Structured Abstract
Background
Though obese patients have high thrombosis rates following injury, the role of obesity in coagulation after trauma remains unknown. We hypothesized that BMI is independently associated with increased measures of hypercoagulability longitudinally after injury.
Methods
Data were prospectively collected for 377 consecutive highest-level trauma activation patients with a body mass index (BMI) ≥ 18.5 kg/m2. Standard coagulation measures, citrated kaolin and functional fibrinogen thromboelastography (TEG), and clotting factors were measured at 0-120h. BMI categories were defined as normal weight (18.5-24.99 kg/m2), overweight (25-29.99 kg/m2), and obese (≥ 30 kg/m2).
Results
The 377 patients were mostly male (81%) and bluntly injured (61%), with median BMI of 25.8 kg/m2. 42% were normal weight (median BMI 22.5 kg/m2). There were no differences in age, gender, ISS or base deficit between groups. There were no differences in admission INR/PTT or factors II, V, VII, VIII, X, ATIII, or protein C. However, obese patients had higher admission platelet counts (303 vs. 269 × 109/L, p=0.004), lower D-dimer (1.88 vs. 4.00 ug/mL, p=0.004), and a trend toward higher factor IX (134 vs. 119 % activity, p=0.042) than normal weight patients. Measured by TEG, clot strength (MA) and functional fibrinogen level (FLEV) were also higher on admission for obese patients (MA 65.7 vs. 63.4 mm, p=0.016; FLEV 407 vs. 351 mg/dL, p=0.008). In multiple linear regression, the relationship of BMI to clot strength, FLEV, and FIX persisted through 24h. Similarly, the relationship of BMI and platelet count persisted through 120h (all p<0.05). In multiple logistic regression, for every 5kg/m2 increase in BMI, there was an 85% increase in odds of thromboembolic complication (OR 1.85, CI 1.13-3.08, p=0.017).
Conclusion
Obese trauma patients are hypercoagulable compared to their similarly-injured normal weight counterparts, which persists longitudinally after injury. The significance of this hypercoagulability requires elucidation for guidance of anticoagulation in this at-risk group.
Level of Evidence
Level III; prognostic
Keywords: Obesity, coagulation, functional testing, thrombosis, trauma
Background
Trauma remains a public health issue of epidemic proportions. It accounts for the majority of deaths in those 1-44 years old. Early death after injury is primarily attributed to uncontrolled hemorrhage (1-3). Because of this, significant interest exists in understanding the post-injury spectrum of clotting dysfunction that spans from hypocoagulability to hypercoagulability. On presentation, nearly one third of severely injured and bleeding patients have acute traumatic coagulopathy (ATC) portending significant morbidity and a four-fold increase in mortality (4-7). In contrast, ensuing clinical hypercoagulability manifested as venous thromboembolism is seen in up to 60% of patients in the subsequent days following acute injury (8).
Analogous to the trauma epidemic, is the global prevalence of obesity. Obesity is rampant with a yearly mean BMI increase of 0.4-0.5 kg/m2 worldwide (9). Notably, one-third of adults and nearly one-quarter of children are obese in the United States (10, 11). Paralleling the shocking prevalence of obesity is the ubiquity of obesity-related illnesses including hypertension, heart disease, diabetes, and cancer (12, 13). Perhaps less elucidated, but as pivotal are the proinflammatory and procoagulant consequences of excess adipose tissue conferring up to a 2.5-fold increase in risk of venous and arterial thromboembolism (14-17). The plethora of metabolic sequelae of excess adipose tissue has been intensely investigated in the non-trauma population. Cytokines including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) contribute to the obesity induced proinflammatory mileau (18-20). Hypercoagulability may be partially due to this chronic low-grade inflammation, but is likely also due to direct effects of adipose tissue on mediators of coagulation.
Recently, much attention has been paid to the clinical role of obesity in morbidity and mortality after trauma (21). Divergent results have added to the debate; in some studies obesity has been found to confer some protection after injury (22, 23), with no effect on mortality (24). Alternatively, other studies have found that obesity is an independent risk factor for complications including thromboembolism and death (25-29). These differing results may reflect an initially protective prothrombotic effect of obesity against early hemorrhagic death, which may later predispose patients to thromboembolic complications contributing to late death and morbidity. Elucidating the interplay of obesity with inflammation and coagulation in the post-injury environment is critical for advancing clinical guidance on prevention of thromboembolism in obese trauma patients.
In order to address the effects of obesity on coagulation after injury, we sought to investigate the influence of obesity on hemostatic function after injury. Functional coagulation testing is beneficial in that it allows for the real time identification of specifics perturbations in clotting (30-33). Thromboelastography (TEG) gives a global assessment in real time of the post-injury clotting profile. From a sample of whole blood, TEG produces a distinctive tracing that measures several parameters representative of clot formation and breakdown in real time. Additionally, the level of functional fibrinogen can be established with functional fibrinogen (FF) TEG. We hypothesized that body mass index (BMI) is independently associated with increased measures of hypercoagulability by TEG longitudinally after injury.
Methods
Demographics, outcomes, and laboratory measures were prospectively collected on arrival and up to 28 days for 377 consecutive highest-level trauma activation patients with a body mass index (BMI) ≥ 18.5 m/kg2, not anti-coagulated, and without liver failure at a single Level 1 urban trauma center from 2005-2013. Standard coagulation measures (INR, platelet count, von Clauss fibrinogen), citrated kaolin (CK) TEG, FF TEG, and an extensive panel of pro- and anti-coagulant clotting factors were measured at 0, 6, 12, 24, 48, and 120 hours after injury.
Our methodology for sample collection and processing has been previously described (34). In brief, ED samples were collected with placement of a 16G or larger peripheral intravenous line, and subsequent samples were collected via indwelling arterial catheters. Standard laboratory 3.2% (0.109 mol/L) sodium citrate vacuum-sealed tubes were used for all collection. Informed consent was obtained with a waiver of consent for initial blood draws, as approved by the University of California Committee on Human Research. Samples for coagulation factor analysis were centrifuged, and plasma stored at –80°C prior to measurement of fibrinogen, the procoagulant factors II, V, VII, VIII, IX, and X, and the endogenous anticoagulants anti-thrombin III (AT III), protein C, and D-dimer with a Stago Compact Coagulation Analyzer (Diagnostica Stago Inc.; Parsippany, NJ) in accordance with manufacturer instructions. TEG was performed with the TEG 5000 (Haemonetics; Niles, Il) immediately after sample collection. One mL of citrated whole blood was added to a manufacturer-standardized vial containing the clotting activator kaolin and mixed. Following this, 340 uL was transferred from the kaolin vial to the TEG cup, warmed to 37°C, and recalcified with 20 uL of 0.2 mol/L CaCl2. For the FF TEG, 500 uL of citrated blood was added to the FF vial (kaolin + glycoprotein IIb/IIIa antagonist) and mixed; 340 uL was then transferred to the TEG cup, and warmed and recalcified as above. TEG parameters measured included: reaction time (R-time) (time to 2mm of clot formation), K-time (time to 20mm of clot formation), alpha angle (alpha) (the slope of the curve between R-time and K-time measuring the rapidity of fibrin crosslinking), maximum amplitude (MA) (maximum clot strength), the LY30 (percent of lysis at 30 minutes), and FLEV (level of functional fibrinogen). Massive transfusion (MT) was defined as transfusion of 10 units of more of packed red blood cells (pRBC) and fresh frozen plasma (FFP) in first 24 hours. Multi-organ failure (MOF) was defined using the Denver Postinjury Multiple Organ Failure Score (35). Acute respiratory distress syndrome (ARDS) was defined by Berlin definition (36). Thromboembolic complication included the development of deep venous thrombosis, pulmonary embolism, or cerebrovascular accident at any time after injury. Body mass index (BMI) categories were defined by standard cutoffs: normal weight (BMI 18.5-24.99 kg/m2), overweight (BMI 25-29.99 kg/m2), and obese (BMI ≥ 30 kg/m2).
Data are presented as mean (SD), median (interquartile range), or percentage; univariate comparisons were made using Student's t test for normally distributed data, Wilcoxon rank sum or Kruskal Wallis testing for skewed data, and Fisher's exact test for proportions. Multiple univariate comparisons between groups were only judged significant when corrected for multiple comparisons using a standard Bonferroni correction. Multiple linear regression was used at each time point to examine the relationship of BMI with clotting measures. Multiple logistic regression was used to define predictors of the development of thromboembolic complications.
Results
The 377 patients were an injured cohort with a mean ISS of 18 and a mean admission base excess of -3 (Table 1). They were mostly male (81%) with a blunt mechanism of injury (61%; Table 1). 14% required a MT and the mortality at discharge was 12% (Table 1). The median BMI of the cohort was 25.8 kg/m2, but only 42% were normal weight (median BMI 22.5 kg/m2; Table 2). 32% were overweight (median BMI 27.1 kg/m2), and 26% were obese (median BMI 33.0 kg/m2; Table 2). There were no major differences in baseline patient characteristics including age and gender, and no major differences in overall severity of injury (ISS or base excess), but the obese patients had a different injury pattern than their normal weight counterparts. They had significantly lower rates of blunt injury and a higher burden of head injury than the normal weight patients (blunt injury rate 55% vs. 72%, p=0.007; median head abbreviated injury score (AIS 0 vs. 2, p=0.008; Table 2).
Table 1. Demographics and outcomes.
| N=377 | |
| Age (years) | 33 (24-49) |
| Male gender | 81% |
| BMI (kg/m2) | 25.8 (22.9-30.1) |
| Blunt injury rate | 61% |
| ISS | 18 +/- 15 |
| ED arrival GCS | 14 (7-15) |
| AIS-head | 0 (0-4) |
| Prehospital crystalloid (mL) | 100 (0-250) |
| ED admit temperature (°) | 36.2 +/- 0.9 |
| Admit pH | 7.31 +/- 0.12 |
| Admit base excess | -3 +/- 6 |
| Admit INR | 1.1 (1-1.2) |
| Admit PTT (s) | 28 (26-31) |
| Admit platelet count (x 109/L) | 274 (225-332) |
| Admit fibrinogen (mg/dL) | 228 +/- 96 |
| Admit Factor II (% activity) | 75 +/- 21 |
| Admit Factor V (% activity) | 40 (24-57) |
| Admit Factor VII (% activity) | 82 (62-107) |
| Admit Factor VIII (% activity) | 167 (85-266) |
| Admit Factor IX (% activity) | 123 +/- 44 |
| Admit Factor × (% activity) | 78 +/- 22 |
| Admit ATIII (% activity) | 74 +/- 27 |
| Admit protein C (% activity) | 82 +/- 28 |
| Admit D-dimer (ug/mL) | 3.34 (0.58-6.77) |
| Admit CK R-time (min) | 4.6 +/- 1.4 |
| Admit CK K-time (min) | 1.3 (1.2-1.7) |
| Admit CK alpha angle (°) | 69.3 +/- 6.1 |
| Admit CK MA (mm) | 64.4 +/- 5.8 |
| Admit CK LY30 (%) | 0.8 (0.1-2.7) |
| Admit FLEV (mg/dL) | 368 +/- 90 |
| pRBC 0-24 hours (units) | 0 (0-3) |
| FFP 0-24 hours (units) | 0 (0-2) |
| PLTS 0-24 hours (units) | 0 (0-0) |
| MT in 24 hours | 14% |
| Total hospital days | 6 (3-17) |
| Ventilator free days | 2 (0-6) |
| VAP rate | 1% |
| ARDS rate | 11% |
| MOF rate | 9% |
| Mortality rate at 6 hours | 1% |
| Mortality rate at 24 hours | 3% |
| Mortality rate at discharge | 12% |
| TE complication rate | 6% |
Patient demographics for the 377 patients. Data are mean +/- SD, median (inter-quartile range), or n (%) as indicated. Data for skewed variables reported as median with inter-quartile ranges. BMI=body mass index. ED=emergency department. GCS=Glascow Coma Scale. ISS=injury severity score. AIS=abbreviated injury score. INR=international normalized ratio. PTT=partial thromboplastic time. ATIII=antithrombin III. CK=citrated kaolin. R-time=reaction time. MA=maximum amplitude. LY30=lysis at 30 min. FLEV=functional fibrinogen level. pRBC=packed red blood cell units. FFP=fresh frozen plasma units. PLTS=platelet units. MT=massive transfusion. Ventilator free days, counted for the first 28 days of hospitalization. Patients who expired received 0 ventilator free days. VAP=ventilator associated pneumonia. ARDS=acute respiratory distress syndrome by Berlin criteria. MOF=multiple organ failure. TE=thromboembolic
Table 2. Demographics and outcomes by BMI category (normal weight, overweight, obese/superobese).
| Normal weight | Overweight | Obese | p-value | p-value (normal weight vs obese) | |
|---|---|---|---|---|---|
| N=160 (42%) | N=120 (32%) | N=97 (26%) | |||
| Age (years) | 34 (24-51) | 33 (26-47) | 33 (24-45) | 0.6642 | 0.3493 |
| Male gender | 78% | 85% | 84% | 0.2380 | 0.2660 |
| BMI (kg/m2) | 22.5 (20.9-23.8) | 27.1 (25.9-28.3) | 33.0 (31.3-36.1) | 0.0001 | 0.0001 |
| Blunt injury rate | 72% | 51% | 55% | 0.0010 | 0.0070 |
| ISS | 18 +/- 15 | 18 +/- 15 | 17 +/- 15 | 0.6313 | 0.3022 |
| ED arrival GCS | 13 (7-15) | 14 (8-15) | 14 (7-15) | 0.1480 | 0.1514 |
| AIS-head | 2 (0-4.5) | 0 (0-3.5) | 0 (0-3) | 0.0129 | 0.0083 |
| Prehospital crystalloid (mL) | 50 (0-250) | 100 (0-250) | 100 (0-250) | 0.4915 | 0.4282 |
| ED admit temperature (°) | 36.1 +/- 0.9 | 36.2 +/- 0.9 | 36.3 +/- 1.0 | 0.6560 | 0.3774 |
| Admit pH | 7.31 +/- 0.12 | 7.31 +/- 0.11 | 7.29 +/- 0.15 | 0.3640 | 0.2349 |
| Admit base excess | -2.4 +/- 5.5 | -3.2 +/- 4.6 | -3.7 +/- 6.5 | 0.2872 | 0.1494 |
| Admit INR | 1.1 (1.1-1.2) | 1.1 (1-1.2) | 1.1 (1-1.2) | 0.3063 | 0.2687 |
| Admit PTT (s) | 28 (26-32) | 28 (26-31) | 28 (26-30) | 0.4731 | 0.2448 |
| Admit platelet count (× 109/L) | 269+/- 83 | 283 +/- 80 | 303 +/- 101 | 0.0105 | 0.0038 |
| Admit fibrinogen (mg/dL) | 230 +/- 94 | 210 +/- 100 | 243 +/- 95 | 0.2050 | 0.4233 |
| Admit Factor II (% activity) | 76 +/- 18 | 72 +/- 25 | 77 +/- 23 | 0.4983 | 0.8298 |
| Admit Factor V (% activity) | 39 (23-58) | 41 (19-53) | 41 (28-61) | 0.3127 | 0.4349 |
| Admit Factor VII (% activity) | 82 (63-107) | 79 (55-100) | 77 (62-111) | 0.4481 | 0.6201 |
| Admit Factor VIII (% activity) | 156 (89-268) | 176 (108-298) | 147 (74-263) | 0.5145 | 0.7304 |
| Admit Factor IX (% activity) | 119 +/- 39 | 118 +/- 46 | 134 +/- 48 | 0.0942 | 0.0416 |
| Admit Factor × (% activity) | 78 +/- 18 | 75 +/- 26 | 81 +/- 24 | 0.3473 | 0.3694 |
| Admit ATIII (% activity) | 79 +/- 26 | 68 +/- 24 | 72 +/- 30 | 0.0711 | 0.3573 |
| Admit protein C (% activity) | 79 +/- 27 | 84 +/- 26 | 84 +/- 31 | 0.5522 | 0.1289 |
| Admit D-dimer (ug/mL) | 4.00 (1.13-7.70) | 2.67 (0.44-6.29) | 1.88 (0.45-4.00) | 0.0128 | 0.0039 |
| Admit CK R-time (min) | 4.4 +/- 1.4 | 4.6 +/- 1.5 | 4.7 +/- 1.3 | 0.2835 | 0.1036 |
| Admit CK K-time (min) | 1.3 (1.2-1.6) | 1.4 (1.2-1.8) | 1.3 (1.2-1.7) | 0.8687 | 0.8955 |
| Admit CK alpha angle (°) | 69.3 +/- 6.4 | 69.2 +/- 5.9 | 69.4 +/- 6.1 | 0.7850 | 0.8857 |
| Admit CK MA (mm) | 63.4 +/- 6.1 | 64.5 +/- 5.0 | 65.7 +/- 6.1 | 0.0374 | 0.0157 |
| Admit CK LY30 (%) | 1.0 (0.1-2.5) | 0.9 (0.1-2.8) | 0.6 (0.1-2.7) | 0.9524 | 0.9456 |
| Admit FLEV (mg/dL) | 351 +/- 84 | 358 +/- 70 | 407 +/- 105 | 0.0670 | 0.0077 |
| pRBC 0-24 hours (units) | 0 (0-2.5) | 0 (0-3.5) | 0 (0-2) | 0.6480 | 0.7743 |
| FFP 0-24 hours (units) | 0 (0-1) | 0 (0-2) | 0 (0-1) | 0.1300 | 0.9672 |
| PLTS 0-24 hours (units) | 0 (0-0) | 0 (0-0) | 0 (0-0) | 0.6655 | 0.5200 |
| MT in 24 hours | 12% | 18% | 5% | 0.2870 | 0.5270 |
| Total hospital days | 7 (3-15) | 7 (2-20) | 6 (3-18) | 0.7482 | 0.4431 |
| Ventilator free days | 26 (21-28) | 27 (19-28) | 27 (20-28) | 0.8412 | 0.6154 |
| VAP rate | 0% | 2% | 0% | 0.1620 | n/d |
| ARDS rate | 12% | 12% | 8% | 0.7330 | 0.2880 |
| MOF rate | 9% | 8% | 9% | 0.9730 | 1.0000 |
| Mortality rate at 6 hours | 1% | 1% | 0% | 0.7900 | 0.5280 |
| Mortality rate at 24 hours | 2% | 3% | 3% | 0.7160 | 0.6760 |
| Mortality rate at discharge | 15% | 9% | 10% | 0.3080 | 0.3440 |
| TE complication rate | 4% | 4% | 9% | 0.2410 | 0.1810 |
Comparisons of the normal weight, overweight, and obese groups. Data are mean +/- SD, median (inter-quartile range), or n (%) as indicated. Data for skewed variables reported as median with inter-quartile ranges. p-value bolded if <0.0167 as corrected for multiple comparisons. BMI=body mass index. ED=emergency department. GCS=Glascow Coma Scale. ISS=injury severity score. AIS=abbreviated injury score. INR=international normalized ratio. PTT=partial thromboplastic time. ATIII=antithrombin III. CK=citrated kaolin. R-time=reaction time. MA=maximum amplitude. LY30=lysis at 30 min. FLEV=functional fibrinogen level. pRBC=packed red blood cell units. FFP=fresh frozen plasma units. PLTS=platelet units. MT=massive transfusion. Ventilator free days, counted for the first 28 days of hospitalization. Patients who expired received 0 ventilator free days. VAP=ventilator associated pneumonia. ARDS=acute respiratory distress syndrome by Berlin criteria. MOF=multiple organ failure. TE=thromboembolic
Baseline Measures of Hemostasis
There were no differences in emergency department (ED) plasma-based coagulation measures (international normalized ratio [INR] or partial thromboplastin time [PTT]) across BMI groups. There were also no differences in factor activity levels for factors II, V, VII, VIII, X, ATIII, or protein C across BMI groups (Table 2). However, notably the obese patients had significantly higher ED platelet counts (303 vs. 269 × 109/L, p=0.004), lower D-dimer levels (1.88 vs. 4.00 ug/mL, p=0.004), and a trend toward higher factor IX activity (134% vs. 119%, p=0.042) thannormal weight patients. Measured by TEG, there was no difference in clot initiation parameters (R-time, K-time, and alpha; p>0.0167 for multiple comparisons; Table 2). However, obese patients had significantly stronger clot strength and higher levels of functioning fibrinogen (MA 65.7 vs. 63.4 mm, p=0.016; FLEV 407 vs. 351 mg/dL, p=0.008; Table 2). Despite the presence of more hemostatic measures of clotting in the obese compare to the normal weight patients, there were no notable univariate differences in transfusion of pRBC, FFP, or platelet apheresis (PLTs) units (all p>0.0167 for multiple comparisons; Table 2). Similarly, there were also no univariate differences in MT, length of stay, or complications including ARDS, MOF, or mortality rates (all p>0.0167 for multiple comparisons; Table 2). However, there was a trend toward higher rates of thromboembolic complications in obese compared to normal weight patients (9% vs. 4%, p=0.1810; Table 2).
Longitudinal Measures of Hemostasis
Given the obese patients demonstrated more hemostatic measures of clotting on admission, we then performed multiple linear regression (controlling for age, injury severity, gender, and all products received up to each timepoint) at serial timepoints after injury (6, 12, 24, 48, and 120 hours) to examine the independent relationship of BMI to functional clotting parameters, factor levels, and INR over time. There were no statistically significant independent relationships or notable trends between BMI and clot initiation parameters (R-time, K-time, alpha angle) or functional measures of fibrinolysis (LY30) at any timepoint after injury (all p>0.05 at all timepoints). Similarly, there were no statistically significant independent relationships or notable trends between BMI and factor levels for the procoagulant factors II, V, VII, VIII, X, protein C, ATIII, or INR at any timepoint after injury (all p>0.05 at all timepoints). However, there was a significant independent increase in Factor IX activity for each 5 kg/m2 increase in BMI at 0, 6, and 12, 48, and 120 hours after injury (Table 3). This relationship was not present at 24 hours (Table 3).
Table 3. Independent relationship of BMI with factor IX and clot strength at serial timepoints after injury.
| Independent relationship of BMI and factor IX activity at serial timepoints after injury | |||||
|---|---|---|---|---|---|
|
| |||||
| Factor IX (% activity) per 5 kg/m2 increase in BMI | CI | p-value | |||
| 0h | 7.79 | 1.51 | - | 14.06 | 0.015 |
| 6h | 13.88 | 4.80 | - | 22.95 | 0.003 |
| 12h | 9.30 | 1.74 | - | 16.87 | 0.016 |
| 24h | 7.83 | -2.44 | - | 18.10 | 0.133 |
| 48h | 15.71 | 3.93 | - | 27.50 | 0.010 |
| 120h | 28.21 | 3.47 | - | 52.93 | 0.027 |
|
| |||||
| Covariates at each timepoint: age, injury severity, gender, and all products (pRBC, FFP, PLTs) received up to that timepoint. P-value bolded for <0.05. | |||||
| Independent relationship of BMI and clot strength (MA) at serial timepoints after injury | |||||
|---|---|---|---|---|---|
|
| |||||
| CK MA change (mm) per 5 kg/m2 increase in BMI | CI | p-value | |||
| 0h | 1.01 | 0.39 | - | 1.62 | 0.002 |
| 6h | 1.24 | 0.39 | - | 2.07 | 0.004 |
| 12h | 1.17 | 0.36 | - | 1.97 | 0.005 |
| 24h | 0.95 | 0.08 | - | 1.82 | 0.032 |
| 48h | 0.35 | -0.57 | - | 1.27 | 0.455 |
| 120h | 0.63 | -1.03 | - | 2.28 | 0.449 |
Covariates at each timepoint: age, injury severity, gender, and all products (pRBC, FFP, PLTs) received up to that timepoint. P-value bolded for <0.05. CK MA= citrated kaolin TEG maximum amplitude (mm).
Similarly, there was a significant independent increase in clot strength (MA) for each 5 kg/m2 increase in BMI at 0, 6, 12, and 24 hours after injury (all p<0.05; Table 3). However, this relationship of BMI to clot strength was not present past 24 hours. Paralleling overall clot strength, BMI and functional fibrinogen levels (FLEV) were positively associated through 24 hours (Table 4), but not beyond. Perhaps the most notable relationship was the significant increase in platelet count with increasing BMI at all timepoints after injury (Table 4). This peaked at 12 hours, where for each 5kg/m2 increase in BMI the platelet count increased by 33 × 109/L (p<0.001; Table 4). Lastly, confirming the lower admission D-dimer in the obese group seen in our univariate comparison, we found that D-dimer independently decreased with increasing BMI out to 12 hours (Table 5).
Table 4. Independent relationship of BMI with functional fibrinogen level and platelet count at serial timepoints after injury.
| Independent relationship of BMI and functional fibrinogen level (FLEV) at serial timepoints after injury | |||||
|---|---|---|---|---|---|
|
| |||||
| FLEV change (ng/mL) per 5 kg/m2 increase in BMI | CI | p-value | |||
| 0h | 23.20 | 10.31 | - | 36.10 | 0.001 |
| 6h | 19.92 | 0.29 | - | 39.55 | 0.047 |
| 12h | 19.85 | 3.84 | - | 35.87 | 0.016 |
| 24h | 15.96 | 0.04 | - | 31.88 | 0.049 |
| 48h | -8.70 | -38.14 | - | 20.73 | 0.545 |
| 120h | -5.20 | -55.84 | - | 45.46 | 0.828 |
|
| |||||
| Covariates at each timepoint: age, injury severity, gender, and all products (pRBC, FFP, PLTs) received up to that timepoint. P-value bolded for <0.05. CK MA= citrated kaolin TEG maximum amplitude (mm). | |||||
| Independent relationship of BMI and platelet count at serial timepoints after injury | |||||
|---|---|---|---|---|---|
|
| |||||
| Platelet count (× 109/L) per 5 kg/m2 increase in BMI | CI | p-value | |||
| 0h | 10.94 | 2.32 | - | 19.56 | 0.013 |
| 6h | 23.30 | 3.79 | - | 42.81 | 0.020 |
| 12h | 33.33 | 16.60 | - | 50.07 | <0.001 |
| 24h | 10.57 | 3.77 | - | 17.38 | 0.002 |
| 48h | 11.57 | 4.86 | - | 18.28 | 0.001 |
| 120h | 12.54 | 0.49 | - | 24.59 | 0.041 |
Covariates at each timepoint: age, injury severity, gender, and all products (pRBC, FFP, PLTs) received up to that timepoint. P-value bolded for <0.05.
Table 5. Independent relationship of BMI with D-dimer at serial timepoints after injury.
| Independent relationship of BMI and D-dimer at serial timepoints after injury | |||||
|---|---|---|---|---|---|
|
| |||||
| Ddimer (ug/mL) per 5 kg/m2 increase in BMI | CI | p-value | |||
| 0h | -1.09 | -1.65 | - | -0.52 | <0.001 |
| 6h | -0.56 | -1.00 | - | -0.12 | 0.014 |
| 12h | -0.41 | -0.85 | - | 0.04 | 0.073 |
| 24h | -0.28 | -0.78 | - | 0.21 | 0.253 |
| 48h | -9.58 | -0.65 | - | 7.25 | 0.260 |
| 120h | 0.21 | -0.66 | - | 1.08 | 0.629 |
Covariates at each timepoint: age, injury severity, gender, and all products (pRBC, FFP, PLTs) received up to that timepoint. P-value bolded for <0.05.
Thromboembolic Complications
Finally, we sought to examine whether the increased factor IX activity, increased overall clot strength, increased functioning levels of fibrinogen, increased platelet count, and decreased fibrinolysis seen longitudinally after injury corresponded with an increased risk of developing a thromboembolic complication. In a multiple logistic regression controlling for injury severity, transfusion, and deep venous thromboembolism (DVT) prophylaxis, we found that for every 5kg/m2 increase in BMI, there was an 85% increase in odds of developing a thromboembolic complication (OR 1.85, CI 1.12-3.08, p=0.017; Table 6).
Table 6. Multivariate predictors of thromboembolic complications.
| Univariate | CI | p | Multivariate | CI | p | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Age (years) | 1.02 | 0.99 | - | 1.04 | 0.195 | |||||
| Male gender | 0.55 | 0.20 | - | 1.47 | 0.231 | |||||
| BMI (5kg/m2) | 1.07 | 1.00 | - | 1.15 | 0.053 | 1.85 | 1.12 | - | 3.08 | 0.017 |
| ISS | 1.03 | 1.01 | - | 1.06 | 0.018 | 0.98 | 0.93 | - | 1.03 | 0.403 |
| DVT prophylaxis given in 1st 5 days | 4.46 | 1.51 | - | 13.22 | 0.007 | 4.99 | 0.99 | - | 25.10 | 0.051 |
| Total product (units) from 0-72 hours | 1.04 | 1.02 | - | 1.06 | <0.001 | 1.06 | 1.01 | - | 1.11 | 0.016 |
n=377. Bolded: p<0.05 for multivariate predictors. AUC=0.83. ISS=injury severity score. DVT=deep venous thromboembolism. Total product= number of units of packed red blood cells, fresh frozen plasma, and platelets
Discussion
With the growing prevalence of obesity coupled with the increased incidence of injury worldwide, elucidating the intimate associations and relationships between these two disease states is critical. Only 42% of our severely injured cohort was normal weight, which highlights that the majority of injured patients suffer from the effects of excess adipose tissue. This excess adipose is far from inert and plays a cardinal role in the biologic and physiologic milieu seen with obesity. Untangling its complex interaction with inflammation and coagulation will help contribute to a better understanding of the clinical outcome differences seen in obese patients after injury and may help with targeted treatment of this at-risk group. We found that following injury, obese patients are hypercoagulable compared to their similarly injured normal weight counterparts. This hypercoagulability persists after injury as demonstrated by increased FIX activity, increased levels of functioning fibrinogen, relative thrombocytosis, stronger clot, and decreased evidence of clot lysis with increasing BMI. The importance of these relationships is highlighted by an independent 85% increased odds of developing a thromboembolic complication after injury for each 5kg/m2 increase in BMI.
Our cohort of obese patients had lower rates of blunt injury and head injury, which corresponds to prior studies demonstrating some potential protective aspects of overall adipose volume to injury patterns (22, 23). However, there was no difference in overall injury severity or mortality rates between obese and normal weight patients (24). Despite this, the obese patients had higher rates of thromboembolic complications and BMI was a significant independent predictor of development of thromboembolic complications even when controlling for injury severity, product transfusion, and DVT prophylaxis.
Obesity induced chronic low-grade inflammation may be partially responsible for this increased rate of thromboembolic complications. However, adipose-specific mediation of coagulation may play a pivotal role in thrombotic potential following injury. Specific pathways that have been investigated include increased thrombin generation due to excess release of and tissue factor from adipose cells (20, 37), thrombogenic modulation of platelet aggregation induced by leptin and adiponectin (15, 20, 38), and decreased fibrinolysis due to excess release of plasminogen activator inhibitor-1 (PAI-1) from adipose cells (39). Additionally, there is speculation that enhanced biosynthesis of coagulation factors including fibrinogen may be due to obesity-induced alterations in liver metabolism. The acute phase hepatic production of fibrinogen may be related to the IL-6 mediated inflammatory state (19, 20). Kaye et al recently studied coagulation in obesity discordant monozygotic twin pairs and found higher activities of fibrinogen, factor IX, XI, XII, and PAI-1 in the obese twins compared to their lean monozygotic pair (40).
Supportive of these pathways, we found that immediately following injury our study's obese patients were relatively hypercoagulable compared to their normal weight counterparts. A balance between clot formation and breakdown determines ultimate clotting potential, and our study demonstrated that obese injured patients exhibited both stronger clot and less fibrinolysis. The stronger clot is presumably due to the significant increases in both of the primary contributors to clot strength: fibrin and platelets. This is evident in our study because the obese patients had significantly higher levels of functioning fibrinogen as well as a significant relative thrombocytosis compared to their normal weight counterparts. Although there was no statistically significant difference in fibrinolysis by TEG between the groups, there was a stepwise trend with the lowest amount of fibrinolysis in the obese patients. This corresponds with the finding of a significantly lower D-dimer in the obese patients compared to their normal weight counterparts. Interestingly, there was no difference in the functional measure of fibrinolysis. However, Raza et al recently demonstrated that functional measures of fibrinolysis are not as sensitive in detection as plasmin-antiplasmin complex levels or D-dimer levels (41).
The hypercoagulability found immediately following injury in the obese patients persisted to at least 24 hours. The BMI dependent increase in factor IX activity and the relative thrombocytosis persisted out to 5 days after injury independent of injury severity or transfusion of pRBC, FFP, or PLTs. However, we found that the BMI dependent increase in clot strength and functional levels of fibrinogen only persisted to 24 hours after injury, and the decrease in fibrinolysis measured by D-dimer only persisted to 12 hours after injury. This increase in clot strength and decreased clot breakdown needs further study, but it appears that several independent relationships between BMI and several mediators of coagulation may contribute to the ultimate increased risk of thromboembolism. It may be that the relationship between fibrinogen function and BMI disappears past 24 hours due to the initiation of heparin based DVT prophylaxis, which does not have any effect on the relative thrombocytosis seen out to 5 days. Unfortunately, we cannot examine this due to our lack of data on the timing of initiation of DVT prophylaxis. Alternatively, it may be that the overwhelming propensity of injury-induced hypercoagulability leads to increasing fibrinogen function in all severely injured patients overcoming the independent effect of BMI past 24 hours. These complex relationships need to be further examined.
We recognize several limitations of our study including the prospective observational nature. We do not know the timing or dosages of DVT prophylaxis in order to adjust for its contribution to the effect of BMI on the functional level of fibrinogen. Additionally, there is no standardized heparin based DVT prophylaxis or standardized algorithm at our institution. Akin to this, we do not perform routine screening for DVT, and therefore only report clinically significant thromboembolic complications. There may be a much higher incidence of non-clinically significant thromboembolism in this population. However, even with a potential underestimate of the true incidence, we found a significant independent association of BMI and thromboembolism.
In examining the independent association of BMI and the mediators of coagulation past 24 hours, the later regression timepoints have fewer patients due to death and discharge. This could cause a type II error and may be a potential explanation for the lack of associations seen between functional fibrinogen level and D-dimer past 24 hours. Lastly, we cannot define any directly causal pathways between increased factor IX activity, increased levels of functional fibrinogen, increased platelet counts, stronger clot, and decreased D-dimer leading to the increased risk of thromboembolism in the obese patients. However the association of BMI with these mediators of hemostasis is supported by previous basic science and cellular investigations of adipose-induced coagulation effects. Future clinical studies with matching uninjured obese patients and animal models of genetically identical obesity discordant subjects will be critical to further elucidate the interplay of obesity, inflammation, and injury.
In conclusion, following injury obese patients are hypercoagulable compared to their similarly injured normal weight counterparts, which persists to at least 24 hours after injury. Additionally, BMI is independently associated with an 85% increased risk of developing a thromboembolic complication after injury. These findings are critical and need to be further investigated to guide management of anticoagulation in this at-risk group.
Acknowledgments
Funding: Supported by DOD W911NF-10-1-0384 (MJC) and NIH T32 GM-008258-25 (LZK)
Footnotes
Conflicts of interest: None
This work was presented at the 73rd annual meeting of the American Association for the Surgery of Trauma, September 10–13, 2014, in Philadelphia, Pennsylvania.
Author Contributions: LZK, BMH, RK, MJC, and RAC contributed to study design, data collection, data analysis, data interpretation, writing, and clinical revision.
BJR and MFN contributed to study design, data collection, and clinical revision.
Contributor Information
Lucy Kornblith, Email: lucy.kornblith@ucsfmedctr.org.
Benjamin Howard, Email: benjamin.howard@ucsfmedctr.org.
Ryan Kunitake, Email: ryan.kunitake@ucsf.edu.
Brittney Redick, Email: redickb@sfghsurg.ucsf.edu.
Mary Nelson, Email: nelsonm@sfghsurg.ucsf.edu.
Mitchell Jay Cohen, Email: mcohen@sfghsurg.ucsf.edu.
Rachael Callcut, Email: callcutr@sfghsurg.ucsf.edu.
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