Fibrinolysis is an important part of homeostasis in the human coagulation system. It ensures that coagulation takes place exclusively in the area of endothelial lesions and not in the presence of intact endothelium. To maintain a local fibrinolysis, tissue plasminogen activator is continuously released by the intact endothelial cells to adhere to a forming clot and by converting plasminogen to plasmin.1 In contrast, hyperfibrinolysis is a pathological state that occurs when the balance between fibrinolytic activators and its inhibitors are disturbed2 and is associated with significantly higher morbidity and mortality.3 Hyperfibrinolysis is commonly found in the following: patients suffering liver failure and during the an-hepatic period of liver transplantation4,5; during brain injury and intracranial surgery6,7; postpartum hemorrhage,8 during the cardiopulmonary bypass period9,10; in a disturbed microcirculation as well as shock conditions11; and in major trauma patients.12 However, the incidence of hyperfibrinolysis is still unknown, and its occurrence has only been estimated for patients with liver disease and major trauma patients in the range of 30% to 46% and 15% to 20%, respectively.513 One reason for the nescience regarding the incidence of hyperfibrinolysis may be that it is often underdiagnosed due to a lack of appropriate and real-time routine laboratory tests.14 Laboratory diagnosis of hyperfibrinolysis is based on the increase of biomarkers like D-Dimer, fibrinogen split products, complexes of plasmin, α 2-antiplasmin, and euglobulin lysis test (ELT). The aforementioned tests are time consuming, have a lack of specificity and sensitivity, and results of these tests are also elevated in other pathological settings,5 e.g., liver cirrhoses.15,16 Currently, thrombelastography (TEG®) and rotational thromboelastometry (ROTEM®) have both been shown to be highly sensitive in detecting real-time hyperfibrinolysis17 in critically ill nontrauma and trauma patients.18–20 In nearly 25% of trauma patients arriving in the emergency room (ER) abnormal coagulation variables are present and the probability of death is about 4 times more likely than in patients without coagulopathy.21
Recently, Schöchl et al. reported a ROTEM-based (TEM International GmbH, Munich, Germany) diagnosis of hyperfibrinolysis predicting outcome in major trauma patients with a mortality rate between 73% and 100%, depending on the degree of hyperfibrinolysis detected.3 So far, the possible association of the hyperfibrinolytic state on outcomes in different patient groups, along with the extent of variations in laboratory values and their existing treatments, has yet to be investigated.
This study was designed to test the following 4 hypotheses:
- Is hyperfibrinolysis an independent factor with significant impact on outcome in severely traumatized patients compared to nontraumatized patients and to traumatized patients without hyperfibrinolysis?
- Does hyperfibrinolysis in trauma independently predict mortality?
- Is there an association between the metabolic state and hyperfibrinolysis?
- Is there any difference in the time of death between trauma patients with hyperfibrinolysis compared to nontraumatized patients suffering hyperfibrinolysis?
This study was performed after obtaining authorization from the local ethics committee (Kantonale Ethikkommission, Kanton Zürich, Switzerland, Study number KEK-ZH-Nr. 2010 to 0234/4). All ROTEM measurements performed in the ER of the University Hospital in Zurich between April 2008 and April 2010 were analyzed retrospectively. Inclusion criteria were all patients in the ER showing hyperfibrinolysis on the ROTEM® measurements using the recommended criteria of fibrinolysis detection from the manufacturer. These patients were then divided into 2 groups, the hyperfibrinolysis group with trauma (trauma hyperfibrinolysis group) and the hyperfibrinolysis group without trauma (nontrauma hyperfibrinolysis group). Additionally, the trauma hyperfibrinolysis group was matched 2:1 with trauma patients without hyperfibrinolysis (matched trauma group). Criteria for matching were the injury severity score (ISS), age of the patient, and gender and areas of sustained injury, particularly traumatic brain injury (TBI).
ROTEM® assesses the kinetics and quality of clot formation and clot lysis in real-time. The maximum lysis is the maximum fibrinolysis detected during the measurement. The hyperfibrinolytic state is being defined by a maximum lysis >15%/h in EXTEM and INTEM, and in APTEM by a recovered clot formation and stability. Hyperfibrinolysis was diagnosed when the maximum lysis was >15%. Further details on ROTEM® measurements have recently been published by Theusinger et al.22,23 They22,23 were also able to show that ROTEM® provides at least 98% of the final maximum clot firmness value after 10 minutes.
Using the hyperfibrinolysis categorization introduced by Schöchl et al.,3 hyperfibrinolysis has been grouped into 3 types based on the time course of clot breakdown: (a) fulminant with a total breakdown of the clot within 30 minutes, (b) intermediate with a total breakdown between 30 and 60 minutes, and (c) late with a breakdown of the clot after 60 minutes (Fig. 1). Of note, fulminant and intermediate type of hyperfibrinolysis are detected much earlier than a 60 minutes running time of the ROTEM® device supporting early decision making for monitoring directed and targeted treatments.
The following variables were collected by blood gas analysis using a multiwavelength hemoxymetry device (ABL 800, Radiometer Medical A/S, Akandevej 21 DK-2700 Bronshoj, Denmark): pH, hematocrit (HCT), hemoglobin (Hb), lactate, base excess (BE), PO2, PCO2, potassium, calcium, and bicarbonate. In addition, Hb, HCT, platelets, international normalized ratio (INR), fibrinogen, factor V, and factor XIII were determined by the institutional hematological laboratory. Further information gathered included demographic data, the ISS in traumatized patients, as well as the use of red blood cells, fresh frozen plasma and platelets, coagulation factor concentrates, and tranexamic acid (TXA) in the ER and during emergency surgery. Data and administered treatments for patients who initially presented at outside hospitals before arriving in our ER could not be completely evaluated.
ROTEM® data, laboratory data, and the clinical outcome of the trauma hyperfibrinolysis group were compared to the nontrauma hyperfibrinolysis group as well as with the matched trauma group. For 2 trauma patients with hyperfibrinolysis only one suitable match was found within trauma patients without hyperfibrinolysis because the age, severity of the injury, and the location of sustained injury, including brain injury, could not be found.
Mortality and 30-day survival were analyzed for all 3 groups.
Data were entered into Microsoft Excel (Microsoft Office 2007, Microsoft Corporation Redmond, WA, US) and analyzed using SPSS (version 17, SPSS Inc. Chicago, IL). Normally distributed continuous variables are summarized as mean ± SD (ISS and age) and not normally distributed continuous variables as median with range. The Mann-Whitney test was used to compare continuous variables between groups.
Thirty-day survival was analyzed using the Kaplan-Meier method and was compared between groups using the log-rank test. Bonferroni correction for multiple comparisons was applied; because 2 comparisons were simultaneously made, the P values have to be adapted to 0.025 or less to be considered significant. Multiple regression analysis was performed using Stata 10.1 (StataCorp, College Station, TX) to determine whether hyperfibrinolysis had an independent influence on mortality. The covariates for which we controlled are the metabolic state, INR, and ISS.
ROTEM® data in 552 ER patients, from April 2008 to April 2010, were analyzed. In 35 patients (13 trauma patients and in 22 nontrauma patients) hyperfibrinolysis was identified. The 13 patients of the trauma hyperfibrinolysis group were matched with 24 trauma patients without hyperfibrinolysis (matched trauma group). Demographic, procedural, and outcome data for all cases are listed in Table 1, A–C.
The mean (±SD) ISS for patients in the trauma hyperfibrinolysis group (55 ± 19) compared with the matched trauma group (43 ± 14) was not significantly different (P = 0.066) (Table 1, A and C), although ISS tended to be lower in the matched trauma group.
In 6 trauma hyperfibrinolysis group patients and in 5 cases of the nontrauma hyperfibrinolysis group patients, fulminant hyperfibrinolysis was found. Five patients in the trauma hyperfibrinolysis group and 8 patients in the nontrauma hyperfibrinolysis group showed an intermediate state of hyperfibrinolysis. A late breakdown of the clot was found in 2 patients of trauma hyperfibrinolysis group and in 9 patients in the nontrauma hyperfibrinolysis group (Table 2).
In the trauma hyperfibrinolysis group, TXA was given as an IV bolus of 1 to 2 g to 9 of 13 patients (83%). In addition to the original IV bolus, 2 patients of those 9 received a TXA continuous infusion administered at a dose of 1.5 mg/kg body weight/hour. Four patients in the trauma hyperfibrinolysis group died within the first 30 minutes before TXA could be administered. Of the nontrauma hyperfibrinolysis group, 11 of 22 patients (50%) received a bolus of 0.4 to 2 g of TXA and in 8 of 11 patients TXA was continuously administered at a dose of 1.5 mg/kg body weight/hour.
Thirty-day mortality in the trauma hyperfibrinolysis group (77% ± 12%) was significantly higher than in the nontrauma hyperfibrinolysis group (41% ± 10%, 95% CI 5%–67%; log-rank test P = 0.001) and in the matched trauma group (33 ± 10 difference 44%, 95% CI 13%–74%; P = 0.009) as shown in Table 2.
Fifty percent of the trauma hyperfibrinolysis group patients with fulminant hyperfibrinolysis died in the ER, 17% during immediate emergency surgery in the operating room, and 17% in the intensive care unit (ICU) with an overall mortality of 83%. Overall mortality of the trauma hyperfibrinolysis group in patients with intermediate hyperfibrinolysis was 60%, 20% died in the ER, and 40% in the ICU. In 2 trauma hyperfibrinolysis group patients with late hyperfibrinolysis, 1 patient died in the ER and 1 in the ICU with a mortality of 100% (Table 1, A).
All deaths in the nontrauma hyperfibrinolysis group with fulminant hyperfibrinolysis occurred in the ICU with a mortality of 60%. For patients with intermediate hyperfibrinolysis, in the nontrauma hyperfibrinolysis group mortality was 38%; 1 patient died in the ER and 2 in the ICU. All deaths in patients suffering late hyperfibrinolysis in the nontrauma hyperfibrinolysis group occurred in the ICU with a mortality of 33% (Table 1, B).
The Kaplan-Meier survival curves (Fig. 2) showed that all deaths in the trauma hyperfibrinolysis group occurred within 4 days after arrival to the hospital. In the nontrauma hyperfibrinolysis group, all deaths occurred within 14 days after arrival to the hospital with 1 exception when a death occurred on day 29. In the matched trauma group after the sixth day all patients survived the 30-day period.
In the blood gas analysis representing the metabolic state, only pH (P = 0.020) and potassium (P = 0.011) were significantly lower and arterial carbon dioxide tension (P < 0.001) was significantly higher in the trauma hyperfibrinolysis group compared to the nontrauma hyperfibrinolysis group (Table 3). The trauma hyperfibrinolysis group received significantly more red blood cells, fibrinogen, and factor XIII compared to the nontrauma hyperfibrinolysis group (Table 3).
In the trauma hyperfibrinolysis group compared to the matched trauma group, pH, Hb, HCT, HCO3−, and fibrinogen levels were significantly lower, and lactate, BE, and INR were significantly higher (Table 4). Patients in the trauma hyperfibrinolysis group received significantly more TXA, platelet packages, and prothrombin complex when compared to the matched trauma group (Table 4).
Multiregression analysis showed that hyperfibrinolysis is a significant independent factor for mortality in trauma patients (P = 0.017).
The subgroup analysis performed between the survivors and the deceased patients for each group regarding age, pH, lactate, BE, INR, and, where indicated, the ISS (Table 5) revealed the following: For the trauma hyperfibrinolysis group and for the matched trauma group, no differences in the metabolic state between survivors and deceased patients were found. In the nontrauma hyperfibrinolysis group, deceased patients had a significantly higher lactate (P < 0.002) and BE (P < 0.001) and a significantly lower pH (P < 0.001) compared to survivors.
The main findings of this investigation are (a) mortality in trauma patients with hyperfibrinolysis was significantly higher than in nontrauma patients suffering hyperfibrinolysis and in trauma patients without hyperfibrinolysis; (b) hyperfibrinolysis independently and significantly predicts mortality in trauma patients; (c) hyperfibrinolysis in trauma patients was associated with significantly worse metabolic disorders compared to hyperfibrinolysis in nontrauma patients; and (d) death occurred earlier in trauma patients with hyperfibrinolysis (within 4 days of admission) when compared to nontrauma patients with hyperfibrinolysis (within 14 days of admission).
Of the 552 trauma and nontrauma patients identified with bleeding in the ER over a 2-year period, 35 (6%) developed a varying degree of hyperfibrinolysis diagnosed by ROTEM®. Similar to the CRASH-2 trial,24 approximately 95% of the patients included in both the trauma hyperfibrinolysis and trauma matched group suffered polytrauma in combination with varying severity of TBI. The distribution of the severity of TBI was nearly similar to those in the CRASH-2 trial.24 Overall mortality in our study was 54% in those patients who presented with hyperfibrinolysis. Detailed analysis showed that the highest mortality was in the trauma hyperfibrinolysis group with mortality of 77%, compared to 41% in the nontrauma hyperfibrinolysis group, and 33% in the matched trauma group.
In 161 trauma patients, Carroll et al.18 reported a 2% incidence of hyperfibrinolysis detected by TEG® with a mortality of 67%; in contrast the overall mortality was 9% in the entire group. All patients suffering hyperfibrinolysis were classified as being in shock. In the Levrat et al.20 study comparing ROTEM® against ELT in trauma patients, hyperfibrinolysis was present in 6% of the patients with a mortality of 100% compared to a mortality of 11% in the control group. In comparison to our study, the major difference was a low mean ISS of 20 in their control group in patients without hyperfibrinolysis. Using the premise that increasing ISS values are associated with increasing mortality,25–26 this explains the higher mortality found in our matched trauma group where the mean ISS was 43 and was clearly higher than in the control group of Levrat et al.20 The ISS of the trauma hyperfibrinolysis group was not significantly different from that of the matched trauma group but showed a trend toward higher values.
The lower mortality found in the current investigation in the nontraumatized patients with hyperfibrinolysis compared to the trauma patients with hyperfibrinolysis is interesting and might be explained by several factors. Shock leads to tissue hypoperfusion with a significant reduction in plasminogen activator inhibitor-1 levels and an increase of tissue plasminogen activator.12 High levels of activated protein C inactivate plasminogen activator inhibitor-1,28 and, particularly in polytraumatized patients with multiple bleeding sites repeated derepression of fibrinolytic activity, may lead to untreatable systemic hyperfibrinolysis or early major multiorgan failure. Most of the nontraumatized patients had only one organ affected by massive bleeding, while in the traumatized patients all were classified as polytrauma. Nine of the 13 trauma patients with hyperfibrinolysis suffered a thoracic trauma mostly associated with hemopneumothorax and disturbances in ventilation that caused hypercapnia. There were significantly different metabolic disorders in traumatized and nontraumatized patients with bleeding who developed hyperfibrinolysis. Traumatized patients with hyperfibrinolysis showed a more severe combined metabolic and respiratory acidosis when we reviewed mean values with a pH of 7.09, PaCO2 of 6.74 kPa, and BE −13.55, compared to those of 7.3, 5.0 kPa and −9.75 in the nontrauma hyperfibrinolysis group (Table 3). Metabolic disorders, coagulopathy, and hypothermia are associated with considerably higher mortality.25–27 Another explanation for the lower mortality found in nontraumatized patients with hyperfibrinolysis might be that only 1 organ was affected by massive bleeding and early treatment stopped the progress of continuing coagulation derailment. In contrast, hemostasis in patients with polytrauma may be demanding and trauma-induced coagulopathy may continue, although anatomic lesions are fixed. The significantly higher need for transfusion of blood products for the trauma hyperfibrinolysis group compared to the nontrauma hyperfibrinolysis group is an additional justification for the significantly lower mortality found in the nontrauma hyperfibrinolysis group.24 These facts might also contribute to an earlier mortality in traumatized patients suffering hyperfibrinolysis compared to those without trauma (fourth day versus 14th day) in this investigation.
The main finding of this study was that hyperfibrinolysis in trauma patients was associated with increased mortality compared to the nontrauma hyperfibrinolysis group and the matched trauma group. Subgroup analysis between patients who died and those who survived in the trauma hyperfibrinolysis group showed no significant difference between age, pH, lactate, BE, INR, and ISS values (Table 5). These data confirm our findings that hyperfibrinolysis was a significant and independent predictor for mortality in the trauma hyperfibrinolysis group. However, contrary to Schöchl et al.,3 in the current investigation no association between of the extent of hyperfibrinolysis detected by ROTEM® and mortality was found in the trauma group. Only in the nontrauma group was there a discernable trend toward increasing mortality with the increasing degree of hyperfibrinolysis (Table 2). In both the trauma and nontrauma group, mortality was the highest if fulminant hyperfibrinolysis was present. In this study, mortality in traumatized patients with fulminant hyperfibrinolysis was 83% and 60% in nontraumatized patients, but not 100% as stated by Schöchl et al.3 Early diagnosis and real-time treatment of hyperfibrinolysis with TXA, especially the fulminant type in traumatized and nontraumatized patients, might reduce mortality as our data suggest. Most recently, the exploratory analysis of the CRASH-2 randomized controlled trial recorded strong evidence that the effect of TXA on death due to bleeding varied according to the time from injury to treatment.29 The CRASH-2 collaborators have shown that early treatment with TXA, <1 hour but also within 1 to 3 hours after injury, significantly reduced the risk of death due to bleeding events in trauma patients as compared with placebo. In most developed countries traumatized patients reach the hospital within 1 to 1.5 hours from the initial injury, so there is a sufficient time window for early detection and targeted treatment.29 Unfortunately, in the nontrauma group with hyperfibrinolysis, only 50% of patients were treated with TXA. It was not possible to retrospectively evaluate the reasons why not all of these patients were treated with TXA. One explanation might be that in many nontrauma patients the extent of hyperfibrinolysis was only from the late type and therefore not accurately detected by the physician. Fulminant hyperfibrinolysis diagnosed by ROTEM® does not automatically predict the probability for mortality to be 100%. However, point-of-care monitoring can guide early goal-directed treatment with antifibrinolytic agents, such as TXA and coagulation factors concentrates, as most recently published (24,30 to 32). ROTEM® provides its first results after approximately 10 minutes23 to guide decisions for correcting the fibrinogen concentration or providing indications for prothromplex concentrate substitution.
In agreement with Schöchl et al.,3 Hb, HCT, and fibrinogen blood concentrations (Table 4) were significantly lower in traumatized patients with hyperfibrinolysis compared to the matched trauma group despite ISS and the proportion of TBI not showing significant difference. This suggests that hyperfibrinolysis, detected by ROTEM®, seems to be associated with developing severe metabolic disturbances most likely by perpetuation of diffuse bleeding in traumatized patients.
There are several limitations of this study. First, the retrospective design of this study was a disadvantage because of error rates caused by a lack of documentation in substantial data. This was evident when trying to obtain documentation on patients transferred from home or from an emergency department of an outside hospital and data on intravascular volume replacement therapy and drug administration before admission. Additionally, only patients with hyperfibrinolysis and the trauma-control group were analyzed and not the whole population. Therefore, this investigation cannot provide a reliable estimation of the incidence of hyperfibrinolysis in trauma and nontrauma emergencies. Second, the power of the study was limited by the relatively small number of patients with hyperfibrinolysis. Finally, hyperfibrinolysis was diagnosed by ROTEM® and was not confirmed by another diagnostic tool, such as plasminogen activator inhibitor-1, D-Dimer, or ELT. However, TEG® and ROTEM® have become the standard in real-time detection of hyperfibrinolysis. Levrat et al.20 reported a sensitivity of 80% to 100% and specificity of 100% of TEG® in detecting hyperfibrinolysis according to ELT.
In conclusion, hyperfibrinolysis is significantly associated with and an independent factor of mortality for trauma patients with hyperfibrinolysis compared to hyperfibrinolysis of nontraumatized patients. Hyperfibrinolysis is significantly and independently associated with higher mortality in trauma patients. Thromboelastometry provides real-time recognition of hyperfibrinolysis and may contribute to a reduction in the extremely high mortality of traumatized patients with fulminant hyperfibrinolysis.
Name: Oliver M. Theusinger, MD.
Contribution: Oliver M. Theusinger designed the study, conducted the study, analyzed the data and wrote the manuscript.
Conflicts of Interest: Oliver M. Theusinger has received honoraria or travel support for consulting or lecturing from the following companies: CSL Behring Schweiz, Zurich, Switzerland, Vifor SA, Villars-sur-Glâne, Switzerland, Roche Pharma (Schweiz) AG, Reinach, Switzerland, Pentapharm AG, München, Germany, TEM International, München, Germany.
Name: Guido A. Wanner, MD.
Contribution: Guido Wanner helped to collect the data, and to write the manuscript.
Conflicts of Interest: Guido A. Wanner has no conflict of interest.
Name: Maximilian Y. Emmert, MD.
Contribution: Maximilian Y. Emmert helped to collect the data and to write the manuscript.
Conflicts of Interest: Maximilian Y. Emmert has no conflict of interest.
Name: Adrian Billeter, MD.
Contribution: Adrian Billeter helped to collect the data and conduct the study.
Conflicts of Interest: Adrian Billeter has no conflict of interest.
Name: Jennifer Eismon, MD.
Contribution: Jennifer Eismon helped to write the manuscript.
Conflicts of Interest: Jennifer Eismon has no conflict of interest.
Name: Burkhardt Seifert, PhD.
Contribution: Burkhardt Seifert made the statistical analysis and helped to write the manuscript.
Conflicts of Interest: Burkhardt Seifert has no conflict of interest.
Name: Hans-Peter Simmen, MD.
Contribution: Hans-Peter Simmen helped to collect the data and to write the manuscript.
Conflicts of Interest: Hans-Peter Simmen has no conflict of interest.
Name: Donat R. Spahn, MD, FRCA.
Contribution: Donat R. Spahn designed the study, conducted the study, and wrote the manuscript.
Conflicts of Interest: Donat R. Spahn's academic department is receiving grant support from the Swiss National Science Foundation, Berne, Switzerland (grant numbers: 33CM30_ 124117 and 406440-131268), the Swiss Society of Anesthesiology and Reanimation (SGAR), Berne, Switzerland (no grant numbers are attributed), the Swiss Foundation for Anesthesia Research, Zurich, Switzerland (no grant numbers are attributed), Bundesprogramm Chancengleichheit, Berne, Switzerland (no grant numbers are attributed), CSL Behring, Berne, Switzerland (no grant numbers are attributed), Vifor SA, Villars-sur-Glâne, Switzerland (no grant numbers are attributed).
Dr. Spahn was the chairman of the ABC Faculty and a member of the ABC Trauma Faculty, both of which are managed by Thomson Physicians World GmbH, Mannheim, Germany and sponsored by an unrestricted educational grant from Novo Nordisk A/S, Bagsvärd, Denmark. In the past 5 years, Dr. Spahn has received honoraria or travel support for consulting or lecturing from the following companies: Abbott AG, Baar, Switzerland, AstraZeneca AG, Zug, Switzerland, Bayer (Schweiz) AG, Zürich, Switzerland, Baxter S.p.A., Roma, Italy, B. Braun Melsungen AG, Melsungen, Germany, Boehringer Ingelheim (Schweiz) GmbH, Basel, Switzerland, Bristol-Myers-Squibb, Rueil-Malmaison Cedex, France, CSL Behring GmbH, Hattersheim am Main, Germany and Bern, Switzerland, Curacyte AG, Munich, Germany, Ethicon Biosurgery, Sommerville, NJ, Fresenius SE, Bad Homburg v.d.H., Germany, Galenica AG, Bern, Switzerland (including Vifor SA, Villars-sur-Glâne, Switzerland), GlaxoSmithKline GmbH & Co. KG, Hamburg, Germany, Janssen-Cilag AG, Baar, Switzerland, Novo Nordisk A/S, Bagsvärd, Denmark, Octapharma AG, Lachen, Switzerland, Organon AG, Pfäffikon/SZ, Switzerland, Oxygen Biotherapeutics, Costa Mesa, CA, Pentapharm GmbH (now tem Innovations GmbH), Munich, Germany, Roche Pharma (Schweiz) AG, Reinach, Switzerland and Schering-Plough International, Inc., Kenilworth, NJ.
Name: Werner Baulig, MD.
Contribution: Werner Baulig designed the study, conducted the study, analyzed the data, and wrote the manuscript.
Conflicts of Interest: Werner Baulig has no conflict of interest.
This manuscript was handled by: Jerrold H. Levy, MD, FAHA.
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