EFFECTIVE USE OF WEIGHT-

BASED ENOXAPARIN FOR

DEEP VEIN THROMBOSIS
CHEMOPROPHYLAXIS IN
PATIENTS WITH TRAUMATIC
BRAIN INJURY
Moderator- Dr Rahul
Presenter- Dr Pallavi
AUTHORS AND PUBLICATIONS
➤ Ashley Taylor, Patricia Martinez, Ellen Huang, et al

➤ Augusta University, Department of Surgery, Division of Trauma/Surgical Critical Care,

Augusta, USA

➤ Published in the American journal of surgery in July 2021

INTRODUCTION
➤ Chemoprophylaxis for deep vein thrombosis (DVT) in the setting of traumatic brain injury
(TBI) continues to be a topic of much discussion.
➤ Approximately two million individuals in the United States present to the emergency
department for evaluation after sustaining a TBI, with approximately 15% requiring
hospitalization based on data collected by the Centers for Disease Control and Prevention
(CDC).

➤ Traumatic injury, in general, places patients at a higher risk for having a venous
thromboembolic (VTE) event. The reported incidence of developing a VTE in this patient
population ranges between 11% to 67%.
➤ Additionally, the presence of a TBI is an independent risk factor associated with the
development of VTE.
➤ Typically, injured patients are initiated on chemoprophylaxis to decrease the risk of
developing VTE, however the presence of a TBI complicates the timing of chemoprophylaxis
initiation due to concern that an intracranial hemorrhage (ICH) may expand.
➤ As noted by Geerts, 58% of TBI patients will develop a DVT if no prophylaxis is initiated.
➤ This DVT incidence is only decreased by half with the addition of sequential compression
devices (SCDs).
➤ A review assessing the use of chemoprophylaxis in the setting of TBI noted that early
chemoprophylaxis (less than 72 h) was a more effective strategy for DVT prophylaxis compared to
late (more than 72 h) or no chemoprophylaxis.
➤ The Brain Trauma Foundation recommends the use of chemoprophylaxis utilizing low molecular
weight heparin (LMWH) or low-dose unfractionated heparin (UF) in addition to mechanical
prophylaxis to prevent DVT in the setting of TBI without specific guidelines for timing or dosing
of the agent used.

➤ While there is still some reticence for initiating chemoprophylaxis in the setting of TBI due to
concerns for ICH expansion, increasing evidence shows that chemoprophylaxis is reasonably safe
in patients whose ICH shows certain characteristics.
➤ This trend was also noted in “The Delayed Versus Early Enoxaparin Prophylaxis I (DEEP I)
study” where TBI patients with small, stable ICH 24 h after initial injury had no clinically
significant ICH expansion and Glasgow Coma Scale (GCS) was not affected.

➤ LMWH is the recommended agent of choice for DVT chemo- prophylaxis in the trauma
population.

➤ While the literature docu- ments the benefits of enoxaparin use in the setting of TBI for
chemoprophylaxis, there is limited data regarding weight-based enoxaparin dosing.
➤ Additionally, the majority of studies evaluating the benefit and safety of weight-based
enoxaparin dosing have excluded TBI patients over concerns for ICH expansion.

➤ Due to the rising VTE rates at this institution, the DVT chemoprophylaxis regimen was
standardized, and an institutional protocol was approved, with weight-based enoxaparin
dosing instead of stan- dard dosing (30 mg twice per day) for all trauma patients who met
criteria.
AIMS
➤ To evaluate the utility of weight-based enoxaparin dosing in preventing VTE events along
with assessing the incidence of ICH expansion.

➤ The study hypothesised that increasing the dose in the setting of monitoring anti-Xa peak
levels would not lead to expansion of ICH.
MATERIALS AND METHODS
➤ Retrospective study

➤ Adult trauma patients admitted between January 1, 2018 to Feb 28, 2019
➤ Protocol
A guideline was developed as part of a multidisciplinary collaboration between the Division
of Trauma & Emergency General Surgery and the Critical Care Pharmacy Specialists.

Based on the approved guideline, patients admitted to the trauma surgery service, both
intensive care unit (ICU) and ward services, were initiated on weight-based enoxaparin dosed
at 0.5 mg/kg subcutaneously every 12 h upon admission, provided they had no
contraindications to prophylactic anticoagulation.
In patients with TBI, chemoprophylaxis was initiated 24 h after the head CT scan
demonstrating no evidence of ICH expansion.

Anti-Xa peak levels were drawn between 3-to-5 hours after either the third or fourth
consecutive dose of enoxaparin, with a targeted goal range of 0.2-0.6 unit/mL.

Obtained anti-Xa peak levels were then assessed by a critical care pharmacy specialist and
dose adjustments of enoxaparin if needed were recommended to the trauma surgery team.
➤ Patients who had received at least three consecutive doses of enoxaparin for DVT prophylaxis
prior to obtaining an anti-Xa peak level, three-to-five hours after the third dose, were
included in the analysis.

➤ Patients with an age <18 years old, no evidence of TBI, a creatinine clearance of 30 mL/min,
a baseline platelet count of 50,000 per mm, a known allergy to heparin, history of heparin-
induced thrombocytopenia, pregnancy, or had received therapeutic anticoagulation
immediately prior to the trauma admission were excluded.
➤ The primary outcome was to assess the incidence of ICH expansion while on weight-based
enoxaparin.

➤ Secondary outcomes measured include the incidence of new symptomatic VTE diag- nosed
by computed tomography angiogram or ultrasonography.
➤ All statistical analyses were preformed using SAS 9.4 and statistical significance was assessed
using an alpha level of 0.05.
➤ Descriptive statistics were completed for all variables, and by anti-Xa peak range categories,
including within and not within the targeted goal range 0.2e0.6 units/mL.

➤ Chi-square or two-sample t-tests were used to examine differences in the incidence of newly
diagnosed symptomatic VTE and incidence of ICH expansion.
➤ Anti-Xa peak range goals categories of <0.2 units/mL, 0.2e0.6 units/mL, and >0.6 units/mL
were also evaluated.
RESULTS
➤ A total of 1043 patients were screened for inclusion during the study period, of which 300
patients received weight-based enoxaparin for three consecutive doses prior to obtaining an
anti-Xa peak level.
➤ Of the 300 patients who received weight-based enoxaparin, 66 of them had a diagnosis of
TBI.

➤ A little over half of the patients (51.5%) had isolated head injury.

➤ The mean ISS was 20.6 with a mean Head-AIS of 3.2 and a GCS mean of 11.4.
➤ Blunt force trauma was the most common mechanism of injury (86.4%) with motor vehicle
collisions and falls being the most common etiology.

➤ Penetrating trauma accounted for only 13.6% of the studied population.

➤ Anti-Xa peak levels were within goal range in 57 patients with 8 patients below goal and 1
above goal.

➤ For those with levels not within goal, dose adjustments were made in 7 patients.
➤ New anti-Xa peak levels were measured in 5 of those patients (71.4%) and each of those
repeat levels were within goal.
➤ ICH expansion was noted in only two of 66 patients while on weight-based enoxaparin, but
this did not approach statistical significance. (3.3%)

➤ Mean time to chemoprophylaxis initiation for these two patients was 4.25 days.
➤ Both patients, who were initially treated non-operatively, required surgical intervention
however neither patient died as a result of this complication.

➤ Mortality due to VTE did not occur.

➤ Each patient diagnosed with a VTE had an anti-Xa peak level within goal range with the first
measurement and no dose adjustment was indicated.
DISCUSSION
➤ Venous thromboembolism remains a concerning complication in the trauma population due to
its associated morbidity and mortality.
➤ Initiation of chemoprophylaxis is crucial in this patient population, particularly with the
diagnosis of TBI.

➤ Over the years there have been studies in the approach to chemoprophylaxis with regards to
the agent and dosing, weight-based enoxaparin in particular.
➤ However, safety, and effectiveness, data are lacking the use of weight-based enoxaparin in the
setting of TBI.
➤ Due to concern for intracranial hemorrhage expansion, these patients tend to be excluded
from the studies that involve doses of low molecular weight heparin greater than the standard
dose (30 mg every 12 h).

➤ In this study, a weight-based enoxaparin regimen for DVT chemoprophylaxis in TBI patients
had an incidence of ICH expansion of 3.3%, a rate similar to other studies on this topic.
➤ Additionally, the incidence of symptomatic VTE was 1.5%, which is no different from other
studies.
➤ Mortality seen during the study period was not secondary to ICH expansion or VTE.
➤ LMWH has been shown to be superior to low-dose UF for DVT prophylaxis in the trauma
population by a number of studies.

➤ On this basis, the Eastern Association for the Surgery of Trauma (EAST) guidelines
recommend this agent for chemoprophylaxis.

➤ Despite recommended guidelines, hesitancy exists in using this agent for early initiation of
chemoprophylaxis in TBI patients who are considered a high-risk patient population.
➤ Norwood et al. studied the effectiveness of enoxaparin in preventing VTE after traumatic
injury in patients considered high risk for developing a VTE. Patients with closed head injury
were included in this study.

➤ DVT chemoprophylaxis using standard enoxaparin dosing, was initiated 24 h after admission
with no bleeding complications noted in the TBI group. All patients were screened with
duplex color flow Doppler ultrasound to assess for the presence of a VTE, with DVT noted in
two patients.
➤ Scudday et al. evaluated DVT chemoprophylaxis initiation using standard doses of either
enoxaparin or low-dose UF in TBI patients. Chemoprophylaxis was started 24-48 h after the
second CT scan of the head if no ICH expansion was noted.

➤ Compared to patients not receiving chemoprophylaxis, the treatment group had fewer patients
with ICH expansion but this was not statistically significant. Furthermore, fewer people in the
treatment group developed VTE compared to the non-treatment group.
➤ In various studies, enoxaparin has demonstrated variable and unreliable pharmacokinetic
properties in critically ill patients.
➤ Some data suggest that this is due to the acquired deficiency of antithrombin seen in the
critically ill patient.

➤ Normally, antithrombin inactivates thrombin and activated factors IXa, Xa, XIa, and XIIa.
Heparinoids exert their anticoagulant effect by binding to antithrombin and potentiating this
process.
➤ Without antithrombin, the needed substrate, UF and/ or LMWH are unable to exert their
effects regardless of the UF or LMWH circulating levels as the ligand-substrate interaction
cannot occur.
➤ Additionally, critically ill patients may have an increase in the UF and/or LMWH volume of
distribution which can be attributed to an increase in extravascular space and the development
of peripheral edema, as seen in patients with capillary leakage secondary to systemic
inflammatory response syndrome.

➤ The above mentioned physiologic changes, may cause erratic absorption of enoxaparin after
subcutaneous administration leading to limited systemic distribution.
➤ The above-mentioned factors combine to decrease the efficacy of enoxaparin for preventing
VTE in the critically ill patient.
➤ Numerous studies document the effectiveness of weight-based enoxaparin compared to
standard dosing, but few have evaluated its use in patients with TBI.

➤ Baharvahdat et al. prospectively evaluated weight-based enoxaparin (0.5 mg/kg/dose every 6

h) versus placebo in TBI patients, while obtaining serial labs and imaging to assess for ICH
expansion.
➤ Chemoprophylaxis was initiated 48 h after admission, and only patients with a GCS 5-8 were
included, with high risk TBI characteristics on CT scan causing exclusion.
➤ Compared to the placebo group, the treatment group had a higher incidence of ICH
expansion, however it did not reach statistical significance.

➤ Despite this increase, patients in the treatment arm had a better recovery and more favorable
outcome at time of hospital discharge than the placebo group.

➤ While the ICH expansion noted in this study is concerning, this study had a small sample size
(26-27 people per arm) and it utilized an enoxaparin dosing that is equivalent to therapeutic
treatment for VTE.
LIMITATIONS
➤ Retrospective study
➤ Small sample size
➤ Additionally, the diagnoses of DVT and PE were made based on clinical symptoms only, as
screening duplexes are not part of the established guideline at this institution based on the
CHEST 2012 recommendations.
➤ Similarly, ICH expansion was diagnosed on head CT scan, which was ordered based on
clinical findings such as diminished GCS that prompted repeat imaging.
➤ Without utilizing routine serial screening duplexes or scheduled repeat head CT scans,
asymptomatic TE and/or subclinical ICH expansion may have been missed.
➤ The timing of DVT chemoprophylaxis is another noted limitation as they were unable to
ascertain why the timing of chemoprophylaxis initiation was varied as it was readily apparent
in the electronic medical record.
➤ This limitation could also have an effect on evaluating for ICH expansion with the current
guideline if timing to initiation was significantly delayed.
➤ However, as the two patients that ICH expansion in this study had delayed chemoprophylaxis
initiation with appropriate anti-Xa peak levels, this effect may be minimal.
➤ Additionally, the patient population demographics are predominantly male with a body mass
index (BMI) within the overweight range, limiting the generalizability of our findings.
CONCLUSION
➤ As guidelines and practices for the management of VTE in the TBI population progress, this
study offers support for the use of weight-based enoxaparin utilization in the TBI population.

➤ The small percentage of patients with ICH expansion identified may represent an acceptable
risk in the attempt to decrease VTE and the associated complications.

➤ In order to fully evaluate this treatment modality, a randomized prospective trial is necessary,
with serial screening duplex and CT imaging included to determine the incidence of
subclinical, as well as clinically evident, VTE or ICH expansion.
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