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Postoperative Deep Vein Thrombosis, Pulmonary Embolism, and Myocardial Infarction: Complications After Therapeutic Anticoagulation in the Patient With Spine Trauma

Shiu, Brian, MD; Le, Elizabeth, MD; Jazini, Ehsan, MD; Weir, Tristan B., MD; Costales, Timothy, MD; Caffes, Nicholas, MD; Paryavi, Ebrahim, MD MPH; O’Hara, Nathan, MHA; Gelb, Daniel E., MD; Koh, Eugene Y., MD PhD; Ludwig, Steven C., MD

doi: 10.1097/BRS.0000000000002513
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Study Design. A retrospective review (2001–2014) was conducted using prospectively collected data at a level I trauma center.

Objective. We sought to determine the incidence and characteristics of complications occurring secondary to therapeutic anticoagulation in adult spine trauma patients.

Summary of Background Data. Numerous studies have assessed prophylactic anticoagulation after spine surgery, but none has investigated the risks of therapeutic doses of anticoagulation for treatment of postoperative thromboembolic events.

Methods. Patients were included if they sustained a postoperative thromboembolic event (deep venous thrombosis, pulmonary embolism, or myocardial infarction). Patients were excluded if anticoagulation was subtherapeutic. Of 1712 patients, 62 who received therapeutic anticoagulation and 174 propensity-matched control patients who did not receive therapeutic anticoagulation were included in the study.

Results. Initial anticoagulation was obtained by heparin infusion (51%), low-molecular-weight heparin (LMWH, 46%), and warfarin (3%). Complications requiring unplanned reoperation occurred in 18% of anticoagulated patients and 10% of nonanticoagulated patients (P = 0.17). The reoperation rate after heparin infusion was 31% and after LMWH was 6.5% (P = 0.02). Epidural hematoma occurred in 3% and 1% of anticoagulated and nonanticoagulated patients, respectively. Multivariate logistic regression analysis of the two groups showed a trend toward increased risk of reoperation in the anticoagulation group. Analysis of the heparin infusion subgroup separate from the LMWH subgroup compared with the control group showed an increased risk of reoperation for any complication (odds ratio, 3.57; P = 0.01) and for bleeding complications (odds ratio, 43.1; P = 0.01).

Conclusion. This is the first study to quantify complications secondary to postoperative therapeutic anticoagulation in spine patients. Postoperative spine trauma patients who underwent therapeutic anticoagulation experienced an unplanned reoperation rate of 18%, including a 3% incidence of spinal epidural hematoma. Therapeutic anticoagulation using heparin infusion seems to drive the overall rate of reoperation (31%) compared with LMWH.

Level of Evidence: 3

Department of Orthopaedics

Department of Neurosurgery, University of Maryland, Baltimore, MD.

Address correspondence and reprint requests to Steven C. Ludwig, MD, Department of Orthopaedics, University of Maryland, 110 South Paca St, 6th Floor, Suite 300, Baltimore, MD 21201; E-mail: sludwig@umoa.umm.edu

Received 1 September, 2017

Revised 2 November, 2017

Accepted 16 November, 2017

The device(s)/drug(s) is/are FDA approved or approved by corresponding national agency for this indication.

No funds were received in support of this work.

Relevant financial activities outside the submitted work: board membership, consultancy, payment for lecture, grants, patents, royalties, stocks, travel/accommodations/meeting expenses.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.spinejournal.com).

The reported incidence of thromboembolic events after spine surgery ranges from 0.3% to 14%.1–5 Therapeutic anticoagulation is the standard of care for treatment of thromboembolic events, including deep venous thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI). Although numerous studies have examined complications incurred after prophylactic doses of anticoagulation,6–9 the incidence of complications associated with therapeutic doses of anticoagulation after thromboembolic events has not been established.

Cain et al 8 conducted a poll of Scoliosis Research Society members to identify the morbidity associated with therapeutic doses of heparin after PE. Six of nine patients recalled by surgeons sustained complications; two of nine sustained neurological compromise. That case series provides level 4 evidence and is the only study in the English language literature that primarily reports on therapeutic anticoagulation complications in spine surgery.

We sought to determine the incidence and characteristics of complications requiring unplanned return to the operating room in the adult spine trauma population treated with and without therapeutic anticoagulation. Our secondary goal was to report the types of complications and the effects of different anticoagulation agents. We hypothesized that patients treated with therapeutic anticoagulation would have a higher rate of return to the operating room compared with patients without anticoagulation.

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MATERIALS AND METHODS

Data Extraction

After receiving institutional review board approval, we conducted a retrospective review of 1712 consecutive patients who underwent spine surgery from 2001 to 2014 at a level I trauma center. The spine surgery was performed by orthopedic spine surgeons and neurosurgeons.

A list of patients with spinal column injuries was compiled based on the Abbreviated Injury Scale body region “spine”; each patient who had undergone a spinal procedure was included on the list. Research personnel then identified those who had sustained DVT, PE, or MI. The following patient factors were collected from our database: age, sex, injury severity score (ISS), comorbidities, and mechanism of injury. The following operative surgical factors were collected based on patient chart reviews: American Society of Anesthesiologists score, spinal level (cervical, thoracic, or lumbar), inferior vena cava filter placement, and American Spinal Injury Association (ASIA) score. The anticoagulation agent (intravenously administered heparin infusion, subcutaneous low-molecular-weight heparin [LMWH], or warfarin) and time from initial surgery to thromboembolic event were recorded.

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Patient Selection

Presence of a thromboembolic complication was used to screen for patients who would have received therapeutic doses of anticoagulation. Initial patient selection criteria included those who underwent surgery for traumatic spinal column injury and sustained a thromboembolic event (DVT, PE, or MI). Patients were excluded if the thromboembolic event was sustained before spinal surgery or anticoagulation was subtherapeutic (partial thromboplastin time [PTT] <60 s or international normalized ratio <2). Of 1712 patients, 62 met the inclusion criteria. Control patients were selected on a 3:1 control-to-case ratio using a nearest-match propensity score technique based on age, sex, and ISS. Of the 186 potential control patients, 12 had incomplete documentation and were excluded (Figure 1). All included patients had Thoracolumbar Injury Classification and Severity10 and Subaxial Cervical Spine Injury Classification System11 scores greater than 4. Our final matched cohort consisted of 236 patients (receiving therapeutic anticoagulation, n = 62; not receiving therapeutic anticoagulation, n = 174).

Figure 1

Figure 1

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Outcomes

The primary outcome was the rate of complications that required unplanned reoperation after surgical stabilization of spinal column injuries in patients with and without therapeutic anticoagulation. Indications for return to the operating room were recorded as either “any complication” (wound infection, wound hematoma, loss of reduction, or pseudarthrosis) or reoperations for bleeding complications unrelated to the spine (e.g., tracheostomy site bleeding). Bleeding complications related to the spine were included in the “any complication” category. All captured surgical operations were performed at our trauma center or university hospital. All patients included in the study had a minimum of 2 years of follow-up.

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Statistical Analysis

Bivariate analyses were conducted using χ 2 and Fischer exact tests, Student t tests, and K-sample tests of median equality. Multivariate logistic regression models were created using a backward stepwise selection procedure for the overall reoperation rate, spinal reoperations, and reoperations for bleeding complications. Our main independent variable of interest, therapeutic anticoagulation status, was forced into the models. The selection procedure was set to remove factors at a P > 0.05 threshold, starting with all variables thought to be associated with reoperation and significant patient characteristics. Separate models were created to analyze subgroups based on the type of anticoagulant administered (heparin, LMWH, heparin vs. LMWH). Reoperation for bleeding complications was not powered for logistic regression in the LMWH versus no anticoagulation and LMWH versus heparin subgroups. Fischer exact tests were conducted to determine significance among subgroups. All statistical analyses were conducted using SPSS version 22.0 (IBM Corp., Armonk, NY). Statistical significance was set at P < 0.05.

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RESULTS

Participants

No significant differences in patient characteristics existed between those who did and did not receive therapeutic anticoagulation (Table 1). Of the 62 patients who received postoperative anticoagulation for sustaining a thromboembolic event, 33 (63%) had PE, 28 (45%) DVT, and one (2%) MI. The average number of postoperative days at which patients sustained a thromboembolic complication and subsequent therapeutic anticoagulation was 9.8 (range, 1–54 days) and 12.1 (range, 2–54 days), respectively. The therapeutic anticoagulation agent used to treat the thromboembolic event was heparin infusion in 29 (47%), LMWH in 31 (50%), and warfarin in 2 (3%) patients. Inferior vena cava filters were placed in 16 patients (26%).

TABLE 1

TABLE 1

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Any Therapeutic Anticoagulation

Table 2 shows the outcomes of therapeutic anticoagulation versus no anticoagulation. Complications requiring reoperation occurred in 11 (17.7%) patients in the anticoagulation group and 18 (10.3%) in the nonanticoagulation group (P = 0.17). The median day of reoperation for patients who received anticoagulation was postoperative day 20 (interquartile range, 13–26 days) and for patients who did not receive anticoagulation was postoperative day 27 (interquartile range, 13–61 days) (P = 0.25). Two (3.2%) anticoagulation patients and two (1.1%) nonanticoagulation patients underwent re-exploration for neurological decline caused by epidural hematoma; both anticoagulation patients initially received heparin infusion. Reoperation for bleeding complications occurred in three (4.8%) patients who received therapeutic anticoagulation versus one (0.6%) who did not (P = 0.057). Controlling for obesity, multivariate logistic regression showed that anticoagulated patients trended toward a higher risk of overall reoperation (adjusted odds ratio [OR], 1.89; P = 0.13) and reoperation for bleeding (OR, 9.5; P = 0.06) (Table 3).

TABLE 2

TABLE 2

TABLE 3

TABLE 3

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Heparin Infusion Versus Low-Molecular-Weight Heparin

The characteristics of anticoagulation patients stratified by heparin infusion (n = 29) versus LMWH (n = 31) are listed in Table 4. The two patients treated with warfarin were not included in the subgroup analysis. Significantly more ASIA grade A patients received LMWH (P = 0.04), and significantly more grade B patients received heparin infusion (P = 0.05). A larger portion of patients who received heparin infusion underwent surgery by orthopedic surgeons, and a larger portion of patients who received LMWH underwent surgery by neurosurgeons (P = 0.02). These significantly different variables were controlled for by using multivariate logistic regression models in Table 5.

TABLE 4

TABLE 4

TABLE 5

TABLE 5

Table 5 compares the rates of reoperation for heparin infusion versus LMWH. A Fischer exact test showed higher overall reoperation rates for patients treated with heparin infusion (31%) versus LMWH (6.5%) (P = 0.01). For patients treated with heparin infusion compared with those who did not receive anticoagulation, increased risks of reoperation were found to be associated with any complication (OR, 3.57; P = 0.01) and with bleeding complications (OR, 43.1; P = 0.01). For patients treated with LMWH compared with those who did not receive anticoagulation, there was no increased risk of reoperation. For patients treated with heparin infusion compared with LMWH, a trend was shown toward increased reoperation with heparin infusion (OR, 5.41; P = 0.06).

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Heparin Subgroup Analysis

Patients treated with heparin infusion were stratified according to reoperation status. No significant differences were shown in age (P = 0.68), sex (P = 0.68), ISS (P = 0.81), or ASIA grade (P = 0.57) for patients who sustained complications requiring reoperation (n = 9) versus those who did not (n = 20) (see Appendix; http://links.lww.com/BRS/B326). Patients who sustained complications requiring reoperation trended toward a longer mean duration of heparin infusion than those without complications (6.4 ± 4.5 vs. 4.2 ± 1.8 days, respectively; P = 0.18) and trended toward more PTT measurements in the therapeutic range of 60 to 80 seconds (6.6 ± 4.6 vs. 4 ± 3 measurements, respectively; P = 0.08). Patients with complications had more supratherapeutic PTT measurements compared with those without complications (5.4 ± 6.5 vs. 2.9 ± 2.8 measurements, respectively; P = 0.28). No significant difference was shown in the mean highest PTT value recorded (144.8 ± 34.9 vs. 140.1 ± 50.9 s; P = 0.78) or the mean PTT value (73.1 ± 12 vs. 68.5 ± 16.5 s; P = 0.46) for patients with and without complications, respectively.

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DISCUSSION

This is the first study to systematically evaluate outcomes in trauma patients undergoing therapeutic anticoagulation for the treatment of thromboembolic disease after spinal surgery. A large proportion of patients (18%) required unplanned return to the operating room for complications associated with therapeutic anticoagulation agent versus those without anticoagulation (10%). Complications associated with therapeutic anticoagulation seem to be driven by the use of heparin infusion (31%) compared with LMWH (6.5%). Spinal decompression for neurological compromise was performed in 3% of anticoagulation patients and 1% of nonanticoagulation patients. These data raise concern regarding the substantial risks associated with therapeutic anticoagulation in the postoperative setting for patients with spine trauma.

The most frequent reasons for unplanned surgery were bleeding complications and wound infections, which is consistent with the orthopedic trauma and joint arthroplasty literature.12,13 With 50% of patients undergoing reoperation between 13 and 26 days postoperatively, the treating surgical, medical, and intensive care teams should monitor patients closely within that timeframe. Unplanned return to the operating room for neurological compromise, however, occurred earlier and within a tighter range for anticoagulation patients (range, 2–14 postoperative days) than for nonanticoagulation patients (range, 3–125 postoperative days).

Cain et al 8 presented the one other study that focuses exclusively on therapeutic doses of anticoagulation in spine surgery. That case series was compiled after surveying 22 members of the Scoliosis Research Society regarding their experience with therapeutic anticoagulation after PE. Among nine patients with PE, six (67%) experienced complications that were attributable to heparinization, including two neurological complications (22%) and five reoperations (56%). The authors acknowledged that no incidence calculation could be determined because of the inherent recall bias.

Bogdan et al 12 retrospectively reviewed 312 orthopedic trauma patients who sustained PE and were treated with therapeutic anticoagulation. Heparin infusion and warfarin were the primary anticoagulation agents. Complications after anticoagulation occurred in 30 patients (10%), with only five (1.7%) returning to the operating room to address bleeding. The authors listed multiple other complications, including persistent hematoma, gastrointestinal bleeding, and anemia, but the incidence of reoperation for the complications was not reported.

A key finding of our results emphasizes that patients who received full anticoagulation (heparin infusion or LMWH) did not have a statistically increased risk of complications compared with controls. However, when the effect of anticoagulation was separated into heparin infusion and LMWH groups, complications from heparin infusion seemed to drive the reoperation rate. This is supported by multivariate analysis, which found significantly greater odds of reoperation among patients treated with heparin infusion compared with controls and a higher trend with heparin infusion compared with LMWH (P = 0.06). Full-dose LMWH alone did not increase the odds of reoperation compared with controls.

Our findings were unanticipated considering the joint arthroplasty literature, which reports an increased risk of complications with LMWH DVT prophylaxis.10,14 However, the effects of prophylactic doses and therapeutic doses may be unrelated. Because 9 of 11 anticoagulation patients who returned to the operating room had received heparin infusion, as had the two anticoagulation patients with epidural hematomas, we conducted a subgroup analysis of patients who received heparin infusion to further investigate its effects.

Our subgroup analysis of patients treated with heparin infusion showed that patients who sustained complications had a greater mean duration of heparin treatment. We postulate that heparin infusion is more prone to supratherapeutic PTT values than is LMWH because of the difficulty in titrating to the medication's therapeutic range of 60 to 80 seconds. Although we did not have the power to detect a significant difference, patients who received heparin and sustained complications had a greater incidence of supratherapeutic PTT values and a longer duration of heparin treatment than those without complications, suggesting a dose-dependent phenomenon. Notably, no significant difference was shown in the maximum PTT value measured between the two groups, which implies that isolated supratherapeutic PTT values do not guarantee unplanned reoperations. We surmise that longer heparin infusion durations incur higher frequencies of supratherapeutic PTT values that place patients at an increased risk of complications.

At our institution, we advise against administering an initial heparin bolus and ask the general trauma team to target the lower therapeutic range. The initial anticoagulant choice is multifactorial, and future studies should assess the safety profiles of heparin infusion and LMWH before definitive recommendations can be made.

This study had several limitations. First, the low incidence of postoperative therapeutic anticoagulation in spine trauma patients necessitated a retrospective study design. With 62 cases over a 14-year period, a prospective study design would not have been reasonable, and the rarity of these events prevented us from powering multiple subgroups. To increase the power of our study, controls were selected based on nearest-match propensity scores at a 3:1 ratio based on age, sex, and ISS, allowing us to establish a baseline complication rate at our institution. Second, we based our statistical analyses on grouping patients according to the initial anticoagulation agent administered, although most patients were ultimately transitioned to another agent (i.e., warfarin). Finally, this study considered only those reoperations that occurred at our institution, leaving the possibility that patients may have had subsequent surgery at an outside hospital.

This study had several strengths. First, despite the rarity of thromboembolic disease in postoperative spine trauma patients, we had a relatively large sample size of 62 patients.11 Unlike large database reviews, we had the ability to search our electronic database and confirm patients’ chart documentation and individual laboratory values to ensure the accuracy of our data.

In summary, this study represents the first attempt to quantify complications secondary to postoperative therapeutic anticoagulation in spine trauma patients. Eighteen percent of patients receiving therapeutic anticoagulation incurred unplanned returns to the operating room, compared with 10% of patients without anticoagulation. Reoperation for epidural hematoma was required in 3% of therapeutically anticoagulated patients versus 1% of nonanticoagulated patients. Our data suggest that initial anticoagulation using heparin infusion (vs. LMWH) may increase the rate of reoperation and likely drive the overall rate of reoperation after full anticoagulation. In addition, patients sustaining complications requiring reoperation were treated with heparin infusion over a longer timeframe, which may increase the number of unintended instances of supratherapeutic PTT values. Ultimately, multicenter studies must be conducted before therapeutic anticoagulation agent recommendations can be made.

  • This is the first study to quantify complications secondary to postoperative therapeutic anticoagulation in spine patients.
  • Postoperative spine trauma patients who underwent therapeutic anticoagulation experienced an unplanned reoperation rate of 18%.
  • Therapeutic anticoagulation using heparin infusion seems to drive the overall rate of reoperation (31%) compared with low-molecular-weight heparin.
  • Large multicenter studies are needed to fully characterize the effect of specific anticoagulation agents on postoperative complications.

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Acknowledgment

The authors thank Dori Kelly, MA, for professional manuscript editing.

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References

1. Dearborn JT, Hu SS, Tribus CB, et al. Thromboembolic complications after major thoracolumbar spine surgery. Spine (Phila Pa 1976) 1999; 24:1471–1476.
2. Ferree BA, Stern PJ, Jolson RS, et al. Deep venous thrombosis after spinal surgery. Spine (Phila Pa 1976) 1993; 18:315–319.
3. Oda T, Fuji T, Kato Y, et al. Deep venous thrombosis after posterior spinal surgery. Spine (Phila Pa 1976) 2000; 25:2962–2967.
4. Rokito SE, Schwartz MC, Neuwirth MG. Deep vein thrombosis after major reconstructive spinal surgery. Spine (Phila Pa 1976) 1996; 21:853–858.
5. Smith MD, Bressler EL, Lonstein JE, et al. Deep venous thrombosis and pulmonary embolism after major reconstructive operations on the spine: a prospective analysis of three hundred and seventeen patients. J Bone Joint Surg Am 1994; 76:980–985.
6. Amiri AR, Fouyas IP, Cro S, et al. Postoperative spinal epidural hematoma (SEH): incidence, risk factors, onset, and management. Spine J 2013; 13:134–140.
7. Awad JN, Kebaish KM, Donigan J, et al. Analysis of the risk factors for the development of post-operative spinal epidural haematoma. J Bone Joint Surg Br 2005; 87:1248–1252.
8. Cain JE Jr, Major MR, Lauerman WC, et al. The morbidity of heparin therapy after development of pulmonary embolus in patients undergoing thoracolumbar or lumbar spinal fusion. Spine (Phila Pa 1976) 1995; 20:1600–1603.
9. Kou J, Fischgrund J, Biddinger A, et al. Risk factors for spinal epidural hematoma after spinal surgery. Spine (Phila Pa 1976) 2002; 27:1670–1673.
10. Stern SH, Wixson RL, O’Connor D. Evaluation of the safety and efficacy of enoxaparin and warfarin for prevention of deep vein thrombosis after total knee arthroplasty. J Arthroplasty 2000; 15:153–158.
11. Pateder DB, Gonzales RA, Kebaish KM, et al. Pulmonary embolism after adult spinal deformity surgery. Spine (Phila Pa 1976) 2008; 33:301–305.
12. Bogdan Y, Tornetta P 3rd, Leighton R, et al. Treatment and complications in orthopaedic trauma patients with symptomatic pulmonary embolism. J Orthop Trauma 2014; 28 (Suppl 1):S6–S9.
13. McDougall CJ, Gray HS, Simpson PM, et al. Complications related to therapeutic anticoagulation in total hip arthroplasty. J Arthroplasty 2013; 28:187–192.
14. Shaieb MD, Watson BN, Atkinson RE. Bleeding complications with enoxaparin for deep venous thrombosis prophylaxis. J Arthroplasty 1999; 14:432–438.
Keywords:

heparin infusion; low-molecular-weight heparin; spine surgery complications; therapeutic anticoagulation; thromboembolic events; warfarin

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