12 – Does the administration of VTE prophylaxis increase the risk for epidural hematoma in patients undergoing orthopaedic procedures? If so, are there differences between the various agents?

12 – Does the administration of VTE prophylaxis increase the risk for epidural hematoma in patients undergoing orthopaedic procedures? If so, are there differences between the various agents?

Jason Kopenitz, Eric S. Schwenk, Eugene R. Viscusi.

Response/Recommendation: Epidural hematoma (EH) is a rare but serious complication of neuraxial anesthesia.  Venous thromboembolism (VTE) prophylaxis for total joint arthroplasty (TJA) has been associated with cases of EH and among the low-molecular-weight heparins (LMWH), enoxaparin appears to carry the greatest risk of the agents currently used, although EH have also been associated with the direct-oral acting anticoagulants (DOAC).  A delay of 12hrs is mandatory between the last LMWH dose and the neuraxial procedure.  No neuraxial anesthesia should be performed in a patient already treated with DOAC no matter what dose was used.  Starting LMWH or DOAC more than 8hrs after the neuraxial procedure is recommended and safe.

Strength of Recommendation: Moderate.

Rationale: EH is a recognized complication of neuraxial anesthesia that is rare but potentially catastrophic.  The estimated risk of neurologic complications from epidural and spinal anesthesia is approximately 1 in 150,000 patients and 1 in 220,000 patients, respectively1.  The addition of LMWH for thromboprophylaxis can add additional risk to patients receiving spinal or epidural anesthesia with the risk of spinal hematoma estimated at 1 in 40,800 and 1 in 3,100 North American patients2.  In Europe, however, this risk is estimated to be much lower (1 in 2.25 million patients) in patients receiving neuraxial anesthesia and LMWH for VTE prophylaxis owing to the reduced dose (20 or 40 mg daily) of enoxaparin versus dosing in North America (30 mg every 12 hours)2.  Additional factors that can increase the likelihood of spinal hematoma development include repetitive and traumatic bloody punctures during neuraxial anesthesia, placement or removal of epidural catheter during peak anticoagulant activity, and administration of concomitant medications that increase bleeding risk, such as aspirin (ASA), non-steroidal anti-inflammatory drugs (NSAID), and other anti-platelet drugs1.

Ozel et al.3, reported one case of spontaneous spinal EH ten days following total hip arthroplasty (THA) in a patient who received combined spinal-epidural.  The patient received enoxaparin 40 mg twelve hours after epidural placement followed by transition to rivaroxaban 10 mg daily upon discharge.  In this case, the symptoms spontaneously resolved, and no surgical intervention was required3.  Another case report documented a neuraxial hematoma following the unsuccessful attempted placement of both a spinal and epidural for a patient undergoing total knee arthroplasty (TKA)4.  During the first two postoperative days ASA alone for VTE prophylaxis was given, followed by therapeutic enoxaparin on postoperative day 3 when a pulmonary embolism was diagnosed.  The patient developed a large EH on postoperative day 4 that led to tetraplegia despite emergent laminectomy4.

Larger studies have demonstrated a low incidence of EH.  A 2016 phase IV, non-interventional study Xarelto® in the prophylaxis of post-surgical venous thromboembolism after elective major orthopaedic surgery of hip or knee (XAMOS) by Haas et al.5, compared the safety and efficacy of rivaroxaban 10 mg to standard of care (LMWH, fondaparinux, or dabigatran) in patients who underwent major orthopaedic surgery.  This study reported no cases of spinal hematoma in the neuraxial anesthesia patients (n=10,355) regardless of postoperative anticoagulant timing.  Rivaroxaban was studied in four phase III trials in patients who underwent THA (RECORD 1 or 2) or TKA (RECORD 3 or 4)6.  The efficacy and safety of rivaroxaban 10 mg given once daily was compared to enoxaparin 40 mg daily (RECORD 1-3) or enoxaparin 30 mg twice daily (RECORD 4)6.  A total of 4,086 patients received rivaroxaban and 4,090 received enoxaparin among those who received either neuraxial anesthesia alone or neuraxial plus general anesthesia7.  There were two spinal hematomas reported, one of which required surgical intervention.  This occurred in a 74-year-old patient with severe renal impairment who underwent TKA with epidural anesthesia.  The catheter was removed 12 hours after receiving the last dose of enoxaparin 40 mg and subsequent enoxaparin dosing resumed six hours after the catheter was removed according to established guidelines7.  The other spinal hematoma occurred during spinal placement due to traumatic puncture prior to the first dose of rivaroxaban7.

In a case-control study by Liu et al.8, the efficacy and safety of preoperative versus postoperative administration of LMWH was studied in 222 patients who underwent hip fracture repair.  Of the 168 patients who received neuraxial anesthesia, there were no reported cases of spinal hematoma regardless of treatment arm8.  Singelyn et al.9, performed a multicenter, international, prospective study involving 5,704 patients who underwent major orthopaedic surgery, 1,553 of whom received epidural analgesia and 78 of whom received a deep peripheral nerve catheter.  Fondaparinux 2.5 mg daily for VTE prophylaxis was held for 48 hours prior to epidural catheter removal and identical dosing was given to those without catheters9.  No neuraxial or perineural hematomas were found in the study9.

A case-control study by Shaieb et al.10, compared patients who received enoxaparin for VTE prophylaxis (n=152) following major lower extremity orthopaedic surgery with those who did not receive VTE prophylaxis (n=152).  There were no statistically significant differences in bleeding complications but there was one documented case of neuraxial hematoma requiring surgical intervention in a patient who received epidural anesthesia10.  This patient received enoxaparin 30 mg twice daily postoperatively for VTE prophylaxis in addition to one dose of an NSAID prior to the development of the EH10.

The large trials and case reports identified have suggested that neuraxial hematomas are rare events in the setting of routine VTE prophylaxis but can occur when additional medications affecting coagulation or platelets are given or when decreased drug clearance, as in renal impairment, is present.  The risk of developing an EH must be weighed against the risk of asymptomatic VTE that exists with TJA in patients without prophylaxis, which may be as high as 50%11.  This topic is addressed in other sections.


1.         Hantler C, Despotis GJ, Sinha R, Chelly JE. Guidelines and alternatives for neuraxial anesthesia and venous thromboembolism prophylaxis in major orthopedic surgery. J Arthroplasty. 2004;19(8):1004-1016. doi:10.1016/j.arth.2004.04.018

2.         Rosencher N. Ximelagatran, a new oral direct thrombin inhibitor, for the prevention of venous thromboembolic events in major elective orthopaedic surgery. Efficacy, safety and anaesthetic considerations. Anaesthesia. 2004;59(8):803-810. doi:10.1111/j.1365-2044.2004.03840.x

3.         Ozel O, Demircay E, Kircelli A, Cansever T. Atypical Presentation of an Epidural Hematoma in a Patient Receiving Rivaroxaban After Total Hip Arthroplasty. Orthopedics. 2016;39(3):e558-560. doi:10.3928/01477447-20160414-01

4.         Bindelglass DF, Rosenblum DS. Neuraxial hematoma and paralysis after enoxaparin administration 3 days after attempted spinal anesthesia for total knee arthroplasty. J Arthroplasty. 2010;25(7):1169.e9-11. doi:10.1016/j.arth.2009.07.022

5.         Haas S, Holberg G, Kreutz R, et al. The effects of timing of prophylaxis, type of anesthesia, and use of mechanical methods on outcome in major orthopedic surgery – subgroup analyses from 17,701 patients in the XAMOS study. Vasc Health Risk Manag. 2016;12:209-218. doi:10.2147/VHRM.S100293

6.         Quinlan DJ, Eriksson BI. Novel oral anticoagulants for thromboprophylaxis after orthopaedic surgery. Best Pract Res Clin Haematol. 2013;26(2):171-182. doi:10.1016/j.beha.2013.07.003

7.         Rosencher N, Llau JV, Mueck W, Loewe A, Berkowitz SD, Homering M. Incidence of neuraxial haematoma after total hip or knee surgery: RECORD programme (rivaroxaban vs. enoxaparin). Acta Anaesthesiol Scand. 2013;57(5):565-572. doi:10.1111/aas.12069

8.         Liu Z, Han N, Xu H, et al. Incidence of venous thromboembolism and hemorrhage related safety studies of preoperative anticoagulation therapy in hip fracture patients undergoing surgical treatment: a case-control study. BMC Musculoskelet Disord. 2016;17:76. doi:10.1186/s12891-016-0917-y

9.         Singelyn FJ, Verheyen CCPM, Piovella F, Van Aken HK, Rosencher N, Investigators  for the ES. The Safety and Efficacy of Extended Thromboprophylaxis With Fondaparinux After Major Orthopedic Surgery of the Lower Limb With or Without a Neuraxial or Deep Peripheral Nerve Catheter: The EXPERT Study. Anesthesia & Analgesia. 2007;105(6):1540-1547. doi:10.1213/01.ane.0000287677.95626.60

10.       Shaieb MD, Watson BN, Atkinson RE. Bleeding complications with enoxaparin for deep venous thrombosis prophylaxis. J Arthroplasty. 1999;14(4):432-438. doi:10.1016/s0883-5403(99)90098-0

11.       Seagrave KG, Fletcher JP, Hitos K. Aspirin for prevention of venous thromboembolism in recipients of major lower-limb orthopedic surgery: a systematic review of Level I evidence. Int Angiol. 2019;38(6):429-442. doi:10.23736/S0392-9590.19.04086-0

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