Noam Shohat, Tony Tannoury, Giedrius Kvederas.

Response/Recommendation: The majority of the clinical studies, largely from total joint arthroplasty (TJA) literature, cite an association between allogeneic blood transfusions and venous thromboembolism (VTE) following orthopaedic surgery.  Along with the scientific rationale, these associations are sufficient to urge surgeons to minimize the use of allogeneic blood transfusions in the peri-operative period.

Strength of Recommendation: Limited.

Rationale: While several risk factors for the development of VTE have been established^1,2, others are still widely debated^2,3.  One potentially modifiable risk factor that has gained attention due to its common and unrestricted use is allogeneic blood transfusion^4–6.  Physicians and orthopedic surgeons in particular tend to overprescribe blood transfusions^7–10.  In fact, orthopaedic surgery represents the most common reason for allogeneic blood transfusion in patients undergoing elective procedures, accounting for nearly 10% of all hospital transfused red blood cell units^8,9.

The biological mechanisms substantiating the increased thrombotic risk following blood transfusion have been well described^11,12.  Several attempts were made to assess this relationship in clinical studies.  Registry data has consistently demonstrated an association between blood transfusions and VTE, although all published studies to date have utilized the same National Surgical Quality Improvement Program (NSQIP) database^4,5, rendering them susceptible to inherent limitations^13,14.  Goel et al., analyzed 750,937 patients from this database, of which 153,320 underwent orthopedic surgery.  The results of their subgroup analysis showed an adjusted odds ratio (OR) of 1.7 (95% confidence interval [CI] 1.5-2.0) for developing VTE following blood transfusion⁴.  Acuña et al., utilized the same database and timeframe to examine the association in 333,463 patients undergoing TKA⁵.  While they found an initial association between perioperative blood transfusions and deep vein thrombosis (DVT) (adjusted OR 1.32, 95% CI 1.14-1.53), their propensity score matched analysis failed to confirm this association.  A significant association between perioperative blood transfusions and pulmonary embolism (PE) was also not detected in both regression analysis and propensity score analysis.  Aoude et al.,¹⁵ on the other hand, utilizing the same database to analyze patients undergoing lumbar fusion, showed a significant association between transfusions and DVT as well as PE (OR 2.69 and 3.55, respectively).  However, an association was not found in patients undergoing thoracic fusion, whereas anterior approaches of the lumbar spine led to a significantly higher rate of VTE postoperatively, suggesting that other factors such as location and surgical approach could have influenced VTE risk in spine surgery patients.

Institutional studies have also examined the association between blood transfusion and VTE.  Jiang et al.,¹⁶ studied a relatively small cohort of 715 patients undergoing TJA.  While their sample size was low, a high event rate was observed (8% developed VTE), allowing the authors to demonstrate a statistically significant association between allogeneic blood transfusions and VTE (OR 3.9, 95% CI 1.8-8.4).  These findings contradicted to those published in a large institutional database study recently⁶.  Jackson et al., failed to show a significant association between perioperative blood transfusions and VTE following primary TJA after multivariate analyses as well as a sensitivity analysis using propensity score matching based on a VTE risk calculator (OR, 0.42; 95% CI, 0.12-1.39).  While the study by Jackson et al., evaluated a large number of 29,000 TJA, the event rate was only 1.04% (the number of VTE in the transfused group), possibly rendering the study underpowered to detect an effect size that may be clinically meaningful.  While the purpose was not to specifically assess the relationship between blood transfusions and VTE, Parvizi et al., evaluated multiple potential risk factors for VTE in an attempt to create a risk stratification calculator.  In the cohort of 1’721,806 TJA patients, blood transfusions (prescribed to 21.7% of the patients) were among the top ten most important factors associated with VTE².

Evidence from spine surgery also suggested an association between blood transfusions and an increased risk of VTE^15,17–19.  Johnson et al.,¹⁸ reported a 4.6% rate of thrombotic events in patients who underwent spinal fusion and received allogeneic blood transfusion compared to 1.1% in those who did not receive a transfusion.  This relationship remained significant after adjusting for confounders (95% CI 1.032-1.194, p=0.003).  Wang et al.,¹⁹ evaluated 1,346 patients undergoing spine surgery that were stratified to elective and emergent procedures.  While blood transfusions were significantly associated with a higher risk of DVT following emergent procedures, no significant association was found following elective surgery.

These contradictory results are a testament to the immense difficulty in isolating a single variable association when the event rate is low, and many confounding variables exist.  Possible reasons for the discrepancy among the abovementioned studies could be the difference in time periods.  Changes in the perioperative care including early mobility, more aggressive rehabilitation, same-day discharge, and transition to aspirin as the chemoprophylactic agent of choice may have confounded the results as well.  Other possible confounding factors include the length and complexity of the surgical procedure.  Patients undergoing long and complex procedures are more likely to require blood transfusion.  These patients have longer surgical times, slower recovery, and potentially, more neurological deficits.  These factors have not been isolated and studied separately as possible risk factors.  Future studies should further assess this relationship using granular data, taking into account the many confounders associated with blood transfusions.  While current literature does not clearly show an association between blood transfusions and VTE, the possible association makes it reasonable to recommend a strict approach to minimize blood loss during surgery, reduce surgical time and discourage the liberal use of allogeneic blood transfusions in the perioperative period.

References:

1.         Zhang Z, Shen B, Yang J, Zhou Z, Kang P, Pei F. Risk factors for venous thromboembolism of total hip arthroplasty and total knee arthroplasty: a systematic review of evidences in ten years. BMC Musculoskeletal Disorders. 2015;16(1):24. doi:10.1186/s12891-015-0470-0

2.         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

3.         Porter SB, White LJ, Osagiede O, Robards CB, Spaulding AC. Tranexamic Acid Administration Is Not Associated With an Increase in Complications in High-Risk Patients Undergoing Primary Total Knee or Total Hip Arthroplasty: A Retrospective Case-Control Study of 38,220 Patients. The Journal of Arthroplasty. 2020;35(1):45-51.e3. doi:10.1016/j.arth.2019.08.015

4.         Goel R, Patel EU, Cushing MM, et al. Association of Perioperative Red Blood Cell Transfusions With Venous Thromboembolism in a North American Registry. JAMA Surg. 2018;153(9):826-833. doi:10.1001/jamasurg.2018.1565

5.         Acuña AJ, Grits D, Samuel LT, Emara AK, Kamath AF. Perioperative Blood Transfusions Are Associated with a Higher Incidence of Thromboembolic Events After TKA: An Analysis of 333,463 TKAs. Clin Orthop Relat Res. 2021;479(3):589-600. doi:10.1097/CORR.0000000000001513

6.         Jackson A, Goswami K, Yayac M, et al. Association of Perioperative Red Blood Cell Transfusion With Symptomatic Venous Thromboembolism Following Total Hip and Knee Arthroplasty. J Arthroplasty. 2021;36(1):325-330. doi:10.1016/j.arth.2020.07.027

7.         Browne JA, Adib F, Brown TE, Novicoff WM. Transfusion rates are increasing following total hip arthroplasty: risk factors and outcomes. J Arthroplasty. 2013;28(8 Suppl):34-37. doi:10.1016/j.arth.2013.03.035

8.         Song K, Pan P, Yao Y, Jiang T, Jiang Q. The incidence and risk factors for allogenic blood transfusion in total knee and hip arthroplasty. Journal of Orthopaedic Surgery and Research. 2019;14(1):273. doi:10.1186/s13018-019-1329-0

9.         Frank SM, Savage WJ, Rothschild JA, et al. Variability in blood and blood component utilization as assessed by an anesthesia information management system. Anesthesiology. 2012;117(1):99-106. doi:10.1097/ALN.0b013e318255e550

10.       Soleimanha M, Haghighi M, Mirbolook A, et al. A Survey on Transfusion Status in Orthopedic Surgery at a Trauma Center. Arch Bone Jt Surg. 2016;4(1):70-74.

11.       Red blood cells in thrombosis | Blood | American Society of Hematology. Accessed April 19, 2021. https://ashpublications.org/blood/article/130/16/1795/36469/Red-blood-cells-in-thrombosis

12.       Valles J, Santos MT, Aznar J, et al. Erythrocytes Metabolically Enhance Collagen-Induced Platelet Responsiveness Via Increased Thromboxane Production, Adenosine Diphosphate Release, and Recruitment. Blood. 1991;78(1):154-162. doi:10.1182/blood.V78.1.154.154

13.       Khera R, Angraal S, Couch T, et al. Adherence to Methodological Standards in Research Using the National Inpatient Sample. JAMA. 2017;318(20):2011-2018. doi:10.1001/jama.2017.17653

14.       Teng TL, Menendez ME, Okike K, Cassidy C, Salzler M. Most Orthopaedic Studies Using the National Inpatient Sample Fail to Adhere to Recommended Research Practices: A Systematic Review. Clin Orthop Relat Res. Published online June 9, 2020. doi:10.1097/CORR.0000000000001355

15.       Aoude A, Nooh A, Fortin M, et al. Incidence, Predictors, and Postoperative Complications of Blood Transfusion in Thoracic and Lumbar Fusion Surgery: An Analysis of 13,695 Patients from the American College of Surgeons National Surgical Quality Improvement Program Database. Global Spine J. 2016;6(8):756-764. doi:10.1055/s-0036-1580736

16.       Jiang T, Song K, Yao Y, Pan P, Jiang Q. Perioperative allogenic blood transfusion increases the incidence of postoperative deep vein thrombosis in total knee and hip arthroplasty. J Orthop Surg Res. 2019;14(1):235. doi:10.1186/s13018-019-1270-2

17.       Yang S-D, Ding W-Y, Yang D-L, et al. Prevalence and Risk Factors of Deep Vein Thrombosis in Patients Undergoing Lumbar Interbody Fusion Surgery: A Single-Center Cross-Sectional Study. Medicine (Baltimore). 2015;94(48):e2205. doi:10.1097/MD.0000000000002205

18.       Johnson DJ, Johnson CC, Cohen DB, Wetzler JA, Kebaish KM, Frank SM. Thrombotic and Infectious Morbidity Are Associated with Transfusion in Posterior Spine Fusion. HSS J. 2017;13(2):152-158. doi:10.1007/s11420-017-9545-9

19.       Wang TY, Sakamoto JT, Nayar G, et al. Independent Predictors of 30-Day Perioperative Deep Vein Thrombosis in 1346 Consecutive Patients After Spine Surgery. World Neurosurg. 2015;84(6):1605-1612. doi:10.1016/j.wneu.2015.07.008