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Inability to predict subprophylactic anti–factor Xa levels in trauma patients receiving early low-molecular-weight heparin

Imran, Jonathan B., MD; Madni, Tarik D., MD; Clark, Audra T., MD; Rizk, Paul; Huang, Emily; Minshall, Christian T., MD, PhD; Taveras, Luis R., MD; Cunningham, Holly B., MD; Eastman, Alexander L., MD, MPH; Koshy, Jojo P., PharmD; Kacir, Cory D., PharmD; Cripps, Michael W., MD, MSCS

Journal of Trauma and Acute Care Surgery: November 2018 - Volume 85 - Issue 5 - p 867–872
doi: 10.1097/TA.0000000000002024
Editor's Choice

BACKGROUND Standard low-molecular-weight heparin dosing may be suboptimal for venous thromboembolism prophylaxis. We aimed to identify independent predictors of subprophylactic Xa (subXa) levels in trauma patients treated under a novel early chemoprophylaxis algorithm.

METHODS A retrospective analysis of trauma patients from July 2016 to June 2017 who received enoxaparin 40 mg twice daily and had peak Xa levels drawn was performed. Patients were divided into cohorts based on having a subXa (<0.2 IU/mL) or prophylactic (≥0.2 IU/mL) Xa level.

RESULTS In all, 124 patients were included, of which 38 (31%) had subXa levels, and 17 (14%) had Xa levels greater than 0.4 IU/mL. Of the subXa cohort, 35 (92%) had their dosage increased, and the repeat Xa testing that was done in 32 revealed that only 75% reached prophylactic levels. The median time to the initiation of chemoprophylaxis was 21.9 hours (interquartile range [IQR], 11.45–35.07 hours). Patients who were defined as having lower risk of having a complication as a result of bleeding had a shorter time to starting prophylaxis than those at higher risk (18.39 hours [IQR 5.76–26.51 hours] vs. 29.5 hours [IQR 16.23–63.07 hours], p < 0.01).

There was no difference in demographics, weight, body mass index, creatinine, creatinine clearance, injury severity score, type of injury, weight-based dose, time to chemoprophylaxis, or bleeding complications between the cohorts. No independent predictors of subXa level were identified on multivariable logistic regression.

CONCLUSIONS A significant number of trauma patients fail to achieve prophylactic Xa levels. Intrinsic factors may prevent adequate prophylaxis even with earlier administration and higher dosing of low-molecular-weight heparin.

LEVEL OF EVIDENCE Therapeutic, level IV

From the Department of Surgery (J.B.I., T.D.M., A.T.C., P.R., E.H., LR.T., H.B.C., A.L.E., M.W.C.), The University of Texas Southwestern Medical Center, Dallas, Texas; Division of Burn, Trauma, and Critical Care, Department of Surgery (A.L.E., M.W.C.), The Rees-Jones Trauma Center at Parkland Hospital and the University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pharmacy (J.P.K., C.D.K.), Parkland Hospital, Dallas, Texas; Department of Trauma and Acute Care Surgery (C.T.M.), Baystate Medical Center, Springfield, Massachusetts.

Submitted: February 7, 2018, Revised: May 8, 2018, Accepted: June 23, 2018, Published online: July 5, 2018.

This original work was presented as a podium presentation at the 48th annual meeting of the Western Trauma Association, February 15, 2018, to March 2, 2018, in Whistler, British Columbia, Canada, and has not been submitted or published elsewhere.

Address for reprints: Michael W. Cripps, MD, MSCS, Division of Burn, Trauma, and Critical Care Department of Surgery, UT Southwestern Medical Center, 5323 Harry Hines Blvd, E5.508 Dallas, TX 75390; email:

The prevention of venous thromboembolism (VTE) after trauma is a major priority for all health care providers. The most commonly used guidelines for VTE prophylaxis were developed by the Eastern Association for the Surgery of Trauma in 2002, which recommend low-molecular-weight heparin (LMWH) for patients with certain injury patterns and severity.1 Although these recommendations have provided the foundation for VTE prevention, there is emerging evidence that current LMWH dosing for trauma patients may be suboptimal, leaving many at risk of VTE.2–6

Enoxaparin is commonly used in many trauma centers throughout the United States and is typically given as a standard dose of 30 mg twice daily (BID).7 As the need for higher initial dosing of LMWH has become apparent, our group has recently developed a VTE prevention algorithm that utilizes a combination of early chemoprophylaxis initiation, a higher initial enoxaparin dose, and anti–factor Xa (anti-Xa) monitoring, which is used as an objective measurement to evaluate enoxaparin dosing.

Despite the recent data regarding increased dosing of enoxaparin, there is still a gap in determining which patients are still subprophylactic. We hypothesized that by providing early, high-dose chemoprophylaxis with anti-Xa–guided dose adjustment we could minimize the number of patients with subprophylactic Xa (subXa) levels in our trauma intensive care unit (ICU) population. In this study, we aimed to determine the incidence of a subprophylactic anti-Xa level and sought to identify independent predictors of subXa level in our trauma population.

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A novel VTE prevention algorithm was initiated at Parkland Health and Hospital System in May 2016. The protocol initially targeted orthopedic trauma patients admitted to the surgical ICU (SICU); however, over time, we expanded the protocol to encompass all trauma patients admitted to our SICU. The VTE algorithm was initiated as a collaborative effort between the trauma, neurosurgery, orthopedic, and pharmacy services. In our ICU, patients are started on enoxaparin 40 mg BID (if weight is >50 kg) when cleared to receive chemoprophylaxis by the admitting trauma surgeon, with the goal to start prior to leaving the trauma bay. An anti-Xa level is drawn 3 hours to 5 hours after the third dose (or greater) of enoxaparin. We use a peak anti-Xa level based on methods used in similar studies3,4 and a prophylactic range of 0.2 IU/mL to 0.49 IU/mL. If a patient is in this range after testing, the enoxaparin dose remains 40 mg BID. If the anti-Xa level is considered subprophylactic (<0.2 IU/mL), the dosage is increased to 60 mg BID, and a repeat anti-Xa level is drawn. In addition to increasing the enoxaparin dose for those with subXa levels, an inferior vena cava filter is placed in patients at high risk of pulmonary embolism (PE). In nonorthopedic trauma patients, PE risk is based on known clinical risk factors, whereas in orthopedic trauma patients it is determined by an assessment tool developed by our institution.8 If the initial anti-Xa level is greater than 0.49, the dosage is held or decreased, depending on the anti-Xa level. For patients weighing less than 50 kg, the same protocol is used except they are started on 30 mg BID, and if the anti-Xa level is considered subprophylactic, the initial dose increase is 40 mg BID, and the rest of the above protocol remains the same (Fig. 1).

Figure 1

Figure 1

After institutional review board approval was obtained for the study, a retrospective analysis was performed on all adult trauma patients admitted to the SICU from July 2016 to June 2017 who initially received enoxaparin 40 mg BID and had peak anti-Xa levels drawn 3 hours to 5 hours after the third dose (or greater). Cohorts were divided based the initial anti-Xa level: subXa (< 0.2 IU/mL) or prophylactic (≥0.2 IU/mL). The primary inclusion criterion was all trauma patients 18 years or older who had appropriately timed draws of anti-Xa levels on enoxaparin 40 mg BID. Patients with inappropriately timed anti-Xa draws, those who were started on an alternative enoxaparin dose, those who received fewer than three doses of enoxaparin, or those who did not receive deep vein thrombosis (DVT) prophylaxis were excluded from the study. Draws of anti-Xa levels were repeated (when possible) in patients who failed to achieve a prophylactic anti-Xa level on initial testing.

Collected data included patient demographics, mechanism of injury, injury type sustained, initial anti-Xa level, subsequent anti-Xa levels, mg/kg/actual body weight dose of enoxaparin, VTE (DVT and PE) events, and bleeding events. For the purpose of evaluating the time to the initiation of chemoprophylaxis, patients at high risk of having a complication as a result of bleeding were defined as those with traumatic brain injury, intracranial hemorrhage, or spine fracture/spinal cord injury. Bleeding complications while on chemoprophylaxis were defined as bleeding events requiring one or more units of packed red blood cells or those requiring surgical or angiographic intervention while admitted to the SICU. Sequential compression devices were used on bilateral lower extremities on admission in all patients who were able to have them placed. Routine imaging for VTE detection was not performed. Diagnostic imaging was performed based on the treating physician's discretion. Plasma anti-Xa levels were determined using the HemosIL Liquid Heparin chromogenic factor Xa inhibition assay/ACLTOP 600 hemostasis system (Instrumentation Laboratory, Bedford, MA).

Statistical analysis was performed using Mann-Whitney U tests and χ2 tests where appropriate. Categorical data are represented as numbers with proportions. Continuous data were summarized using medians with interquartile range (IQR). Significance was set at α = 0.05. Multivariable logistic regression was used to identify independent predictors of subXa level in our trauma population. Statistical analysis was performed in SPSS (version; IBM, Redmond, WA).

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During the study period, there were 458 trauma ICU admissions, and of those, 143 patients had anti-Xa levels drawn when initially on 40 mg enoxaparin BID. Overall, 124 trauma patients admitted to the SICU with appropriately drawn anti-Xa levels were included for analysis. The median time to the initiation of chemoprophylaxis in the 124 trauma patients was 21.9 hours (IQR, 11.45–35.07 hours; Table 1). Patients who were defined as having lower risk of having a complication as a result of bleeding had a shorter time to starting prophylaxis compared with those at higher risk (18.39 hours [IQR 5.76–26.51 hours] vs. 29.5 hours [IQR 16.23–63.07 hours], p < 0.01). Of the 124 patients, 38 (31%) had subXa levels and 17 (14%) had anti-Xa levels greater than 0.4 IU/mL. Of the subXa cohort, 35 (92%) had their dosage increased. Repeat anti-Xa testing was done in 32 patients and revealed that only 75% reached prophylactic levels after dose increase.



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Predictors of a Subprophylactic Anti-Xa Level

Complete patient demographics can be found in Table 1. There was no difference in age, gender, median weight, body mass index (BMI), serum creatinine, creatinine clearance, injury severity score, mechanism of injury, type of injury sustained, weight-based dose, or time to chemoprophylaxis between the cohorts (Table 2). Further, no independent predictors of a subXa level were identified on multivariable logistic regression.



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The VTE rate for all patients was 8% (seven DVT, three PE). No statistically significant differences in VTE rates (11% vs. 7%, p = 0.5) or bleeding complications (18% vs. 9%, p = 0.15) were identified between those with a subXa versus prophylactic anti-Xa level. Seven bleeding complications occurred in patients with an initial anti-Xa level of less than 0.2 IU/mL, and eight occurred in those with a level of 0.2 IU/mL or greater. There were six patients with an anti-Xa level greater than 0.49, and no bleeding complications occurred.

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There is increasing evidence that enoxaparin 30 mg BID may be inadequate for VTE prophylaxis in trauma patients2,5; however, it is still commonly used by many trauma providers and is recommended in several guidelines.1,9 Additionally, there is often a lag in initiating chemoprophylaxis after injury.10 We hypothesized that starting early chemoprophylaxis, using a higher initial enoxaparin dose, and anti-Xa–guided dose adjustment when necessary would decrease the numbers of patient who are initially subprophylactic as defined by anti-Xa levels. Despite this, we did not prove our hypothesis; 31% of patients failed to achieve prophylactic anti-Xa levels on initial testing, and of those who received dosage adjustment, eight (25%) failed to reach a prophylactic anti-Xa level after repeat testing. Other studies using an initial enoxaparin dose of 40 mg BID had an incidence of an initial sub–anti-Xa level ranging from 9% to 21%.3,11

The main goal of using anti-Xa levels to guide LMWH dosing in trauma is to achieve adequate chemoprophylaxis levels and decrease VTE rates.12 In our institution, anti-Xa–guided dosing is relatively inexpensive to perform, is available within a few hours, and provides an objective measure to provide more patient-specific care. Various other VTE prevention strategies have been used, including weight-based and thrombelastography-guided dosing, and each has its own strengths and potential weaknesses.11,13–15 Current anti-Xa assays measure the cleavage of a chromogenic substrate after the addition of a known amount of antithrombin and factor Xa to patient plasma containing enoxaparin.16 In our study, peak anti-Xa levels were chosen as they have been shown to be more predictive of LMWH efficacy than trough levels.17 The ideal anti-Xa range for DVT prophylaxis has been debated, and an anti-Xa level between 0.2 IU/mL and 0.5 IU/mL is currently considered the target range for VTE prophylaxis.18 However, Kopelman et al.4 showed that increasing the lower limit of the prophylactic anti-Xa range to 0.3 IU/mL decreased DVT rates when compared with a historical control. At our institution, we use a range of 0.2 IU/mL to 0.49 IU/mL.

Determining why certain patients do not reach prophylactic anti-Xa levels has proven to be difficult. A recent study published by Karcutskie et al.19 did not identify any variables associated with an inability to reach a prophylactic anti-Xa level in patients initially receiving enoxaparin 30 mg BID. Prior to this, Chapman et al.20 reported that patients who fail to achieve anti-Xa levels of 0.2 IU/mL or greater have statistically significant differences in creatinine clearance and the weight-based dose of enoxaparin from those who achieve prophylactic levels. However, only 13 of 51 patients initially received enoxaparin 40 mg BID, and 69% of them had an initial anti-Xa level of less than 0.2 IU/mL.20 Another group has shown that patient weight is the most important predictor of an adequate response to enoxaparin.11 However, no consensus has been reached to this point.

We evaluated several variables as possible independent predictors of a subXa level, such as age, gender, weight, BMI, serum creatinine, creatinine clearance, injury severity score, type of injury, weight-based dose (mg/kg/actual body weight), and time to initiation of chemoprophylaxis, and similar to Karcutskie et al.,19 we did not identify any predictors in this study. This leads us to believe that despite the protocol interventions described, there may be factors that we are not currently accounting for that are contributing to the failure to achieve adequate chemical VTE prophylaxis. One possibility is these patients have an antithrombin III deficiency, which decreases the efficacy of enoxaparin. Antithrombin III deficiency is known to present in 19% to 61% of trauma patients.13,21 Another may be the altered pharmacokinetics of LMWH in critically ill patients, which may be difficult to measure.22,23 The early initiation of VTE prophylaxis has been long considered a goal in the care of this patient population. However, those with traumatic brain injuries and spine injuries have relative contraindications to early prophylaxis because of increased bleeding risk. We were able to achieve an overall median time to initiation of chemoprophylaxis of 21.9 hours for all patients. This was even shorter (18.39 hours) in those considered at lower risk of having a complication as a result of bleeding.

Our study has some limitations. First, the VTE algorithm was instituted in May of 2016 and took several months for it to become widely accepted by all groups involved in the care of our trauma patients. Hence, only 143 patients had Xa levels drawn, of the 458 ICU admissions during the study period. Second, the study was not powered to detect differences in VTE rates between those with subXa or prophylactic anti-Xa level. We showed no statistically significant difference in VTE rates between groups (11% subXa vs. 7% prophylactic, p = 0.5); it is possible that by evaluating a larger sample size treated using our algorithm we may be able to detect a statistically significant difference in VTE rates. Moreover, we did not have a historical control group to compare the patients treated under our new algorithm to those treated prior to the initiation of the protocol to determine if there was a difference in VTE events. Lastly, we found that without a defined time frame for follow-up anti-Xa levels, there were patients who were transferred out of the SICU during the intermediate window from dose adjustment without having their follow-up anti-Xa level obtained on the ward. This occurred for both those who were subprophylactic and those who were therapeutic (supraprophylactic). In addition, there were a few patients who required two dosage adjustments, but the second repeat anti-Xa level was not consistently obtained. This has led to a practical change in our algorithm and should be a caution for those who adopt a similar strategy at their institution.

Future research will be needed to prospectively evaluate the temporal changes in platelet function, thrombin generation, and antithrombin III levels in patients treated under our chemoprophylaxis algorithm. Our goal is to identify factors that may be contributing to the inability for certain patients to achieve prophylactic anti-Xa levels, which may place them at higher risk of VTE.

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Despite earlier administration and higher doses of LMWH than current guidelines suggest, a significant number of trauma patients failed to achieve prophylactic Xa levels. In these patients, it is likely that there are intrinsic factors at play that prevent us from reaching adequate chemoprophylaxis.

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J.B.I., J.K., T.D.M., E.H., and M.W.C. performed the literature search. J.B.I., J.K., T.D.M., C.T.M., M.W.C, and A.L.E. contributed to study design. J.B.I., T.D.M., P.R., A.T.C., L.R.T., E.H., J.K, C.K., and M.W.C. collected the data, and J.B.I., T.D.M., A.T.C., E.H., C.T.M., J.K., L.R.T., and M.W.C. interpreted them. J.B.I., C.T.M., M.W.C., and A.L.E. wrote the article, and T.D.M., A.T.C., H.B.C., P.R., E.H., L.R.T., J.K., and M.W.C. performed critical revisions. All authors approved the final version of the article.

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The authors thank Dave Primm for help in editing this manuscript.

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The authors declare no conflicts of interest.

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1. Rogers FB, Cipolle MD, Velmahos G, Rozycki G, Luchette FA. Practice management guidelines for the prevention of venous thromboembolism in trauma patients: the EAST practice management guidelines work group. J Trauma. 2002;53(1):142–164.
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4. Kopelman TR, Walters JW, Bogert JN, Basharat U, Pieri PG, Davis KM, Quan AN, Vail SJ, Pressman MA. Goal directed enoxaparin dosing provides superior chemoprophylaxis against deep vein thrombosis. Injury. 2017;48(5):1088–1092.
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Editorial Critique

In the early 1990s, the San Francisco General Trauma Center was the first center in the United States to have access to the low-molecular weight drug enoxaparin to use for prophylaxis against VTE in trauma patients. We believed that subcutaneous doses of unfractionated heparin that was the standard in other surgical patients (5000 units given subcutaneously twice daily) offered inadequate protection in high-risk trauma patients, a hypothesis proven by the study in Canada by Geerts et al.(1) At the time, we were unclear as to the dose of enoxaparin to be utilized, so we borrowed from the orthopedic literature and advocated for 30 mg given subcutaneously twice daily. Similar to the Canadian study, we were impressed with the very low incidence of DVT in patients receiving enoxaparin and who were prospectively being followed with venous duplex exams.(2) However, it would be foolish to assume that the metabolism of enoxaparin would be the same in all patients, regardless of age, renal function, and the nature and severity of their injuries. Indeed, as Imran and his co-authors have demonstrated, the “one size fits all” mentality needs to be abandoned for a more precise algorithm if we wish to make VTE a “zero event” after injury.(3)

As pointed out by the authors, various approaches to improving the dosing of enoxaparin have been studied including weight-based, TEG-driven, and anti-Xa activity measurements. To date, none of these methods have proven beneficial. Indeed, in the above study, less than 50% of the patients were in the therapeutic range, with 33% being sub-therapeutic and, perhaps even more worrisome, 14% were super-therapeutic using this aggressive approach, creating the potential for bleeding. As our understanding of the changes in coagulation after injury has improved, newer approaches to VTE prevention and treatment will follow, including investigations into the role of inflammation, fibrinogen and platelets in clot formation and clot lysis. Not only must we adjust our prophylactic methods to fit the patient, but perhaps it is time to approach DVT and PE as two separate but related entities. Clearly we are in need of prospective, multi-center, hypothesis-driven research in this important area of trauma care.

1. Geerts WH, Jay RM, Code KI et al: A comparison of low-dose heparin with low-molecular weight heparin as prophylaxis against venous thromboembolism after major trauma. New Engl J Med 1996;335:701–7.

2. Knudson MM, Morabito D, Paiement GD, Shackelford S: The use of low molecular weight heparin in preventing thromboembolism in trauma patients. J Trauma 1996;41:446–459.

3. Imran J, Madni TK, Clark AT et al: Inability to predict sub-prophylactic anti-factor Xa levels in trauma patients receiving early low molecular-weight heparin. J Trauma Acute Care Surg 2018.

Peggy Knudson, MD

San Francisco, CA


Anti-Xa; enoxaparin; trauma; venous thromboembolism

© 2018 Lippincott Williams & Wilkins, Inc.