, quality control, and safety. If key interventions and measures adhered to a formally fixed clinical guideline or algorithm, negative outcomes from trauma, including hemorrhage and mortality and other complication rates, are likely to be reduced [60,61]. However, local algorithms can only consider products, measures and actions that are locally available; not all resources that would compose an optimal clinical pathway may be available. Therefore, adopted algorithms need to reflect local infrastructures and logistics. An example clinical algorithm for early hemostatic control using POC ROTEM test assays is shown in Fig. 3. Specific attention is given to the early and targeted substitution of fibrinogen through cryoprecipitate; fibrinogen is considered as the substrate of the clotting process and the first coagulation factor to reach critical levels during acute blood loss.

Fig. 3.

Example of a stepwise, evidence-based clinical treatment alogorithm for early rotational thromboelastometry (ROTEM; Werfen)-guided hemostatic management (test result after 5 minutes of ROTEM operation, A5) in bleeding trauma patients including a recommendation for FIBTEM-guided fibrinogen substitution through the administration of cryoprecipitate using a dose calculator. The ROTEM triggers for the given interventions are based upon consensus from a multidisciplinary conference held in the United States in 2014 [36]. TIC, trauma-induced coagulopathy; ABG, arterial blood gas analysis; TXA, tranexamic acid; EXTEM, extrinsic thromboelastometry; INTEM, intrinsic thromboelas­tometry; FIBTEM, fibrinogen thromboelastometry (platelet-inhibited thromboelastometry); APTEM, aprotinine thromboelastometry (antifibrinolytic thromboelastometry); EX, ROTEM EXTEM assay; FIB, ROTEM FIBTEM assay; ML, maximum lysis; MCF, maximum clot firmness; BW, body weight; CT, clotting time; FFP, fresh frozen plasma.

LIMITATIONS OF VET

VET has limitations and cannot sufficiently uncover the entire spectrum of coagulation failure. For example, von Willebrand factor deficiencies cannot be detected through VET. Only TEG supplies an assay that allows for the assessment of impaired platelet function through TEG platelet mapping. Although endogenous heparinization is being considered among the key drivers of TIC (Fig. 1), comparisons between INTEM and HEPTEM times have failed to demonstrate any differences in major trauma patients prone to this phenomenon [62].

CONCLUSION

POC VET provides a comprehensive picture of the important aspects of the coagulation process and can rapidly identify underlying hemostatic disorders in the context of severe trauma hemorrhage. Its early application allows for targeted and individualized therapy along the lines of clinically proven algorithms. Several studies have indicated reductions in transfusion requirements with less exposure to harmful blood products, translating into less morbidity. Some researchers and clinicians have linked VET-guided coagulation support to increased survival.

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Notes