Fibrinolysis and Trauma Outcomes

Severe trauma can cause dramatic changes in hemostasis resulting in a severe coagulopathic state.^1–3  There has been heightened interest in the fibrinolytic system for its role in exacerbating or increasing this risk of bleeding during the acute post-trauma period, and its relationship with subsequent patient outcomes.^2,3 

In this issue, Rossetto et al.⁴  report on predictive utility of rotational thromboelastometry (ROTEM)–detected fibrinolysis on admission and at 24 h to identify multiorgan dysfunction syndrome and late mortality. Patients were grouped by maximum lysis according to ROTEM into low, normal, and high fibrinolytic activity based on established criteria. Multivariable logistic regression analysis was used to identify the independent effect of the fibrinolytic states on both multiorgan dysfunction syndrome and mortality. They first examined fibrinolytic transition patterns in 432 (of 731) patients who did not receive tranexamic acid (an antifibrinolytic). The highest incidence of late mortality occurred in patients who had an apparently normal fibrinolytic state on admission but developed hypofibrinolysis at 24 h (see fig. 1 in Rossetto et al.⁴ ). There were also strong associations between hypofibrinolysis on admission and at 24 h, with multiorgan dysfunction syndrome and late mortality on univariate testing. Some of the associations disappeared after multivariable adjustment, with admission hypofibrinolysis no longer statistically significant.

It is not that surprising that trauma patients with normal fibrinolysis had better outcomes—the extent and severity of trauma determines the release of tissue-type plasminogen activator from endothelial cells and neurons.^2,5  What remains unclear, however, is what the driving force that seemingly and impressively shuts down fibrinolysis on admission is, as seen in 35% of those patients not treated with tranexamic acid in the Rossetto study.⁴  The same authors previously reported elevated markers of hyperfibrinolysis and high D-dimer concentrations in some trauma patients, but no evidence of hyperfibrinolysis was seen by ROTEM.¹  While such findings further highlight the insensitivities of ROTEM to measure hyperfibrinolysis, it would have been valuable for Rossetto et al. to have measured plasmin–antiplasmin complex and D-dimer concentrations on admission in the current study⁴  to better characterize fibrinolysis, together with plasminogen activator inhibitor-1 (which increases after trauma and surgery), to counter this response. Plasmin–antiplasmin complex, D-dimer, and plasminogen activator inhibitor-1 concentrations are specific laboratory indicators of the presence and extent of fibrinolysis.^3,6,7  Such laboratory tests are not routinely available, even in major trauma centers, and may not necessarily reflect the immediate clinical situation.⁸  Point-of-care methods such as thromboelastography and ROTEM are the only currently available approaches to evaluating functional fibrinolysis in real time.

The presence and purported mechanisms of a trauma-induced “hypofibrinolytic” state are controversial.⁹  Could a hypofibrinolytic state occur immediately, or is this the aftermath of a hyperfibrinolytic state that rapidly reversed itself (“fibrinolytic shutdown”)? Fibrinolytic shutdown has been attributed to increases in plasminogen activator inhibitor-1.^3,10  The ensuing hypofibrinolytic state, due to whatever mechanism, has led to concerns about the safety of routine administration of tranexamic acid in that setting.³  Although tranexamic acid has been shown to reduce mortality in major trauma,¹¹  there is residual concern about potential prothrombotic effect of tranexamic acid in patients without fibrinolysis.^3,12  However, others question this concern because of a lack of any evidence of tranexamic acid increasing risk of thrombotic complications in trauma,⁹  or surgery.^13,14  Rossetto et al.⁴  also found that tranexamic acid mostly abolished fibrinolytic activity for at least 24 h. Interestingly, mortality within 24 h was lower in patients who received tranexamic acid before the admission ROTEM testing: tranexamic acid 29% versus no tranexamic acid 14%, P = 0.015. The incidence of multiorgan dysfunction syndrome and venous thromboembolism were higher in patients who received tranexamic acid but still had persistently low fibrinolytic activity. However, these patients had greater degrees of shock on admission and received more blood component therapy.⁴ 

Readers should note that the data used in the current Rossetto et al. study⁴  was derived from an ongoing observational cohort study of severe injury and bleeding after major trauma.¹  The current study thus relied upon retrospectively analyzed data (during a 10-yr span) from a single center, and the analyses were unblinded and conducted after the data were accessed. Fibrinolytic activity was characterized only by ROTEM. There is ongoing uncertainty as to the accuracy of thromboelastography or ROTEM in the ability to discriminate between different degrees of fibrinolysis,¹  as opposed to being no more than an indicator of coagulopathy.^12,15,16  Results do not always match the clinical condition.³ 

The findings in the article by Rossetto et al.⁴  should not lead to the conclusion that hypofibrinolysis detected by ROTEM has a causal impact on trauma outcomes. The association between hypofibrinolysis and poor trauma outcomes could be explained by residual confounding (especially trauma severity and type, shock [base deficit], and large volume transfusions) and multivariable statistical adjustment for these may be incomplete.¹⁷  Untangling causal and noncausal associations can be clarified by developing a conceptual model that includes a mediation analysis, aiming to shed light on the exposure-outcome relationship.^18–21  (A conceptual model of exposure, outcome, mediator, and confounders can be found in Supplemental Digital Content 1, https://links.lww.com/ALN/C766.)

Rossetto et al.⁴  have shown that trauma patients with hypofibrinolysis detected by ROTEM are at greater risk of poor outcomes; this finding is prognostically important. The mechanisms by which this occurs remain unresolved. Tranexamic acid should not be dismissed as a valuable therapy if there is ongoing evidence of bleeding. Rossetto et al.⁴  found that mortality within 24 h was lower in patients who received tranexamic acid before the admission sample (i.e., without knowledge of ROTEM results), and to their credit, they continue to recommend use of tranexamic acid in major trauma.