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High Rate of Fibrinolytic Shutdown and Venous Thromboembolism in Patients With Severe Pelvic Fracture
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High Rate of Fibrinolytic Shutdown and Venous Thromboembolism in Patients With Severe Pelvic Fracture Jesse T. Nelson, BS,a Julia R. Coleman, MD, MPH,b,* Heather Carmichael, MD,b Cyril Mauffrey, MD,c David Rojas Vintimilla, MD,c Jason M. Samuels, MD,b Angela Sauaia, MD, PhD,b,d and Ernest E. Moore, MDb,e a
Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois Department of Surgery, University of Colorado-Denver, Aurora, Colorado c Department of Orthopedics, Denver Health Medical Center, Denver, Colorado d Department of Health Systems, Management and Policy, University of Colorado-Denver, School of Public Health, Aurora, Colorado e Department of Surgery, Denver Health Medical Center, Denver, Colorado b
article info
abstract
Article history:
Background: Trauma patients with pelvic fractures have a high rate of venous thrombo-
Received 1 March 2019
embolism (VTEs). The reason for this high rate is unknown. We hypothesize that fibrino-
Received in revised form
lysis shutdown (SD) predicts VTE in patients with severe pelvic fracture.
31 August 2019
Methods: Retrospective chart review of trauma patients who presented with pelvic fracture
Accepted 12 September 2019
from 2007 to 2017 was performed. Inclusion criteria were injury severity score > 15,
Available online xxx
abdomen/pelvis abbreviated injury scale >/¼ 3, blunt mechanism, admission citrated rapid thrombelastography (TEG). Fibrinolytic phenotypes were defined by fibrinolysis on citrated
Keywords:
rapid TEG as hyperfibrinolysis, physiologic lysis, and SD. Univariate analysis of TEG mea-
Fibrinolysis
surements and clinical outcomes, followed by multivariable logistic regression (MV) with
Fibrinolysis shutdown
stepwise selection, was performed.
Venous thromboembolism
Results: Overall, 210 patients were included. Most patients (59%) presented in fibrinolytic
Pelvic fracture
shutdown. VTE incidence was 11%. There were no significant differences in fibrinolytic
Trauma
phenotypes or other TEG measurements between those who developed VTE and those who
Coagulation
did not. There was a higher rate of VTE in patients who underwent pelvic external fixation or resuscitative thoracotomy. On MV, pelvic fixation and resuscitative thoracotomy were independent predictors of VTE. Conclusions: In severely injured patients with pelvic fractures, there was a high rate of VTE and the majority presented in SD. However, we were unable to correlate initial SD
This work was presented at the 2019 American Surgical Congress in Houston, Texas by Jesse Nelson, BS. * Corresponding author. Department of Surgery, University of Colorado-Denver, 12631 E. 17th Avenue, Aurora, CO, 80045. Tel.: þ614 406 8829; fax: þ303 724 6310. E-mail address: [email protected] (J.R. Coleman). 0022-4804/$ e see front matter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2019.09.012
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with VTE. Ultimately, the high rate of VTE in this patient population supports the concept of implementing VTE chemoprophylaxis measures as soon as hemostasis is achieved. ª 2019 Elsevier Inc. All rights reserved.
Introduction Pelvic fractures are one of the most common injuries in severely injured trauma patients and are associated with a significant morbidity and mortality risk, with a populationadjusted incidence of 34 per 100,000 capita and mortality rates ranging from 2.8% to 8.3%.1,2 The hospital course of a patient with pelvic fracture is often fraught with complications, due to the injury itself, the associated concomitant injuries, the surgical repair required, and associated prolonged hospitalization.3,4 Thrombotic morbidity poses a particularly significant risk for patients with pelvic fracture, with reports of venous thromboembolism (VTE) rates as high as 18%.5 This high rate has invigorated debate among trauma and orthopedic surgery providers on the best approach to VTE prevention and treatment in patients with major pelvic fractures. The reason for the high rate of thrombotic complications in pelvic fracture is unclear, and is likely due to a composite of risk factors related to the severity of injury itself, associated vascular injuries, concomitant hemorrhagic shock, and sustained immobilization.6-9 Among the spectrum of driving factors, the relationship of the hemostatic profile of patients with pelvic fractures has not been explored within the context of thrombotic risk. It has yet to be established if the high rate of VTE in patients with pelvic fracture is due to the mechanics of the injury itself or a true physiological coagulopathy. In the spectrum of trauma-induced coagulopathy among polytrauma patients, fibrinolytic shutdown, or cessation of clot breakdown, is associated with a higher rate of VTE.10,11 However, examination of the fibrinolytic profile of patients with major pelvic fracture has yet to be performed, and it is uncertain whether this relationship with fibrinolysis shutdown and VTE exists in these severely injured patients. This study is the first to elucidate the coagulation profile of patients with pelvic fracture and investigate the relationship between fibrinolysis shutdown and thrombotic events in this population. In this study, we aim to describe the hemostatic profile of trauma patients with severe pelvic fractures by viscoelastic analysis, as well as to identify any correlation to the incidence of VTE. We hypothesize that fibrinolysis shutdown predicts VTE in patients with severe pelvic fracture.
Methods This study is a retrospective chart review of all traumatically injured patients with pelvic fractures who presented to Denver Health Medical Center, an American College of Surgeonseverified and Colorado stateecertified academic level-1 trauma center, from 2007 to 2017. Data was solicited from an internal trauma registry after institutional review board approval (COMIRB 18-0279). The inclusion criteria were severely injured patients (injury severity score [ISS] > 15) with
a severe pelvic fracture (abbreviated injury scale > 3) who presented after blunt mechanism and had an initial citrated rapid thrombelastography (CR-TEG) collected on hospital arrival. Once the cohort was selected with these filters, the presence of a pelvic fracture was confirmed via crossreference with our internal trauma database, which contains all patients with pelvic fracture. Clinical data collected included age, sex, mechanism, body mass index, ISS, hospital arrival systolic blood pressure (SBP), Glasgow Coma Scale (GCS), concomitant injuries, procedures performed, complications, length of stay, and clinical outcomes. Concomitant injuries, surgical procedures, mechanism of injury, and complications were ascertained from the ICD-9 and ICD-10 codes from the patient’s chart. Concomitant injury categories included rib fracture, upper extremity fracture, femur fracture, lower extremity fractures (distal to femur), splenic laceration, renal laceration, liver laceration, bladder injury, traumatic brain injury (TBI; presence of intraparenchymal hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, or epidural hemorrhage), spine fractures, and major vascular injuries (of named vessels). All concomitant injury classifications were determined a priori based on categories from our trauma registry and individually confirmed with the internal orthopedic trauma database. Surgical procedure categories included external pelvic fixation, open reduction and internal fixation, fixation of lower or upper extremity fractures, exploratory laparotomy, resuscitative thoracotomy, bladder repair, splenectomy, small or large bowel resection, spinal surgery, major vascular repair, and neurosurgical procedure (including craniectomy or craniotomy, bolt placement). All resuscitative thoracotomies were emergency department (ED) thoracotomies, which were confirmed by individual chart review. Complication categories included wound dehiscence, acute renal failure, acute respiratory distress syndrome, pneumonia, sepsis, surgical site infection, urinary train infection, ileus, deep tissue injury, multiorgan failure, abdominal compartment syndrome, myocardial infarction, cerebrovascular accident, and VTE (including deep venous thrombosis [DVT] or pulmonary embolus [PE]). Complications were determined from the ICD-9 and ICD-10 codes; given VTE was the primary outcome of interest, VTE diagnosis was also confirmed by individual chart review. All VTE that were diagnosed were clinically relevant, symptomatic VTE, diagnosed by venous duplex for DVT and computerized tomography angiography of the chest for PE. CR-TEG was performed with blood from initial hospital draw by the clinical laboratory with the Haemonetics 5000 as per manufacturer instructions. CR-TEG yields the following variables: activating clotting time (ACT; time elapsed from initiation of test until onset of clot formation), angle (rate of clot propagation), maximum amplitude (MA; maximal clot strength achieved), and percentage clot lysis 30 min after reaching MA (LY30). LY30, regardless of assay, because of its
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multimodal distribution, was expressed as three categories, as previously published: fibrinolysis shutdown (0.0%-0.8%), physiologic (0.9%-2.9%), and hyperfibrinolysis (3.0%).12 Specific differences in chemoprophylaxis practices were not considered in our analysis, although the established practice at our institution is to start all trauma patients on 40 mg of enoxaparin BID within 48 h of admission, not to hold chemoprophylaxis for operative procedures, and to place all patients on sequential compression devices. In addition, because the practice at our institution is to administer tranexamic acid based on clinical discretion but only if TEG measurements show evidence of hyperfibrinolysis, the charts of all patients who presented in hyperfibrinolysis were reviewed to confirm they did not receive tranexamic acid. All statistical analyses were performed in R.13 Descriptive analysis was performed using chi-square tests for proportional comparisons and ManneWhitney U-test for comparison of non-normally distributed continuous variables. This was followed by multivariable logistic regression with stepwise selection. Variables with P < 0.25 on descriptive analysis were included in multivariable modeling. Patients with vascular repairs, pre-existing need for anticoagulation, and death within 48 h were excluded from multivariable analysis. Significance was determined at P < 0.05.
Results Overall, 210 patients were included in this study (Table 1). The median age was 44 y (interquartile range [IQR], 25-58) and the majority (64%, n ¼ 134) were male. The median ISS was 34 (2743 IQR). As per inclusion criteria, all patients presented after blunt mechanism of injury. Although all of the patients were severely injured, shock did not predominate, with a median SBP of 108 mm Hg (90-122 IQR). Most patients presented with polytrauma, with the most common concomitant injuries being rib fractures (47%, n ¼ 99), spine fractures (27%, n ¼ 56), femur fractures (21%, n ¼ 44), and distal lower extremity fractures (21%, n ¼ 44). 23% (n ¼ 49) of patients presented with a TBI, and the median GCS was 14 (3-15 IQR). Overall, rates of additional injuries such as solid organ injury were low. Most patients (59%, n ¼ 123) presented in fibrinolytic shutdown, whereas only 45 patients (21%) presented in physiologic lysis and 42 patients (20%) in hyperfibrinolysis. Among all patients, the median ACT was 121 s (113-128 IQR), the median angle was 72.0 (65.6-76.0 IQR), and the median MA was 58.1 mm (51.6-64.1 IQR). The median LY30 was 0.5% (0.0%1.9%) among all patients, reflecting the predominance of shutdown in the cohort. The overall VTE incidence was 11% (n ¼ 23). On univariate analysis, there was no difference between patients who developed VTE versus those who did not in terms of age (45 versus 43 y, P ¼ 0.92), sex (74% versus 63% male, P ¼ 0.28), degree of tissue injury (ISS 38 versus 34, P ¼ 0.14), or degree of shock (SBP 101 versus 110, P ¼ 0.57) (Table 2). There was no difference in mechanism of injury between those who developed VTE and those who did not (Table 2). There was also no difference in associated injuries, with similar rates of concomitant rib fractures, upper and lower extremity
Table 1 e Characteristics of cohort (n [ 210). Demographics Age (y) Male sex (%)
44 (25,58) 134 (63.8)
Injury pattern and physiology Injury severity score Initial systolic blood pressure (mm Hg) Glasgow Coma Scale Ischium fracture (%)
34 (27,43) 108 (90,122) 14 (3,15) 4 (1.9)
Ilium fracture (%)
13 (6.2)
Pubis fracture (%)
42 (20.0)
Acetabulum fracture (%)
4 (1.9)
Traumatic brain injury (%)
49 (23.3)
Rib fractures (%)
99 (47.1)
Upper extremity fracture (%)
10 (4.8)
Femur fracture (%)
44 (21.0)
Other lower extremity fracture (%)
26 (12.4)
Splenic laceration (%)
15 (7.1)
Renal laceration (%)
8 (3.8)
Liver laceration (%)
20 (9.5)
Bladder injury (%)
24 (11.4)
Spine fracture (%)
56 (26.7)
Major vascular injury (%)
44 (21.0)
Thrombelastography (TEG) Activating clotting time (s)
121 (113,128)
Angle (degrees)
72 (66,76)
Maximum amplitude (mm)
58 (52,64)
LY30 (%)
5.5 (0,1.9)
Fibrinolysis phenotype (%) Hyperfibrinolysis
42 (20.0)
Physiologic lysis
45 (21.4)
Fibrinolysis shutdown
123 (58.6)
Hospital course and clinical outcomes Pelvic fixation (%) Exploratory laparotomy (%) Resuscitative thoracotomy (%)
135 (64.3) 75 (35.7) 9 (4.3)
Intensive care unit length of stay (d)
6.2 (2.7,12.4)
Ventilator days (d)
5.8 (2.0,10.8)
Hospital length of stay (d)
16 (10,25)
Death (%)
29 (13.8)
LY30 ¼ lysis 30 min after maximum amplitude. Data presented as median (interquartile range) and raw numbers (%) as appropriate.
fractures, splenic, renal, and liver lacerations, bladder injuries, TBI, spinal fractures, and major vascular injuries (Table 2). There was no significant difference in the prevalence of fibrinolytic shutdown in those who developed a VTE versus those who did not (61% versus 58%), and there was also no difference in the prevalence of hyperfibrinolysis (26% versus 19%) or physiological fibrinolysis (13% versus 23%) (P ¼ 0.51). Comparing VTE with non-VTE groups, there were no significant differences in other TEG measurements including ACT
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Table 2 e Comparison of patients who developed VTE to those who did not (no VTE). No VTE (n ¼ 187)
VTE (n ¼ 23)
43 (25, 58)
45 (26, 58)
0.92
17 (73.9)
0.28
P-value
Demographics Age (y) Male sex (%)
117 (62.6)
Injury pattern and physiology Injury severity score
34 (26, 43)
38 (31 45)
Mechanism (%)dtop 5 Autopedestrian
44 (24)
7 (30)
Motor vehicle collision
72 (39)
6 (26)
Motorcycle collision
21 (11)
4 (17)
Cyclist
12 (6)
2 (9)
Fall
10 (5)
2 (9)
Initial systolic blood pressure (mm Hg)
0.14 0.64
110 (90, 122)
101 (86, 117)
0.57
Glasgow Coma Scale
14 (3, 15)
13 (3, 15)
0.77
Traumatic brain injury (%)
45 (24)
Rib fractures (%)
88 (47.1)
Upper extremity fracture (%) Femur fracture (%)
4 (17)
0.65
11 (47.8)
0.94
10 (5.3)
0 (0.0)
0.26
39 (20.9)
5 (21.7)
0.92
Other lower extremity fracture (%)
21 (11.2)
5 (21.7)
0.80
Splenic laceration (%)
12 (6.4)
3 (13.0)
0.24
Renal laceration (%)
7 (3.7)
1 (4.3)
0.89
Liver laceration (%)
19 (10.2)
1 (4.3)
0.37
Bladder injury (%)
23 (12.3)
1 (4.3)
0.25
Spine fracture (%)
51 (27.3)
5 (21.7)
0.57
Major vascular injury (%)
37 (19.8)
7 (30.4)
0.24
Thrombelastography Activating clotting time (s)
121 (113, 128)
113 (105, 121)
0.10
Angle (degrees)
72 (66, 76)
70 (65, 74)
0.27
Maximum amplitude (mm)
58 (52, 64)
55 (47, 59)
0.08
LY30 (%)
0.5 (0.0, 1.9)
0.0 (0.0, 2.7)
0.38
Fibrinolytic phenotype (%) Hyperfibrinolysis Physiologic lysis Fibrinolysis shutdown
0.51 36 (19.3)
6 (26.1)
42 (22.5)
3 (13.0)
109 (58.3)
14 (60.9)
116 (62.0)
19 (82.6)
0.05
Hospital course and clinical outcomes Pelvic fixation (%)
33 (17.6)
10 (43.5)
<0.01
ORIF/percutaneous (%)
102 (54.5)
15 (65.2)
0.45
Exploratory laparotomy (%)
65 (34.8)
10 (43.5)
0.41
6 (3.2)
3 (13.0)
0.03
External fixation (%)
Resuscitative thoracotomy (%) Intensive care unit length of stay (d)
5.4 (2.5, 11.7)
11.4 (7.8, 16.9)
<0.01
Ventilator days (d)
4.2 (1.7, 10.3)
9.5 (4.9, 12.3)
0.01
Hospital length of stay (d)
16 (10, 24)
19 (17, 28)
Death (%)
28 (15.0)
1 (4.3)
0.16
Any complication (%)
55 (29.4)
4 (17.4)
0.34
Coagulopathy/bleeding (%)
10 (5.3)
0 (0.0)
0.54
Multiorgan failure (%)
2 (1.1)
0 (0.0)
1
Acute renal failure (%)
4 (2.1)
0 (0.0)
1
Adult respiratory distress syndrome (%)
2 (1.1)
0 (0.0)
1
23 (12.3)
3 (13.0)
1
Pneumonia (%)
0.02
(continued)
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Table 2 e (continued ) No VTE (n ¼ 187)
VTE (n ¼ 23) 1 (4.3)
P-value
Sepsis/bacteremia (%)
6 (3.2)
Surgical site infection (%)
6 (3.2)
0 (0.0)
1 0.84
Urinary tract infection (%)
14 (7.5)
0 (0.0)
0.36
LY30 ¼ lysis 30 min after maximum amplitude; ORIF ¼ open reduction and internal fixation; VTE ¼ venous thromboembolism. Data presented as median (interquartile range) and raw numbers (%) as appropriate.
(113 versus 121 s, P ¼ 0.10), angle (70.3 versus 72.1 , P ¼ 0.27), MA (54.8 versus 58.2 mm, P ¼ 0.08), or LY30 (0.0% versus 0.5%, P ¼ 0.38). There were notable differences in clinical course and outcomes of patients with VTE compared with those without. There was a higher rate of VTE in patients who underwent pelvic fixation (16% versus 6%, P ¼ 0.047) or resuscitative thoracotomy (33% versus 10%, P ¼ 0.028). Regarding differences in pelvic fixation, external fixation was strongly associated with VTE (P ¼ 0.009) whereas open reduction internal fixation was not significantly related to thrombotic events (P ¼ 0.453). Patients with VTE had a longer length of stay (19 d versus 16 d, P ¼ 0.02) and more intensive care unit days (11 versus 5 d P ¼ 0.001) and ventilator days (10 versus 4 d, P ¼ 0.01). There was no difference in rates complications between groups (Table 2). On multivariable analysis, both pelvic fixation (4.5 OR, 95% CI 1.2-16.2) and resuscitative thoracotomy (8.7 OR, 95% CI 1.841.7) remained associated with increased risk of VTE (Table 3). However, this model demonstrated only moderate predictive performance, with area under receiver operator curve of 0.65. There were no TEG variables that were retained as predictors of VTE on multivariable analysis.
Discussion In this study, we sought to describe the coagulation profile of trauma patients with severe pelvic fractures through viscoelastic analysis, as well as to identify any correlation of viscoelastic variables to the incidence of VTE. In these reported data, most patients presented in fibrinolytic shutdown on arrival; however, we were unable to correlate fibrinolytic shutdown or any other initial TEG measurements with VTE. Instead, we found that operative procedures including resuscitative thoracotomy and pelvic fixation were independent predictors of VTE. This work contributes to the literature by exploring fibrinolytic phenotypes and coagulation profiles of trauma patients with pelvic fractures in the context of thrombotic morbidity. This study is the first to our knowledge
Table 3 e Multivariable analysis (n [ 180 patients). Odds ratio
95% Confidence interval
P-value
Resuscitative thoracotomy
8.7
1.8 e 41.7
<0.001
Pelvic fixation
4.5
1.2 e 16.2
0.006
to investigate if fibrinolytic shutdown is the driving factor behind the elevated rate of VTE in this population. The risk of thrombotic morbidity is particularly significant for orthopedic trauma patients, and our results support previous literature, with a VTE rate of 11% in our study population. The previously reported incidence of VTE among patients with pelvic fractures varies, but ranges from 10 to 15% for clinical DVT, 2%-10% for nonfatal PE, and 0.5%2% for fatal PE.14-17 Perhaps even more alarming, previous studies utilizing screening ultrasound have reported the incidence of VTE after pelvic trauma to be up to 61%.18 What is driving this high rate is unclear. It may be due to the severity of injury mechanism to cause pelvic fracture itself or the prolonged immobility and surgical fixation associated with pelvic fractures. Previous literature examining thromboembolism after major trauma has shown VTE to be associated with older age, hospital days immobilized, need for blood transfusions, the presence of pelvic or lower extremity fractures, and GCS less than 8.9,19,20 Numerous other risk factors have been associated with the development of VTE in trauma patients, such as severe injury, mechanical ventilation, cancer, history of DVT/PE, major venous repair, surgery, and spinal cord injury.7 These risk factors have a cumulative effect for the development of VTE and the high rate observed in our patients may be a complex interplay between these factors. In the reported data, most (59%) patients presented in fibrinolytic shutdown, which has previously been correlated with the development of VTE.10,21 Our group has previously found the rate of fibrinolytic shutdown in trauma patients to range from 46% to 64%, but the specific rate of shutdown has not been calculated for patients with pelvic fracture specifically.12,22 Experimental animal models have found that tissue injury provokes fibrinolytic shutdown, although the exact mechanism behind tissue injury driving fibrinolysis shutdown is still not clear.23,24 Given the injury severity of pelvic fracture, it is not surprising that we found a higher rate in these patients. Yet, we found that shutdown was not predictive of VTE on initial assessment. What may be more likely is that the duration of fibrinolysis shutdown over time is more predictive of VTE, such that prolonged fibrinolysis over a series of hours or days (versus initial fibrinolysis itself) is predictive of high thrombotic risk.25 In a prospective study of pediatric patients with TBI, Leeper et. al. demonstrated that prolonged fibrinolytic shutdown or transitioning to fibrinolytic shutdown from another phenotype was associated with death, disability, and DVT.11 In addition, in a large multicenter cohort study, Roberts et al. found that approximately 70% of trauma patients who present in fibrinolytic shutdown persist in this
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phenotype for 120 h after injury, whereas all patients who presented in hyperfibrinolysis transitioned into another phenotype or died.26 It has been shown that if a patient presents in fibrinolytic shutdown, they are more likely to remain in shutdown than to convert to physiologic fibrinolysis.27,28 Sumislawski et al. demonstrated a considerable number of patients convert to a hypercoagulable state within 24 h of admission.29 Thus, it is likely that some of our patients who initially presented in hyperfibrinolysis or physiologic fibrinolysis may have transitioned into shutdown before the development of VTE, and therefore the relationship between shutdown and VTE may be underestimated based on initial labs. Resuscitative thoracotomy and pelvic fixation were independent predictors of VTE. All of the resuscitative thoracotomies were ED thoracotomies (performed in patients who presented pulseless or became pulseless in the ED). These are extremely morbid patients, and the systemic coagulopathic and inflammatory response to cardiac arrest could certainly be driving the higher VTE rate because of the inherent stasis of blood flow. Previous literature has shown patients after cardiac arrest are often in fibrinolytic shutdown, which leads to the development of multisystem organ dysfunction.30 In addition, previous experimental animal models have demonstrated that supraceliac and infrarenal aortic crossclamping results in fibrinolytic shutdown after release of the aortic clamp.31 Therefore, there may be a relationship with the fibrinolysis profile in these thoracotomy patients that we were underpowered to detect. The relationship between pelvic fixation and VTE has been extensively explored in the orthopedic trauma literature. Although we found external pelvic fixation to be an independent predictor of VTE, it may be that external fixation is only serving as a proxy for high levels of injury severity and/or immobility, both of which have been associated with higher rates of VTE. A prospective study by Park et al. showed that high-energy hip fractures are associated with preoperative VTE occurrence of 28%,5 and therefore, it is important to consider the ideal timing of pelvic fixation. Although previous studies have shown pelvic fixation expedites patient recovery (and minimizes the prolonged hospitalization and immobilization that is linked to VTE risk itself),32-35 it is unclear when is the optimal timing, as premature fixation before resuscitation, may cause a “second hit” insult, releasing inflammatory mediators which exacerbate VTE risk. The Early Appropriate Care model published by Vallier et al. recommends definitive fixation in 36 h for most of severely injured patient with unstable pelvic fractures, although the bleeding and inflammation related to early fixation can be detrimental to patients insufficiently resuscitated before the operation.35 In a prospective multicenter cohort study examining inflammatory response after pelvic fracture operations, Pape et al. found that the release of proinflammatory cytokines was higher in pelvic fracture operations that were performed early (hospital day 1 or 2) when compared with a delayed operation.36 Timing of pelvic fixation was not considered in the scope of this project, but current efforts are underway to analyze this in the reported data. Both mechanical and chemoprophylaxis are standard in the prevention of VTE in patients with traumatic pelvic
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fractures, although there are no well-established prophylaxis guidelines and there is a general lack of clarity regarding the ideal method of VTE prevention in this high-risk population. The importance of chemoprophylaxis was highlighted in a previous study examining rates of VTE after fixation of lowerextremity fractures in patients without chemoprophylaxis, reporting VTE rates of 29% in an early surgery group and 45% in a delayed surgery group.37 In a study reviewing the incidence and methodology of VTE chemoprophylaxis in pelvic trauma patients, Chana-Rodrı´guez et al. found the reported rate of VTE in patients with traumatic pelvic fracture on chemoprophylaxis to vary greatly from 2% to 33%. Furthermore, their study highlights that trauma patients frequently present in an acute hypocoagulable state, but once stabilized, can progress to a hypercoagulable state.38 This change in hemostasis may explain why current chemoprophylaxis are insufficient in the setting of the hypercoagulability and fibrinolysis shutdown associated with pelvic fractures, suggesting perhaps patients with pelvic fractures should be considered for screening ultrasounds or pharmacologically guided VTE chemoprophylaxis. Limitations of this study include the retrospective nature; therefore, we are limited to the initial laboratory assessment and the clinical information collected prospectively in the chart. Another limitation is the small sample size; because VTE remains a relatively infrequent phenomena, we recognize we may be underpowered to detect an association between fibrinolysis profiles with VTE incidence. In addition, we only considered patients’ initial fibrinolytic phenotype on presentation, rather than following the trend of fibrinolysis and persistence of fibrinolytic shutdown throughout their inpatient stay, which may have a greater impact on their VTE risk. Another limitation of this study is that we were unable to stratify pelvic fracture mechanism of injury using Young-Burgess classification because of the high number of patients in our cohort. We also did not examine the impact of variables such as activity status, ambulation, transfusion practices, timing of pelvic fixation, pelvic packing, or chemoprophylaxis practice on VTE risk, all of which are being investigated in a larger study. We recognize that not considering differences in VTE chemoprophylaxis strategies is a major limitation to this study, as this ultimately affects patients’ coagulation profile and VTE risk. Because the focus of this study was solely to investigate the coagulation profile of patients with pelvic fracture and the association with thrombotic incidence, we are obtaining granular data on VTE chemoprophylaxis strategies in a larger study to evaluate this variable. Finally, we did not evaluate the impact of damage control external fixation placement or interventional radiology embolization on VTE risk. In conclusion, this study is the first to describe the viscoelastic profile of trauma patients with severe pelvic fractures. In the reported data, there was a high rate of VTE and a predominance of fibrinolytic shutdown on initial presentation. The high rate of VTE in this patient population supports the concept of implementing VTE chemoprophylaxis measures as soon as hemostasis is achieved. Further investigation is merited to define more reliable predictors of VTE in this patient population.
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Acknowledgment 12.
Authors’ contributions: JTN originated experimental hypothesis under mentorship of JRC and EEM, gathered clinical data, and composed the manuscript. HC and AS assisted with data organization and cleaning, statistical analysis, data interpretation, and manuscript composition. CM, DRV, JMS, JRC, and EEM assisted with experimental conduct, data interpretation, and manuscript editing. Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health (T32 GM008315). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other sponsors of the project.
14.
Disclosure
17.
13.
15.
16.
There are no conflicts of interest to report. 18.
references
1. Buller LT, Best MJ, Quinnan SM. A Nationwide analysis of pelvic ring fractures: incidence and trends in treatment, length of stay, and mortality. Geriatr Orthop Surg Rehabil. 2016;7:9e17. 2. Yoshihara H, Yoneoka D. Demographic epidemiology of unstable pelvic fracture in the United States from 2000 to 2009: trends and in-hospital mortality. J Trauma Acute Care Surg. 2014;76:380e385. 3. Almahmoud K, Pfeifer R, Al-Kofahi K, et al. Impact of pelvic fractures on the early clinical outcomes of severely injured trauma patients. Eur J Trauma Emerg Surg. 2018;44:155e162. 4. Hermans E, Biert J, Edwards MJR. Epidemiology of pelvic ring fractures in a level 1 trauma center in The Netherlands. Hip Pelvis. 2017;29:253e261. 5. Park JS, Jang JH, Park KY, Moon NH. High energy injury is a risk factor for preoperative venous thromboembolism in the patients with hip fractures: a prospective observational study. Injury. 2018;49:1155e1161. 6. Childs BR, Verhotz DR, Moore TA, Vallier HA. Presentation coagulopathy and persistent acidosis predict complications in orthopaedic trauma patients. J Orthop Trauma. 2017;31:617e623. 7. Van gent JM, Calvo RY, Zander AL, et al. Risk factors for deep vein thrombosis and pulmonary embolism after traumatic injury: a competing risks analysis. J Trauma Acute Care Surg. 2017;83:1154e1160. 8. 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;240:490e496. 9. Knudson MM, Lewis FR, Clinton A, Atkinson K, Megerman J. Prevention of venous thromboembolism in trauma patients. J Trauma. 1994;37:480e487. 10. Nicolau-Raducu R, Beduschi T, Vianna R, et al. Fibrinolytic shutdown is associated with thrombotic and hemorrhagic complications and poorer outcomes after liver transplantation. Liver Transpl. 2018;25:380e387. 11. Leeper CM, Neal MD, McKenna CJ, Gaines BA. Trending fibrinolytic dysregulation: fibrinolysis shutdown in the days
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after injury is associated with poor outcome in severely injured children. Ann Surg. 2017;266:508e515. Moore HB, Moore EE, Liras IN, et al. Acute fibrinolysis shutdown after injury occurs frequently and increases mortality: a multicenter evaluation of 2,540 severely injured patients. J Am Coll Surg. 2016;222:347e355. dyplyr, Wickham H, Franc¸ois R, Henry L, Mu¨ller K. Dplyr: a Grammar of data Manipulation. R package version 0.7.7. 2018. Available at: https://CRAN.R-project.org/package¼dplyr. Accessed August 30, 2019. Montgomery KD, Geerts WH, Potter HG, Helfet DL. Thromboembolic complications in patients with pelvic trauma. Clin Orthop Relat Res. 1996:68e87. Gruen GS, McClain EJ, Gruen RJ. The diagnosis of deep vein thrombosis in the multiply injured patient with pelvic ring or acetabular fractures. Orthopedics. 1995;18:253e257. White RH, Goulet JA, Bray TJ, Daschbach MM, Mcgahan JP, Hartling RP. Deep-vein thrombosis after fracture of the pelvis: assessment with serial duplex-ultrasound screening. J Bone Joint Surg Am. 1990;72:495e500. Buerger PM, Peoples JB, Lemmon GW, McCarthy MC. Risk of pulmonary emboli in patients with pelvic fractures. Am Surg. 1993;59:505e508. Geerts WH, Code KI, Jay RM, Chen E, Szalai JP. A prospective study of venous thromboembolism after major trauma. N Engl J Med. 1994;331:1601e1606. Knudson MM, Collins JA, Goodman SB, McCrory DW. Thromboembolism following multiple trauma. J Trauma. 1992;32:2e11. Karcutskie CA, Meizoso JP, Ray JJ, et al. Association of mechanism of injury with risk for venous thromboembolism after trauma. JAMA Surg. 2017;152:35e40. Leeper CM, Neal MD, McKenna C, Sperry JL, Gaines BA. Abnormalities in fibrinolysis at the time of admission are associated with deep vein thrombosis, mortality, and disability in a pediatric trauma population. J Trauma Acute Care Surg. 2017;82:27e34. Moore HB, Moore EE, Gonzalez E, et al. Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spectrum of postinjury fibrinolysis and relevance to antifibrinolytic therapy. J Trauma Acute Care Surg. 2014;77:811e817. Moore HB, Moore EE, Lawson PJ, et al. Fibrinolysis shutdown phenotype masks changes in rodent coagulation in tissue injury versus hemorrhagic shock. Surgery. 2015;158:386e392. Macko AR, Moore HB, Cap AP, Meledeo MA, Moore EE, Sheppard FR. Tissue injury suppresses fibrinolysis after hemorrhagic shock in nonhuman primates (rhesus macaque). J Trauma Acute Care Surg. 2017;82:750e757. Meizoso JP, Karcutskie CA, Ray JJ, Namias N, Schulman CI, Proctor KG. Persistent fibrinolysis shutdown is associated with increased mortality in severely injured trauma patients. J Am Coll Surg. 2017;224:575e582. Roberts DJ, Kalkwarf KJ, Moore HB, et al. Time course and outcomes associated with transient versus persistent fibrinolytic phenotypes after injury: a nested, prospective, multicenter cohort study. J Trauma Acute Care Surg. 2019;86:206e213. Coleman JR, Kay A, Moore EE, et al. It’s sooner than you think: blunt solid organ injury patients are hypercoagulable upon hospital admission e results of a bi-institutional, prospective study. Am J Surg. 2019. In press. Moore HB, Moore EE, Neal MD, et al. Fibrinolysis shutdown in trauma: historical review and clinical implications. Anesth Analg. 2019;129:762e773. Sumislawski JJ, Kornblith LZ, Conroy AS, Callcut RA, Cohen MJ. Dynamic coagulability after injury: is delaying
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venous thromboembolism chemoprophylaxis worth the wait? J Trauma Acute Care Surg. 2018;85:907e914. Wada T, Gando S, Mizugaki A, et al. Coagulofibrinolytic changes in patients with disseminated intravascular coagulation associated with post-cardiac arrest syndrome– fibrinolytic shutdown and insufficient activation of fibrinolysis lead to organ dysfunction. Thromb Res. 2013;132:e64ee69. Anagnostopoulos PV, Shepard AD, Pipinos II II, et al. Hemostatic alterations associated with supraceliac aortic cross-clamping. J Vasc Surg. 2002;35:100e108. Childs BR, Nahm NJ, Moore TA, Vallier HA. Multiple procedures in the initial surgical setting: when do the benefits outweigh the risks in patients with multiple system trauma? J Orthop Trauma. 2016;30:420e425. Vallier HA, Super DM, Moore TA, Wilber JH. Do patients with multiple system injury benefit from early fixation of unstable axial fractures? The effects of timing of surgery on initial hospital course. J Orthop Trauma. 2013;27:405e412.
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34. Latenser BA, Gentilello LM, Tarver AA, Thalgott JS, Batdorf JW. Improved outcome with early fixation of skeletally unstable pelvic fractures. J Trauma. 1991;31:28e31. 35. Vallier HA, Moore TA, Como JJ, et al. Complications are reduced with a protocol to standardize timing of fixation based on response to resuscitation. J Orthop Surg Res. 2015; 10:155. 36. Pape HC, Griensven MV, Hildebrand FF, et al. Systemic inflammatory response after extremity or truncal fracture operations. J Trauma. 2008;65:1379e1384. 37. Niikura T, Sakai Y, Lee SY, Iwakura T, Kuroda R, Kurosaka M. Rate of venous thromboembolism after complex lower-limb fracture surgery without pharmacological prophylaxis. J Orthop Surg. 2015;23:37e40. 38. Chana-Rodriguez F, Mananes RP, Rojo-Manaute J, Haro JA. Vaquero-martin J methods and guidelines for venous thromboembolism prevention in polytrauma patients with pelvic and acetabular fractures. Open Orthop J. 2015;9:313e320.
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High Rate of Fibrinolytic Shutdown and Venous Thromboembolism in Patients With Severe Pelvic Fracture Jesse T. Nelson, BS,a Julia R. Coleman, MD, MPH,b,* Heather Carmichael, MD,b Cyril Mauffrey, MD,c David Rojas Vintimilla, MD,c Jason M. Samuels, MD,b Angela Sauaia, MD, PhD,b,d and Ernest E. Moore, MDb,e a
Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois Department of Surgery, University of Colorado-Denver, Aurora, Colorado c Department of Orthopedics, Denver Health Medical Center, Denver, Colorado d Department of Health Systems, Management and Policy, University of Colorado-Denver, School of Public Health, Aurora, Colorado e Department of Surgery, Denver Health Medical Center, Denver, Colorado b
article info
abstract
Article history:
Background: Trauma patients with pelvic fractures have a high rate of venous thrombo-
Received 1 March 2019
embolism (VTEs). The reason for this high rate is unknown. We hypothesize that fibrino-
Received in revised form
lysis shutdown (SD) predicts VTE in patients with severe pelvic fracture.
31 August 2019
Methods: Retrospective chart review of trauma patients who presented with pelvic fracture
Accepted 12 September 2019
from 2007 to 2017 was performed. Inclusion criteria were injury severity score > 15,
Available online xxx
abdomen/pelvis abbreviated injury scale >/¼ 3, blunt mechanism, admission citrated rapid thrombelastography (TEG). Fibrinolytic phenotypes were defined by fibrinolysis on citrated
Keywords:
rapid TEG as hyperfibrinolysis, physiologic lysis, and SD. Univariate analysis of TEG mea-
Fibrinolysis
surements and clinical outcomes, followed by multivariable logistic regression (MV) with
Fibrinolysis shutdown
stepwise selection, was performed.
Venous thromboembolism
Results: Overall, 210 patients were included. Most patients (59%) presented in fibrinolytic
Pelvic fracture
shutdown. VTE incidence was 11%. There were no significant differences in fibrinolytic
Trauma
phenotypes or other TEG measurements between those who developed VTE and those who
Coagulation
did not. There was a higher rate of VTE in patients who underwent pelvic external fixation or resuscitative thoracotomy. On MV, pelvic fixation and resuscitative thoracotomy were independent predictors of VTE. Conclusions: In severely injured patients with pelvic fractures, there was a high rate of VTE and the majority presented in SD. However, we were unable to correlate initial SD
This work was presented at the 2019 American Surgical Congress in Houston, Texas by Jesse Nelson, BS. * Corresponding author. Department of Surgery, University of Colorado-Denver, 12631 E. 17th Avenue, Aurora, CO, 80045. Tel.: þ614 406 8829; fax: þ303 724 6310. E-mail address: [email protected] (J.R. Coleman). 0022-4804/$ e see front matter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2019.09.012
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with VTE. Ultimately, the high rate of VTE in this patient population supports the concept of implementing VTE chemoprophylaxis measures as soon as hemostasis is achieved. ª 2019 Elsevier Inc. All rights reserved.
Introduction Pelvic fractures are one of the most common injuries in severely injured trauma patients and are associated with a significant morbidity and mortality risk, with a populationadjusted incidence of 34 per 100,000 capita and mortality rates ranging from 2.8% to 8.3%.1,2 The hospital course of a patient with pelvic fracture is often fraught with complications, due to the injury itself, the associated concomitant injuries, the surgical repair required, and associated prolonged hospitalization.3,4 Thrombotic morbidity poses a particularly significant risk for patients with pelvic fracture, with reports of venous thromboembolism (VTE) rates as high as 18%.5 This high rate has invigorated debate among trauma and orthopedic surgery providers on the best approach to VTE prevention and treatment in patients with major pelvic fractures. The reason for the high rate of thrombotic complications in pelvic fracture is unclear, and is likely due to a composite of risk factors related to the severity of injury itself, associated vascular injuries, concomitant hemorrhagic shock, and sustained immobilization.6-9 Among the spectrum of driving factors, the relationship of the hemostatic profile of patients with pelvic fractures has not been explored within the context of thrombotic risk. It has yet to be established if the high rate of VTE in patients with pelvic fracture is due to the mechanics of the injury itself or a true physiological coagulopathy. In the spectrum of trauma-induced coagulopathy among polytrauma patients, fibrinolytic shutdown, or cessation of clot breakdown, is associated with a higher rate of VTE.10,11 However, examination of the fibrinolytic profile of patients with major pelvic fracture has yet to be performed, and it is uncertain whether this relationship with fibrinolysis shutdown and VTE exists in these severely injured patients. This study is the first to elucidate the coagulation profile of patients with pelvic fracture and investigate the relationship between fibrinolysis shutdown and thrombotic events in this population. In this study, we aim to describe the hemostatic profile of trauma patients with severe pelvic fractures by viscoelastic analysis, as well as to identify any correlation to the incidence of VTE. We hypothesize that fibrinolysis shutdown predicts VTE in patients with severe pelvic fracture.
Methods This study is a retrospective chart review of all traumatically injured patients with pelvic fractures who presented to Denver Health Medical Center, an American College of Surgeonseverified and Colorado stateecertified academic level-1 trauma center, from 2007 to 2017. Data was solicited from an internal trauma registry after institutional review board approval (COMIRB 18-0279). The inclusion criteria were severely injured patients (injury severity score [ISS] > 15) with
a severe pelvic fracture (abbreviated injury scale > 3) who presented after blunt mechanism and had an initial citrated rapid thrombelastography (CR-TEG) collected on hospital arrival. Once the cohort was selected with these filters, the presence of a pelvic fracture was confirmed via crossreference with our internal trauma database, which contains all patients with pelvic fracture. Clinical data collected included age, sex, mechanism, body mass index, ISS, hospital arrival systolic blood pressure (SBP), Glasgow Coma Scale (GCS), concomitant injuries, procedures performed, complications, length of stay, and clinical outcomes. Concomitant injuries, surgical procedures, mechanism of injury, and complications were ascertained from the ICD-9 and ICD-10 codes from the patient’s chart. Concomitant injury categories included rib fracture, upper extremity fracture, femur fracture, lower extremity fractures (distal to femur), splenic laceration, renal laceration, liver laceration, bladder injury, traumatic brain injury (TBI; presence of intraparenchymal hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, or epidural hemorrhage), spine fractures, and major vascular injuries (of named vessels). All concomitant injury classifications were determined a priori based on categories from our trauma registry and individually confirmed with the internal orthopedic trauma database. Surgical procedure categories included external pelvic fixation, open reduction and internal fixation, fixation of lower or upper extremity fractures, exploratory laparotomy, resuscitative thoracotomy, bladder repair, splenectomy, small or large bowel resection, spinal surgery, major vascular repair, and neurosurgical procedure (including craniectomy or craniotomy, bolt placement). All resuscitative thoracotomies were emergency department (ED) thoracotomies, which were confirmed by individual chart review. Complication categories included wound dehiscence, acute renal failure, acute respiratory distress syndrome, pneumonia, sepsis, surgical site infection, urinary train infection, ileus, deep tissue injury, multiorgan failure, abdominal compartment syndrome, myocardial infarction, cerebrovascular accident, and VTE (including deep venous thrombosis [DVT] or pulmonary embolus [PE]). Complications were determined from the ICD-9 and ICD-10 codes; given VTE was the primary outcome of interest, VTE diagnosis was also confirmed by individual chart review. All VTE that were diagnosed were clinically relevant, symptomatic VTE, diagnosed by venous duplex for DVT and computerized tomography angiography of the chest for PE. CR-TEG was performed with blood from initial hospital draw by the clinical laboratory with the Haemonetics 5000 as per manufacturer instructions. CR-TEG yields the following variables: activating clotting time (ACT; time elapsed from initiation of test until onset of clot formation), angle (rate of clot propagation), maximum amplitude (MA; maximal clot strength achieved), and percentage clot lysis 30 min after reaching MA (LY30). LY30, regardless of assay, because of its
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j o u r n a l o f s u r g i c a l r e s e a r c h f e b r u a r y 2 0 2 0 ( 2 4 6 ) 1 8 2 e1 8 9
multimodal distribution, was expressed as three categories, as previously published: fibrinolysis shutdown (0.0%-0.8%), physiologic (0.9%-2.9%), and hyperfibrinolysis (3.0%).12 Specific differences in chemoprophylaxis practices were not considered in our analysis, although the established practice at our institution is to start all trauma patients on 40 mg of enoxaparin BID within 48 h of admission, not to hold chemoprophylaxis for operative procedures, and to place all patients on sequential compression devices. In addition, because the practice at our institution is to administer tranexamic acid based on clinical discretion but only if TEG measurements show evidence of hyperfibrinolysis, the charts of all patients who presented in hyperfibrinolysis were reviewed to confirm they did not receive tranexamic acid. All statistical analyses were performed in R.13 Descriptive analysis was performed using chi-square tests for proportional comparisons and ManneWhitney U-test for comparison of non-normally distributed continuous variables. This was followed by multivariable logistic regression with stepwise selection. Variables with P < 0.25 on descriptive analysis were included in multivariable modeling. Patients with vascular repairs, pre-existing need for anticoagulation, and death within 48 h were excluded from multivariable analysis. Significance was determined at P < 0.05.
Results Overall, 210 patients were included in this study (Table 1). The median age was 44 y (interquartile range [IQR], 25-58) and the majority (64%, n ¼ 134) were male. The median ISS was 34 (2743 IQR). As per inclusion criteria, all patients presented after blunt mechanism of injury. Although all of the patients were severely injured, shock did not predominate, with a median SBP of 108 mm Hg (90-122 IQR). Most patients presented with polytrauma, with the most common concomitant injuries being rib fractures (47%, n ¼ 99), spine fractures (27%, n ¼ 56), femur fractures (21%, n ¼ 44), and distal lower extremity fractures (21%, n ¼ 44). 23% (n ¼ 49) of patients presented with a TBI, and the median GCS was 14 (3-15 IQR). Overall, rates of additional injuries such as solid organ injury were low. Most patients (59%, n ¼ 123) presented in fibrinolytic shutdown, whereas only 45 patients (21%) presented in physiologic lysis and 42 patients (20%) in hyperfibrinolysis. Among all patients, the median ACT was 121 s (113-128 IQR), the median angle was 72.0 (65.6-76.0 IQR), and the median MA was 58.1 mm (51.6-64.1 IQR). The median LY30 was 0.5% (0.0%1.9%) among all patients, reflecting the predominance of shutdown in the cohort. The overall VTE incidence was 11% (n ¼ 23). On univariate analysis, there was no difference between patients who developed VTE versus those who did not in terms of age (45 versus 43 y, P ¼ 0.92), sex (74% versus 63% male, P ¼ 0.28), degree of tissue injury (ISS 38 versus 34, P ¼ 0.14), or degree of shock (SBP 101 versus 110, P ¼ 0.57) (Table 2). There was no difference in mechanism of injury between those who developed VTE and those who did not (Table 2). There was also no difference in associated injuries, with similar rates of concomitant rib fractures, upper and lower extremity
Table 1 e Characteristics of cohort (n [ 210). Demographics Age (y) Male sex (%)
44 (25,58) 134 (63.8)
Injury pattern and physiology Injury severity score Initial systolic blood pressure (mm Hg) Glasgow Coma Scale Ischium fracture (%)
34 (27,43) 108 (90,122) 14 (3,15) 4 (1.9)
Ilium fracture (%)
13 (6.2)
Pubis fracture (%)
42 (20.0)
Acetabulum fracture (%)
4 (1.9)
Traumatic brain injury (%)
49 (23.3)
Rib fractures (%)
99 (47.1)
Upper extremity fracture (%)
10 (4.8)
Femur fracture (%)
44 (21.0)
Other lower extremity fracture (%)
26 (12.4)
Splenic laceration (%)
15 (7.1)
Renal laceration (%)
8 (3.8)
Liver laceration (%)
20 (9.5)
Bladder injury (%)
24 (11.4)
Spine fracture (%)
56 (26.7)
Major vascular injury (%)
44 (21.0)
Thrombelastography (TEG) Activating clotting time (s)
121 (113,128)
Angle (degrees)
72 (66,76)
Maximum amplitude (mm)
58 (52,64)
LY30 (%)
5.5 (0,1.9)
Fibrinolysis phenotype (%) Hyperfibrinolysis
42 (20.0)
Physiologic lysis
45 (21.4)
Fibrinolysis shutdown
123 (58.6)
Hospital course and clinical outcomes Pelvic fixation (%) Exploratory laparotomy (%) Resuscitative thoracotomy (%)
135 (64.3) 75 (35.7) 9 (4.3)
Intensive care unit length of stay (d)
6.2 (2.7,12.4)
Ventilator days (d)
5.8 (2.0,10.8)
Hospital length of stay (d)
16 (10,25)
Death (%)
29 (13.8)
LY30 ¼ lysis 30 min after maximum amplitude. Data presented as median (interquartile range) and raw numbers (%) as appropriate.
fractures, splenic, renal, and liver lacerations, bladder injuries, TBI, spinal fractures, and major vascular injuries (Table 2). There was no significant difference in the prevalence of fibrinolytic shutdown in those who developed a VTE versus those who did not (61% versus 58%), and there was also no difference in the prevalence of hyperfibrinolysis (26% versus 19%) or physiological fibrinolysis (13% versus 23%) (P ¼ 0.51). Comparing VTE with non-VTE groups, there were no significant differences in other TEG measurements including ACT
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n e l s o n e t a l fi b r i n o l y s i s a n d v t e i n p e l v i c f r a c t u r e s
Table 2 e Comparison of patients who developed VTE to those who did not (no VTE). No VTE (n ¼ 187)
VTE (n ¼ 23)
43 (25, 58)
45 (26, 58)
0.92
17 (73.9)
0.28
P-value
Demographics Age (y) Male sex (%)
117 (62.6)
Injury pattern and physiology Injury severity score
34 (26, 43)
38 (31 45)
Mechanism (%)dtop 5 Autopedestrian
44 (24)
7 (30)
Motor vehicle collision
72 (39)
6 (26)
Motorcycle collision
21 (11)
4 (17)
Cyclist
12 (6)
2 (9)
Fall
10 (5)
2 (9)
Initial systolic blood pressure (mm Hg)
0.14 0.64
110 (90, 122)
101 (86, 117)
0.57
Glasgow Coma Scale
14 (3, 15)
13 (3, 15)
0.77
Traumatic brain injury (%)
45 (24)
Rib fractures (%)
88 (47.1)
Upper extremity fracture (%) Femur fracture (%)
4 (17)
0.65
11 (47.8)
0.94
10 (5.3)
0 (0.0)
0.26
39 (20.9)
5 (21.7)
0.92
Other lower extremity fracture (%)
21 (11.2)
5 (21.7)
0.80
Splenic laceration (%)
12 (6.4)
3 (13.0)
0.24
Renal laceration (%)
7 (3.7)
1 (4.3)
0.89
Liver laceration (%)
19 (10.2)
1 (4.3)
0.37
Bladder injury (%)
23 (12.3)
1 (4.3)
0.25
Spine fracture (%)
51 (27.3)
5 (21.7)
0.57
Major vascular injury (%)
37 (19.8)
7 (30.4)
0.24
Thrombelastography Activating clotting time (s)
121 (113, 128)
113 (105, 121)
0.10
Angle (degrees)
72 (66, 76)
70 (65, 74)
0.27
Maximum amplitude (mm)
58 (52, 64)
55 (47, 59)
0.08
LY30 (%)
0.5 (0.0, 1.9)
0.0 (0.0, 2.7)
0.38
Fibrinolytic phenotype (%) Hyperfibrinolysis Physiologic lysis Fibrinolysis shutdown
0.51 36 (19.3)
6 (26.1)
42 (22.5)
3 (13.0)
109 (58.3)
14 (60.9)
116 (62.0)
19 (82.6)
0.05
Hospital course and clinical outcomes Pelvic fixation (%)
33 (17.6)
10 (43.5)
<0.01
ORIF/percutaneous (%)
102 (54.5)
15 (65.2)
0.45
Exploratory laparotomy (%)
65 (34.8)
10 (43.5)
0.41
6 (3.2)
3 (13.0)
0.03
External fixation (%)
Resuscitative thoracotomy (%) Intensive care unit length of stay (d)
5.4 (2.5, 11.7)
11.4 (7.8, 16.9)
<0.01
Ventilator days (d)
4.2 (1.7, 10.3)
9.5 (4.9, 12.3)
0.01
Hospital length of stay (d)
16 (10, 24)
19 (17, 28)
Death (%)
28 (15.0)
1 (4.3)
0.16
Any complication (%)
55 (29.4)
4 (17.4)
0.34
Coagulopathy/bleeding (%)
10 (5.3)
0 (0.0)
0.54
Multiorgan failure (%)
2 (1.1)
0 (0.0)
1
Acute renal failure (%)
4 (2.1)
0 (0.0)
1
Adult respiratory distress syndrome (%)
2 (1.1)
0 (0.0)
1
23 (12.3)
3 (13.0)
1
Pneumonia (%)
0.02
(continued)
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Table 2 e (continued ) No VTE (n ¼ 187)
VTE (n ¼ 23) 1 (4.3)
P-value
Sepsis/bacteremia (%)
6 (3.2)
Surgical site infection (%)
6 (3.2)
0 (0.0)
1 0.84
Urinary tract infection (%)
14 (7.5)
0 (0.0)
0.36
LY30 ¼ lysis 30 min after maximum amplitude; ORIF ¼ open reduction and internal fixation; VTE ¼ venous thromboembolism. Data presented as median (interquartile range) and raw numbers (%) as appropriate.
(113 versus 121 s, P ¼ 0.10), angle (70.3 versus 72.1 , P ¼ 0.27), MA (54.8 versus 58.2 mm, P ¼ 0.08), or LY30 (0.0% versus 0.5%, P ¼ 0.38). There were notable differences in clinical course and outcomes of patients with VTE compared with those without. There was a higher rate of VTE in patients who underwent pelvic fixation (16% versus 6%, P ¼ 0.047) or resuscitative thoracotomy (33% versus 10%, P ¼ 0.028). Regarding differences in pelvic fixation, external fixation was strongly associated with VTE (P ¼ 0.009) whereas open reduction internal fixation was not significantly related to thrombotic events (P ¼ 0.453). Patients with VTE had a longer length of stay (19 d versus 16 d, P ¼ 0.02) and more intensive care unit days (11 versus 5 d P ¼ 0.001) and ventilator days (10 versus 4 d, P ¼ 0.01). There was no difference in rates complications between groups (Table 2). On multivariable analysis, both pelvic fixation (4.5 OR, 95% CI 1.2-16.2) and resuscitative thoracotomy (8.7 OR, 95% CI 1.841.7) remained associated with increased risk of VTE (Table 3). However, this model demonstrated only moderate predictive performance, with area under receiver operator curve of 0.65. There were no TEG variables that were retained as predictors of VTE on multivariable analysis.
Discussion In this study, we sought to describe the coagulation profile of trauma patients with severe pelvic fractures through viscoelastic analysis, as well as to identify any correlation of viscoelastic variables to the incidence of VTE. In these reported data, most patients presented in fibrinolytic shutdown on arrival; however, we were unable to correlate fibrinolytic shutdown or any other initial TEG measurements with VTE. Instead, we found that operative procedures including resuscitative thoracotomy and pelvic fixation were independent predictors of VTE. This work contributes to the literature by exploring fibrinolytic phenotypes and coagulation profiles of trauma patients with pelvic fractures in the context of thrombotic morbidity. This study is the first to our knowledge
Table 3 e Multivariable analysis (n [ 180 patients). Odds ratio
95% Confidence interval
P-value
Resuscitative thoracotomy
8.7
1.8 e 41.7
<0.001
Pelvic fixation
4.5
1.2 e 16.2
0.006
to investigate if fibrinolytic shutdown is the driving factor behind the elevated rate of VTE in this population. The risk of thrombotic morbidity is particularly significant for orthopedic trauma patients, and our results support previous literature, with a VTE rate of 11% in our study population. The previously reported incidence of VTE among patients with pelvic fractures varies, but ranges from 10 to 15% for clinical DVT, 2%-10% for nonfatal PE, and 0.5%2% for fatal PE.14-17 Perhaps even more alarming, previous studies utilizing screening ultrasound have reported the incidence of VTE after pelvic trauma to be up to 61%.18 What is driving this high rate is unclear. It may be due to the severity of injury mechanism to cause pelvic fracture itself or the prolonged immobility and surgical fixation associated with pelvic fractures. Previous literature examining thromboembolism after major trauma has shown VTE to be associated with older age, hospital days immobilized, need for blood transfusions, the presence of pelvic or lower extremity fractures, and GCS less than 8.9,19,20 Numerous other risk factors have been associated with the development of VTE in trauma patients, such as severe injury, mechanical ventilation, cancer, history of DVT/PE, major venous repair, surgery, and spinal cord injury.7 These risk factors have a cumulative effect for the development of VTE and the high rate observed in our patients may be a complex interplay between these factors. In the reported data, most (59%) patients presented in fibrinolytic shutdown, which has previously been correlated with the development of VTE.10,21 Our group has previously found the rate of fibrinolytic shutdown in trauma patients to range from 46% to 64%, but the specific rate of shutdown has not been calculated for patients with pelvic fracture specifically.12,22 Experimental animal models have found that tissue injury provokes fibrinolytic shutdown, although the exact mechanism behind tissue injury driving fibrinolysis shutdown is still not clear.23,24 Given the injury severity of pelvic fracture, it is not surprising that we found a higher rate in these patients. Yet, we found that shutdown was not predictive of VTE on initial assessment. What may be more likely is that the duration of fibrinolysis shutdown over time is more predictive of VTE, such that prolonged fibrinolysis over a series of hours or days (versus initial fibrinolysis itself) is predictive of high thrombotic risk.25 In a prospective study of pediatric patients with TBI, Leeper et. al. demonstrated that prolonged fibrinolytic shutdown or transitioning to fibrinolytic shutdown from another phenotype was associated with death, disability, and DVT.11 In addition, in a large multicenter cohort study, Roberts et al. found that approximately 70% of trauma patients who present in fibrinolytic shutdown persist in this
n e l s o n e t a l fi b r i n o l y s i s a n d v t e i n p e l v i c f r a c t u r e s
phenotype for 120 h after injury, whereas all patients who presented in hyperfibrinolysis transitioned into another phenotype or died.26 It has been shown that if a patient presents in fibrinolytic shutdown, they are more likely to remain in shutdown than to convert to physiologic fibrinolysis.27,28 Sumislawski et al. demonstrated a considerable number of patients convert to a hypercoagulable state within 24 h of admission.29 Thus, it is likely that some of our patients who initially presented in hyperfibrinolysis or physiologic fibrinolysis may have transitioned into shutdown before the development of VTE, and therefore the relationship between shutdown and VTE may be underestimated based on initial labs. Resuscitative thoracotomy and pelvic fixation were independent predictors of VTE. All of the resuscitative thoracotomies were ED thoracotomies (performed in patients who presented pulseless or became pulseless in the ED). These are extremely morbid patients, and the systemic coagulopathic and inflammatory response to cardiac arrest could certainly be driving the higher VTE rate because of the inherent stasis of blood flow. Previous literature has shown patients after cardiac arrest are often in fibrinolytic shutdown, which leads to the development of multisystem organ dysfunction.30 In addition, previous experimental animal models have demonstrated that supraceliac and infrarenal aortic crossclamping results in fibrinolytic shutdown after release of the aortic clamp.31 Therefore, there may be a relationship with the fibrinolysis profile in these thoracotomy patients that we were underpowered to detect. The relationship between pelvic fixation and VTE has been extensively explored in the orthopedic trauma literature. Although we found external pelvic fixation to be an independent predictor of VTE, it may be that external fixation is only serving as a proxy for high levels of injury severity and/or immobility, both of which have been associated with higher rates of VTE. A prospective study by Park et al. showed that high-energy hip fractures are associated with preoperative VTE occurrence of 28%,5 and therefore, it is important to consider the ideal timing of pelvic fixation. Although previous studies have shown pelvic fixation expedites patient recovery (and minimizes the prolonged hospitalization and immobilization that is linked to VTE risk itself),32-35 it is unclear when is the optimal timing, as premature fixation before resuscitation, may cause a “second hit” insult, releasing inflammatory mediators which exacerbate VTE risk. The Early Appropriate Care model published by Vallier et al. recommends definitive fixation in 36 h for most of severely injured patient with unstable pelvic fractures, although the bleeding and inflammation related to early fixation can be detrimental to patients insufficiently resuscitated before the operation.35 In a prospective multicenter cohort study examining inflammatory response after pelvic fracture operations, Pape et al. found that the release of proinflammatory cytokines was higher in pelvic fracture operations that were performed early (hospital day 1 or 2) when compared with a delayed operation.36 Timing of pelvic fixation was not considered in the scope of this project, but current efforts are underway to analyze this in the reported data. Both mechanical and chemoprophylaxis are standard in the prevention of VTE in patients with traumatic pelvic
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fractures, although there are no well-established prophylaxis guidelines and there is a general lack of clarity regarding the ideal method of VTE prevention in this high-risk population. The importance of chemoprophylaxis was highlighted in a previous study examining rates of VTE after fixation of lowerextremity fractures in patients without chemoprophylaxis, reporting VTE rates of 29% in an early surgery group and 45% in a delayed surgery group.37 In a study reviewing the incidence and methodology of VTE chemoprophylaxis in pelvic trauma patients, Chana-Rodrı´guez et al. found the reported rate of VTE in patients with traumatic pelvic fracture on chemoprophylaxis to vary greatly from 2% to 33%. Furthermore, their study highlights that trauma patients frequently present in an acute hypocoagulable state, but once stabilized, can progress to a hypercoagulable state.38 This change in hemostasis may explain why current chemoprophylaxis are insufficient in the setting of the hypercoagulability and fibrinolysis shutdown associated with pelvic fractures, suggesting perhaps patients with pelvic fractures should be considered for screening ultrasounds or pharmacologically guided VTE chemoprophylaxis. Limitations of this study include the retrospective nature; therefore, we are limited to the initial laboratory assessment and the clinical information collected prospectively in the chart. Another limitation is the small sample size; because VTE remains a relatively infrequent phenomena, we recognize we may be underpowered to detect an association between fibrinolysis profiles with VTE incidence. In addition, we only considered patients’ initial fibrinolytic phenotype on presentation, rather than following the trend of fibrinolysis and persistence of fibrinolytic shutdown throughout their inpatient stay, which may have a greater impact on their VTE risk. Another limitation of this study is that we were unable to stratify pelvic fracture mechanism of injury using Young-Burgess classification because of the high number of patients in our cohort. We also did not examine the impact of variables such as activity status, ambulation, transfusion practices, timing of pelvic fixation, pelvic packing, or chemoprophylaxis practice on VTE risk, all of which are being investigated in a larger study. We recognize that not considering differences in VTE chemoprophylaxis strategies is a major limitation to this study, as this ultimately affects patients’ coagulation profile and VTE risk. Because the focus of this study was solely to investigate the coagulation profile of patients with pelvic fracture and the association with thrombotic incidence, we are obtaining granular data on VTE chemoprophylaxis strategies in a larger study to evaluate this variable. Finally, we did not evaluate the impact of damage control external fixation placement or interventional radiology embolization on VTE risk. In conclusion, this study is the first to describe the viscoelastic profile of trauma patients with severe pelvic fractures. In the reported data, there was a high rate of VTE and a predominance of fibrinolytic shutdown on initial presentation. The high rate of VTE in this patient population supports the concept of implementing VTE chemoprophylaxis measures as soon as hemostasis is achieved. Further investigation is merited to define more reliable predictors of VTE in this patient population.
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j o u r n a l o f s u r g i c a l r e s e a r c h f e b r u a r y 2 0 2 0 ( 2 4 6 ) 1 8 2 e1 8 9
Acknowledgment 12.
Authors’ contributions: JTN originated experimental hypothesis under mentorship of JRC and EEM, gathered clinical data, and composed the manuscript. HC and AS assisted with data organization and cleaning, statistical analysis, data interpretation, and manuscript composition. CM, DRV, JMS, JRC, and EEM assisted with experimental conduct, data interpretation, and manuscript editing. Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health (T32 GM008315). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other sponsors of the project.
14.
Disclosure
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13.
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There are no conflicts of interest to report. 18.
references
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