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J Trauma Acute Care Surg. Author manuscript; available in PMC 2024 Mar 1.
Published in final edited form as:
J Trauma Acute Care Surg. 2023 Mar 1; 94(3): 479–483.
Published online 2022 Dec 6. doi:10.1097/TA.0000000000003853
PMCID: PMC9974825
NIHMSID: NIHMS1854391
PMID: 36729880
Navpreet K Dhillon, MD,1 Elliott R Haut, MD, PhD,2,3,4 Michelle A Price, PhD,5 Todd W Costantini, MD,6 Amanda L Teichman, MD,7 Bryan A Cotton, MD, MPH,8 and Eric J Ley, MD9
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The publisher's final edited version of this article is available at J Trauma Acute Care Surg
Abstract
Trauma patients are at high risk for venous thromboembolism (VTE). Despite evidence-based guidelines and concerted efforts in trauma centers to implement optimal chemoprophylaxis strategies, VTE remains a frequent diagnosis in trauma patients. Current chemoprophylaxis strategies focus largely on the subcutaneous injection of low molecular weight heparin which is administered twice daily. Novel approaches to pharmacologic VTE prophylaxis have the potential to reduce VTE rates by improving patient compliance through oral administration or through their ability to target alternative pathways that mediate thrombosis. While novel pharmacologic VTE prophylaxis strategies have been studied in non-trauma patients, there is a paucity of literature in trauma patients where the risk of thrombosis versus hemorrhage must be carefully considered. As a component of the 2022 Consensus Conference to Implement Optimal VTE Prophylaxis in Trauma, this review provides an update of the novel chemoprophylaxis agents for potential use in trauma patients. Here, we will consider the relative risks and benefits related to the use of these drugs, evaluate the current literature in non-trauma patients, and consider future directions that could potentially improve post-trauma VTE prophylaxis.
Introduction
Recent advances in the approach to optimizing venous thromboembolism (VTE) prophylaxis in trauma patients, including early initiation and higher doses of chemoprophylaxis, have led to lower VTE rates.1,2 VTE prevention after trauma requires vigilance and focused measures to mitigate their development. Despite successful efforts to optimize chemoprophylaxis strategies, VTE events continue to occur with unacceptable frequency in injured patients. While subcutaneous administration of low molecular weight heparin (LMWH) is standard of care, further research is needed to better understand the role and efficacy of alternative chemoprophylactic agents which have the potential to revolutionize current VTE prevention strategies in trauma patients.
Alternative agents for pharmacologic VTE prophylaxis may be suitable for use in trauma patients and could potentially be advantageous compared to current heparin-based regimens. Oral agents including aspirin and direct oral anticoagulants (DOACs), such as rivaroxaban or apixaban, are currently the leading candidates for use as novel chemoprophylactic agents. While these drugs may be ideal due to ease of administration via the oral route, issues with prolonged half-life, inability to rapidly reverse their anticoagulant effects, and overall risk of bleeding are concerns when use in trauma patients is considered. Unfortunately, randomized clinical studies in trauma patients have been limited.
The 2022 Consensus Conference to Implement Optimal Venous Thromboembolism (VTE) Prophylaxis in Trauma was convened to define evidence-based guidelines and to address gaps in clinical care and research related to VTE.3 One of the defined goals of this conference was to discuss novel approaches to post-injury VTE prophylaxis that could potentially improve patient compliance and further decrease VTE risk. The aim of this review is to discuss drugs that could be utilized as novel chemoprophylaxis agents for use in trauma patients, identify benefits and risks related to use of these drugs, evaluate the current literature in non-trauma patients and consider future directions that could allow improvements in post-trauma VTE prophylaxis.
Current Strategies in VTE Chemoprophylaxis
While specific VTE prophylaxis strategies vary by institution, there are recent consensus, evidence-based guidelines from the Western Trauma Association, the American Association for the Surgery of Trauma, and the American College of Surgeons – Committee on Trauma that provide recommendations to achieve optimal VTE prophylaxis after trauma.4,5 The two typical agents used for chemoprophylaxis are unfractionated heparin (UH) or LMWH. LMWH is recommended over UH in most trauma patients given its superior pharmaco*kinetic properties in terms of bioavailability and longer half-life.6 Additionally, concerns for complications such as heparin induced thrombocytopenia (HIT) occur rarely with LMWH.7 Higher doses of LMWH may be needed to achieve appropriate prophylaxis, with recent consensus guidelines now recommending enoxaparin 40mg twice daily as the initial dose in most trauma patients..8 LMWH is currently not recommended for all patients. Impaired renal clearance associated with acute kidney injury or chronic renal failure is a common reason to utilize UH as the chemoprophylactic agent of choice.
Challenges with Current VTE Chemoprophylaxis Strategies
While improvements have been made in the timing of initiation and dosing of VTE prophylaxis, there are a number of limitations with current chemoprophylaxis dosing regimens. Perhaps the most obvious limitation is that patients receive a painful subcutaneous injection of the medication which can lead to patient dissatisfaction, noncompliance, and missed doses of VTE prophylaxis. Haac et al. performed a randomized controlled trial wherein orthopedic trauma patients were discharged from the hospital with either aspirin 81mg twice daily or LMWH 30mg twice daily.9 Patients were contacted between 10 to 21 days after discharge and adherence scores were measured. While adherence was overall high, LMWH was associated with a lower rate of adherence, even when adjusted for age, sex, health insurance status, and if the agent was administered by a provider.
Varied rates of adherence with current chemoprophylaxis may stem from the fact that patients generally prefer oral options over subcutaneous injections. Of 227 patients surveyed about VTE prophylaxis preferences, 60.4% preferred oral medications provided that they were equally as effective as subcutaneous alternatives.10 Subcutaneous injections of LMWH or UH for VTE prophylaxis are one of the most commonly refused medication in hospitalized patients.11,12 However, it would be too simple to state that patients only prefer oral agents under any circ*mstance. Haac and colleagues performed a discrete choice experiment on trauma patients at their Level 1 trauma center where they gave patients different, hypothetical scenarios and gauged preferences accordingly.13 While patients generally favored oral agents, subcutaneous agents were preferred when certain statistics were given for complications such as bleeding, VTE, and death. This finding suggests that preferences may change based on risk-based information provided to patients, however, it is unclear understanding the risks of refusing subcutaneous chemoprophylaxis results in changes in behavior and increased compliance.
Additionally, cost needs to be considered when delivering VTE chemoprophylaxis. Older studies cite substantially higher costs with LMWH compared to alternatives although without considering the increased HIT rate with UH.14,15 The cost-effectiveness of current management strategies for VTE chemoprophylaxis in trauma patients require additional analysis.
As Simple as Aspirin?
Salicylates have solidified their presence in medical history for centuries, with acetylsalicylic acid, commonly known as aspirin, being introduced in the 1890s.16 Aspirin irreversibly inactivates cyclooxygenase enzyme which is required for thromboxane and prostaglandin synthesis, leading to impaired platelet aggregation (Table 1).
Table 1:
Properties of Potential Novel Therapeutics
| Agent | Mechanism of action | Formulations | Prophylactic Dosing Investigated | Bioavailability | Half-Life | Metabolism/ elimination |
|---|---|---|---|---|---|---|
| Aspirin | Inactivates cyclooxygenase enzyme | Per os or per rectum | 81mg twice daily | 50-75% | 15-20 minutes (however effects of aspirin last the duration of platelet life which is approximately 10 days) | Metabolized in plasma and liver; excreted through kidney |
| Apixaban | Directly binds to Factor Xa | Per os | 2.5mg twice daily | 50% | 12 hours | Metabolized by liver; excreted through kidney, biliary, and fecal |
| Rivaroxaban | Directly binds to Factor Xa | Per os | 10mg once daily | 80%-100% | 5-9 hours | Metabolized by liver; excreted through kidney |
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The literature regarding platelet physiology and pathophysiology following injury has been growing over the last decade. Thromboelastography with platelet mapping has suggested that platelets play a significant role in trauma-induced hypercoagulability.17,18 Platelet dysfunction is implicated in microthrombotic disease after trauma, however its role in VTE formation is unknown.19,20 Matthay and colleagues examined several coagulation parameters among patients with and without VTE.21 The authors found that patients with impaired platelet aggregation had a higher risk of developing VTE, suggesting that platelet dysfunction may play a role in VTE formation.
Clinical studies evaluating the efficacy of aspirin for VTE chemoprophylaxis in the general trauma population are limited. Brill et al performed a retrospective case-control study where patients with lower extremity DVTs were matched by demographics, injury characteristics, probability of death, and other DVT risk factors.22 Preinjury aspirin use was found to be protective against VTE. This association was more pronounced when a heparinoid chemoprophylaxis was administered during the patient’s hospital admission. This may be because heparinoid agents and antiplatelet agents act on different targets which are necessary for thrombin and clot formation. In contrast, another study determined that prehospital aspirin was a predictor for increased risk of VTE, possibly due to a rebound in platelet physiology.23
To better understand the potential benefits of aspirin as VTE chemoprophylaxis in trauma patients, the orthopedic literature provides some guidance. One of the largest studies to date regarding aspirin use is a retrospective cohort study using a large quality initiative registry of 41,537 patients undergoing total knee arthroplasty from 29 hospitals in Michigan.24 Aspirin alone was compared to other anticoagulants including LMWH, warfarin, and factor Xa inhibitors, an anticoagulant in addition to aspirin, and no agents at all. The authors demonstrated that aspirin was noninferior to other anticoagulants with respect to VTE prophylaxis and proposed that it may be a suitable alternative for pharmacologic prophylaxis. Additionally, aspirin is generally preferred by orthopedic surgeons due to a lower risk of bleeding and wound complications.25,26 These studies have been instrumental in establishing guidelines which include aspirin as the chemoprophylactic agent of choice for certain orthopedic surgery patients.27 The question then becomes if this regimen can be used for trauma patients with orthopedic injuries which was the premise for the A Different Approach to Preventing Thrombosis (ADAPT) trial.28
The ADAPT trial was a single-center prospective randomized controlled trial comparing aspirin twice daily to LMWH in orthopedic trauma patients at a Level 1 trauma center (Table 2). The study included trauma patients with an operative extremity, hip, or acetabular fracture. Those randomized to LMWH could undergo dose adjustments guided by body mass index or factor Xa activity. The investigators sought to determine the probability of treatment superiority with LMWH over aspirin by using a combination of statistical methods. There were no statistical differences in the VTE rate when LMWH was compared to aspirin in this study. The ADAPT trial provided insight in how aspirin may be used as chemoprophylaxis in trauma patients with specific orthopedic injuries and introduced the potential for aspirin use in a wider variety of trauma patients.
Table 2:
Summary of Prospective Trials Using Potential Novel Therapeutics
| Agent | Study Name | Study Design | Patient Population | Summary |
|---|---|---|---|---|
| Aspirin | ADAPT: A Different Approach to Preventing Thrombosis | Single-center, randomized control trial | Orthopedic trauma patients | LMWH 30mg twice daily had a 50.4% (95% CI, 47.7-53.2%, p=0.73) probability of superiority over aspirin 81mg twice daily using a Global Rank test |
| PREVENT CLOT: PREVENTion of Clots in Orthopaedic Trauma | Multicenter, randomized control trial | Orthopedic trauma patients | Published results pending | |
| Apixaban | ADOPT: Apixaban Dosing to Optimize Protection from Thrombosis | Multicenter, randomized controlled trial | Medical patients hospitalized with congestive heart failure, acute respiratory failure, infection, acute rheumatic disorder, or inflammatory bowel disease | Apixaban 2.5mg twice daily for 30 days was similar to LMWH 40mg once daily for 6 to 14 days with respect to VTE; major bleeding occurred more frequently in the apixaban arm (relative risk, 2.58; 95% CI, 1.02-7.24, p=0.04). |
| Rivaroxaban | MAGELLAN: Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Acutely Ill Medical Patients Comparing Rivaroxaban with Enoxaparin | Multicenter, randomized controlled trial | Medical patients hospitalized with acute illness | Rivaroxaban 10mg once daily was noninferior to enoxaparin 40mg once daily (relative risk, 0.97; 95% CI: 0.71-1.31), p<0.01 for noninferiority). |
| RECORD 1: Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty | Multicenter, randomized controlled trial | Patients undergoing elective total hip arthroplasty | Rivaroxaban 10mg once daily was more effective than LMWH 40mg once daily (absolute risk reduction for DVT, nonfatal PE, or death 2.6%, 95% CI 1.5%-3.7%, p<0.01). | |
| RECORD 3: Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Total Knee Arthroplasty | Multicenter, randomized controlled trial | Patients undergoing total knee arthroplasty | Rivaroxaban 10mg once daily was superior to enoxaparin 40mg once daily (absolute risk reduction for DVT, nonfatal PE, or death 9.2%; 95% CI 5.9%-12.4%, p<0.01). |
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Abbreviations: CI, confidence interval; DVT, deep vein thrombosis; LMWH, low molecular weight heparin; PE, pulmonary embolism; VTE, venous thromboembolism
The results of PREVENTion of CLots in Orthopaedic Trauma (PREVENT CLOT), a multicenter randomized trial with over 12,000 patients admitted to 21 centers will provide clarity.29 The study, which includes orthopedic trauma patients with and without additional injuries, compares aspirin and LMWH and aims to determine outcome differences with respect to mortality, PE, DVT, and additional safety outcomes including bleeding, and wound complications.
DOACs as Novel Prophylactic Agents
DOACs, are increasingly prescribed in the general medical population. DOACs can be used for a number of medical conditions such as VTE, mechanical valves, stroke prevention, and in select patients with vascular disease.30 Dosing with DOACs is relatively easier to accomplish compared to traditional anticoagulants, thus making it a more attractive option for both providers and patients.
The Apixaban Dosing to Optimize Protection from Thrombosis (ADOPT) trial intended to establish DOACs as a viable option for VTE prevention.31 In this international, multi-center, double-blinded, randomized controlled trial, medical patients received either apixaban 2.5mg twice daily or enoxaparin 40mg once daily for 6 to 14 days. These medical patients included individuals who were admitted for at least three days with congestive heart failure, respiratory failure, infection, acute rheumatic disorder, or inflammatory bowel disease. While the investigators initially hypothesized that apixaban would be superior, they saw similar VTE outcomes and observed more bleeding events with apixaban.
The Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Acutely Ill Medical Patients Comparing Rivaroxaban with Enoxaparin (MAGELLAN) was published in 2013 and compared an extended course of rivaroxaban to enoxaparin in medical patients.32 The study was designed to detect both symptomatic and asymptomatic VTE by screening all patients after receiving the last dose of medication. With over 8,000 patients enrolled, extended administration of rivaroxaban for 35 days was found to reduce VTE risk. However, similar to apixaban in the ADOPT trial, rivaroxaban was associated with a higher bleeding risk.
The role of DOACs in surgical patients requires investigation given the observed bleeding risk in the aforementioned studies. Similar to aspirin, most relevant data originate from the orthopedic surgery literature. Eriksson et al conducted a phase 3 trial (RECORD1) comparing rivaroxaban 10mg once daily to enoxaparin 40mg once daily in patients undergoing total hip arthroplasty.33 Patients randomized to rivaroxaban had fewer VTEs. This study was followed by RECORD3, by Lassan et al., which studied rivaroxaban compared to enoxaparin in patients following total knee arthroplasties.34 Rivaroxaban was superior to enoxaparin in preventing VTE and unlike other trials, was associated with similar bleeding events. The frequency of drug related complications was also similar.
While the aforementioned studies show that DOACs are potential alternatives for VTE prophylaxis in surgical patients, they lend little insight into how DOACs can be specifically used in the trauma population. A single-center propensity matched study at a Level 1 trauma center showed that patients given rivaroxaban for VTE prophylaxis had similar rates of VTE compared to those that received enoxaparin.35 It is important to note the injury profiles represented in this study as approximately one in three patients had severe injuries to the head and/or neck. Additionally, there were fewer patients with severe chest and abdominal injuries in the rivaroxaban cohort despite the patients being matched. Another propensity matched study focused on trauma patients with lower extremity fractures using the American College of Surgeons - Trauma Quality Improvement Program database.36 Before matching, patients who were given DOACs had lower rates of traumatic brain injury, rib, pelvic, and spinal fractures but had a substantially higher rate of femur fractures. The VTE rate was similar with a slightly lower need for bleeding control interventions, but this did not reach statistical significance.
Prospective studies investigating DOAC use in trauma patients are absent. Future studies are needed to understand which patients would benefit from this class of drugs, in addition to their safety profiles and efficacy.
Future Directions
While the foundational research has established the potential for aspirin and DOAC use as possible alternatives for chemoprophylaxis in trauma patients, additional studies are needed before these agents can be recommended and included in the related practice guidelines.
If the PREVENT CLOT study demonstrates that aspirin is as equally effective as LMWH, questions will inevitably arise about the optimal dosing of aspirin and LMWH. The study randomized patients to aspirin 81mg twice daily. Does daily dosing or aspirin 325mg have differing results? If aspirin is not superior to LMWH, would adding aspirin to LMWH provide an advantage? How does optimal dosing of aspirin compare to optimal dosing of LMWH? Can the same results apply to trauma patients without orthopedic injury? Each of these questions should be potentially addressed in future clinical research studies.
The heterogeneity of injury patterns and bleeding risk after major trauma make generalized recommendations regarding the optimal novel chemoprophylactic strategy difficult to define and implement. There are challenges with initiating and dosing chemoprophylaxis in trauma patients with traumatic brain injury, spinal injury, and solid organ injuries even with current regimens.37-39 Establishing that oral agents are safe in these specific injuries and in patients with polytrauma will require further studies.
Another added challenge is the issue of enteral access, bioavailability, and related pharmaco*kinetics. Injuries to the gastrointestinal tract, ileus, bowel obstruction, and inability to take medications per os may preclude individuals from taking aspirin or a DOAC. While aspirin can alternatively be delivered rectally, which in itself has added challenges, DOACs cannot.
Conclusions
Although the trauma community has made substantial improvements in VTE prevention with contemporary practices, there are limitations with current standards. Alternative agents, namely aspirin and DOACs, may serve as suitable alternatives. While literature exists for the appropriateness of these agents outside of trauma, more research is required to establish their efficacy and safety in trauma patients.
Acknowledgments
Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number R13HL158206 (“Consensus Conference to Implement Optimal VTE Prophylaxis in Trauma”). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Disclosures of Funding:
Dr. Haut reports research funding from The Patient-Centered Outcomes Research Institute (PCORI), the Agency for Healthcare Research and Quality (AHRQ), the NIH/NHLBI, and the DOD/Army Medical Research Acquisition Activity.
Footnotes
Conflicts of Interest Statement:
The authors have no conflicts of interest to disclose.
References
1. Dhillon NK, Barmparas G, Lin TL, Linaval NT, Yang AR, Sekhon HK, et al. A Systems-based Approach to Reduce Deep Venous Thrombosis and Pulmonary Embolism in Trauma Patients. World J Surg. 2021;45(3):738–745. [PubMed] [Google Scholar]
2. Machado-Aranda DA, Jakubus JL, Wahl WL, Cherry-Bukowiec JR, To KB, Park PK, et al. Reduction in Venous Thromboembolism Events: Trauma Performance Improvement and Loop Closure Through Participation in a State-Wide Quality Collaborative. J Am Coll Surg. 2015;221(3):661–668. [PubMed] [Google Scholar]
3. Haut ER, Byrne JP, Price MA, Bixby P, Bulger EM, Lake L, et al. Proceedings from the 2022 Consensus Conference to Implement Optimal Venous Thromboembolism (VTE) Prophylaxis in Trauma. J Trauma Acute Care Surg (in press) [PMC free article] [PubMed] [Google Scholar]
4. Ley EJ, Brown CVR, Moore EE, Sava JA, Peck K, Ciesla DJ, et al. Updated guidelines to reduce venous thromboembolism in trauma patients: A Western Trauma Association critical decisions algorithm. J Trauma Acute Care Surg. 2020;89(5):971–981. [PMC free article] [PubMed] [Google Scholar]
5. Yorkgitis BK, Berndtson AE, Cross A, Kennedy R, Kochuba MP, Tignanelli C, et al. American Association for the Surgery of Trauma/American College of Surgeons-Committee on Trauma Clinical Protocol for inpatient venous thromboembolism prophylaxis after trauma. J Trauma Acute Care Surg. 2022;92(3):597–604. [PubMed] [Google Scholar]
6. Gaitanidis A, Breen KA, Christensen MA, Saillant NN, Kaafarani HMA, Velmahos GC, et al. Low-Molecular Weight Heparin is Superior to Unfractionated Heparin for Elderly Trauma Patients. J Surg Res. 2021;268:432–439. [PubMed] [Google Scholar]
7. Fareed J, Hoppensteadt D, Walenga J, Iqbal O, Ma Q, Jeske W, et al. Pharmacodynamic and pharmaco*kinetic properties of enoxaparin : implications for clinical practice. Clin Pharmaco*kinet. 2003;42(12):1043–1057. [PubMed] [Google Scholar]
8. Rodier SG, Bukur M, Moore S, Frangos SG, Tandon M, et al. Weight-based enoxaparin with anti-factor Xa assay-based dose adjustment for venous thromboembolic event prophylaxis in adult trauma patients results in improved prophylactic range targeting. Eur J Trauma Emerg Surg. 2021;47(1):145–151. [PubMed] [Google Scholar]
9. Haac BE, Van Besien R, O’Hara NN, Slobogean GP, Manson TT, O’Toole RV, et al. Post-discharge adherence with venous thromboembolism prophylaxis after orthopedic trauma: Results from a randomized controlled trial of aspirin versus low molecular weight heparin. J Trauma Acute Care Surg. 2018;84(4):564–574. [PubMed] [Google Scholar]
10. Wong A, Kraus PS, Lau BD, Streiff MB, Haut ER, Hobson DB, et al. Patient preferences regarding pharmacologic venous thromboembolism prophylaxis. J Hosp Med. 2015;10(2):108–111. [PubMed] [Google Scholar]
11. Popoola VO, Tavakoli F, Lau BD, Lankiewicz M, Ross P, Kraus P, et al. Exploring the impact of route of administration on medication acceptance in hospitalized patients: Implications for venous thromboembolism prevention. Thromb Res. 2017;160:109–113. [PubMed] [Google Scholar]
12. Popoola VO, Lau BD, Tan E, Shaffer DL, Kraus PS, Farrow NE, et al. Nonadministration of medication doses for venous thromboembolism prophylaxis in a cohort of hospitalized patients. Am J Health Syst Pharm. 2018;75(6):392–397. [PubMed] [Google Scholar]
13. Haac BE, O’Hara NN, Mullins CD, Stein DM, Manson TT, Johal H, et al. Patient preferences for venous thromboembolism prophylaxis after injury: a discrete choice experiment. BMJ Open. 2017;7(8):e016676. [PMC free article] [PubMed] [Google Scholar]
14. O’Brien BJ, Anderson DR, Goeree R. Cost-effectiveness of enoxaparin versus warfarin prophylaxis against deep-vein thrombosis after total hip replacement. CMAJ. 1994;150(7):1083–1090. [PMC free article] [PubMed] [Google Scholar]
15. Spandorfer JM, Lynch S, Weitz HH, Fertel S, Merli GJ. Use of enoxaparin for the chronically anticoagulated patient before and after procedures. Am J Cardiol. 1999;84(4):478–480, A10. [PubMed] [Google Scholar]
16. Awtry EH, Loscalzo J. Aspirin. Circulation. 2000;101(10):1206–1218. [PubMed] [Google Scholar]
17. Kornblith LZ, Kutcher ME, Redick BJ, Calfee CS, Vilardi RF, Cohen MJ. Fibrinogen and platelet contributions to clot formation: implications for trauma resuscitation and thromboprophylaxis. J Trauma Acute Care Surg. 2014;76(2):255–256; discussion 262-263. [PMC free article] [PubMed] [Google Scholar]
18. Harr JN, Moore EE, Chin TL, Ghasabyan A, Gonzalez E, Wohlauer MV, et al. Platelets are dominant contributors to hypercoagulability after injury. J Trauma Acute Care Surg. 2013;74(3):756–762; discussion 762-765. [PMC free article] [PubMed] [Google Scholar]
19. Jacoby RC, Owings JT, Holmes J, Battistella FD, Gosselin RC, Paglieroni TG. Platelet activation and function after trauma. J Trauma. 2001;51(4):639–647. [PubMed] [Google Scholar]
20. Kutcher ME, Redick BJ, McCreery RC, Crane IM, Greenberg MD, Cachola LM, et al. Characterization of platelet dysfunction after trauma. J Trauma Acute Care Surg. 2012;73(1):13–19. [PMC free article] [PubMed] [Google Scholar]
21. Matthay ZA, Hellmann ZJ, Nunez-Garcia B, Fields AT, Cuschieri J, Neal MD, et al. Post-Injury Platelet Aggregation and Venous Thromboembolism. J Trauma Acute Care Surg.
22. Brill JB, Calvo RY, Wallace JD, Lewis PR, Bansal V, Sise MJ, et al. Aspirin as added prophylaxis for deep vein thrombosis in trauma: A retrospective case-control study. J Trauma Acute Care Surg. 2016;80(4):625–630. [PubMed] [Google Scholar]
23. Barmparas G, Jain M, Mehrzadi D, Melo N, Chung R, Bloom M, et al. Aspirin Increases the Risk of Venous Thromboembolism in Surgical Patients. The American Surgeon. 2014;80(10):920–925. [PubMed] [Google Scholar]
24. Hood BR, Cowen ME, Zheng HT, Hughes RE, Singal B, Hallstrom BR. Association of Aspirin With Prevention of Venous Thromboembolism in Patients After Total Knee Arthroplasty Compared With Other Anticoagulants: A Noninferiority Analysis. JAMA Surg. 2019;154(1):65–72. [PMC free article] [PubMed] [Google Scholar]
25. Vulcano E, Gesell M, Esposito A, Ma Y, Memtsoudis SG, Gonzalez Della Valle A. Aspirin for elective hip and knee arthroplasty: a multimodal thromboprophylaxis protocol. Int Orthop. 2012;36(10):1995–2002. [PMC free article] [PubMed] [Google Scholar]
26. Raphael IJ, Tischler EH, Huang R, Rothman RH, Hozack WJ, Parvizi J. Aspirin: an alternative for pulmonary embolism prophylaxis after arthroplasty?Clin Orthop Relat Res. 2014;472(2):482–488. [PMC free article] [PubMed] [Google Scholar]
27. Falck-Ytter Y, Francis CW, Johanson NA, Curley C, Dahl OE, Schulman S, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e278S–e325S. [PMC free article] [PubMed] [Google Scholar]
28. Haac BE, O’Hara NN, Manson TT, Slobogean GP, Castillo RC, O’Toole RV, et al. Aspirin versus low-molecular-weight heparin for venous thromboembolism prophylaxis in orthopaedic trauma patients: A patient-centered randomized controlled trial. PLoS One. 2020;15(8):e0235628. [PMC free article] [PubMed] [Google Scholar]
29. O’Toole RV, Stein DM, Frey KP, O’Hara NN, Scharfstein DO, Slobogean GP, et al. PREVENTion of CLots in Orthopaedic Trauma (PREVENT CLOT): a randomised pragmatic trial protocol comparing aspirin versus low-molecular-weight heparin for blood clot prevention in orthopaedic trauma patients. BMJ Open. 2021;11(3):e041845. [PMC free article] [PubMed] [Google Scholar]
30. Chen A, Stecker E, A Warden B. Direct Oral Anticoagulant Use: A Practical Guide to Common Clinical Challenges. J Am Heart Assoc. 2020;9(13):e017559. [PMC free article] [PubMed] [Google Scholar]
31. Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011;365(23):2167–2177. [PubMed] [Google Scholar]
32. Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368(6):513–523. [PubMed] [Google Scholar]
33. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765–2775. [PubMed] [Google Scholar]
34. Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776–2786. [PubMed] [Google Scholar]
35. Kingdon LK, Miller EM, Savage SA. The Utility of Rivaroxaban as Primary Venous Thromboprophylaxis in an Adult Trauma Population. J Surg Res. 2019;244:509–515. [PubMed] [Google Scholar]
36. Nederpelt CJ, Breen KA, El Hechi MW, Krijnen P, Huisman MV, Schipper IB, et al. Direct Oral Anticoagulants Are a Potential Alternative to Low-Molecular-Weight Heparin for Thromboprophylaxis in Trauma Patients Sustaining Lower Extremity Fractures. J Surg Res. 2021;258:324–331. [PubMed] [Google Scholar]
37. Dhillon NK, Hashim YM, Berezin N, Yong F, Conde G, Mason R, et al. Characterizing the delays in adequate thromboprophylaxis after TBI. Trauma Surg Acute Care Open. 2021;6(1):e000686. [PMC free article] [PubMed] [Google Scholar]
38. Christie S, Thibault-Halman G, Casha S. Acute pharmacological DVT prophylaxis after spinal cord injury. J Neurotrauma. 2011;28(8):1509–1514. [PMC free article] [PubMed] [Google Scholar]
39. Murphy PB, de Moya M, Karam B, Menard L, Holder E, Inaba K, et al. Optimal timing of venous thromboembolic chemoprophylaxis initiation following blunt solid organ injury: meta-analysis and systematic review. Eur J Trauma Emerg Surg.
