Systemic intraoperative anticoagulation during arterial injury repair: Implications for patency and bleeding

Maher, Zoё MD; Frank, Brian MD; Saillant, Noelle MD; Goldenberg, Anna DO; Dauer, Elizabeth MD; Hazelton, Joshua P. DO; Lubitz, Andrea MD; Zhao, Huaqing PhD; Cannon, Jeremy W. MD; Seamon, Mark J. MD

Journal of Trauma and Acute Care Surgery: April 2017 - Volume 82 - Issue 4 - p 680–686
doi: 10.1097/TA.0000000000001384
AAST Plenary Papers
Editor's Choice

BACKGROUND: The role of systemic intraoperative anticoagulation (SIAC) during surgical repair of major arterial injuries is controversial. Any potential improvement in arterial patency must be weighed against the risk of hemorrhage in these critically injured patients. We hypothesized that SIAC would increase arterial patency without increasing bleeding complications.

METHODS: We conducted a multi-institution, retrospective cohort study of trauma patients with major vascular injury from 2005 to 2013 in three Level I centers. Arterial injuries of the neck, torso, and proximal extremities requiring operative management were included. Our primary endpoint was maintenance of arterial patency during index hospitalization. Complications related to bleeding were assessed. The association between SIAC and arterial patency was evaluated using chi-square, t test, and multiple logistic regression modeling.

RESULTS: Of 323 study patients, most were male (88%) and injured by gunshot wounds (69%). Patients repaired with SIAC (n = 154) were compared to those repaired without SIAC (n = 169). No difference in age, gender, mechanism, admission heart rate, or concomitant injury was detected between the groups (all p > 0.05). SIAC use was associated with greater arterial patency rates (93% vs. 85%, p = 0.02) without increasing return to OR for bleeding (4% vs. 6%, p = 0.29). After controlling for gender, admission hemodynamics, ISS, injury location, and postoperative anticoagulation, multivariable regression determined that SIAC patients were 2.6 times more likely (OR 2.6, 95% CI 1.1–6.2, p = 0.03) to maintain patency. Patients who maintained arterial patency were then less likely to return to the OR (9% vs. 78%, p < 0.001) with shorter intensive care unit (median 3 vs. 9 days, p < 0.01) and hospital length of stay (median 13 vs. 21 days, p < 0.01).

CONCLUSION: Patients who underwent operative repair of arterial injuries utilizing SIAC experienced better arterial patency without additional bleeding complications as compared to those repaired without SIAC. Our data suggest that SIAC may improve arterial patency rates after repair and the attributable bleeding risk of SIAC may be overstated.

LEVEL OF EVIDENCE: Therapeutic/care management, level IV.

From the Temple University School of Medicine (Z.M., E.D., A.L., H.Z.), Philadelphia; Geisinger Health System (B.F.), Danville, Pennsylvania; Massachusetts General Hospital (N.S.), Boston, Massachusetts; Cooper University (A.G., J.P.H.), Camden, New Jersey; and Perelman School of Medicine, University of Pennsylvania (J.W.C., M.J.S.), Philadelphia, Pennsylvania.

Submitted: September 9, 2016, Revised: December 19, 2016, Accepted: January 3, 2017, Published online: January 17, 2017.

This study was presented at the 76th annual meeting of the American Association for the Surgery of Trauma, September 13–16, 2016, in Waikoloa, Hawaii.

Address for reprints: Zoё Maher, MD, 3401 N Broad Street, 4th Floor Parkinson Pavilion, Suite 401 Philadelphia, PA 19129; email: zoe.maher@tuhs.temple.edu.

Article Outline

The intraoperative management of traumatic arterial injury has largely been informed by advances in the surgical treatment of peripheral vascular disease. Among the most significant advances allowing the successful reconstruction of blood vessels was the discovery of heparin in 1916.1 Murray and colleagues were then the first to describe the application of heparin in human subjects undergoing surgery in 1940.2 Since that time, local and systemic heparin has been an essential component of elective peripheral vascular surgery. However, there are no randomized controlled clinical trials demonstrating its optimal use. This dearth of Level I, scientific evidence has led to varying applications of heparin in elective peripheral vascular surgery, ranging from local heparin administration to high-dose systemic anticoagulation.3–6

Despite the wide-spread use of systemic heparin in elective vascular procedures, its risk-benefit profile in patients with operative vascular injuries is unclear. Traumatic injury may be a contraindication to full systemic anticoagulation during index arterial repair following trauma.7 The recently published Eastern Association for the Surgery of Trauma guidelines for the management of penetrating lower extremity arterial injury notably do not include any recommendations regarding the role of systemic intraoperative anticoagulation (SIAC), citing a lack of consensus on the controversial topic.8 The potential bleeding risk of systemic anticoagulation in the trauma population is not well established, although ongoing studies are currently evaluating this issue.9,10

Given the importance of arterial patency after operative vascular injury, it is critical to understand the optimal application of intraoperative anticoagulation and its associated risks.11 We hypothesized that SIAC would improve short-term arterial patency rates without increasing likelihood of bleeding complications.

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METHODS

We conducted a multi-institution, retrospective cohort study of trauma patients with operative vascular injury from 2005 to 2013 in three urban, Level I trauma centers. Adults (≥14 years) with arterial injuries of the neck, torso, and proximal extremities (proximal to and including brachial and popliteal arteries) requiring operative management were included. Patients with isolated venous injuries, concomitant traumatic brain injuries, death within 24 hours of presentation, embolization only, or who underwent nonoperative management were excluded from study analysis.

Demographic, physiologic, anatomic injury pattern, intraoperative, and outcome data were collected. Associated injuries, including extremity fracture, hollow viscous, solid organ, spine, rib fracture, and concomitant venous injury were also tracked. Patients repaired with SIAC were compared to those repaired without SIAC, where SIAC was defined as systemic intravenous unfractionated heparin, with or without initial bolus. Information on the dose of heparin was unavailable for inclusion in analysis. The administration of SIAC was at the discretion of the operating surgeon at each of the three participating centers. The use of dextran or local heparinized saline only was not considered in SIAC.

The primary study endpoint was maintenance of postoperative arterial patency during the index hospitalization, defined by the absence of clinical or radiographic evidence of arterial thrombosis. Secondary endpoints included return to the OR for bleeding, other bleeding complications (i.e. post-operative bleeding from an operative site requiring either transfusion or intervention), limb salvage, intensive care unit (ICU) length of stay (LOS), hospital LOS, and mortality.

Study data were collected and managed using REDCap, an electronic data capture tool hosted at the University of Pennsylvania.12 Continuous data were expressed as means with standard deviations and categorical or ordinal data as proportions (%). The Wilcoxon-Mann-Whitney test was used to compare distributions of continuous variables, and either Pearson’s chi square or Fisher’s exact test was used to compare proportions of categorical variables. Descriptive statistics and logistic regression were used to measure associations between risk factors and each outcome of interest, arterial patency, and bleeding complications. Statistical analysis was conducted utilizing STATA software, version 14.0 (StataCorp LP, College Station, TX). All statistical tests were two-tailed, and statistical significance was considered when p ≤ 0.05.

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RESULTS

The study sample of 323 study patients in Table 1 was comprised primarily of young (30.8 ± 13.6 years [mean ± SD]) men (87.9%) injured by penetrating wounds (81.7%) whereas motor vehicle collisions (7.0%), motorcycle collisions (2.6%), pedestrians struck (2.6%), falls (2.2%), and assaults (1.9%) also resulted in arterial injuries requiring operative intervention. Most study patients (62.4%) had documented hard signs of vascular injury upon presentation, whereas preoperative massive transfusion protocol activation was utilized in 25.2% of patients after arterial injuries of the neck (3.7%), upper extremity (24.8%), torso (17.0%), and lower extremity (53.3%). Two patients had multiple arterial injuries in multiple anatomic regions. Systemic anticoagulation was commonly utilized both in the operative suite (47.7%) and during the postoperative period (22.6%) but infrequently resulted in nonoperatively managed bleeding complications (7.1%) or required return to the operating room for bleeding (5.3%). Nineteen patients ultimately required amputations resulting from injuries of the external iliac (n = 2), common femoral (n = 3), superficial femoral (n = 3), and popliteal (n = 7) arteries. Overall, 88.5% of arterial repairs remained patent, and 96.3% of study patients survived their hospitalization.

Patients who maintained arterial patency following repair (n = 286) were compared to those who lost arterial patency (n = 37) during their index hospitalization (Table 2). No differences between these comparison groups were detected with respect to age, mechanism, ISS, hemodynamics, anatomic injury location, associated fractures or major venous injuries, surgeon subspecialty, utilization of damage control techniques, fasciotomies, or type of repair (all p > 0.05). Patients who maintained patency were more likely to have utilized SIAC (50.0% vs. 29.7%, p = 0.02) but less likely to have been treated with postoperative systemic anticoagulation (20.6% vs. 37.8%, p = 0.02) than patients who did not maintain arterial patency. In turn, those with patent repairs less often returned to the operative suite (8.8% vs. 78.4%, p < 0.001) and had shorter ICU (median [IQR], 3 [2–6] vs. 9 [4–17] days, p < 0.01) and hospital LOS (13 [7–22] vs. 21 [13–41] days, p < 0.01).

Patients who underwent arterial repair with SIAC (n = 154) were also compared to those repaired without SIAC (n = 169; Table 3). No difference in age, gender, injury mechanism, admission heart rate, time to OR, associated venous injury, or fracture was detected between SIAC and no SIAC groups (all p > 0.05). Differences in the groups were detected. Patients repaired with SIAC were more likely to have lower extremity arterial injuries (68.8% vs. 34.3%, p < 0.001) with hard signs of vascular injury (51.8% vs. 74%, p < 0.001) and less likely to have arterial injuries of the torso (4.6% vs. 28.4%, p < 0.001) than those treated without SIAC. In addition, when patients repaired with SIAC were compared to those repaired without SIAC, ISS, ICU, and hospital LOS were lower (18.9 vs.12.2, p < 0.001, median [IQR], 5 [2–13] vs. 3 [2–5], p < 0.001 and 17 [9–32] vs. 12 [7–18], p < 0.001).

Use of SIAC during arterial repair was associated with greater arterial patency rates (Figure 1; 92.9% vs. 84.6%, p = 0.02). After controlling for gender, admission hemodynamics, ISS, anatomic injury location, and the use of postoperative systemic anticoagulation, multiple variable logistic regression (Table 4) determined that patients repaired with SIAC were 2.6 times more likely to maintain arterial patency (OR 2.6, 95% CI 1.1–6.2, p = 0.03) than those repaired without SIAC. No significant increase in limb salvage was associated with the use of SIAC however (p = 0.23).

Importantly, the benefit of SIAC to arterial repair patency did not appear to come at the expense of increased bleeding complications. There was no increase in the return to operative suite rate for bleeding (SIAC, 3.9% vs. no SIAC, 6.5%, p = 0.29) or overall bleeding complications (SIAC, 3.9% vs. no SIAC, 10.1%, p = 0.03) in those administered SIAC. Patients with torso injuries (OR 3.5, 95% CI 1.5–8.3, p = 0.005) or those treated with postoperative anticoagulation (OR 3.4, 95% CI 1.5–7.6; p = 0.003) were more likely to have bleeding complications when controlling for age, ISS, admission hemodynamics, anatomic location of arterial injury, postoperative anticoagulation, and SIAC (Table 5). However, SIAC was not independently associated with bleeding complications when controlling for these factors (p = 0.31).

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DISCUSSION

The most important finding of this multi-institution study is that the use of systemic heparin during the operative repair of arterial injuries leads to improved short-term arterial patency without an associated increase in bleeding complications. We believe that these findings should embolden surgeons tasked with repairing arterial injuries to consider more liberal use of SIAC.

The discovery, purification, and application of heparin in peripheral vascular surgery revolutionized the field.1,2,13,14 Thrombus formation along suture lines and areas of stasis because of large amounts of tissue thromboplastin and other procoagulant factors could now be countered, allowing bypass grafts to remain patent.4,15 Subsequently, intraoperative systemic heparinization during arterial reconstruction was nearly universally accepted without challenge, as evidenced by the lack of prospective, randomized, controlled trials evaluating its use in this context to date.6,15–17

Many developments in the field of vascular surgery have been driven by elective peripheral vascular surgery and subsequently evaluated in the setting of vascular trauma. Literature focused on factors influencing vascular bypass patency infrequently consider the impact of SIAC and instead have focused largely on the use of antiplatelet agents,18–25 as systemic heparinization is nearly universally accepted in peripheral vascular surgery. However, the frequency of SIAC application in vascular trauma is unclear. In the current series, only 47.7% of patients with operative arterial injuries received SIAC, including the cohort of patients with isolated lower extremity arterial injury in which a mere 62.9% received SIAC. However, those patients seemed to clearly benefit from the anticoagulation, as our multivariate logistic regression model demonstrated patients repaired with SIAC were 2.6 times more likely to maintain arterial patency when other potential risk factors were controlled.

Although SIAC is not uniformly evaluated as a factor contributing to patency rates, several publications have supported its use. Melton et al. found that intraoperative use of systemic heparin or local urokinase was the only directly controllable factor associated with limb salvage in a study of 102 patients with popliteal artery injuries.26 Guerrero et al. also evaluated the factors associated with limb salvage in patients with lower extremity arterial injuries. The investigators found an increase in limb salvage without a concomitant increase in bleeding complications associated with the use of intraoperative anticoagulation.7 These authors therefore advocated for the use of systemic anticoagulation to maximize limb salvage during the repair of popliteal artery injuries.

Although arterial patency was improved with the use of SIAC in the current series, we were unable to demonstrate an improvement in limb salvage rates with the use of SIAC. Our study sample though was composed of arterial injuries of varied anatomic locations, not entirely the high-risk popliteal area. Unlike the isolated popliteal artery literature, our cohort was mixed, including patients with amputations following injuries to the iliac, femoral, popliteal, and axillary arteries, in which arterial patency was likely not the only factor influencing limb salvage. Other factors, such as degree of soft tissue injury, delayed compartment syndrome, infection, and the effects of concomitant injury are often difficult to capture in a retrospective analysis. Importantly, although we demonstrated only a possible “trend” toward improved limb salvage rates in patients who underwent arterial repair with SIAC (p = 0.16), we did demonstrate an improvement in arterial patency and, in turn, patients with patent repairs less often returned to the operative suite and had shorter ICU and hospital LOS.

Although we have demonstrated that arterial repair with SIAC is associated with improved arterial patency, associated bleeding risks may limit its applicability in the trauma population. The bleeding risk attributable to full-dose anticoagulation has been most fully evaluated in the medical population and is estimated between 0 and 44%.27–31 These rates reflect patients who are primarily on long-term anticoagulation for indications including venous thromboembolic disease, atrial fibrillation, valvular pathology, ischemic stroke, and acute coronary syndrome. The patient population represented in these medical reports is older and more often with significant comorbidities than the young trauma population.27 According to the CHEST guidelines, the risk of bleeding associated with intravenous unfractionated heparin in patients with acute venous thromboembolism is <3% in recent trials, but the risk is increased in patients >70 years of age and in those with baseline renal insufficiency.32 The mean age of our study sample patients was 30.8, and rates of preexisting renal insufficiency are presumably quite low.

Unlike the anticoagulated medical patient population, the elective vascular surgery population has the added risk factor for bleeding from an operative field. Although this would suggest that there should be higher rates of bleeding, several studies on the topic have failed to substantiate this risk.17 The traumatic arterial injury cohort has an additional risk factor for bleeding in the presence of associated injuries, at times spanning multiple body cavities. In our study population, each of the 323 patient study sample had associated injuries. Despite this, we did not detect any increase in the rate of postoperative bleeding complications requiring intervention, including blood transfusion or return to the operating room for patients with associated injuries.

Although SIAC was not related to any measured bleeding complication in our analysis, multivariate logistic regression modeling did determine that patients with arterial injuries of the torso were more likely to have bleeding complications than those of other injured anatomic areas. Caution and careful intraoperative surgical decision-making before utilizing SIAC in this setting seems prudent. It is likely that the good judgment of the operating surgeon contributed to the decision not to use SIAC in this cohort of patients.

In addition, it is likely that this very same good judgment led to the observed differences between the cohort of patients receiving SIAC and those not receiving SIAC. On the basis of the increased ISS, ICU, and hospital LOS in the no SIAC cohort, it is possible that those patients not given SIAC were at higher baseline risk of bleeding complications.

Conversely, patients with isolated lower extremity arterial injuries often have minimal risk for bleeding after SIAC. In the current series, only 62.9% of patients in this particular low-risk subset were given SIAC. These and other injured patients with limited bleeding risk then offer a potential opportunity to improve clinical care and outcomes in patients with operative vascular injuries. Sound surgical judgment and proper patient selection is critical to the appropriate application of SIAC.

We acknowledge our study limitations. Limitations to this study include the retrospective nature of this report and potential limitations inherent to this study design. The decision to utilize SIAC was left to the discretion of the operating surgeon, not a study-defined protocol. As such, an unmeasured study bias may exist. Our analysis was also restricted to the use of SIAC defined as systemic heparinization. As such, we did not evaluate the potential impact that regional heparin administration had on the outcomes of interest. Finally, we did not evaluate the intraoperative anticoagulant effect of SIAC with either thromboelastography or laboratory values. Trauma patients may present with trauma-induced coagulopathy, which manifests in hypocoaguable or hypercoagulable states.33 A future prospective study that includes functional coagulation assays upon both presentation and operative repair would further the evidentiary basis for patient selection for SIAC administration during arterial repairs.

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CONCLUSION

Patients who underwent operative repair of arterial injuries utilizing SIAC appear to have better arterial patency without additional bleeding complications as compared to those repaired without SIAC. Our data suggest that (1) SIAC may improve arterial patency rates after operative vascular injury and (2) the attributable bleeding risk of SIAC may be overstated. Despite these suggestions, the safe application of SIAC relies on sound clinical judgment and the utilization in the right clinical scenario. Further investigation to clarify the patient population in whom these findings apply.

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AUTHORSHIP

Z.M., N.S., J.W.C., and M.J.S. designed this study. Z.M. and N.S. conducted the literature search. Z.M., B.F., N.S., A.G., E.D., J.P.H., and A.L. contributed to data collection. All authors participated in data analysis. Z.M., B.F., A.G., E.D., J.P.H., A.L., H.Z., J.W.C., and M.J.S. performed data interpretation. Z.M. and M.J.S. wrote the manuscript, which all authors critically revised.

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DISCLOSURE

The authors declare no conflicts of interest.

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REFERENCES

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DISCUSSION

Dr. Ian Civil (Auckland, New Zealand): I appreciate the opportunity to discuss this paper which is the second on this program at this meeting addressing heparin and vascular trauma. And for those of you who heard the earlier paper, the results seem in contradistinction to that.

Despite the scientific basis of modern medicine there are still many aspects where practice is based on tradition. And the use of heparin in acute vascular trauma is one of these.

All trauma and vascular surgeons are caught by the conundrum that while it is likely that heparin will be helpful in preventing thrombosis in the vascular system, the risks of bleeding in other injured areas, particular the brain and solid organs, may make its use counterproductive.

Vascular trauma is relatively uncommon and this retrospective cohort study only managed to amass 323 patients over nine years in three Level I trauma centers, which speaks to the difficulty in addressing the underlying question.

In addition, the difference between a severe blunt injury with a popliteal artery disruption, a gunshot wound to the abdomen with multiple visceral and solid organ injuries, as well as an iliac artery injury, and a patient who simply puts their arm through a plate glass window and lacerates the brachial artery are so great that it’s hard to see how these can be studied collectively.

Nevertheless, the authors combined these groups and had equal numbers in those receiving heparin and those not. There was a small but statistically significant improvement in patency rates in those receiving heparin and no increase in return to the operating room for bleeding.

So does this mean it’s safe and beneficial for everyone to receive heparin? I suspect not. It may well be, given the small numbers, that despite the apparent statistical similarity between the groups given heparin and those not, the heparin group were, in fact, in some way less injured and the heparin did help patency without the penalty of increased bleeding.

The result probably means the clinicians finely judged the safety of giving heparin and managed to give it in situations where it did not actually result in the return to the operating room at a small patency advantage.

The statistics in small patient numbers like this are always going to be complex and I suspect that maybe some of the non-significant results are so just because of small numbers.

I have three questions.

Firstly, was there any difference in outcome between those who were repaired or reconstructed with vein versus prosthetic?

Secondly, what dose of heparin was given on average? Was it likely to be that necessary to therapeutically anticoagulate the patient or was it less than that given in the elective setting, recognizing the potential for bleeding at other sites?

And, thirdly, this study focused on patients getting operative intervention but we know nowadays with our common investigations we find a lot of patients who have vascular injury that don’t need operative intervention but, nonetheless, may need or may benefit from anticoagulation. Do you have plans to study that group or can you make any comments on that group from the work that you’ve done?

Thank you for a nice presentation of a challenging clinical issue and I thank the Association for the privilege of being able to discuss this paper.

Dr. Anthony A. Meyer (Chapel Hill, North Carolina): I enjoyed the paper. I think the comment or evidence that you can’t fear giving systemic heparin in a significant arterial injury— but I think, as was pointed out by Dr. Civil, the frequency of these injuries is not so great that you can rely on a series of 500 to tell you what to do.

This is really where judgment and experience comes in to know which patient might not get systemic heparin but, again, not to fear giving it when it seems to be appropriate with an isolated or largely isolated vascular injury.

Dr. Ronald I. Simon (Brooklyn, New York): I enjoyed the paper. I’m just wondering if there isn’t a real selection bias in how you are looking at things.

In my experience with vascular surgeons and vascular repairs, the vascular repairs that look really good after they’re done don’t get anticoagulation. The ones where they say, “I don’t know whether this is going to stay open,” those are the ones that get post-operative anticoagulation. How did you control for that?

Thank you.

Dr. Scott d’Amours (Sydney, Australia): Thank you, I enjoyed your presentation. I’m just wondering if any of the patients in either group received other forms of perioperative (pre- or post-operative) anticoagulation, fractionated or unfractionated heparin, or antiplatelet therapy. These other forms could impact your results significantly.

Dr. Zoe Maher (Philadelphia, Pennsylvania): Thank you for your insightful comments and, Dr. Civil, I appreciate the review.

Regarding the first question on the outcomes between vein and prosthetic graft, we did look at that. Again, many of you have touched on the issue of when the N is so low it’s very difficult to make conclusions that are valid in these kind of analyses.

Looking at those two groups there was no difference in patency rate. There was no difference in the utilization of systemic intraoperative anticoagulation between those two groups. But, again, the numbers in each group are fairly small and I would be hesitant to make any strong suggestions based on that data.

Regarding the dosing of heparin, unfortunately, this is the problem with a retrospective cohort review. We build a dataset, we collect a ton of variables and then you get to the end and you wish you had more. And that is one of the variables that I wish we had collected. We did not.

I will say based on the experience at our institution our vascular surgeons when they are involved in repairs tend to give the standard dosing that they give during elective vascular surgery; but there were several patients in the cohort who actually received infusions.

It was a very small number of patients who did not actually get bolus. So there is some variability in the application certainly in the trauma patient population.

And then regarding the need to investigate the non-operatively managed vascular injured patient, we did not collect any data on that, though we have a consortium now in Philadelphia and I think that would be an excellent next project for us. Thank you for the suggestion.

Regarding the issue of judgment and experience, I couldn’t agree more. As someone with a fairly small number of years of experience and lots of people around me with great judgment, certainly we rely on that to figure out which patients should be heparinized and which should no.

What I found really fascinating was that when we looked at the population of patients who had isolated lower extremity injuries with or without fracture, with or without associated significant injuries, the rates of utilization of heparin is still extremely low. In fact, only 70% of patients with isolated lower extremity injury who underwent bypass were heparinized.

So I would say that there is actually a real opportunity, at least amongst our institutions, to sort of more liberally utilize heparin in the patient population that’s fairly low-risk for bleeding, which I would consider the isolated, lower-extremity injured patient to be.

Regarding the issue of selection bias and the use of postoperative anticoagulation, surely this is true. This is a very, very complex issue. And there are lots of things that can induce a selection bias in patients like this.

We did, during our multivariate logistic regression, including postoperative anticoagulation as a factor that was controlled for and, therefore, I feel confident that systemic anticoagulation use was, in fact, a significant difference.

And, then, finally, regarding the use of perioperative anticoagulants, including therapeutic and a prophylactic dose as well as aspirin, we did look at that. Actually, 50% of patients in the patent group received postoperative aspirin and 35% in the failure of patency received postoperative aspirin.

I have to go back to the data to really elucidate the timing of that because presumably in a patient who has arterial thrombosis early-on and has either a revision or a ligation as their ultimate outcome, there may be no need for postoperative aspirin. So I will have to look at that for the manuscript.

I thank you very much.

Keywords:

Major vascular injury; systemic anticoagulation; bleeding risk; arterial patency

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