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Activated Thrombin-Activatable Fibrinolysis Inhibitor (TAFIa) Levels are decreased in Patients With Trauma-Induced Coagulopathy
Thrombosis Research 131 (2013) e26–e30
Contents lists available at SciVerse ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Activated Thrombin-Activatable Fibrinolysis Inhibitor (TAFIa) Levels are decreased in Patients With Trauma-Induced Coagulopathy T. Lustenberger a,⁎, B. Relja a, B. Puttkammer a, E.C. Gabazza b, E. Geiger a, Y. Takei c, J. Morser d, I. Marzi a a
Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt am Main, Frankfurt, Germany Department of Immunology, Mie University Graduate School of Medicine, Tsu, Mie, Japan Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Mie, Japan d Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA b c
a r t i c l e
i n f o
Article history: Received 16 September 2012 Received in revised form 13 October 2012 Accepted 1 November 2012 Available online 20 November 2012
a b s t r a c t Introduction: The thrombin-activatable fibrinolysis inhibitor (TAFI) is a potent inhibitor of fibrinolysis. However, the time course of TAFI and its activated form (TAFIa) following trauma, in particular in patients suffering trauma-induced coagulopathy, has been poorly examined. Methods: A total of 26 severely injured trauma patients were prospectively enrolled. TAFI and TAFIa levels were measured upon arrival and through hospital days one to 10. Trauma-induced coagulopathy was defined as elevated international normalized ratio (INR), and/or prolonged activated partial thromboplastin time (aPTT) and/or thrombocytopenia within one day of admission. Results: TAFIa and TAFI levels showed the largest decrease on days one and two, respectively, with a progressive increase thereafter. Overall, 11 patients developed coagulopathy. No statistically significant differences were found for TAFI levels between the two groups. For TAFIa, however, coagulopathic patients experienced significantly lower levels on admission and on days six to eight (all pb 0.05). Statistically significant correlations were found between TAFIa level on admission and the amount of packed red blood cells (p=0.011; Spearman's correlation coefficient=−0.5) and fresh frozen plasma (p=0.044; Spearman's correlation coefficient=−0.405) transfused within the initial 24 hours. Conclusion: Depletion of TAFIa may contribute to the development of trauma-induced coagulopathy. © 2012 Elsevier Ltd. All rights reserved.
Introduction Acute traumatic coagulopathy is a well-recognized and frequently occurring sequela following major injury and is associated with a significantly higher mortality, increased transfusion requirements, septic complications, and longer hospital and intensive care unit lengths of stay [1–6]. Recent data suggest that hyperfibrinolysis may represent an important factor to the disturbed coagulation process following trauma [2,7]. The thrombin activatable fibrinolysis inhibitor (TAFI; also known as procarboxypeptidase B2, pCPB2 or procarboxypeptidase U, pCPU) is a carboxypeptidase B-like proenzyme and is activated by the thrombin-thrombomodulin complex at the vascular endothelial surface [8]. In its activated form (TAFIa), it inhibits fibrinolysis by removing carboxy-terminal lysine residues from fibrin which are required for efficient plasmin formation [9–11]. In recent years, the role of TAFI in thrombotic and hemorrhagic diseases has been investigated mainly in non-trauma populations [12–19]. In patients with acute ⁎ Corresponding author at: Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt / Main, Germany. Tel.: +49 69 6301 6123; fax: +49 69 6301 6439. E-mail address: [email protected] (T. Lustenberger). 0049-3848/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2012.11.005
ischemic stroke, TAFI levels were significantly higher compared to healthy volunteers [15]. Increased TAFI levels were likewise found in patients with stable angina or coronary artery disease [19]. For trauma patients however, very few studies exist examining the role of either TAFI, or its activated form, following major insults [20]. Data regarding the association between TAFI levels and traumainduced coagulopathy are likewise scarce [20]. Thus, we set out to study the time course of changes in the levels of TAFI and TAFIa in the plasma of severely injured trauma patients as well as to describe differences in plasma levels between patients with and without acute trauma-induced coagulopathy.
Patients and Methods Ethics This study was performed at the Hospital of the J. W. Goethe University with institutional ethics committee approval (167/05, in accordance with the Declaration of Helsinki and following STROBE-guidelines). All enrolled patients signed the informed consent forms, or informed consent was obtained from their legal representative.
T. Lustenberger et al. / Thrombosis Research 131 (2013) e26–e30
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Patients
Results
Inclusion criteria consisted of a history of acute blunt or penetrating trauma, an Injury Severity Score (ISS) ≥ 16, and age ≥ 18 and ≤ 80 years. Patients with known pre-existing immunological disorders, immunosuppressive and anticoagulant medications, burn patients, and patients with concomitant thromboembolic events and/ or lethal injuries were excluded from the study. All patients were treated according to the Advanced Trauma Life Support (ATLS®) guidelines. Hemodynamically stable patients underwent whole body computed tomography, whereas immediate surgery was performed in hemodynamically unstable patients ahead of further diagnostic measures. Blood samples were obtained from 26 consecutive multiply traumatized patients on admission to the emergency department (ED), and daily for 10 days following trauma. All patients had a complete blood count, chemistry panel, and coagulation panel including platelet (PLT) count, International Normalized Ratio (INR), activated partial thromboplastin time (aPTT) and plasma fibrinogen level, drawn on admission and thereafter on a daily basis. Demographic and clinical data collected included age, gender, mechanism of injury (blunt versus penetrating), blood pressure on admission, ISS, and the Abbreviated Injury Scale (AIS) score for each body region (head, chest, abdomen, and extremity). The numbers of packed red blood cells (PRBC) and fresh frozen plasma (FFP) units transfused within the initial 24 hours were recorded. Acute trauma-induced coagulopathy was defined as an INR>1.5 and/ or aPTT>40 seconds and/or thrombocytopenia (PLT countb 100,000 per mm3), within one day of admission.
The study cohort included 21 males and five females. Mean patient age was 51.5 ± 4.1 years (range: 18 to 80 years), and the mean ISS was 29.6 ± 2.0 (range: 16 to 51). All patients suffered blunt trauma. Table 1 delineates the demographics, clinical injury characteristics and a blood component summary for the first 24 hours, stratified into coagulopathic and non-coagulopathic patients. Overall, 11 patients (42.3%) developed coagulation abnormalities on admission to the ED or in the hospital during the first day. Coagulopathic patients had a significantly higher ISS and higher AIS chest and AIS extremity scores than non-coagulopathic patients. Significant bleeding sites were found in 5 patients (splenic rupture, n = 2; liver laceration, n = 1; pelvic fracture type vertical shear, n = 2). A trend towards prolonged intensive care unit length of stay was observed in coagulopathic vs. non-coagulopathic patients (19.6 ±4.5 vs. 8.9 ± 1.7 days; p = 0.054). Mean hospital length of stay was not statistically significant different between the two groups (coagulopathic vs. non-coagulopathic patients, 30.5± 4.6 vs. 24.3± 3.5 days; p = 0.33). All patients survived to hospital discharge. The routinely performed blood profile throughout the hospital stay showed no statistically significant differences comparing mean bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in coagulopathic and non-coagulopathic patients respectively. The plasma levels of TAFI were determined over the time course from ED admission through to hospital day 10 (Fig. 1). A decrease was seen by the second day in hospital, followed by a progressive increase, peaking on hospital day nine. Comparing coagulopathic and non-coagulopathic patients, no statistically significant differences were found in TAFI levels. The plasma levels of TAFIa were measured by a specific enzyme assay from time of admittance to the ED until hospital day 10 (Fig. 2). A decrease was observed on hospital day one and the highest value was found on hospital day eight. In the non-coagulopathic cohort, the mean TAFIa value showed an initial drop on hospital day one but it then started to increase progressively thereafter. Within the coagulopathic group, the
Blood Processing and Analysis The first blood samples were obtained as early as possible following admission of the patient to the ED in pre-chilled ethylenediaminetetraacetic acid (EDTA) or heparin vacuum tubes (BD vacutainer, Becton Dickinson Diagnostics, Aalst, Belgium) and kept on ice. Blood was centrifuged at 2000 ×g for 15 min at 4 °C. The supernatant was stored at − 80 °C until analysis. The mean time between injury and the acquisition of the first blood sample was 81 ± 8 min. Specimens were used for duplicate measurement of TAFI and TAFIa levels. TAFI was determined using a commercially available ELISA (IMUCLONE™ TAFI ELISA, American Diagnostica Inc., USA), according to the manufacturer's instructions. The TAFI antigen level is expressed as a percentage of pooled normal plasma (which is assigned as 100%). The lower limit of detection was ≤5%. TAFIa was determined in heparinized samples using ACTICHROME™ TAFI Activity Assay (American Diagnostica Inc., USA) according to the manufacturer's instructions.
Statistical Analysis The plasma concentrations of TAFI and TAFIa did not have a Gaussian distribution by the Kolmogoroff-Smirnoff-Lilieford's test. The p values for categorical variables were derived from the twosided Fisher's exact test, and for continuous variables from the Mann-Whitney U test. Spearman's correlation coefficients were calculated to determine correlations between TAFI/TAFIa levels and other variables. Receiver-operator curves (ROC) were generated to analyze optimal cut-off values. Values are reported as mean±standard error of the mean (SEM) for continuous variables and as percentages for categorical variables. A p value b 0.05 was considered statistically significant. All analyses were performed using the Statistical Package for Social Sciences (SPSS for Mac©), version 16.0 (SPSS Inc., Chicago, IL).
Table 1 Demographic and clinical characteristics including coagulation profile and transfusion requirements of study population.
Age (y), mean ± SEM Age ≥ 55 years Male SBP b90 mmHg Temperature ED (°C), mean ± SEM ISS, mean ± SEM ISS ≥ 25 Head AIS ≥ 3 Chest AIS ≥ 3 Abdomen AIS ≥ 3 Extremity AIS ≥ 3 Hemoglobin ED (g/dL), mean ± SEM aPTT ED (s), mean ± SEM INR ED, mean ± SEM PLT count ED (x103), mean ± SEM Fibrinogen ED (mg/dL), mean ± SEM PRBC transfusion within 24 h (Units), mean ± SEM FFP transfusion within 24 h (Units), mean ± SEM
Total (n = 26)
Cpthy (+) (n = 11)
Cpthy (−) (n = 15)
p Value
51.5 ± 4.1 46.2% (12) 80.8% (21) 11.5% (3) 35.9 ± 0.2
55.6 ± 7.1 54.5% (6) 81.8% (9) 18.2% (2) 35.7 ± 0.4
48.6 ± 4.9 40.0% (6) 80.0% (12) 6.7% (1) 36.1 ± 0.2
0.384 0.692 1.000 0.556 0.534
29.6 ± 2.0 65.4% (17) 53.8% (14) 73.1% (19) 11.5% (3) 30.8% (8) 12.1 ± 0.6
36.8 ± 3.1 90.9% (10) 54.5% (6) 100% (11) 9.1% (1) 54.5% (6) 10.7 ± 1.1
24.3 ± 1.5 46.7% (7) 53.3% (8) 53.3% (8) 13.3% (2) 13.3% (2) 13.1 ± 0.5
0.002 0.036 1.000 0.010 1.000 0.038 0.121
34.1 ± 1.2 1.38 ± 0.07 215.0 ± 14.2
37.7 ± 1.9 1.58 ± 0.10 202.9 ± 15.6
31.0 ± 1.0 1.19 ± 0.05 225.2 ± 22.9
0.009 0.003 0.649
210.3 ± 19.5
221.5 ± 32.8
199.1 ± 22.9
0.721
4.4 ± 1.2
9.2 ± 2.0
0.8 ± 0.5
b0.001
3.2 ± 1.0
7.0 ± 1.7
0.4 ± 0.4
b0.001
Abbreviations: AIS, Abbreviated Injury Scale; Cpthy, Coagulopathy; ED, Emergency Department; FFP, Fresh Frozen Plasma; INR, International Normalized Ratio; ISS, Injury Severity Score; PLT, Platelet; PRBC, Packed Red Blood Cells; aPTT, activated Partial Thromboplastin Time; SBP, Systolic Blood Pressure.
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mean TAFIa values stayed at a low level until hospital day seven before rising to a peak on hospital day nine. Comparing the two groups, coagulopathic patients showed statistically significantly lower mean TAFIa values on ED admission, and on hospital days six, seven, and eight (ED: 2.19 ± 0.86 μg/mL vs. 4.73 ± 0.88 μg/mL, p = 0.019; day six: 2.91 ± 0.59 μg/mL vs. 7.10 ± 0.94 μg/mL, p = 0.002; day seven: 3.52± 0.57 μg/mL vs. 6.84 ±0.89 μg/mL, p = 0.002; day eight: 4.12 ± 0.88 μg/mL vs. 7.93 ± 1.07 μg/mL, p = 0.021). To investigate if TAFI or TAFIa values on ED admission could be prognostic markers for acute trauma-induced coagulpathy, their predictive power was calculated using ROC. While the ROC analysis for TAFI did not show a statistically significant area under the ROC curve (AUC), TAFIa showed an optimal cutoff at 1.95 μg/mL with 70% sensitivity and 79% specificity on ED admission for predicting acute trauma-induced coagulopathy. The AUC was 0.79 (p=0.019; 95% CI: 0.58-0.99). Correlations between TAFI and TAFIa levels on ED admission, and various clinical and laboratory parameters are presented in Table 2 and Fig. 3. For TAFI levels, no statistically significant Spearman rank correlation was found with any variable included in the analysis. However, for admission TAFIa levels, statistically significant associations were noted between the coagulation profile (aPTT [Fig. 3a], INR [Fig. 3b], and PLT count) and the number of PRBC and FFP Units transfused within the initial 24 hours of admission. Discussion Both hypercoagulability and hyperfibrinolysis are important contributary mechanisms to the trauma-induced coagulopathy [2,4]. TAFI is a zymogen that is physiologically activated by the thrombin/ thrombomodulin complex to generate an enzyme with carboxypeptidase B activity, TAFIa [8,21]. Amongst other activities, TAFIa removes lysine residues from fibrin, which are essential for the binding of tPA and plasminogen to fibrin, reducing the rate at which plasmin is generated. In addition plasmin binding to fibrin is also reduced. Both these mechanisms result in an inhibition of the rate of degradation of the fibrin clot [9]. However, the role and time course of TAFI and its activated form TAFIa following major trauma has been poorly described in the literature. In the present study, decreasing TAFI values were observed until day two, presumably due to increased turn-over and consumption following major trauma while the highest level of TAFI zymogen were found on hospital day seven to nine (Fig. 1). A similar time course was found for TAFIa levels, with the lowest value seen on day one and the highest value observed on hospital day eight (Fig. 2). Overall, these
Fig. 2. Time course of TAFIa levels in severely injured trauma patients stratified into patients with and without coagulopathy. Values are given as mean ± SEM. * p b 0.05. Abbreviations: Cpthy, Coagulopathy; ED, Emergency Department; TAFIa, Activated Thrombin-Activatable Fibrinolysis Inhibitor.
time courses for TAFI and TAFIa, mirror the current understanding of trauma-associated hemostatic changes, recently described by Gando et al. [4], with an initial activation of coagulation and fibrinolysis followed by a suppression of fibrinolysis. For non-trauma patients, Watanabe and coauthors [17], found that patients with disseminated intravascular coagulation (DIC) had both lower plasma TAFI antigen and TAFIa activity than non-DIC patients. They concluded, that TAFI might play an important role in the development of DIC and that the decrease in TAFI levels might result from increased utilization during DIC. In contrast, Chen et al. [12] did not find significant differences in TAFI antigen levels between DIC- and non-DIC patients. Likewise, in a recently published study analyzing various coagulation and fibrinolysis parameters in 57 trauma patients, DIC and non-DIC patients showed no statistically significant differences in TAFI antigen levels [20]. In the current study, we did not utilize DIC criteria to identify patients with coagulopathy, but instead used global coagulation markers such as INR and aPTT, which are readily available shortly after arrival of the trauma patient to the ED. However, although traumatic coagulopathy is multifactorial, recent clinical and experimental evidence indicates that DIC with the fibrinolytic phenotype is the predominant and initial pathogenesis of coagulopathy at the early stage of trauma, making our analysis similar to earlier studies [4,22]. Comparing
Table 2 Spearman correlations between TAFI and TAFIa levels on ED admission and various clinical and laboratory parameters. TAFI ED
Age ISS Hemoglobin, ED aPTT, ED⁎ INR, ED# Fibrinogen, ED PLT Count, ED PRBC Transfusion 24 h FFP Transfusion 24 h Fig. 1. Time course of TAFI levels in severely injured trauma patients stratified into patients with and without coagulopathy. Values are given as mean ± SEM. Abbreviations: Cpthy, Coaguloapthy; ED, Emergency Department; TAFI, Thrombin-Activatable Fibrinolysis Inhibitor.
TAFIa ED
Spearman's Correlation Coefficient
p value
Spearman's Correlation Coefficient
p value
0.187 0.089 0.085 −0.234 −0.182 0.112 0.316 −0.045 0.024
0.361 0.667 0.680 0.271 0.395 0.680 0.133 0.827 0.906
0.228 −0.269 0.452 −0.512⁎ −0.476# 0.493 0.446 −0.500 −0.405
0.296 0.194 0.023 0.012⁎ 0.022# 0.062 0.033 0.011 0.044
Abbreviations: ED, Emergency Department; FFP, Fresh Frozen Plasma; INR, International Normalized Ratio; ISS, Injury Severity Score; PLT, Platelet; PRBC, Packed Red Blood Cells; aPTT, activated Partial Thromboplastin Time. ⁎ see Fig. 3a. # see Fig. 3b.
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possible. Coagulopathy was defined using crude markers of coagulation that do not describe the global fibrinolytic state. Further important variables contributing to the balance between coagulation and fibrinolysis, in particular plasminogen activator inhibitor-1 (PAI-1) and alpha-2antiplasmin should be included in future studies. Furthermore, the changes of TAFI and TAFIa might have been affected by liver dysfunction following trauma. In fact, significantly lower TAFI and TAFIa levels were noted in patients with liver cirrhosis compared to control patients [13]. However, in the present study, none of the patients included had a known pre-injury liver dysfunction; liver enzyme levels were comparable in coagulopathic and non-coagulopathic patients from the time of admission through to hospital day 10. Finally, coagulopathic patients had a higher ISS, indicating a higher amount of tissue injury, which potentially leads to a higher blood loss and a higher risk to develop coagulation disorders. However, differences in the extent of tissue damage between the two groups were not corrected for in the present analysis. In conclusion, following major trauma, both TAFI and TAFIa levels reached their nadir on hospital day two and one, respectively, with a subsequent progressive increase in their levels. While TAFI levels did not differ significantly between patients with or without traumainduced coagulopathy, TAFIa levels were reduced in coagulopathic patients. The role of TAFI and TAFIa in the development of traumainduced coagulation abnormalities and its clinical relevance warrants further investigation. Conflict of Interest Statement The authors state that they have no conflict of interest. References
Fig. 3. Correlations between TAFIa levels on ED admission and aPTT (Fig. 3a) and INR (Fig. 3b). Abbreviations: ED, Emergency Department; TAFIa, Activated ThrombinActivatable Fibrinolysis Inhibitor; aPTT, activated Partial Thromboplastin Time; INR, International Normalized Ratio.
patients with and without trauma-induced coagulopathy, we found no differences in TAFI levels, which is consistent with previous studies. However, for TAFIa levels, statistically significant differences were observed comparing the two groups at ED admission and on hospital days five to seven. These differences may be explained by our definition of coagulopathy itself; by using the coagulation markers as variables to define coagulopathy, patients with low thrombin levels and/or thrombin activity were grouped into the coagulopathic cohort. As a result, in these patients, the TAFIa activity is lower, leading to a higher vulnerability of the fibrin clot to fibrinolysis. Depletion of TAFIa might also explain these findings, although TAFI antigen levels were equal between the two groups. The predictive power of measurement of TAFIa levels on ED admission as a prognostic test for the development of acute post-traumatic coagulopathy delivered reasonable results when analyzed by ROC. To confirm its predictive efficacy, however, further clinical studies with larger sample size will be required. In our analysis, TAFIa, but not TAFI, significantly correlated with multiple laboratory and clinical parameters. From the clinical point of view, most importantly, TAFIa levels on ED admission negatively correlated with the amount of PRBC and FFP transfusion required within the first 24 hours of hospitalization. These results indicate a potentially important role for TAFIa in the regulation of excessive fibrinolysis following trauma, and implicate the need for evaluating the effect of antifibrinolytic drugs in the treatment of trauma-induced coagulopathy. The present study has several limitations, the most important being the limited sample size. Due to the small number of patients included, a more detailed analysis of the coagulation abnormalities was not
[1] Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, identification and effect. Curr Opin Crit Care 2007;13:680-5. [2] Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg 2007;245:812-8. [3] Brohi K, Cohen MJ, Ganter MT, Schultz MJ, Levi M, Mackersie RC, et al. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma 2008;64:1211-7 [discussion 1217]. [4] Gando S, Sawamura A, Hayakawa M. Trauma, shock, and disseminated intravascular coagulation: lessons from the classical literature. Ann Surg 2011;254:10-9. [5] Maegele M, Lefering R, Yucel N, Tjardes T, Rixen D, Paffrath T, et al. AG Polytrauma of the German Trauma Society (DGU). Early coagulopathy in multiple injury: an analysis from the German Trauma Registry on 8724 patients. Injury 2007;38: 298-304. [6] Lustenberger T, Talving P, Kobayashi L, Inaba K, Lam L, Plurad D, et al. Time course of coagulopathy in isolated severe traumatic brain injury. Injury 2010;41:924-8. [7] Schochl H, Frietsch T, Pavelka M, Jambor C. Hyperfibrinolysis after major trauma: differential diagnosis of lysis patterns and prognostic value of thrombelastometry. J Trauma 2009;67:125-31. [8] Bajzar L, Morser J, Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J Biol Chem 1996;271:16603-8. [9] Bouma BN, Mosnier LO. Thrombin activatable fibrinolysis inhibitor (TAFI) at the interface between coagulation and fibrinolysis. Pathophysiol Haemost Thromb 2003;33:375-81. [10] Bajzar L, Jain N, Wang P, Walker JB. Thrombin activatable fibrinolysis inhibitor: not just an inhibitor of fibrinolysis. Crit Care Med 2004;32:S320-4. [11] Boffa MB, Koschinsky ML. Curiouser and curiouser: recent advances in measurement of thrombin-activatable fibrinolysis inhibitor (TAFI) and in understanding its molecular genetics, gene regulation, and biological roles. Clin Biochem 2007;40:431-42. [12] Chen CC, Lee KD, Gau JP, Yu YB, You JY, Lee SC, et al. Plasma antigen levels of thrombin-activatable fibrinolysis inhibitor did not differ in patients with or without disseminated intravascular coagulation. Ann Hematol 2005;84:675-80. [13] Colucci M, Binetti BM, Branca MG, Clerici C, Morelli A, Semeraro N, et al. Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis. Hepatology 2003;38:230-7. [14] Gresele P, Binetti BM, Branca G, Clerici C, Asciutti S, Morelli A, et al. TAFI deficiency in liver cirrhosis: relation with plasma fibrinolysis and survival. Thromb Res 2008;121:763-8. [15] Montaner J, Ribo M, Monasterio J, Molina CA, Alvarez-Sabin J. Thrombin-activable fibrinolysis inhibitor levels in the acute phase of ischemic stroke. Stroke 2003;34: 1038-40. [16] Mosnier LO, Lisman T, van den Berg HM, Nieuwenhuis HK, Meijers JC, Bouma BN. The defective down regulation of fibrinolysis in haemophilia A can be restored by increasing the TAFI plasma concentration. Thromb Haemost 2001;86:1035-9.
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[17] Watanabe R, Wada H, Watanabe Y, Sakakura M, Nakasaki T, Mori Y, et al. Activity and antigen levels of thrombin-activatable fibrinolysis inhibitor in plasma of patients with disseminated intravascular coagulation. Thromb Res 2001;104:1-6. [18] Zeerleder S, Schroeder V, Hack CE, Kohler HP, Wuillemin WA. TAFI and PAI-1 levels in human sepsis. Thromb Res 2006;118:205-12. [19] Silveira A, Schatteman K, Goossens F, Moor E, Scharpe S, Stromqvist M, et al. Plasma procarboxypeptidase U in men with symptomatic coronary artery disease. Thromb Haemost 2000;84:364-8. [20] Hayakawa M, Sawamura A, Gando S, Kubota N, Uegaki S, Shimojima H, et al. Disseminated intravascular coagulation at an early phase of trauma is associated
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Contents lists available at SciVerse ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Activated Thrombin-Activatable Fibrinolysis Inhibitor (TAFIa) Levels are decreased in Patients With Trauma-Induced Coagulopathy T. Lustenberger a,⁎, B. Relja a, B. Puttkammer a, E.C. Gabazza b, E. Geiger a, Y. Takei c, J. Morser d, I. Marzi a a
Department of Trauma, Hand and Reconstructive Surgery, Goethe University Frankfurt am Main, Frankfurt, Germany Department of Immunology, Mie University Graduate School of Medicine, Tsu, Mie, Japan Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Mie, Japan d Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA b c
a r t i c l e
i n f o
Article history: Received 16 September 2012 Received in revised form 13 October 2012 Accepted 1 November 2012 Available online 20 November 2012
a b s t r a c t Introduction: The thrombin-activatable fibrinolysis inhibitor (TAFI) is a potent inhibitor of fibrinolysis. However, the time course of TAFI and its activated form (TAFIa) following trauma, in particular in patients suffering trauma-induced coagulopathy, has been poorly examined. Methods: A total of 26 severely injured trauma patients were prospectively enrolled. TAFI and TAFIa levels were measured upon arrival and through hospital days one to 10. Trauma-induced coagulopathy was defined as elevated international normalized ratio (INR), and/or prolonged activated partial thromboplastin time (aPTT) and/or thrombocytopenia within one day of admission. Results: TAFIa and TAFI levels showed the largest decrease on days one and two, respectively, with a progressive increase thereafter. Overall, 11 patients developed coagulopathy. No statistically significant differences were found for TAFI levels between the two groups. For TAFIa, however, coagulopathic patients experienced significantly lower levels on admission and on days six to eight (all pb 0.05). Statistically significant correlations were found between TAFIa level on admission and the amount of packed red blood cells (p=0.011; Spearman's correlation coefficient=−0.5) and fresh frozen plasma (p=0.044; Spearman's correlation coefficient=−0.405) transfused within the initial 24 hours. Conclusion: Depletion of TAFIa may contribute to the development of trauma-induced coagulopathy. © 2012 Elsevier Ltd. All rights reserved.
Introduction Acute traumatic coagulopathy is a well-recognized and frequently occurring sequela following major injury and is associated with a significantly higher mortality, increased transfusion requirements, septic complications, and longer hospital and intensive care unit lengths of stay [1–6]. Recent data suggest that hyperfibrinolysis may represent an important factor to the disturbed coagulation process following trauma [2,7]. The thrombin activatable fibrinolysis inhibitor (TAFI; also known as procarboxypeptidase B2, pCPB2 or procarboxypeptidase U, pCPU) is a carboxypeptidase B-like proenzyme and is activated by the thrombin-thrombomodulin complex at the vascular endothelial surface [8]. In its activated form (TAFIa), it inhibits fibrinolysis by removing carboxy-terminal lysine residues from fibrin which are required for efficient plasmin formation [9–11]. In recent years, the role of TAFI in thrombotic and hemorrhagic diseases has been investigated mainly in non-trauma populations [12–19]. In patients with acute ⁎ Corresponding author at: Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt / Main, Germany. Tel.: +49 69 6301 6123; fax: +49 69 6301 6439. E-mail address: [email protected] (T. Lustenberger). 0049-3848/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2012.11.005
ischemic stroke, TAFI levels were significantly higher compared to healthy volunteers [15]. Increased TAFI levels were likewise found in patients with stable angina or coronary artery disease [19]. For trauma patients however, very few studies exist examining the role of either TAFI, or its activated form, following major insults [20]. Data regarding the association between TAFI levels and traumainduced coagulopathy are likewise scarce [20]. Thus, we set out to study the time course of changes in the levels of TAFI and TAFIa in the plasma of severely injured trauma patients as well as to describe differences in plasma levels between patients with and without acute trauma-induced coagulopathy.
Patients and Methods Ethics This study was performed at the Hospital of the J. W. Goethe University with institutional ethics committee approval (167/05, in accordance with the Declaration of Helsinki and following STROBE-guidelines). All enrolled patients signed the informed consent forms, or informed consent was obtained from their legal representative.
T. Lustenberger et al. / Thrombosis Research 131 (2013) e26–e30
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Patients
Results
Inclusion criteria consisted of a history of acute blunt or penetrating trauma, an Injury Severity Score (ISS) ≥ 16, and age ≥ 18 and ≤ 80 years. Patients with known pre-existing immunological disorders, immunosuppressive and anticoagulant medications, burn patients, and patients with concomitant thromboembolic events and/ or lethal injuries were excluded from the study. All patients were treated according to the Advanced Trauma Life Support (ATLS®) guidelines. Hemodynamically stable patients underwent whole body computed tomography, whereas immediate surgery was performed in hemodynamically unstable patients ahead of further diagnostic measures. Blood samples were obtained from 26 consecutive multiply traumatized patients on admission to the emergency department (ED), and daily for 10 days following trauma. All patients had a complete blood count, chemistry panel, and coagulation panel including platelet (PLT) count, International Normalized Ratio (INR), activated partial thromboplastin time (aPTT) and plasma fibrinogen level, drawn on admission and thereafter on a daily basis. Demographic and clinical data collected included age, gender, mechanism of injury (blunt versus penetrating), blood pressure on admission, ISS, and the Abbreviated Injury Scale (AIS) score for each body region (head, chest, abdomen, and extremity). The numbers of packed red blood cells (PRBC) and fresh frozen plasma (FFP) units transfused within the initial 24 hours were recorded. Acute trauma-induced coagulopathy was defined as an INR>1.5 and/ or aPTT>40 seconds and/or thrombocytopenia (PLT countb 100,000 per mm3), within one day of admission.
The study cohort included 21 males and five females. Mean patient age was 51.5 ± 4.1 years (range: 18 to 80 years), and the mean ISS was 29.6 ± 2.0 (range: 16 to 51). All patients suffered blunt trauma. Table 1 delineates the demographics, clinical injury characteristics and a blood component summary for the first 24 hours, stratified into coagulopathic and non-coagulopathic patients. Overall, 11 patients (42.3%) developed coagulation abnormalities on admission to the ED or in the hospital during the first day. Coagulopathic patients had a significantly higher ISS and higher AIS chest and AIS extremity scores than non-coagulopathic patients. Significant bleeding sites were found in 5 patients (splenic rupture, n = 2; liver laceration, n = 1; pelvic fracture type vertical shear, n = 2). A trend towards prolonged intensive care unit length of stay was observed in coagulopathic vs. non-coagulopathic patients (19.6 ±4.5 vs. 8.9 ± 1.7 days; p = 0.054). Mean hospital length of stay was not statistically significant different between the two groups (coagulopathic vs. non-coagulopathic patients, 30.5± 4.6 vs. 24.3± 3.5 days; p = 0.33). All patients survived to hospital discharge. The routinely performed blood profile throughout the hospital stay showed no statistically significant differences comparing mean bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in coagulopathic and non-coagulopathic patients respectively. The plasma levels of TAFI were determined over the time course from ED admission through to hospital day 10 (Fig. 1). A decrease was seen by the second day in hospital, followed by a progressive increase, peaking on hospital day nine. Comparing coagulopathic and non-coagulopathic patients, no statistically significant differences were found in TAFI levels. The plasma levels of TAFIa were measured by a specific enzyme assay from time of admittance to the ED until hospital day 10 (Fig. 2). A decrease was observed on hospital day one and the highest value was found on hospital day eight. In the non-coagulopathic cohort, the mean TAFIa value showed an initial drop on hospital day one but it then started to increase progressively thereafter. Within the coagulopathic group, the
Blood Processing and Analysis The first blood samples were obtained as early as possible following admission of the patient to the ED in pre-chilled ethylenediaminetetraacetic acid (EDTA) or heparin vacuum tubes (BD vacutainer, Becton Dickinson Diagnostics, Aalst, Belgium) and kept on ice. Blood was centrifuged at 2000 ×g for 15 min at 4 °C. The supernatant was stored at − 80 °C until analysis. The mean time between injury and the acquisition of the first blood sample was 81 ± 8 min. Specimens were used for duplicate measurement of TAFI and TAFIa levels. TAFI was determined using a commercially available ELISA (IMUCLONE™ TAFI ELISA, American Diagnostica Inc., USA), according to the manufacturer's instructions. The TAFI antigen level is expressed as a percentage of pooled normal plasma (which is assigned as 100%). The lower limit of detection was ≤5%. TAFIa was determined in heparinized samples using ACTICHROME™ TAFI Activity Assay (American Diagnostica Inc., USA) according to the manufacturer's instructions.
Statistical Analysis The plasma concentrations of TAFI and TAFIa did not have a Gaussian distribution by the Kolmogoroff-Smirnoff-Lilieford's test. The p values for categorical variables were derived from the twosided Fisher's exact test, and for continuous variables from the Mann-Whitney U test. Spearman's correlation coefficients were calculated to determine correlations between TAFI/TAFIa levels and other variables. Receiver-operator curves (ROC) were generated to analyze optimal cut-off values. Values are reported as mean±standard error of the mean (SEM) for continuous variables and as percentages for categorical variables. A p value b 0.05 was considered statistically significant. All analyses were performed using the Statistical Package for Social Sciences (SPSS for Mac©), version 16.0 (SPSS Inc., Chicago, IL).
Table 1 Demographic and clinical characteristics including coagulation profile and transfusion requirements of study population.
Age (y), mean ± SEM Age ≥ 55 years Male SBP b90 mmHg Temperature ED (°C), mean ± SEM ISS, mean ± SEM ISS ≥ 25 Head AIS ≥ 3 Chest AIS ≥ 3 Abdomen AIS ≥ 3 Extremity AIS ≥ 3 Hemoglobin ED (g/dL), mean ± SEM aPTT ED (s), mean ± SEM INR ED, mean ± SEM PLT count ED (x103), mean ± SEM Fibrinogen ED (mg/dL), mean ± SEM PRBC transfusion within 24 h (Units), mean ± SEM FFP transfusion within 24 h (Units), mean ± SEM
Total (n = 26)
Cpthy (+) (n = 11)
Cpthy (−) (n = 15)
p Value
51.5 ± 4.1 46.2% (12) 80.8% (21) 11.5% (3) 35.9 ± 0.2
55.6 ± 7.1 54.5% (6) 81.8% (9) 18.2% (2) 35.7 ± 0.4
48.6 ± 4.9 40.0% (6) 80.0% (12) 6.7% (1) 36.1 ± 0.2
0.384 0.692 1.000 0.556 0.534
29.6 ± 2.0 65.4% (17) 53.8% (14) 73.1% (19) 11.5% (3) 30.8% (8) 12.1 ± 0.6
36.8 ± 3.1 90.9% (10) 54.5% (6) 100% (11) 9.1% (1) 54.5% (6) 10.7 ± 1.1
24.3 ± 1.5 46.7% (7) 53.3% (8) 53.3% (8) 13.3% (2) 13.3% (2) 13.1 ± 0.5
0.002 0.036 1.000 0.010 1.000 0.038 0.121
34.1 ± 1.2 1.38 ± 0.07 215.0 ± 14.2
37.7 ± 1.9 1.58 ± 0.10 202.9 ± 15.6
31.0 ± 1.0 1.19 ± 0.05 225.2 ± 22.9
0.009 0.003 0.649
210.3 ± 19.5
221.5 ± 32.8
199.1 ± 22.9
0.721
4.4 ± 1.2
9.2 ± 2.0
0.8 ± 0.5
b0.001
3.2 ± 1.0
7.0 ± 1.7
0.4 ± 0.4
b0.001
Abbreviations: AIS, Abbreviated Injury Scale; Cpthy, Coagulopathy; ED, Emergency Department; FFP, Fresh Frozen Plasma; INR, International Normalized Ratio; ISS, Injury Severity Score; PLT, Platelet; PRBC, Packed Red Blood Cells; aPTT, activated Partial Thromboplastin Time; SBP, Systolic Blood Pressure.
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mean TAFIa values stayed at a low level until hospital day seven before rising to a peak on hospital day nine. Comparing the two groups, coagulopathic patients showed statistically significantly lower mean TAFIa values on ED admission, and on hospital days six, seven, and eight (ED: 2.19 ± 0.86 μg/mL vs. 4.73 ± 0.88 μg/mL, p = 0.019; day six: 2.91 ± 0.59 μg/mL vs. 7.10 ± 0.94 μg/mL, p = 0.002; day seven: 3.52± 0.57 μg/mL vs. 6.84 ±0.89 μg/mL, p = 0.002; day eight: 4.12 ± 0.88 μg/mL vs. 7.93 ± 1.07 μg/mL, p = 0.021). To investigate if TAFI or TAFIa values on ED admission could be prognostic markers for acute trauma-induced coagulpathy, their predictive power was calculated using ROC. While the ROC analysis for TAFI did not show a statistically significant area under the ROC curve (AUC), TAFIa showed an optimal cutoff at 1.95 μg/mL with 70% sensitivity and 79% specificity on ED admission for predicting acute trauma-induced coagulopathy. The AUC was 0.79 (p=0.019; 95% CI: 0.58-0.99). Correlations between TAFI and TAFIa levels on ED admission, and various clinical and laboratory parameters are presented in Table 2 and Fig. 3. For TAFI levels, no statistically significant Spearman rank correlation was found with any variable included in the analysis. However, for admission TAFIa levels, statistically significant associations were noted between the coagulation profile (aPTT [Fig. 3a], INR [Fig. 3b], and PLT count) and the number of PRBC and FFP Units transfused within the initial 24 hours of admission. Discussion Both hypercoagulability and hyperfibrinolysis are important contributary mechanisms to the trauma-induced coagulopathy [2,4]. TAFI is a zymogen that is physiologically activated by the thrombin/ thrombomodulin complex to generate an enzyme with carboxypeptidase B activity, TAFIa [8,21]. Amongst other activities, TAFIa removes lysine residues from fibrin, which are essential for the binding of tPA and plasminogen to fibrin, reducing the rate at which plasmin is generated. In addition plasmin binding to fibrin is also reduced. Both these mechanisms result in an inhibition of the rate of degradation of the fibrin clot [9]. However, the role and time course of TAFI and its activated form TAFIa following major trauma has been poorly described in the literature. In the present study, decreasing TAFI values were observed until day two, presumably due to increased turn-over and consumption following major trauma while the highest level of TAFI zymogen were found on hospital day seven to nine (Fig. 1). A similar time course was found for TAFIa levels, with the lowest value seen on day one and the highest value observed on hospital day eight (Fig. 2). Overall, these
Fig. 2. Time course of TAFIa levels in severely injured trauma patients stratified into patients with and without coagulopathy. Values are given as mean ± SEM. * p b 0.05. Abbreviations: Cpthy, Coagulopathy; ED, Emergency Department; TAFIa, Activated Thrombin-Activatable Fibrinolysis Inhibitor.
time courses for TAFI and TAFIa, mirror the current understanding of trauma-associated hemostatic changes, recently described by Gando et al. [4], with an initial activation of coagulation and fibrinolysis followed by a suppression of fibrinolysis. For non-trauma patients, Watanabe and coauthors [17], found that patients with disseminated intravascular coagulation (DIC) had both lower plasma TAFI antigen and TAFIa activity than non-DIC patients. They concluded, that TAFI might play an important role in the development of DIC and that the decrease in TAFI levels might result from increased utilization during DIC. In contrast, Chen et al. [12] did not find significant differences in TAFI antigen levels between DIC- and non-DIC patients. Likewise, in a recently published study analyzing various coagulation and fibrinolysis parameters in 57 trauma patients, DIC and non-DIC patients showed no statistically significant differences in TAFI antigen levels [20]. In the current study, we did not utilize DIC criteria to identify patients with coagulopathy, but instead used global coagulation markers such as INR and aPTT, which are readily available shortly after arrival of the trauma patient to the ED. However, although traumatic coagulopathy is multifactorial, recent clinical and experimental evidence indicates that DIC with the fibrinolytic phenotype is the predominant and initial pathogenesis of coagulopathy at the early stage of trauma, making our analysis similar to earlier studies [4,22]. Comparing
Table 2 Spearman correlations between TAFI and TAFIa levels on ED admission and various clinical and laboratory parameters. TAFI ED
Age ISS Hemoglobin, ED aPTT, ED⁎ INR, ED# Fibrinogen, ED PLT Count, ED PRBC Transfusion 24 h FFP Transfusion 24 h Fig. 1. Time course of TAFI levels in severely injured trauma patients stratified into patients with and without coagulopathy. Values are given as mean ± SEM. Abbreviations: Cpthy, Coaguloapthy; ED, Emergency Department; TAFI, Thrombin-Activatable Fibrinolysis Inhibitor.
TAFIa ED
Spearman's Correlation Coefficient
p value
Spearman's Correlation Coefficient
p value
0.187 0.089 0.085 −0.234 −0.182 0.112 0.316 −0.045 0.024
0.361 0.667 0.680 0.271 0.395 0.680 0.133 0.827 0.906
0.228 −0.269 0.452 −0.512⁎ −0.476# 0.493 0.446 −0.500 −0.405
0.296 0.194 0.023 0.012⁎ 0.022# 0.062 0.033 0.011 0.044
Abbreviations: ED, Emergency Department; FFP, Fresh Frozen Plasma; INR, International Normalized Ratio; ISS, Injury Severity Score; PLT, Platelet; PRBC, Packed Red Blood Cells; aPTT, activated Partial Thromboplastin Time. ⁎ see Fig. 3a. # see Fig. 3b.
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possible. Coagulopathy was defined using crude markers of coagulation that do not describe the global fibrinolytic state. Further important variables contributing to the balance between coagulation and fibrinolysis, in particular plasminogen activator inhibitor-1 (PAI-1) and alpha-2antiplasmin should be included in future studies. Furthermore, the changes of TAFI and TAFIa might have been affected by liver dysfunction following trauma. In fact, significantly lower TAFI and TAFIa levels were noted in patients with liver cirrhosis compared to control patients [13]. However, in the present study, none of the patients included had a known pre-injury liver dysfunction; liver enzyme levels were comparable in coagulopathic and non-coagulopathic patients from the time of admission through to hospital day 10. Finally, coagulopathic patients had a higher ISS, indicating a higher amount of tissue injury, which potentially leads to a higher blood loss and a higher risk to develop coagulation disorders. However, differences in the extent of tissue damage between the two groups were not corrected for in the present analysis. In conclusion, following major trauma, both TAFI and TAFIa levels reached their nadir on hospital day two and one, respectively, with a subsequent progressive increase in their levels. While TAFI levels did not differ significantly between patients with or without traumainduced coagulopathy, TAFIa levels were reduced in coagulopathic patients. The role of TAFI and TAFIa in the development of traumainduced coagulation abnormalities and its clinical relevance warrants further investigation. Conflict of Interest Statement The authors state that they have no conflict of interest. References
Fig. 3. Correlations between TAFIa levels on ED admission and aPTT (Fig. 3a) and INR (Fig. 3b). Abbreviations: ED, Emergency Department; TAFIa, Activated ThrombinActivatable Fibrinolysis Inhibitor; aPTT, activated Partial Thromboplastin Time; INR, International Normalized Ratio.
patients with and without trauma-induced coagulopathy, we found no differences in TAFI levels, which is consistent with previous studies. However, for TAFIa levels, statistically significant differences were observed comparing the two groups at ED admission and on hospital days five to seven. These differences may be explained by our definition of coagulopathy itself; by using the coagulation markers as variables to define coagulopathy, patients with low thrombin levels and/or thrombin activity were grouped into the coagulopathic cohort. As a result, in these patients, the TAFIa activity is lower, leading to a higher vulnerability of the fibrin clot to fibrinolysis. Depletion of TAFIa might also explain these findings, although TAFI antigen levels were equal between the two groups. The predictive power of measurement of TAFIa levels on ED admission as a prognostic test for the development of acute post-traumatic coagulopathy delivered reasonable results when analyzed by ROC. To confirm its predictive efficacy, however, further clinical studies with larger sample size will be required. In our analysis, TAFIa, but not TAFI, significantly correlated with multiple laboratory and clinical parameters. From the clinical point of view, most importantly, TAFIa levels on ED admission negatively correlated with the amount of PRBC and FFP transfusion required within the first 24 hours of hospitalization. These results indicate a potentially important role for TAFIa in the regulation of excessive fibrinolysis following trauma, and implicate the need for evaluating the effect of antifibrinolytic drugs in the treatment of trauma-induced coagulopathy. The present study has several limitations, the most important being the limited sample size. Due to the small number of patients included, a more detailed analysis of the coagulation abnormalities was not
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