Mohammad T. Ghazavi, Asep Santoso, Francesco Zambianchi, Fabio Catani.
Response/Recommendation: Patients with a systemic infection undergoing orthopaedic procedures have a higher risk of postoperative venous thromboembolism (VTE). This relationship for local infection is not proven.
Strength of Recommendation: Moderate.
Rationale: The incidence of the VTE after musculoskeletal procedures on patients with the diagnosis of infection has not been well studied in the literature1. Grimnes et al., found that hospitalization with acute infection was a strong VTE trigger with a 20-fold higher risk2. Other studies also supported this finding, showing that hospitalization with infection cases were an independent risk factor for VTE3–6.
Amaro et al.6, in a study on the relationship between C-reactive protein (CRP) and VTE prevalence in pediatric population with musculoskeletal infection (MSKI), demonstrated that the rate of VTE in children with MSKI was markedly elevated compared with hospitalized children in general. The results of their study showed that every 20mg/L increase in peak CRP was associated with a 29% increased risk of thrombosis (p < 0.001). Peak and total CRP were strong predictors of thrombosis6. Baker et al., reported that surgery for infection was the procedure with the highest VTE rate (1.2%) in a cohort of 14,776 pediatric orthopaedic procedures7. Bokshan et al., in a study on risk factors for deep venous thrombosis (DVT) or pulmonary embolism (PE) following anterior cruciate ligament reconstruction, reviewed 9,146 cases and found that presence of wound infection was associated with increased risk of developing VTE8. Parvizi et al., in a study on individualized risk model for VTE, utilized the National Inpatient Sample (NIS) data. They identified 1’721,806 patients undergoing total joint arthroplasty (TJA), among whom 15,775 (0.9%) developed VTE after index arthroplasty. They identified all independent predictors of VTE after TJA and determined the weight for each factor. Systemic sepsis was among the highest scores in predicting VTE after arthroplasty9. Accordingly, in a recent meta-analysis including 672,495 primary total shoulder and elbow replacements, Kunutsor et al., reported that there is evidence of statistically significant associations of VTE with urinary tract infection10.
The pathogenesis of VTE in infection cases has been linked to neutrophil activation and release of neutrophil extracellular traps (NET) via a process called NETosis11. While effective for bacterial clearance, the innate immune response could also trigger vascular thrombosis11. The case of infection also has been found to contribute to the pathogenesis of VTE by accelerating the effects of immobilization12. Furthermore, the presence of bacteremia (either community-acquired or hospital-acquired) has been reported to be associated with a higher risk of VTE13–15. Kaplan et al., reported that the systemic inflammatory milieu in sepsis is believed to uniquely predispose patients to VTE16. A nationwide population-based cohort study in China reported that the risk of developing DVT was 2.49-fold in patients with chronic osteomyelitis compared with the comparative group after adjusting for age, sex, and comorbidities17. Perioperative infections were associated with a higher risk for VTE in patients who received total hip arthroplasty (THA) and total knee arthroplasty (TKA)18,19.
A number of studies reported patients with an underlying diagnosis of infection undergoing orthopaedic procedures have a higher risk of VTE1,20–22. Boddapati et al., studied differences in 30-day outcomes including postoperative complications in revision TKA between revisions for infection and revisions for non-infection causes. They included and compared 162,981 primary TKA with 12,780 revision TKA, of which 2,196 were performed for periprosthetic joint infection (PJI). They found greater risk of short-term morbidity and mortality including higher rate of VTE in patients who underwent implant revision for infection. Incidence of VTE was 0.85% in non-infection revisions and 1.37% in revisions for infection20. Courtney et al., in a study on incidence of VTE in revision THA within 30 days from surgery, reviewed 74,405 patients including 7,566 revision cases. They found that, although revision THA alone was not an independent risk factor for DVT and PE when compared to primary THA, patients undergoing an arthroplasty procedure for infection, operating time > 3 hours, and age > 70 years were at higher risk for VTE21.
Despite few publications in favor of relationship between infection and rate of VTE, there are some publications that do not draw the same conclusion. Boylan et al., in a study on comparing rate of VTE in revision and primary TKA, compared 208,954 primaries and 16,630 revisions for the incidence of VTE in 30 and 90 postoperative days. They found the risk of VTE was lower for revision TKA compared with primary TKA23. They did not exclude revisions for infection cases. Georgopoulos et al., in another study on 143,808 admissions of children for elective surgery found that overall rate of VTE was 0.05%. They found that VTE happened more frequently in cases of increasing age, admission type, diagnosis of metabolic conditions, obesity, and/or syndromes, and complications of implanted devices and/or surgical procedures. They did not find infection as a factor for increasing incidence of VTE24.
In the absence of concrete evidence, it is the opinion of this workgroup that patients with systemic sepsis undergoing orthopaedic procedures are at increased risk of VTE. The relationship between local infections (such as urinary tract infection, PJI, etc.) and the risk for subsequent VTE remains unknown.
1. Bass AR, Zhang Y, Mehta B, et al. Periprosthetic Joint Infection Is Associated with an Increased Risk of Venous Thromboembolism Following Revision Total Knee Replacement: An Analysis of Administrative Discharge Data. J Bone Joint Surg Am. 2021;103(14):1312-1318. doi:10.2106/JBJS.20.01486
2. Grimnes G, Isaksen T, Tichelaar YIGV, Brækkan SK, Hansen J-B. Acute infection as a trigger for incident venous thromboembolism: Results from a population-based case-crossover study. Res Pract Thromb Haemost. 2018;2(1):85-92. doi:10.1002/rth2.12065
3. Cohoon KP, Ashrani AA, Crusan DJ, Petterson TM, Bailey KR, Heit JA. Is Infection an Independent Risk Factor for Venous Thromboembolism? A Population-Based, Case-Control Study. Am J Med. 2018;131(3):307-316.e2. doi:10.1016/j.amjmed.2017.09.015
4. Schmidt M, Horvath-Puho E, Thomsen RW, Smeeth L, Sørensen HT. Acute infections and venous thromboembolism. J Intern Med. 2012;271(6):608-618. doi:10.1111/j.1365-2796.2011.02473.x
5. Cowan LT, Lutsey PL, Pankow JS, Cushman M, Folsom AR. Hospitalization with infection and incident venous thromboembolism: The ARIC study. Thromb Res. 2017;151:74-78. doi:10.1016/j.thromres.2017.01.008
6. Amaro E, Marvi TK, Posey SL, et al. C-Reactive Protein Predicts Risk of Venous Thromboembolism in Pediatric Musculoskeletal Infection. J Pediatr Orthop. 2019;39(1):e62-e67. doi:10.1097/BPO.0000000000001256
7. Baker D, Sherrod B, McGwin G, Ponce B, Gilbert S. Complications and 30-day Outcomes Associated With Venous Thromboembolism in the Pediatric Orthopaedic Surgical Population. J Am Acad Orthop Surg. 2016;24(3):196-206. doi:10.5435/JAAOS-D-15-00481
8. Bokshan SL, DeFroda SF, Panarello NM, Owens BD. Risk Factors for Deep Vein Thrombosis or Pulmonary Embolus Following Anterior Cruciate Ligament Reconstruction. Orthop J Sports Med. 2018;6(6):2325967118781328. doi:10.1177/2325967118781328
9. Parvizi J, Huang R, Rezapoor M, Bagheri B, Maltenfort MG. Individualized Risk Model for Venous Thromboembolism After Total Joint Arthroplasty. J Arthroplasty. 2016;31(9 Suppl):180-186. doi:10.1016/j.arth.2016.02.077
10. Kunutsor SK, Barrett MC, Whitehouse MR, Blom AW. Venous thromboembolism following 672,495 primary total shoulder and elbow replacements: Meta-analyses of incidence, temporal trends and potential risk factors. Thromb Res. 2020;189:13-23. doi:10.1016/j.thromres.2020.02.018
11. Kimball AS, Obi AT, Diaz JA, Henke PK. The Emerging Role of NETs in Venous Thrombosis and Immunothrombosis. Front Immunol. 2016;7:236. doi:10.3389/fimmu.2016.00236
12. Frasson S, Gussoni G, Di Micco P, et al. Infection as cause of immobility and occurrence of venous thromboembolism: analysis of 1635 medical cases from the RIETE registry. J Thromb Thrombolysis. 2016;41(3):404-412. doi:10.1007/s11239-015-1242-2
13. Dalager-Pedersen M, Søgaard M, Schønheyder HC, Thomsen RW, Baron JA, Nielsen H. Venous thromboembolism after community-acquired bacteraemia: a 20-year danish cohort study. PloS One. 2014;9(1):e86094. doi:10.1371/journal.pone.0086094
14. Mejer N, Westh H, Schønheyder HC, et al. Increased risk of venous thromboembolism within the first year after Staphylococcus aureus bacteraemia: a nationwide observational matched cohort study. J Intern Med. 2014;275(4):387-397. doi:10.1111/joim.12147
15. Wilson Dib R, Chaftari A-M, Hachem RY, Yuan Y, Dandachi D, Raad II. Catheter-Related Staphylococcus aureus Bacteremia and Septic Thrombosis: The Role of Anticoagulation Therapy and Duration of Intravenous Antibiotic Therapy. Open Forum Infect Dis. 2018;5(10):ofy249. doi:10.1093/ofid/ofy249
16. Kaplan D, Casper TC, Elliott CG, et al. VTE Incidence and Risk Factors in Patients With Severe Sepsis and Septic Shock. Chest. 2015;148(5):1224-1230. doi:10.1378/chest.15-0287
17. Lin T-Y, Chen Y-G, Huang W-Y, et al. Association between chronic osteomyelitis and deep-vein thrombosis. Analysis of a nationwide population-based registry. Thromb Haemost. 2014;112(3):573-579. doi:10.1160/TH14-01-0012
18. Keller K, Hobohm L, Barco S, et al. Venous thromboembolism in patients hospitalized for hip joint replacement surgery. Thromb Res. 2020;190:1-7. doi:10.1016/j.thromres.2020.03.019
19. Keller K, Hobohm L, Barco S, et al. Venous thromboembolism in patients hospitalized for knee joint replacement surgery. Sci Rep. 2020;10(1):22440. doi:10.1038/s41598-020-79490-w
20. Boddapati V, Fu MC, Mayman DJ, Su EP, Sculco PK, McLawhorn AS. Revision Total Knee Arthroplasty for Periprosthetic Joint Infection Is Associated With Increased Postoperative Morbidity and Mortality Relative to Noninfectious Revisions. J Arthroplasty. 2018;33(2):521-526. doi:10.1016/j.arth.2017.09.021
21. Courtney PM, Boniello AJ, Levine BR, Sheth NP, Paprosky WG. Are Revision Hip Arthroplasty Patients at Higher Risk for Venous Thromboembolic Events Than Primary Hip Arthroplasty Patients? J Arthroplasty. 2017;32(12):3752-3756. doi:10.1016/j.arth.2017.07.028
22. Dai W-L, Lin Z-M, Shi Z-J, Wang J. Outcomes following Revision Total Knee Arthroplasty Septic versus Aseptic Failure: A National Propensity-Score-Matched Comparison. J Knee Surg. 2021;34(11):1227-1236. doi:10.1055/s-0040-1702187
23. Boylan MR, Perfetti DC, Kapadia BH, Delanois RE, Paulino CB, Mont MA. Venous Thromboembolic Disease in Revision vs Primary Total Knee Arthroplasty. J Arthroplasty. 2017;32(6):1996-1999. doi:10.1016/j.arth.2016.12.051
24. Georgopoulos G, Hotchkiss MS, McNair B, Siparsky G, Carry PM, Miller NH. Incidence of Deep Vein Thrombosis and Pulmonary Embolism in the Elective Pediatric Orthopaedic Patient. J Pediatr Orthop. 2016;36(1):101-109. doi:10.1097/BPO.0000000000000391