Temporal Transitions in Fibrinolysis after Trauma: Adverse Outcome Is Principally Related to Late Hypofibrinolysis

Abstract

Background The relationship between late clinical outcomes after injury and early dynamic changes between fibrinolytic states is not fully understood. The authors hypothesized that temporal transitions in fibrinolysis states using rotational thromboelastometry (ROTEM) would aid stratification of adverse late clinical outcomes and improve understanding of how tranexamic acid modulates the fibrinolytic response and impacts mortality. Methods The authors conducted a secondary analysis of previously collected data from trauma patients enrolled into an ongoing prospective cohort study (International Standard Randomised Controlled Trial Number [ISRCTN] 12962642) at a major trauma center in the United Kingdom. ROTEM was performed on admission and at 24 h with patients retrospectively grouped into three fibrinolysis categories: tissue factor–activated ROTEM maximum lysis of less than 5% (low); tissue factor–activated ROTEM maximum lysis of 5 to 15% (normal); or tissue factor–activated ROTEM maximum lysis of more than 15% (high). Primary outcomes were multiorgan dysfunction syndrome and 28-day mortality. Results Seven-hundred thirty-one patients were included: 299 (41%) were treated with tranexamic acid and 432 (59%) were untreated. Two different cohorts with low-maximum lysis at 24 h were identified: (1) severe brain injury and (2) admission shock and hemorrhage. Multiple organ dysfunction syndrome was greatest in those with low-maximum lysis on admission and at 24 h, and late mortality was four times higher than in patients who remained normal during the first 24 h (7 of 42 [17%] vs. 9 of 223 [4%]; P = 0.029). Patients that transitioned to or remained in low-maximum lysis had increased odds of organ dysfunction (5.43 [95% CI, 1.43 to 20.61] and 4.85 [95% CI, 1.83 to 12.83], respectively). Tranexamic acid abolished ROTEM hyperfibrinolysis (high) on admission, increased the frequency of persistent low-maximum lysis (67 of 195 [34%]) vs. 8 of 79 [10%]; P = 0.002), and was associated with reduced early mortality (28 of 195 [14%] vs. 23 of 79 [29%]; P = 0.015). No increase in late deaths, regardless of fibrinolysis transition patterns, was observed. Conclusions Adverse late outcomes are more closely related to 24-h maximum lysis, irrespective of admission levels. Tranexamic acid alters early fibrinolysis transition patterns, but late mortality in patients with low-maximum lysis at 24 h is not increased. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Hyperfibrinolysis and fibrinolysis shutdown in patients with traumatic brain injury

“…Gando et al 34 and Wada et al 37 showed that disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype in the acute phase of TBI develops into DIC with the thrombotic phenotype (fibrinolysis shutdown) at a high rate and has a poor prognosis due to organ dysfunction from thrombus deposition. In a secondary analysis of previously collected data from a prospective cohort study, Rossetto et al 38 showed that the development of hypofibrinolytic state (fibrinolysis shutdown) after 24 h with rotational thromboelastometry (ROTEM®; TEM International GmbH, Munich, Germany) was associated with severe TBI patients and increased incidence of multiple organ failure and late mortality. The results of these studies support the findings of our study.…”

Plasma-based assays distinguish hyperfibrinolysis and shutdown subgroups in trauma-induced coagulopathy

“…Whether these results can be extrapolated to other groups of patients with differential sensitivity to tPA or patients with later onset shutdown warrant further investigation. 48 Second, similar to other studies of trauma, our study included patients with diverse injuries; patients in the hyperfibrinolysis subgroup were generally more severely injured and had greater mortality than shutdown samples. However, inclusion of these patients with clearly distinguished phenotypes increased our ability to identify differences between groups.…”

Update on Applications and Limitations of Perioperative Tranexamic Acid

“…85 Changes in fibrinolytic signal in acute trauma victims are dynamic, likely associated with resuscitation and develop over time. 86 Teleologically, abrupt elevation in tissue plasminogen activator after massive injury is followed by a rise in plasminogen-activator inhibitor and potential hypofibrinolysis, which may manifest over the course of resuscitation. 87 The current dilemma of TXA use in acute trauma is the necessity to intervene early (<3 hours) to maximize possible benefit in the highest risk period for hemorrhagic death, balanced with unknown fibrinolytic status until data from viscoelastic or other assays become available.…”

“…85 Changes in fibrinolytic signal in acute trauma victims are dynamic, likely associated with resuscitation and develop over time. 86 Teleologically, abrupt elevation in tissue plasminogen activator after massive injury is followed by a rise in plasminogen-activator inhibitor and potential hypofibrinolysis, which may manifest over the course of resuscitation. 87…”

“…Testing should be repeated to follow the developing fibrinolytic patterns. 86 In the absence of pharmacokinetic data in the trauma population, a loading dose of 1 gram is recommended, and an infusion of the second gram over 4 to 8 hours should be supported by viscoelastic evidence and stopped if/when there is evidence of hypofibrinolysis. Proactive chemical thromboprophylaxis should be initiated as soon as clinically feasible after the initial control of hemorrhage given the likelihood of developing postresuscitation hypercoagulability.…”