ORIGINAL ARTICLE
Hypercoagulability and other risk factors in trauma intensive care unit patients with venous thromboembolism Robert M. Van Haren, MD, MSPH, Evan J. Valle, MD, Chad M. Thorson, MD, MSPH, Jassin M. Jouria, MD, Alexander M. Busko, BS, Gerardo A. Guarch, MD, Nicholas Namias, MD, MBA, Alan S. Livingstone, MD, and Kenneth G. Proctor, PhD, Miami, Florida
Thromboelastography (TEG) on hospital admission can identify hypercoagulable trauma patients at risk for venous thromboembolism (VTE), but the value of TEGs obtained after multiple interventions, including tranexamic acid (TXA), has not been defined. We test the following hypotheses. (1) TEG on intensive care unit (ICU) admission can help stratify patients screened with Greenfield’s risk assessment profile (RAP) for VTE. (2) TXA is a VTE risk factor, and its effect on fibrinolysis can be identified with TEG. METHODS: Trauma patients who survived to the ICU with RAP Q 10 received serial venous duplex ultrasound examinations and blood samples for coagulation analysis at admission to the ICU and weekly thereafter. RESULTS: Six hundred seventy-eight patients were screened and 121 were enrolled; 76% blunt injury, Injury Severity Score (ISS) 27, 13% mortality. Thromboprophylaxis was administered to 90% of the patients and was started a median of 2 days after hospital admission. VTE was detected in 28% (n = 34) of the patients (27 deep vein thrombosis and 7 pulmonary emboli) and occurred a median 10 days after admission. Twenty-nine percent (n = 10) of VTE occurred within 2 days of admission. Most variables were similar between those with and without VTE, but the VTE group received more operations (3 (2) vs. 2 (2), p = 0.044), had increased ICU days (25 (34) days vs. 15 (18) days, p = 0.004), and was more likely to have abdominal injury with Abbreviated Injury Scale (AIS) score 9 2 (59% vs. 39%, p = 0.050). Upon ICU admission, standard coagulation markers were within normal limits, while TEG demonstrated hypercoagulability, but neither was associated with VTE. Repeat TEG one week after admission (n = 58) remained hypercoagulable but transitioned to a different pattern with increased clot strength. TXA was associated with reduced fibrinolysis on initial TEG (p G 0.05) but was not associated with VTE. CONCLUSION: Trauma ICU patients with RAP Q 10 are hypercoagulable at admission to ICU and remain so during recovery. They have a Q 25% rate of VTE, despite thromboprophylaxis. TXA is associated with reduced fibrinolysis but does not increase VTE rates. Neither TEG nor standard coagulation markers (measured on ICU admission) stratify high-risk patients who develop VTE from those who do not. (J Trauma Acute Care Surg. 2014;76: 443Y449. Copyright * 2014 by Lippincott Williams & Wilkins) LEVEL OF EVIDENCE: Prognostic study, level III. KEY WORDS: Thromboelastography; tranexamic acid; venous duplex ultrasound. BACKGROUND:
T
rauma alters coagulation1,2 and is associated with deep vein thrombosis (DVT) and pulmonary embolism (PE), which increases morbidity, mortality, and hospital length of stay.3Y5 Risk factors associated with venous thromboemboism (VTE) include hypercoagulability, preexisting conditions, location and severity of injury, as well as iatrogenic interventions (e.g., central venous catheters [CVCs], transfusions, surgery).6Y8 Collectively, these factors have been assembled into a risk assessment profile (RAP) for trauma.9 Submitted: July 19, 2013, Revised: August 13, 2013, Accepted: August 13, 2013. From the Dewitt-Daughtry Family Department of Surgery, University of Miami Miller School of Medicine and Ryder Trauma Center, Miami, Florida. Portions of these data were presented at Society of Critical Care Medicine Annual Congress, January 19Y23, 2013, in San Juan, Puerto Rico, and at the American College of Surgeons 2013 Clinical CongressVSurgical Forum October 6Y10, 2013, in Washington, District of Columbia. Address for reprints: Kenneth G. Proctor, PhD, Divisions of Trauma and Surgical Critical Care, Daughtry Family Department of Surgery, University of Miami School of Medicine, Ryder Trauma Center, 1800 NW 10th Ave, Miami, FL; email: [email protected]. DOI: 10.1097/TA.0b013e3182a9d11d
Another potential risk factor for VTE is tranexamic acid (TXA), which is now widely used during trauma resuscitation. TXA is a synthetic derivative of lysine that competitively inhibits the activation of plasminogen to plasmin, which reduces fibrinolysis. There is strong evidence that TXA reduces mortality in bleeding trauma patients, but there is concern about potential adverse events.10Y12 The VTE rate in a given population depends on the number of risk factors. Most trauma patients are relatively healthy, and the VTE rate is G 5%,6Y12 whereas in a previous study, we identified a 9 25% VTE rate in trauma intensive care unit (ICU) patients with RAP Q 10.13 Thromboelastography (TEG) provides a comprehensive overview of clotting and fibrinolysis and is more sensitive than prothrombin time (PT) and activated partial thromboplastin time (aPTT) for diagnosing hypercoagulability.14 TEG on hospital admission can diagnose injury-induced hypocoagulability or hypercoagulability15Y19 and can identify patients who will develop VTE.20 However, the value of a TEG later during the hospitalization has not been well defined. Many different factors during the diagnostic workup and initial resuscitation
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(e.g. TXA, blood product transfusions, surgical intervention) can potentially alter a TEG value. Even placement of a CVC can produce hypercoagulability.21,22 To our knowledge, no previous study has tested the hypotheses that (1) TEG on ICU admission can help to stratify RAP-screened trauma patients at high risk for VTE and (2) TXA is a VTE risk factor and its effect on fibrinolysis can be identified with TEG.
PATIENTS AND METHODS An institutional review boardYapproved prospective observational trial was conducted with informed consent between August 2011 and March 2013. Individuals who were pregnant, incarcerated, G 18 years of age, and with delayed presentation were excluded. All ICU admissions were screened with RAP.9,13 Patients with a RAP Q 10 and an indwelling CVC or arterial catheter were enrolled. Our cutoff of a RAP Q 10 was arbitrary but based on a balance of missing a rare event (i.e., VTE) versus wasting money (i.e., unnecessary venous duplex ultrasound [VDU]) in a population who receives routine thromboprophylaxis. Upon admission to the ICU, it is divisional practice to order bilateral lower extremity VDU and blood samples for those with RAP Q 10. Repeat VDU and blood samples were obtained weekly for those who remained in the ICU. VDU evaluated the deep venous systems of lower extremities from the ankle to the inguinal ligament, as previously described.13 Additional VDU were ordered in between weekly surveillance for symptoms such as leg swelling. Surveillance VDU of the upper extremities was not performed. DVT was defined as a VDU abnormality, such as dilated, noncompressible veins or intraluminal shadows consistent with thrombosis. PEs were diagnosed with CT angiography after symptoms of hypoxemia, tachycardia, or both. PE was defined as a filling defect of pulmonary vasculature on CT angiography. Blood was drawn into two vacuum-sealed tubes containing sodium citrate (6 mL). After 15 minutes, an aliquot (340 HL) was transferred to the TEG (Thrombelastograph Hemostasis Analyzer Model 5000 System, Braintree, MA) and reconstituted using 20 HL of calcium chloride. TEG was performed in duplicate on native whole blood samples with no activation material.19 TEG parameters included: reaction time (R), k time (K), > angle (in degree), maximum amplitude (MA), G value (G), and LY30.19 Hypercoagulability was defined by values outside standard reference ranges, specifically R G 9 minutes, K G 2 minutes, > angle 9 58-, or MA of 9 64 mm. The normal range of LY30 in healthy adults is 0% to 7.5%.23 However, LY30 9 3% may be clinically significant.23,24 TXA was administered according to divisional practice within 3 hours of admission (only in patients with suspected life-threatening hemorrhage) as a 1-g bolus IV, followed by a 1-g infusion over 8 hours.25 Similarly, heparin (5,000 IU SQ three times daily) or dalteparin (5,000 IU SQ once daily) was administered according to divisional practice for chemical thromboprophylaxis, as guided by the hospital formulary. There is no written protocol for either. Mechanical prophylaxis was used if not prohibited by plaster immobilizers or external fixators. 444
Data were analyzed using SPSS (IBM Corporation, Armonk, NY) and reported as mean T standard deviation if normally distributed or median(interquartile range) if not normally distributed. Independent data were compared with Student’s t test and Mann-Whitney U-test for parametric and nonparametric data, respectively. Categorical data were compared with W2 or Fisher’s exact test. For paired data, analysis was conducted using paired t or Wilcoxon signed-rank tests, and McNemar tests for categorical data. Multiple logistic regression was performed to identify factors independently associated with VTE. Variables with p G 0.2 on bivariate analysis were included in the regression analysis. Significance was assessed at p G 0.05.
RESULTS There were 678 patients screened and 121 enrolled and analyzed (Fig. 1), age 48(33) years, 81% male, 76% blunt trauma, ISS 27 T 11, 17(22) ICU days, and 13% mortality. Chemical VTE thromboprophylaxis was administered to 90% and was started 2 (3) days after hospital admission. Of the patients, 50% received heparin, 38% received dalteparin, 2% heparin drip, and 10% received no prophylaxis. VTE was detected in 28% (n = 34) and occurred 10 (15) days after admission. Twenty-nine percent of VTE (n = 10) occurred within two days of admission. The majority were DVT (n = 27, 79%), and the remaining were PE (n = 7, 21%). Half were asymptomatic, and half were symptomatic (n = 10 DVT and n = 7 PE). Among the patients with PE, only one patient
Figure 1. CONSORT flow diagram. * 2014 Lippincott Williams & Wilkins
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TABLE 1. Patients with VTE vs. No VTE
Age Sex, male, % Mechanism, blunt, % Traumatic brain injury, % RAP score ISS Emergency operations, % No. operations TXA, % 24-h blood products PRBC, U Fresh frozen plasma, U Platelets, U Cryoprecipitate, U Coagulation values TEG R, min TEG K, min TEG >,TEG MA, mm TEG G, dyn/cm2 PT, s INR aPTT s Platelets, 103/HL Outcome ICU days Length of stay Mortality, %
No VTE (n = 87)
VTE (n = 34)
p
51 (33) 79 78 48 15 (6) 26 T 11 63 2 (2) 21
47 (28) 85 71 38 15 (5) 29 T 13 74 3 (2) 27
0.058 0.451 0.380 0.319 0.241 0.238 0.281 0.044 0.492
4 (8) 2 (7) 0 (1) 0 (0)
6 (8) 3 (6) 0 (1) 0 (0)
0.216 0.353 0.672 0.405
7.1 (2.8) 1.9 (0.7) 63.9 (8.9) 60.0 T 6.9 7,592 (2,826) 12.0 (1.9) 1.0 (0.2) 26.6 (6.6) 239 (80)
7.7 (3.8) 2.1 (0.5) 61.8 (8.2) 58.6 T 7.2 6,784 (2,857) 11.5 (1.5) 1.0 (0.1) 26.0 (6.4) 232 (123)
0.283 0.272 0.263 0.333 0.307 0.958 0.978 0.571 0.363
15 (18) 28 (27) 16
25 (34) 33 (49) 6
0.004 0.060 0.227
Table 1 shows that most variables were similar between VTE and no-VTE groups, including conventional coagulation parameters (INR, PT, and PTT) and TEG (R, K, > angle, MA, or G). The only differences were that the VTE group received more operations (3 (2) vs. 2 (2), p = 0.044), had increased ICU days (25 (34) days vs. 15 (18) days, p = 0.004), and was more likely to have abdominal injury with Abbreviated Injury Scale (AIS) score 92 (59% vs. 39%, p = 0.050). No other risk factors were different between groups (Table 2). Repeat samples were obtained from 58 patients one week after admission (Table 3). There was an increase in VTE risk factors including CVC/peripherally inserted central catheter (PICC) (76% vs. 95%, p = 0.001) and percentage of those who received surgery (67% vs. 88%, p = 0.021). In this cohort, 91% had at least one TEG value outside the normal reference range indicating initial hypercoagulability. The repeat TEG demonstrated not only increased MA (60.1 T 7.3 mm vs. 73.3 T 8.2 mm) and increased G (7,902 (3,091) dyn/cm2 vs. 14,884 (8,548) dyn/cm2) (all p G 0.001) but also a paradoxically prolonged R (7.6 (3.0) vs. 9.5 (4.5) minutes, p G 0.001). The most striking change was that MA was outside the reference range in 33% at ICU admission but in 93% at Week 1 ( p G 0.001).
TABLE 2. Risk Factors No VTE (n = 87) VTE (n = 34)
had concurrent DVT. Because all PEs were symptomatic, not all patients received VDU on the same day as diagnosis of PE. Three patients had VDU on the same day as PE diagnosis, one of which identified DVT. Three patients had VDU 1Y5 days before PE diagnosis, and all were negative. One patient did not have VDU at the time of PE diagnosis. There was no difference in VTE rates between patients who received heparin and dalteparin thromboprophylaxis (23% vs. 26%, p = 0.708), between thromboprophylaxis and no thromboprophylaxis (26% vs. 50%, p = 0.094), or between early (within 2 days) and delayed (92 days) thromboprophylaxis (30% vs. 23%, p = 0.426). The average time from admission to hospital to initial TEG was 1.7 T 0.6 days. TEG was hypercoagulable in 86% of the patients, based on at least one value outside the normal reference range. R was decreased in 78%, K was decreased in 56%, > angle was increased in 75%, and MA was increased in 27%. Most (n = 89, 74%) had more than one abnormality. The population values were: R = 7.1 (2.9) minutes; K = 1.9 (0.7) minutes; > angle, 63.1- (8.9-), and MA = 60.3 (9.0) mm. There was no significant difference in VTE rates between patients who were or were not hypercoagulable on admission (27% vs. 35%, p = 0.562).
RAP variables Obesity, (BMI 9 30 kg/m2) Malignancy Abnormal coagulation factors History of VTE Femoral line 94 transfusions in 24 h OR 9 2 h Vascular injury AIS chest 9 2 AIS abdomen 9 2 AIS head 9 2 GCS score G 8 Lower-extremity fracture Pelvic fracture Spinal cord injury Age 40Y59 y Age 60Y75 y Age 9 75 y Additional risk factors Central line Central/PICC line Arterial line PPX, % Days to PPX Switched PPX Mechanical PPX
p
37% 2% 53% 1% 21% 70% 52% 32% 49% 39% 47% 36% 32% 43% 3% 28% 29% 9%
35% 0% 65% 0% 18% 79% 65% 44% 53% 59% 41% 41% 38% 47% 12% 41% 9% 6%
0.878 1.0 0.238 1.0 0.706 0.302 0.197 0.218 0.728 0.050 0.555 0.571 0.527 0.652 0.096 0.148 0.020 0.724
64% 67% 97% 93% 3 (3) 14% 83%
68% 74% 97% 82% 2 (3) 11% 91%
0.733 0.465 1.0 0.094 0.563 1.0 0.714
AIS, Abbreviated Injury Scale; BMI, body mass index; GCS, Glasgow Coma Scale; OR, operative intervention; PPX, thromboprophylaxis.
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TABLE 3. Initial and 1-Week Repeat Samples n = 58 TEG Values R, min K, min >,MA, mm G, dyn/cm2 Values based on TEG reference range % hypercoagulable R % hypercoagulable K % hypercoagulable > % hypercoagulable MA At least 1 variable hypercoagulable, % 91 variable hypercoagulable, % Risk factors Central line, % Central/PICC line, % Arterial line, % OR before TEG
Initial
Repeat 1 wk
p
7.6 (3.0) 1.8 (0.6) 62.8 (7.1) 60.0 T 7.3 7,902 (3,091)
9.5 (4.5) 1.8 (1.5) 67.6 (13.6) 73.3 T 8.2 14,884 (8,548)
G0.001 0.677 0.080 G0.001 G0.001
81 60 78 33 91
45 60 74 93 95
G0.001 1.0 0.815 G0.001 0.727
87
76
0.503
71 76 95 67
81 95 90 88
0.109 0.001 0.375 0.021
OR, operative intervention.
TABLE 4. Patients Administered TXA Versus No TXA No TXA (n = 94)
Table 4 compares trauma patients who received TXA with those who did not. Age and sex were similar, but the TXA group was more critically injured with decreased blood pressure (97 T 25 mm Hg vs. 128 T 39 mm Hg, p G 0.001), pH (7.24 (0.13) vs. 7.35 (0.12), p = 0.003) and more blood products in the first 24 hours (packed red blood cell, fresh frozen plasma, platelet, and cryoprecipitate; all p G 0.001). TXA was associated with reduced fibrinolysis on initial TEG, as reflected by decreased LY30 (0.1 (0.3) vs. 0.6 (1.2), p G 0.001). TXA did not significantly affect R, K, > angle, MA, or G. There was no significant difference in VTE rates (27% vs. 33%, p = 0.492), despite higher RAP score after TXA (16 (4) vs. 14 (5), p = 0.005) and several additional risk factors such as: 9 4 transfusions (100% vs. 65%, p G 0.001), major vascular injury (74% vs. 25%, p G 0.001), CVC/PICC (85% vs. 64%, p = 0.035), and number of operations (3 (4) vs. 2 (2), p = 0.001). Repeat samples at one week (n = 13) demonstrated restoration of fibrinolysis with increased LY30 (0.2 (0.3) vs. 1.3 (9.6), p = 0.021). On multivariate logistic regression, variables independently associated with VTE development were no thromboprophylaxis (odds ratio, 5.32; p = 0.025), ICU days (odds ratio, 1.04; p = 0.002), and age (odds ratio, 0.974; p = 0.044). TXA and hypercoagulable TEG values were not independently associated with VTE development.
DISCUSSION There are several new findings in this present study. Most trauma patients with a RAP Q 10 (985%) were hypercoagulable on ICU admission, albeit by TEG not standard coagulation markers. Most of these patients remained hypercoagulable on 446
TEG after one week in the ICU, despite thromboprophylaxis. Patients who developed VTE received more operations, had increased ICU days, and were more likely to have abdominal injury. TEG on ICU admission did not discriminate between those with and without VTE. TXA was associated with reduced fibrinolysis that was restored at one week, and TXA was not associated with increased VTE rates in this high-risk cohort of trauma patients. To our knowledge, this is the first study to demonstrate TXA’s effects on fibrinolysis with TEG in trauma ICU patients at the highest risk for VTE. Thus, the variables independently associated with VTE development included no thromboprophylaxis, increased ICU days, and decreased age, but not TEG or TXA. Since all patients in this study population had RAP Q 10 and were screened with weekly VDU, a high VTE rate is expected. Other studies have also demonstrated that VTE rates depend on the RAP score.8,9,26,27 Altogether, these data further support the idea that VTEs should not be considered a ‘‘never’’ event,13 at least in the trauma ICU and especially when patients have high RAP scores.
TXA (n = 27)
Age 49 (36) 48 (19) Sex, male, % 82 78 Mechanism, blunt, % 80 63 TBI, % 48 37 RAP score 14 (5) 16 (4) ISS 26 T 10 31 T 15 OR, % 62 82 No. operations 2 (2) 3 (4) Admission vital signs and laboratory values GCS 14 (9) 9 (12) Heart rate 102 T 27 108 T 24 Systolic blood pressure 128 T 39 97 T 25 pH 7.35 (0.12) 7.24 (0.13) Base excess j5.0 (5.5) j6.0 (9.5) 24-h blood products PRBC 4 (4) 16 (14) FFP 2 (4) 9 (9) Platelet 0 (1) 1 (2) Cryoprecipitate 0 (0) 0 (1) TEG values R, min 7.0 (2.7) 7.7 (3.2) K, min 1.8 (0.7) 2.1 (0.6) >,63.8 (9.8) 62.4 (6.7) MA, mm 59.8 T 6.7 59.0 T 7.9 G, dyn/cm2 7,822 (2,705) 6,589 (2,872) LY30, % 0.6 (1.2) 0.1 (0.3) Outcomes VTE, % 27 33 ICU days 16 (21) 22 (31) Length of stay 29 (28) 36 (41) Mortality, % 12 15
p 0.983 0.629 0.071 0.319 0.005 0.117 0.056 0.001
0.166 0.080 G0.001 0.003 0.064 G0.001 G0.001 0.001 G0.001 0.180 0.179 0.540 0.609 0.287 G0.001 0.492 0.242 0.185 0.740
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Neither standard coagulation markers nor TEG on ICU admission predicted VTE development in these conditions. Van et al26 compared enoxaparin-neutralized and enoxaparinactive TEGs in the ICU; they observed a 28% DVT rate, and R time was 1.5 minutes shorter in patients with DVT. Cotton et al17 performed rapid TEG (r-TEG) on 2,070 consecutive trauma activations; they observed a 2.5% PE rate, and MA was 3 mm higher in those with PE. Recently, in burn patients, we reported a reduced R time in those who developed DVT.19 In all these previous studies, including our own, the difference in TEG was ‘‘statistically’’ significant, but it might be difficult to make clinical decisions based on an R or MA values that are only slightly outside the normal range. There are several possible reasons why we were unable to reproduce the finding that TEG discriminates trauma patients who develop VTE. One is that we only obtained blood samples from those with preexisting catheters. Our two previous studies showed that indwelling catheters can cause almost 50% reductions in TEG values.21,22 Another concerns the characteristics of study population. Cotton et al17 evaluated consecutive trauma admissions and included patients with hypo-, hyper-, or normo-coagulation status on hospital admission. Others likewise evaluated consecutive patients, and the VTE rates were relatively low.18,20,24 In contrast, our study focused on G 20% of those trauma patients who survived to the ICU, all of whom had a RAP Q 10, and the VTE rates were almost 10 times higher. This was obviously nonconsecutive and a small fraction of overall admissions to the trauma center. Most of these patients (985%) were hypercoagulable from a combination of comorbidities, injury-related factors, and numerous iatrogenic interventions. Regardless of the role of TEG, per se, hypercoagulability is only one of several risk factors for VTE. The available evidence suggests that hypercoagulability is neither necessary nor sufficient for VTE development. Hypercoagulability can be broadly defined based on special coagulation tests and/or TEG, but there is little consensus. There is no routine laboratory test for hypercoagulability, and shortened PT or PTT have little relevance. Various studies identify differences in TEG R time,19,26 MA,17 and platelet numbers or function.28 In this present study, hypercoagulability was defined as one or more TEG variables outside the standard reference range. Sensitivity of other viscoelastic methods, such as r-TEG compared with conventional TEG, probably cannot explain the inability to predict VTE. Lee et al29 demonstrated a strong correlation between r-TEG and conventional TEG for MA (r = 0.80). However, other variables had weaker correlations: G (r = 0.70), K (r = 0.66), > angle (r = 0.38), and LY30 (r = 0.19).27 They also reported that both TEG and r-TEG failed to differentiate VTE.29 The most conservative interpretation of these present results, in context with the earlier work, is that numerous iatrogenic interventions during diagnostic workup and stabilization promote a hypercoagulable state, so that a TEG obtained on ICU admission cannot reliably stratify VTE risk. Timing is a critical determinant of the predictive ability of TEG. Repeat samples at one week remained hypercoagulable despite thromboprophylaxis. There was a transition to increased overall clot strength (increased MA and G) with an increased R. The combination of increased overall clot strength and increased
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MA may reflect the increased contribution of platelets to overall coagulation. In fact, Harr et al28 demonstrated that platelets are dominant contributors to hypercoagulability. This transition was associated with changes in risk factors such as increased CVC/ PICC and operative intervention. We observed that TXA treatment during fluid resuscitation was associated with reduced fibrinolysis at admission to the ICU, characterized by decreased LY30. These changes were temporary, and fibrinolysis was restored at one week. Patients who received TXA had higher RAP scores and several increased risk factors such as: 9 4 transfusions in 24 hours, major vascular injury, CVC/PICC, and surgery. Despite these increased risk factors, there was no significant difference in VTE rates (27% vs. 33%, p = 0.492). This finding is important because in the MATTERs study from the battlefields of Iraq and Afghanistan, Morrison et al11 reported increased VTE in those who received TXA. There are several differences that must be considered between the MATTERs study11 and this present study. First, the military patients were younger (25 years vs. 50 years) and a higher proportion was male (95% vs. 82%). Second, the injuries were different (70% explosion vs. 0% explosion). Third, more were hypocoagulable at admission (25% vs. G5%), which is relevant because hypocoagulable and hyperfibrinolytic patients are most responsive to TXA.30 Fourth, more received transfusions. Fifth, no thromboprophylaxis was mentioned in the MATTERs study, but thromboprophylaxis was administered to 90% of the patients in our study. Thus, further work is necessary to establish the risk/benefit and determine if salutary effects associated with TXA are caused by its antifibrinolytic properties or to mechanisms such as reduced inflammation.30 TEG has been used to guide intraoperative blood product administration during transplant and cardiac surgery.31,32 In trauma, TEG has been used to identify coagulopathy and manage blood transfusion.20,33Y36 Recently, TEG has been used to guide thromboprophylaxis. Harr et al.28 performed a randomized clinical trial comparing TEG-guided dosing of dalteparin to standard dosing. There were no differences in VTE rates between groups. Furthermore, escalating doses of dalteparin had no effect on TEG parameters such as R and G, suggesting that trauma patients develop a hypercoagulability that is resistant to heparin-based thromboprophylaxis. A better understanding of coagulation pathophysiology is needed to effectively implement TEG strategies into thromboprophylaxis guidelines. The traditional paradigm is that DVT and PE are different temporal phases of the VTE disease process. However, that idea has recently been challenged in patients with severe blunt injury. Brakenridge et al.37 showed that DVT and PE had different risk factor profiles in blunt trauma patients. Independent risk factors associated with DVT include thromboprophylaxis initiation after 48 hours, thoracic AIS Q 3, and abdominal AIS Q 3, while independent risk factors for PE were serum lactate level 9 5, male sex, and thoracic AIS Q 3. Both DVT and PE exhibited differing risk factor profiles from the classic composite end point of VTE. They speculated that DVT and PE after injury may represent a broad spectrum of pathologic thrombotic processes as opposed to the current conventional wisdom of peripheral thrombosis and subsequent embolus. Our
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results are consistent with this novel idea because, among seven patients with PE, only one patient had concurrent DVT. There are some major assumptions and several limitations to this observational, single-center study. Most importantly, the population was composed of only trauma patients who survived to the ICU with RAP Q 10 and who received VDU. This may have created a selection and surveillance bias. Furthermore, there are other scoring systems that may be more valid. In any case, no medical decisions were based on the results. TEG was only performed after TXA administration and therefore can only demonstrate an association with reduced fibrinolysis, not absolute cause and effect. Initial TEG was performed at admission to the ICU, rather than before and after, so multiple iatrogenic (operations, line placements, etc.) as well as temporal factors could confound that value. TEG was only performed weekly and may not capture coagulation status at the time of VTE development. Our study was also underpowered to identify some statistically significant differences when clinically significant differences were apparent (i.e., prophylaxis vs. no prophylaxis). In conclusion, high-risk trauma ICU patients with RAP Q 10 are hypercoagulable on admission to ICU and remain so during recovery. They have a high rate of VTE, despite thromboprophylaxis. TXA is associated with reduced fibrinolysis but does not increase VTE rates. Neither TEG nor standard coagulation markers stratify high-risk patients who develop VTE and those who do not. AUTHORSHIP R.M.V.H. is directly responsible for all aspects of this study. He participated in the conception and experimental design; collection, analysis, and interpretation of data; as well as drafting and revision of the manuscript, figures, and tables. E.J.V. participated in the collection of data as well as revision of the manuscript, figures, and tables. C.M.T. participated in the conception and experimental design, collection of data, as well as revision of the manuscript, figures, and tables. J.M.J. participated in the collection of data. A.M.B. participated in the collection of data. G.A.G. participated in the collection of data. N.N. was medically responsible for the patients in this study; treatments were administered at his discretion. In addition, he participated in the conception and experimental design, analysis and interpretation of data, as well as revision of the manuscript, figures, and tables. A.S.L. participated in the conception and experimental design, analysis and interpretation of data, as well as revision of the manuscript, figures, and tables. K.G.P. had overall responsibility for the study, including conception and experimental design; analysis and interpretation of data; drafting and revision of the manuscript, figures, and tables; statistical expertise and evaluation; obtaining funding for this project; as well as supervision.
DISCLOSURE This study was supported in part by grant #N140610670 from the Office of Naval Research and grant #09078015 from the US Army Medical Research and Materiel Command.
REFERENCES 1. Selby R, Geerts W, Ofosu FA, Craven S, Dewar L, Phillips A, Szalai JP. Hypercoagulability after trauma: hemostatic changes and relationship to venous thromboembolism. Thromb Res. 2009;124(3):281Y287. 2. Differding JA, Underwood SJ, Van PY, Khaki RA, Spoerke NJ, Schreiber MA. Trauma induces a hypercoagulable state that is resistant to hypothermia as measured by thrombelastogram. Am J Surg. 2011;201(5): 587Y591.
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3. Geerts WH, Code KI, Jay RM, Chen E, Szalai JP. A prospective study of venous thromboembolism after major trauma. N Engl J Med. 1994; 331(24):1601Y1606. 4. Knudson MM, Ikossi DG, Khaw L, Morabito D, Speetzen LS. Thromboembolism after trauma: an analysis of 1602 episodes from the American College of Surgeons National Trauma Data Bank. Ann Surg. 2004; 240(3):490Y496; discussion 496Y498. 5. Knudson MM, Gomez D, Haas B, Cohen MJ, Nathens AB. Three thousand seven hundred thirty-eight posttraumatic pulmonary emboli: a new look at an old disease. Ann Surg. 2011;254(4):625Y632. 6. Gearhart MM, Luchette FA, Proctor MC, Lutomski DM, Witsken C, James L, Davis K Jr, Johannigman JA, Hurst JM, Frame SB. The risk assessment profile score identifies trauma patients at risk for deep vein thrombosis. Surgery. 2000;128(4):631Y640. 7. Haut ER, Chang DC, Pierce CA, Colantuoni E, Efron DT, Haider AH, Cornwell EE 3rd, Pronovost PJ. Predictors of posttraumatic deep vein thrombosis (DVT): hospital practice versus patient factors-an analysis of the National Trauma Data Bank (NTDB). J Trauma. 2009;66(4):994Y999; discussion 999Y1001. 8. Rogers FB, Cipolle MD, Velmahos G, Rozycki G, Luchette FA. Practice management guidelines for the prevention of venous thromboembolism in trauma patients: the EAST practice management guidelines work group. J Trauma. 2002;53(1):142Y164. 9. Greenfield LJ, Proctor MC, Rodriguez JL, Luchette FA, Cipolle MD, Cho J. Posttrauma thromboembolism prophylaxis. J Trauma. 1997;42(1): 100Y103. 10. CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-Sayed H, Gogichaishvili T, Gupta S, Herrera J, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376(9734):23Y32. 11. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) study. Arch Surg. 2012;147(2):113Y119. 12. Pusateri AE, Weiskopf RB, Bebarta V, Butler F, Cestero RF, Chaudry IH, Deal V, Dorlac WC, Gerhardt RT, Given MB, et al.; US DoD Hemorrhage and Resuscitation Research and Development Steering Committee. Tranexamic acid and trauma: current status and knowledge gaps with recommended research priorities. Shock. 2013;39(2):121Y126. 13. Thorson CM, Ryan ML, Van Haren RM, Curia E, Barrera JM, Guarch GA, Busko AM, Namias N, Livingstone AS, Proctor KG. Venous thromboembolism after trauma: a never event? Crit Care Med. 2012;40(11): 2967Y2973. 14. Park MS, Martini WZ, Dubick MA, Salinas J, Butenas S, Kheirabadi BS, Pusateri AE, Vos JA, Guymon CH, Wolf SE, et al. Thromboelastography as a better indicator of hypercoagulable state after injury than prothrombin time or activated partial thromboplastin time. J Trauma. 2009;67(2):266Y275; discussion 275Y276. 15. Kaufmann CR, Dwyer KM, Crews JD, Dols SJ, Trask AL. Usefulness of thrombelastography in assessment of trauma patient coagulation. J Trauma. 1997;42(4):716Y720; discussion 720Y722. 16. Kashuk JL, Moore EE, Sabel A, Barnett C, Haenel J, Le T, Pezold M, Lawrence J, Biffl WL, Cothren CC, et al. Rapid thrombelastography (r-TEG) identifies hypercoagulability and predicts thromboembolic events in surgical patients. Surgery. 2009;146(4):764Y772; discussion 772Y774. 17. Cotton BA, Minei KM, Radwan ZA, Matijevic N, Pivalizza E, Podbielski J, Wade CE, Kozar RA, Holcomb JB. Admission rapid thrombelastography predicts development of pulmonary embolism in trauma patients. J Trauma Acute Care Surg. 2012;72(6):1470Y1475; discussion 1475Y1477. 18. Schreiber MA, Differding J, Thorborg P, Mayberry JC, Mullins RJ. Hypercoagulability is most prevalent early after injury and in female patients. J Trauma. 2005;58(3):475Y480; discussion 480Y481. 19. Van Haren RM, Thorson CM, Valle EJ, Busko AM, Guarch GA, Andrews DM, Pizano LR, Schulman CI, Namias N, Proctor KG. Hypercoagulability after burn injury. J Trauma Acute Care Surg. 2013;75(1):37Y43. 20. Cotton BA, Faz G, Hatch QM, Radwan ZA, Podbielski J, Wade C, Kozar RA, Holcomb JB. Rapid thrombelastography delivers real-time results that predict transfusion within 1 hour of admission. J Trauma. 2011;71(2):407Y414; discussion 414Y417.
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21. King DR, Cohn SM, Feinstein AJ, Proctor KG. Systemic coagulation changes caused by pulmonary artery catheters: laboratory findings and clinical correlation. J Trauma. 2005;59(4):853Y857; discussion 857Y859. 22. Ryan ML, Thorson CM, King DR, Van Haren RM, Manning RJ, Andrews DM, Livingstone AS, Proctor KG. Insertion of central venous catheters induces a hypercoagulable state. J Trauma Acute Care Surg. 2012;73(2): 385Y390. 23. Cotton BA, Harvin JA, Kostousouv V, Minei KM, Radwan ZA, Scho¨chl H, Wade CE, Holcomb JB, Matijevic N. Hyperfibrinolysis at admission is an uncommon but highly lethal event associated with shock and prehospital fluid administration. J Trauma Acute Care Surg. 2012;73(2):365Y370; discussion 370. 24. Holcomb JB, Minei KM, Scerbo ML, Radwan ZA, Wade CE, Kozar RA, Gill BS, Albarado R, McNutt MK, Khan S, et al. Admission rapid thrombelastography can replace conventional coagulation tests in the emergency department: experience with 1974 consecutive trauma patients. Ann Surg. 2012;256(3):476Y486. 25. Napolitano LM, Cohen MJ, Cotton BA, Schreiber MA, Moore EE. Tranexamic acid in trauma: how should we use it? J Trauma Acute Care Surg. 2013;74(6):1575Y1586. 26. Van PY, Cho SD, Underwood SJ, Morris MS, Watters JM, Schreiber MA. Thrombelastography versus AntiFactor Xa levels in the assessment of prophylactic-dose enoxaparin in critically ill patients. J Trauma. 2009; 66(6):1509Y1515; discussion 1515Y1517. 27. Bandle J, Shackford SR, Kahl JE, Sise CB, Calvo RY, Shackford MC, Sise MJ. The value of lower-extremity duplex surveillance to detect deep vein thrombosis in trauma patients. J Trauma Acute Care Surg. 2013;74(2): 575Y580. 28. Harr JN, Moore EE, Chin TL, Ghasabyan A, Gonzalez E, Wohlauer MV, Banerjee A, Silliman CC, Sauaia A. Platelets are dominant contributors to hypercoagulability after injury. J Trauma Acute Care Surg. 2013;74(3): 756Y762; discussion 762Y765. 29. Lee TH, McCully BH, Underwood SJ, Cotton BA, Cohen MJ, Schreiber MA. Correlation of conventional thrombelastography and rapid thrombelastography in trauma. Am J Surg. 2013;205(5):521Y527; discussion 527.
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30. Jimenez JJ, Iribarren JL, Lorente L, Rodriguez JM, Hernandez D, Nassar I, Perez R, Brouard M, Milena A, Martinez R, et al. Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial. Crit Care. 2007;11(6):R117. 31. Wang SC, Shieh JF, Chang KY, Chu YC, Liu CS, Loong CC, Chan KH, Mandell S, Tsou MY. Thromboelastography-guided transfusion decreases intraoperative blood transfusion during orthotopic liver transplantation: randomized clinical trial. Transplant Proc. 2010;42(7):2590Y2593. 32. Johansson PI, Sølbeck S, Genet G, Stensballe J, Ostrowski SR. Coagulopathy and hemostatic monitoring in cardiac surgery: an update. Scand Cardiovasc J. 2012;46(4):194Y202. 33. Kashuk JL, Moore EE, Wohlauer M, Johnson JL, Pezold M, Lawrence J, Biffl WL, Burlew CC, Barnett C, Sawyer M, et al. Initial experiences with point-of-care rapid thrombelastography for management of life-threatening postinjury coagulopathy. Transfusion. 2012;52(1):23Y33. 34. Kashuk JL, Moore EE, Sawyer M, Wohlauer M, Pezold M, Barnett C, Biffl WL, Burlew CC, Johnson JL, Sauaia A. Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma. Ann Surg. 2010;252(3):434Y442; discussion 443Y444. 35. Kashuk JL, Moore EE, Sawyer M, Le T, Johnson J, Biffl WL, Cothren CC, Barnett C, Stahel P, Sillman CC, et al. Postinjury coagulopathy management: goal directed resuscitation via POC thrombelastography. Ann Surg. 2010;251(4):604Y614. 36. Tapia NM, Chang A, Norman M, Welsh F, Scott B, Wall MJ Jr, Mattox KL, Suliburk J. TEG-guided resuscitation is superior to standardized MTP resuscitation in massively transfused penetrating trauma patients. J Trauma Acute Care Surg. 2013;74(2):378Y385; discussion 385Y386. 37. Brakenridge SC, Henley SS, Kashner TM, Golden RM, Paik DH, Phelan HA, Cohen MJ, Sperry JL, Moore EE, Minei JP, et al.; Inflammation and the Host Response to Injury Investigators. Comparing clinical predictors of deep venous thrombosis versus pulmonary embolus after severe injury: a new paradigm for posttraumatic venous thromboembolism? J Trauma Acute Care Surg. 2013;74(5):1231Y1237; discussion 1237Y1238.
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Hypercoagulability and other risk factors in trauma intensive care unit patients with venous thromboembolism Robert M. Van Haren, MD, MSPH, Evan J. Valle, MD, Chad M. Thorson, MD, MSPH, Jassin M. Jouria, MD, Alexander M. Busko, BS, Gerardo A. Guarch, MD, Nicholas Namias, MD, MBA, Alan S. Livingstone, MD, and Kenneth G. Proctor, PhD, Miami, Florida
Thromboelastography (TEG) on hospital admission can identify hypercoagulable trauma patients at risk for venous thromboembolism (VTE), but the value of TEGs obtained after multiple interventions, including tranexamic acid (TXA), has not been defined. We test the following hypotheses. (1) TEG on intensive care unit (ICU) admission can help stratify patients screened with Greenfield’s risk assessment profile (RAP) for VTE. (2) TXA is a VTE risk factor, and its effect on fibrinolysis can be identified with TEG. METHODS: Trauma patients who survived to the ICU with RAP Q 10 received serial venous duplex ultrasound examinations and blood samples for coagulation analysis at admission to the ICU and weekly thereafter. RESULTS: Six hundred seventy-eight patients were screened and 121 were enrolled; 76% blunt injury, Injury Severity Score (ISS) 27, 13% mortality. Thromboprophylaxis was administered to 90% of the patients and was started a median of 2 days after hospital admission. VTE was detected in 28% (n = 34) of the patients (27 deep vein thrombosis and 7 pulmonary emboli) and occurred a median 10 days after admission. Twenty-nine percent (n = 10) of VTE occurred within 2 days of admission. Most variables were similar between those with and without VTE, but the VTE group received more operations (3 (2) vs. 2 (2), p = 0.044), had increased ICU days (25 (34) days vs. 15 (18) days, p = 0.004), and was more likely to have abdominal injury with Abbreviated Injury Scale (AIS) score 9 2 (59% vs. 39%, p = 0.050). Upon ICU admission, standard coagulation markers were within normal limits, while TEG demonstrated hypercoagulability, but neither was associated with VTE. Repeat TEG one week after admission (n = 58) remained hypercoagulable but transitioned to a different pattern with increased clot strength. TXA was associated with reduced fibrinolysis on initial TEG (p G 0.05) but was not associated with VTE. CONCLUSION: Trauma ICU patients with RAP Q 10 are hypercoagulable at admission to ICU and remain so during recovery. They have a Q 25% rate of VTE, despite thromboprophylaxis. TXA is associated with reduced fibrinolysis but does not increase VTE rates. Neither TEG nor standard coagulation markers (measured on ICU admission) stratify high-risk patients who develop VTE from those who do not. (J Trauma Acute Care Surg. 2014;76: 443Y449. Copyright * 2014 by Lippincott Williams & Wilkins) LEVEL OF EVIDENCE: Prognostic study, level III. KEY WORDS: Thromboelastography; tranexamic acid; venous duplex ultrasound. BACKGROUND:
T
rauma alters coagulation1,2 and is associated with deep vein thrombosis (DVT) and pulmonary embolism (PE), which increases morbidity, mortality, and hospital length of stay.3Y5 Risk factors associated with venous thromboemboism (VTE) include hypercoagulability, preexisting conditions, location and severity of injury, as well as iatrogenic interventions (e.g., central venous catheters [CVCs], transfusions, surgery).6Y8 Collectively, these factors have been assembled into a risk assessment profile (RAP) for trauma.9 Submitted: July 19, 2013, Revised: August 13, 2013, Accepted: August 13, 2013. From the Dewitt-Daughtry Family Department of Surgery, University of Miami Miller School of Medicine and Ryder Trauma Center, Miami, Florida. Portions of these data were presented at Society of Critical Care Medicine Annual Congress, January 19Y23, 2013, in San Juan, Puerto Rico, and at the American College of Surgeons 2013 Clinical CongressVSurgical Forum October 6Y10, 2013, in Washington, District of Columbia. Address for reprints: Kenneth G. Proctor, PhD, Divisions of Trauma and Surgical Critical Care, Daughtry Family Department of Surgery, University of Miami School of Medicine, Ryder Trauma Center, 1800 NW 10th Ave, Miami, FL; email: [email protected]. DOI: 10.1097/TA.0b013e3182a9d11d
Another potential risk factor for VTE is tranexamic acid (TXA), which is now widely used during trauma resuscitation. TXA is a synthetic derivative of lysine that competitively inhibits the activation of plasminogen to plasmin, which reduces fibrinolysis. There is strong evidence that TXA reduces mortality in bleeding trauma patients, but there is concern about potential adverse events.10Y12 The VTE rate in a given population depends on the number of risk factors. Most trauma patients are relatively healthy, and the VTE rate is G 5%,6Y12 whereas in a previous study, we identified a 9 25% VTE rate in trauma intensive care unit (ICU) patients with RAP Q 10.13 Thromboelastography (TEG) provides a comprehensive overview of clotting and fibrinolysis and is more sensitive than prothrombin time (PT) and activated partial thromboplastin time (aPTT) for diagnosing hypercoagulability.14 TEG on hospital admission can diagnose injury-induced hypocoagulability or hypercoagulability15Y19 and can identify patients who will develop VTE.20 However, the value of a TEG later during the hospitalization has not been well defined. Many different factors during the diagnostic workup and initial resuscitation
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(e.g. TXA, blood product transfusions, surgical intervention) can potentially alter a TEG value. Even placement of a CVC can produce hypercoagulability.21,22 To our knowledge, no previous study has tested the hypotheses that (1) TEG on ICU admission can help to stratify RAP-screened trauma patients at high risk for VTE and (2) TXA is a VTE risk factor and its effect on fibrinolysis can be identified with TEG.
PATIENTS AND METHODS An institutional review boardYapproved prospective observational trial was conducted with informed consent between August 2011 and March 2013. Individuals who were pregnant, incarcerated, G 18 years of age, and with delayed presentation were excluded. All ICU admissions were screened with RAP.9,13 Patients with a RAP Q 10 and an indwelling CVC or arterial catheter were enrolled. Our cutoff of a RAP Q 10 was arbitrary but based on a balance of missing a rare event (i.e., VTE) versus wasting money (i.e., unnecessary venous duplex ultrasound [VDU]) in a population who receives routine thromboprophylaxis. Upon admission to the ICU, it is divisional practice to order bilateral lower extremity VDU and blood samples for those with RAP Q 10. Repeat VDU and blood samples were obtained weekly for those who remained in the ICU. VDU evaluated the deep venous systems of lower extremities from the ankle to the inguinal ligament, as previously described.13 Additional VDU were ordered in between weekly surveillance for symptoms such as leg swelling. Surveillance VDU of the upper extremities was not performed. DVT was defined as a VDU abnormality, such as dilated, noncompressible veins or intraluminal shadows consistent with thrombosis. PEs were diagnosed with CT angiography after symptoms of hypoxemia, tachycardia, or both. PE was defined as a filling defect of pulmonary vasculature on CT angiography. Blood was drawn into two vacuum-sealed tubes containing sodium citrate (6 mL). After 15 minutes, an aliquot (340 HL) was transferred to the TEG (Thrombelastograph Hemostasis Analyzer Model 5000 System, Braintree, MA) and reconstituted using 20 HL of calcium chloride. TEG was performed in duplicate on native whole blood samples with no activation material.19 TEG parameters included: reaction time (R), k time (K), > angle (in degree), maximum amplitude (MA), G value (G), and LY30.19 Hypercoagulability was defined by values outside standard reference ranges, specifically R G 9 minutes, K G 2 minutes, > angle 9 58-, or MA of 9 64 mm. The normal range of LY30 in healthy adults is 0% to 7.5%.23 However, LY30 9 3% may be clinically significant.23,24 TXA was administered according to divisional practice within 3 hours of admission (only in patients with suspected life-threatening hemorrhage) as a 1-g bolus IV, followed by a 1-g infusion over 8 hours.25 Similarly, heparin (5,000 IU SQ three times daily) or dalteparin (5,000 IU SQ once daily) was administered according to divisional practice for chemical thromboprophylaxis, as guided by the hospital formulary. There is no written protocol for either. Mechanical prophylaxis was used if not prohibited by plaster immobilizers or external fixators. 444
Data were analyzed using SPSS (IBM Corporation, Armonk, NY) and reported as mean T standard deviation if normally distributed or median(interquartile range) if not normally distributed. Independent data were compared with Student’s t test and Mann-Whitney U-test for parametric and nonparametric data, respectively. Categorical data were compared with W2 or Fisher’s exact test. For paired data, analysis was conducted using paired t or Wilcoxon signed-rank tests, and McNemar tests for categorical data. Multiple logistic regression was performed to identify factors independently associated with VTE. Variables with p G 0.2 on bivariate analysis were included in the regression analysis. Significance was assessed at p G 0.05.
RESULTS There were 678 patients screened and 121 enrolled and analyzed (Fig. 1), age 48(33) years, 81% male, 76% blunt trauma, ISS 27 T 11, 17(22) ICU days, and 13% mortality. Chemical VTE thromboprophylaxis was administered to 90% and was started 2 (3) days after hospital admission. Of the patients, 50% received heparin, 38% received dalteparin, 2% heparin drip, and 10% received no prophylaxis. VTE was detected in 28% (n = 34) and occurred 10 (15) days after admission. Twenty-nine percent of VTE (n = 10) occurred within two days of admission. The majority were DVT (n = 27, 79%), and the remaining were PE (n = 7, 21%). Half were asymptomatic, and half were symptomatic (n = 10 DVT and n = 7 PE). Among the patients with PE, only one patient
Figure 1. CONSORT flow diagram. * 2014 Lippincott Williams & Wilkins
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TABLE 1. Patients with VTE vs. No VTE
Age Sex, male, % Mechanism, blunt, % Traumatic brain injury, % RAP score ISS Emergency operations, % No. operations TXA, % 24-h blood products PRBC, U Fresh frozen plasma, U Platelets, U Cryoprecipitate, U Coagulation values TEG R, min TEG K, min TEG >,TEG MA, mm TEG G, dyn/cm2 PT, s INR aPTT s Platelets, 103/HL Outcome ICU days Length of stay Mortality, %
No VTE (n = 87)
VTE (n = 34)
p
51 (33) 79 78 48 15 (6) 26 T 11 63 2 (2) 21
47 (28) 85 71 38 15 (5) 29 T 13 74 3 (2) 27
0.058 0.451 0.380 0.319 0.241 0.238 0.281 0.044 0.492
4 (8) 2 (7) 0 (1) 0 (0)
6 (8) 3 (6) 0 (1) 0 (0)
0.216 0.353 0.672 0.405
7.1 (2.8) 1.9 (0.7) 63.9 (8.9) 60.0 T 6.9 7,592 (2,826) 12.0 (1.9) 1.0 (0.2) 26.6 (6.6) 239 (80)
7.7 (3.8) 2.1 (0.5) 61.8 (8.2) 58.6 T 7.2 6,784 (2,857) 11.5 (1.5) 1.0 (0.1) 26.0 (6.4) 232 (123)
0.283 0.272 0.263 0.333 0.307 0.958 0.978 0.571 0.363
15 (18) 28 (27) 16
25 (34) 33 (49) 6
0.004 0.060 0.227
Table 1 shows that most variables were similar between VTE and no-VTE groups, including conventional coagulation parameters (INR, PT, and PTT) and TEG (R, K, > angle, MA, or G). The only differences were that the VTE group received more operations (3 (2) vs. 2 (2), p = 0.044), had increased ICU days (25 (34) days vs. 15 (18) days, p = 0.004), and was more likely to have abdominal injury with Abbreviated Injury Scale (AIS) score 92 (59% vs. 39%, p = 0.050). No other risk factors were different between groups (Table 2). Repeat samples were obtained from 58 patients one week after admission (Table 3). There was an increase in VTE risk factors including CVC/peripherally inserted central catheter (PICC) (76% vs. 95%, p = 0.001) and percentage of those who received surgery (67% vs. 88%, p = 0.021). In this cohort, 91% had at least one TEG value outside the normal reference range indicating initial hypercoagulability. The repeat TEG demonstrated not only increased MA (60.1 T 7.3 mm vs. 73.3 T 8.2 mm) and increased G (7,902 (3,091) dyn/cm2 vs. 14,884 (8,548) dyn/cm2) (all p G 0.001) but also a paradoxically prolonged R (7.6 (3.0) vs. 9.5 (4.5) minutes, p G 0.001). The most striking change was that MA was outside the reference range in 33% at ICU admission but in 93% at Week 1 ( p G 0.001).
TABLE 2. Risk Factors No VTE (n = 87) VTE (n = 34)
had concurrent DVT. Because all PEs were symptomatic, not all patients received VDU on the same day as diagnosis of PE. Three patients had VDU on the same day as PE diagnosis, one of which identified DVT. Three patients had VDU 1Y5 days before PE diagnosis, and all were negative. One patient did not have VDU at the time of PE diagnosis. There was no difference in VTE rates between patients who received heparin and dalteparin thromboprophylaxis (23% vs. 26%, p = 0.708), between thromboprophylaxis and no thromboprophylaxis (26% vs. 50%, p = 0.094), or between early (within 2 days) and delayed (92 days) thromboprophylaxis (30% vs. 23%, p = 0.426). The average time from admission to hospital to initial TEG was 1.7 T 0.6 days. TEG was hypercoagulable in 86% of the patients, based on at least one value outside the normal reference range. R was decreased in 78%, K was decreased in 56%, > angle was increased in 75%, and MA was increased in 27%. Most (n = 89, 74%) had more than one abnormality. The population values were: R = 7.1 (2.9) minutes; K = 1.9 (0.7) minutes; > angle, 63.1- (8.9-), and MA = 60.3 (9.0) mm. There was no significant difference in VTE rates between patients who were or were not hypercoagulable on admission (27% vs. 35%, p = 0.562).
RAP variables Obesity, (BMI 9 30 kg/m2) Malignancy Abnormal coagulation factors History of VTE Femoral line 94 transfusions in 24 h OR 9 2 h Vascular injury AIS chest 9 2 AIS abdomen 9 2 AIS head 9 2 GCS score G 8 Lower-extremity fracture Pelvic fracture Spinal cord injury Age 40Y59 y Age 60Y75 y Age 9 75 y Additional risk factors Central line Central/PICC line Arterial line PPX, % Days to PPX Switched PPX Mechanical PPX
p
37% 2% 53% 1% 21% 70% 52% 32% 49% 39% 47% 36% 32% 43% 3% 28% 29% 9%
35% 0% 65% 0% 18% 79% 65% 44% 53% 59% 41% 41% 38% 47% 12% 41% 9% 6%
0.878 1.0 0.238 1.0 0.706 0.302 0.197 0.218 0.728 0.050 0.555 0.571 0.527 0.652 0.096 0.148 0.020 0.724
64% 67% 97% 93% 3 (3) 14% 83%
68% 74% 97% 82% 2 (3) 11% 91%
0.733 0.465 1.0 0.094 0.563 1.0 0.714
AIS, Abbreviated Injury Scale; BMI, body mass index; GCS, Glasgow Coma Scale; OR, operative intervention; PPX, thromboprophylaxis.
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TABLE 3. Initial and 1-Week Repeat Samples n = 58 TEG Values R, min K, min >,MA, mm G, dyn/cm2 Values based on TEG reference range % hypercoagulable R % hypercoagulable K % hypercoagulable > % hypercoagulable MA At least 1 variable hypercoagulable, % 91 variable hypercoagulable, % Risk factors Central line, % Central/PICC line, % Arterial line, % OR before TEG
Initial
Repeat 1 wk
p
7.6 (3.0) 1.8 (0.6) 62.8 (7.1) 60.0 T 7.3 7,902 (3,091)
9.5 (4.5) 1.8 (1.5) 67.6 (13.6) 73.3 T 8.2 14,884 (8,548)
G0.001 0.677 0.080 G0.001 G0.001
81 60 78 33 91
45 60 74 93 95
G0.001 1.0 0.815 G0.001 0.727
87
76
0.503
71 76 95 67
81 95 90 88
0.109 0.001 0.375 0.021
OR, operative intervention.
TABLE 4. Patients Administered TXA Versus No TXA No TXA (n = 94)
Table 4 compares trauma patients who received TXA with those who did not. Age and sex were similar, but the TXA group was more critically injured with decreased blood pressure (97 T 25 mm Hg vs. 128 T 39 mm Hg, p G 0.001), pH (7.24 (0.13) vs. 7.35 (0.12), p = 0.003) and more blood products in the first 24 hours (packed red blood cell, fresh frozen plasma, platelet, and cryoprecipitate; all p G 0.001). TXA was associated with reduced fibrinolysis on initial TEG, as reflected by decreased LY30 (0.1 (0.3) vs. 0.6 (1.2), p G 0.001). TXA did not significantly affect R, K, > angle, MA, or G. There was no significant difference in VTE rates (27% vs. 33%, p = 0.492), despite higher RAP score after TXA (16 (4) vs. 14 (5), p = 0.005) and several additional risk factors such as: 9 4 transfusions (100% vs. 65%, p G 0.001), major vascular injury (74% vs. 25%, p G 0.001), CVC/PICC (85% vs. 64%, p = 0.035), and number of operations (3 (4) vs. 2 (2), p = 0.001). Repeat samples at one week (n = 13) demonstrated restoration of fibrinolysis with increased LY30 (0.2 (0.3) vs. 1.3 (9.6), p = 0.021). On multivariate logistic regression, variables independently associated with VTE development were no thromboprophylaxis (odds ratio, 5.32; p = 0.025), ICU days (odds ratio, 1.04; p = 0.002), and age (odds ratio, 0.974; p = 0.044). TXA and hypercoagulable TEG values were not independently associated with VTE development.
DISCUSSION There are several new findings in this present study. Most trauma patients with a RAP Q 10 (985%) were hypercoagulable on ICU admission, albeit by TEG not standard coagulation markers. Most of these patients remained hypercoagulable on 446
TEG after one week in the ICU, despite thromboprophylaxis. Patients who developed VTE received more operations, had increased ICU days, and were more likely to have abdominal injury. TEG on ICU admission did not discriminate between those with and without VTE. TXA was associated with reduced fibrinolysis that was restored at one week, and TXA was not associated with increased VTE rates in this high-risk cohort of trauma patients. To our knowledge, this is the first study to demonstrate TXA’s effects on fibrinolysis with TEG in trauma ICU patients at the highest risk for VTE. Thus, the variables independently associated with VTE development included no thromboprophylaxis, increased ICU days, and decreased age, but not TEG or TXA. Since all patients in this study population had RAP Q 10 and were screened with weekly VDU, a high VTE rate is expected. Other studies have also demonstrated that VTE rates depend on the RAP score.8,9,26,27 Altogether, these data further support the idea that VTEs should not be considered a ‘‘never’’ event,13 at least in the trauma ICU and especially when patients have high RAP scores.
TXA (n = 27)
Age 49 (36) 48 (19) Sex, male, % 82 78 Mechanism, blunt, % 80 63 TBI, % 48 37 RAP score 14 (5) 16 (4) ISS 26 T 10 31 T 15 OR, % 62 82 No. operations 2 (2) 3 (4) Admission vital signs and laboratory values GCS 14 (9) 9 (12) Heart rate 102 T 27 108 T 24 Systolic blood pressure 128 T 39 97 T 25 pH 7.35 (0.12) 7.24 (0.13) Base excess j5.0 (5.5) j6.0 (9.5) 24-h blood products PRBC 4 (4) 16 (14) FFP 2 (4) 9 (9) Platelet 0 (1) 1 (2) Cryoprecipitate 0 (0) 0 (1) TEG values R, min 7.0 (2.7) 7.7 (3.2) K, min 1.8 (0.7) 2.1 (0.6) >,63.8 (9.8) 62.4 (6.7) MA, mm 59.8 T 6.7 59.0 T 7.9 G, dyn/cm2 7,822 (2,705) 6,589 (2,872) LY30, % 0.6 (1.2) 0.1 (0.3) Outcomes VTE, % 27 33 ICU days 16 (21) 22 (31) Length of stay 29 (28) 36 (41) Mortality, % 12 15
p 0.983 0.629 0.071 0.319 0.005 0.117 0.056 0.001
0.166 0.080 G0.001 0.003 0.064 G0.001 G0.001 0.001 G0.001 0.180 0.179 0.540 0.609 0.287 G0.001 0.492 0.242 0.185 0.740
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Neither standard coagulation markers nor TEG on ICU admission predicted VTE development in these conditions. Van et al26 compared enoxaparin-neutralized and enoxaparinactive TEGs in the ICU; they observed a 28% DVT rate, and R time was 1.5 minutes shorter in patients with DVT. Cotton et al17 performed rapid TEG (r-TEG) on 2,070 consecutive trauma activations; they observed a 2.5% PE rate, and MA was 3 mm higher in those with PE. Recently, in burn patients, we reported a reduced R time in those who developed DVT.19 In all these previous studies, including our own, the difference in TEG was ‘‘statistically’’ significant, but it might be difficult to make clinical decisions based on an R or MA values that are only slightly outside the normal range. There are several possible reasons why we were unable to reproduce the finding that TEG discriminates trauma patients who develop VTE. One is that we only obtained blood samples from those with preexisting catheters. Our two previous studies showed that indwelling catheters can cause almost 50% reductions in TEG values.21,22 Another concerns the characteristics of study population. Cotton et al17 evaluated consecutive trauma admissions and included patients with hypo-, hyper-, or normo-coagulation status on hospital admission. Others likewise evaluated consecutive patients, and the VTE rates were relatively low.18,20,24 In contrast, our study focused on G 20% of those trauma patients who survived to the ICU, all of whom had a RAP Q 10, and the VTE rates were almost 10 times higher. This was obviously nonconsecutive and a small fraction of overall admissions to the trauma center. Most of these patients (985%) were hypercoagulable from a combination of comorbidities, injury-related factors, and numerous iatrogenic interventions. Regardless of the role of TEG, per se, hypercoagulability is only one of several risk factors for VTE. The available evidence suggests that hypercoagulability is neither necessary nor sufficient for VTE development. Hypercoagulability can be broadly defined based on special coagulation tests and/or TEG, but there is little consensus. There is no routine laboratory test for hypercoagulability, and shortened PT or PTT have little relevance. Various studies identify differences in TEG R time,19,26 MA,17 and platelet numbers or function.28 In this present study, hypercoagulability was defined as one or more TEG variables outside the standard reference range. Sensitivity of other viscoelastic methods, such as r-TEG compared with conventional TEG, probably cannot explain the inability to predict VTE. Lee et al29 demonstrated a strong correlation between r-TEG and conventional TEG for MA (r = 0.80). However, other variables had weaker correlations: G (r = 0.70), K (r = 0.66), > angle (r = 0.38), and LY30 (r = 0.19).27 They also reported that both TEG and r-TEG failed to differentiate VTE.29 The most conservative interpretation of these present results, in context with the earlier work, is that numerous iatrogenic interventions during diagnostic workup and stabilization promote a hypercoagulable state, so that a TEG obtained on ICU admission cannot reliably stratify VTE risk. Timing is a critical determinant of the predictive ability of TEG. Repeat samples at one week remained hypercoagulable despite thromboprophylaxis. There was a transition to increased overall clot strength (increased MA and G) with an increased R. The combination of increased overall clot strength and increased
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MA may reflect the increased contribution of platelets to overall coagulation. In fact, Harr et al28 demonstrated that platelets are dominant contributors to hypercoagulability. This transition was associated with changes in risk factors such as increased CVC/ PICC and operative intervention. We observed that TXA treatment during fluid resuscitation was associated with reduced fibrinolysis at admission to the ICU, characterized by decreased LY30. These changes were temporary, and fibrinolysis was restored at one week. Patients who received TXA had higher RAP scores and several increased risk factors such as: 9 4 transfusions in 24 hours, major vascular injury, CVC/PICC, and surgery. Despite these increased risk factors, there was no significant difference in VTE rates (27% vs. 33%, p = 0.492). This finding is important because in the MATTERs study from the battlefields of Iraq and Afghanistan, Morrison et al11 reported increased VTE in those who received TXA. There are several differences that must be considered between the MATTERs study11 and this present study. First, the military patients were younger (25 years vs. 50 years) and a higher proportion was male (95% vs. 82%). Second, the injuries were different (70% explosion vs. 0% explosion). Third, more were hypocoagulable at admission (25% vs. G5%), which is relevant because hypocoagulable and hyperfibrinolytic patients are most responsive to TXA.30 Fourth, more received transfusions. Fifth, no thromboprophylaxis was mentioned in the MATTERs study, but thromboprophylaxis was administered to 90% of the patients in our study. Thus, further work is necessary to establish the risk/benefit and determine if salutary effects associated with TXA are caused by its antifibrinolytic properties or to mechanisms such as reduced inflammation.30 TEG has been used to guide intraoperative blood product administration during transplant and cardiac surgery.31,32 In trauma, TEG has been used to identify coagulopathy and manage blood transfusion.20,33Y36 Recently, TEG has been used to guide thromboprophylaxis. Harr et al.28 performed a randomized clinical trial comparing TEG-guided dosing of dalteparin to standard dosing. There were no differences in VTE rates between groups. Furthermore, escalating doses of dalteparin had no effect on TEG parameters such as R and G, suggesting that trauma patients develop a hypercoagulability that is resistant to heparin-based thromboprophylaxis. A better understanding of coagulation pathophysiology is needed to effectively implement TEG strategies into thromboprophylaxis guidelines. The traditional paradigm is that DVT and PE are different temporal phases of the VTE disease process. However, that idea has recently been challenged in patients with severe blunt injury. Brakenridge et al.37 showed that DVT and PE had different risk factor profiles in blunt trauma patients. Independent risk factors associated with DVT include thromboprophylaxis initiation after 48 hours, thoracic AIS Q 3, and abdominal AIS Q 3, while independent risk factors for PE were serum lactate level 9 5, male sex, and thoracic AIS Q 3. Both DVT and PE exhibited differing risk factor profiles from the classic composite end point of VTE. They speculated that DVT and PE after injury may represent a broad spectrum of pathologic thrombotic processes as opposed to the current conventional wisdom of peripheral thrombosis and subsequent embolus. Our
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results are consistent with this novel idea because, among seven patients with PE, only one patient had concurrent DVT. There are some major assumptions and several limitations to this observational, single-center study. Most importantly, the population was composed of only trauma patients who survived to the ICU with RAP Q 10 and who received VDU. This may have created a selection and surveillance bias. Furthermore, there are other scoring systems that may be more valid. In any case, no medical decisions were based on the results. TEG was only performed after TXA administration and therefore can only demonstrate an association with reduced fibrinolysis, not absolute cause and effect. Initial TEG was performed at admission to the ICU, rather than before and after, so multiple iatrogenic (operations, line placements, etc.) as well as temporal factors could confound that value. TEG was only performed weekly and may not capture coagulation status at the time of VTE development. Our study was also underpowered to identify some statistically significant differences when clinically significant differences were apparent (i.e., prophylaxis vs. no prophylaxis). In conclusion, high-risk trauma ICU patients with RAP Q 10 are hypercoagulable on admission to ICU and remain so during recovery. They have a high rate of VTE, despite thromboprophylaxis. TXA is associated with reduced fibrinolysis but does not increase VTE rates. Neither TEG nor standard coagulation markers stratify high-risk patients who develop VTE and those who do not. AUTHORSHIP R.M.V.H. is directly responsible for all aspects of this study. He participated in the conception and experimental design; collection, analysis, and interpretation of data; as well as drafting and revision of the manuscript, figures, and tables. E.J.V. participated in the collection of data as well as revision of the manuscript, figures, and tables. C.M.T. participated in the conception and experimental design, collection of data, as well as revision of the manuscript, figures, and tables. J.M.J. participated in the collection of data. A.M.B. participated in the collection of data. G.A.G. participated in the collection of data. N.N. was medically responsible for the patients in this study; treatments were administered at his discretion. In addition, he participated in the conception and experimental design, analysis and interpretation of data, as well as revision of the manuscript, figures, and tables. A.S.L. participated in the conception and experimental design, analysis and interpretation of data, as well as revision of the manuscript, figures, and tables. K.G.P. had overall responsibility for the study, including conception and experimental design; analysis and interpretation of data; drafting and revision of the manuscript, figures, and tables; statistical expertise and evaluation; obtaining funding for this project; as well as supervision.
DISCLOSURE This study was supported in part by grant #N140610670 from the Office of Naval Research and grant #09078015 from the US Army Medical Research and Materiel Command.
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