Ömer Serdar Hakyemez, Ibrahim Azboy.
Response/Recommendation: Given the incidence and severe outcomes of major bleeding events following orthopaedic procedures, there is a definite need for risk stratification prior to surgery. While much attention has been put into the identification of venous thromboembolism (VTE) risk factors and multiple guidelines exist attempting to mitigate this risk, major bleeding events (MBE) are serious complications that received less attention. Unjustifiably, MBE is often examined as a secondary outcome and therefore cohorts are too small to allow adequate statistical power for examining this issue. While current literature cannot support one chemoprophylaxis agent over the other in terms of MBE risk, it is important to consider that any potential benefit in terms of VTE risk reduction should be weighed against a potential increase in bleeding risk.
Strength of Recommendation: Limited.
Rationale: MBE are potential and serious complications following orthopaedic procedures. In a recent systematic review, the rate of clinically important bleeding was 3%, which was much higher compared to VTE event rate1. This raises the question of whether our focus has been too much on VTE at the expense of bleeding complications. MBE have been shown to increase the risk for blood transfusion and have been associated with increased cost, a longer length of stay, allergic reactions, and increased rates of deep venous thrombosis (DVT), surgical site infections, and mortality2,3. Therefore, blood loss prevention strategies including the use of tranexamic acid, spinal anesthesia, early mobilization, same-day discharge, use of compression devices, and transition to aspirin (ASA) for prophylaxis have gained popularity in the last decade and may have a beneficial effect.
Personalized medicine and patient optimization including risk stratification models have gained popularity in recent years and there are currently several VTE stratification strategies available4,5. The work done in the field of VTE has taught us that different patient characteristic, co-morbidities, and genetic factors all play a role in the overall risk for event. As such, risk stratification for MBE may lead to better preoperative workup and optimization as well as induce intraoperative and postoperative modalities to avoid this increased risk. Identifying high-risk patients for MBE is therefore paramount prior to orthopaedic surgery.
To minimize bleeding and prevent VTE adequately, it is important to identify patients that are at high risk for MBE. Some previous studies have shown several significant risk factors for MBE after total joint arthroplasty (TJA). In their study, Prasad et al., suggested that there is a significant perioperative blood loss in males, as well as with increased tourniquet time and surgical time after total knee arthroplasty (TKA)6. Another study by Pugely et al., demonstrated lower blood transfusions rates when spinal anesthesia was compared to general anesthesia in patients undergoing TKA7. Frisch et al., suggested that female gender, age, higher body mass index (BMI), creatinine level, procedure type (TKA compared to total hip arthroplasty [THA]), increased surgical time, intraoperative blood loss, preoperative hemoglobin, and intra-operative fluids may be associated with postoperative blood transfusion rates2. Type of chemoprophylaxis may also play a significant role in MBE risk. In their study, Zufferey et al., found that the risk of MBE with fondaparinux thromboprophylaxis is highest in the first days after the operation. The authors have suggested that male sex, lower BMI and increased duration of drug exposure may increase the risk for major bleeding as well. Since fondaparinux is eliminated through kidneys, in case of moderate renal impairment lowering the dose of the drug may reduce the risk of major bleeding8.
The International Society on Thrombosis and Hemostasis (ISTH) defines major bleeding as blood transfusion ≥2 units within 1 day of surgery9. In the coronary artery disease (CAD) population, the incidence of both thrombotic and bleeding events is higher than in the non-CAD population. In arthroplasty literature, “major bleeding” term contains intracranial bleeding, gastrointestinal bleeding, bleeding that requires ≥2 units of blood transfusion, and hematoma formation which requires reoperation10. Oberweis et al., reported that procedure type (Spinal surgery > THA > TKA), active cancer, female sex, CAD, and chronic obstructive pulmonary disease (COPD) are independent risk factors for MBE11. Previous perioperative bleeding and active cancer are known as risk factors for MBE after surgical procedures 12,13 In a recent study, Tafur et al., found that hypertension is also a risk factor for perioperative bleeding14. In a systematic review performed by Borre et al., in a patient group with 322,010 patients, patients with chronic kidney disease are at increased risk for MBE (moderate strength of evidence)15. An international normalized ratio (INR), age, prior stroke, presence of heart disease, diabetes mellitus, sex, cancer, race/ethnicity, and cognitive impairment are also suggested as risk factors for MBE, however, the evidence was not enough to support these conclusions15.
Numerous anticoagulant drugs are begin used for VTE prophylaxis. However, these drugs especially potent anticoagulants may increase the risk of bleeding16–18 which may result in periprosthetic joint infection (PJI), extended length of hospital stays, and higher costs19,20. The 2011 American Academy of Orthopaedic Surgeons (AAOS) guidelines on VTE prophylaxis recommend that a balance must be obtained to minimize bleeding while providing adequate VTE prevention21. Although the risk of VTE is well defined, the risk factors that may result in MBE in patients undergoing orthopaedic procedures are not well defined. Identifying bleeding risk factors and staying away from potent anticoagulants may help patients from bleeding and transfusion-related complication. Rivaroxaban, a highly selective oral factor Xa inhibitor was found to be effective in preventing VTE and is not highly associated with MBE22. In a study comparing ASA and rivaroxaban in a cohort of 3,424 patients, the rate of MBE was 0.47% in the ASA group and 0.29% in the rivaroxaban group. There was no clinical significance regarding bleeding between these two drugs23. In a pool-analysis of phase III randomized clinical trials (RCT), Nieto et al., compared dabigatran, rivaroxaban, and apixaban (new direct oral anticoagulants [DOAC]) vs. enoxaparin regarding thromboprophylaxis and bleeding complications. MBE rates were similar in patients treated with DOAC (0.8%) compared to those treated with enoxaparin (0.8%). In the same study, the rivaroxaban group was more likely to have increased MBE rates compared to the enoxaparin group. In the other trials apixaban favorably, and equally, dabigatran, were superior to enoxaparin regarding bleeding episodes24. In a study by Vulcano et al., they found the percentage of bleeding, minor bleeding, and MBE as 0.3 %, 0%, and 0.3% respectively for patients who received ASA and 1.6%,0.9%, 0.7% respectively for patients who received warfarin. Although not statistically significant, ASA tends to be safer than warfarin25. In 2017 a systematic review comparing low-molecular-weight heparin (LMWH) with the control group, warfarin, and dabigatran has been performed by Suen et al., the risk for surgical site bleeding episodes was increased in the LMWH group in contrast to the control (warfarin, and dabigatran) group. And this difference was statistically significant in both groups16. Several studies have shown a higher incidence of MBE with warfarin use compared to ASA17–19.
Our search results showed that there are no high-level studies with a primary outcome aimed to define risk factors for bleeding in patients undergoing TJA. Studies on possible risk factors for MBE are retrospective cohorts. Furthermore, these risk factors are mostly reported as secondary outcome values. With the available data, possible risk factors for bleeding after orthopaedic procedures are listed in Table 1.
To summarize, MBE occur at a similar and even increased rate compared to VTE events1,23. There is therefore an urgent need for MBE risk stratification models for patients undergoing orthopaedic procedures. RCT with adequate power are called for the identification of risk factors associated with MBE. Furthermore, developing a risk score calculator for bleeding risk is necessary for better patient optimization, blood loss prophylaxis, and reducing blood transfusion-related complications.
Table 1. Risk factors associated to MBE.
|Surgical procedure type (Spine > THA > TKA)|
|Anesthesia type (General > Spinal)|
|Intraoperative blood loss|
|Increased creatinine level|
|Preoperative hemoglobin level|
|Increased surgical time|
|Increased tourniquet time|
|History of previous bleeding|
MBE=Major bleeding event; THA=Total hip arthroplasty; TKA=Total knee arthroplasty.
1. Chan NC, Siegal D, Lauw MN, et al. A systematic review of contemporary trials of anticoagulants in orthopaedic thromboprophylaxis: suggestions for a radical reappraisal. J Thromb Thrombolysis. 2015;40(2):231-239. doi:10.1007/s11239-014-1153-7
2. Frisch NB, Wessell NM, Charters MA, Yu S, Jeffries JJ, Silverton CD. Predictors and complications of blood transfusion in total hip and knee arthroplasty. J Arthroplasty. 2014;29(9 Suppl):189-192. doi:10.1016/j.arth.2014.03.048
3. Hart A, Khalil JA, Carli A, Huk O, Zukor D, Antoniou J. Blood transfusion in primary total hip and knee arthroplasty. Incidence, risk factors, and thirty-day complication rates. J Bone Joint Surg Am. 2014;96(23):1945-1951. doi:10.2106/JBJS.N.00077
4. 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
5. Azboy I, Barrack R, Thomas AM, Haddad FS, Parvizi J. Aspirin and the prevention of venous thromboembolism following total joint arthroplasty: Commonly asked questions. Bone and Joint Journal. 2017;99B(11):1420-1430. doi:10.1302/0301-620X.99B11.BJJ-2017-0337.R2
6. Prasad N, Padmanabhan V, Mullaji A. Blood loss in total knee arthroplasty: an analysis of risk factors. Int Orthop. 2007;31(1):39-44. doi:10.1007/s00264-006-0096-9
7. Pugely AJ, Martin CT, Gao Y, Mendoza-Lattes S, Callaghan JJ. Differences in short-term complications between spinal and general anesthesia for primary total knee arthroplasty. J Bone Joint Surg Am. 2013;95(3):193-199. doi:10.2106/JBJS.K.01682
8. Zufferey PJ, Ollier E, Delavenne X, Laporte S, Mismetti P, Duffull SB. Incidence and risk factors of major bleeding following major orthopaedic surgery with fondaparinux thromboprophylaxis. A time-to-event analysis. Br J Clin Pharmacol. 2018;84(10):2242-2251. doi:10.1111/bcp.13663
9. Schulman S, Angerås U, Bergqvist D, et al. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost. 2010;8(1):202-204. doi:10.1111/j.1538-7836.2009.03678.x
10. Azboy I, Groff H, Goswami K, Vahedian M, Parvizi J. Low-Dose Aspirin Is Adequate for Venous Thromboembolism Prevention Following Total Joint Arthroplasty: A Systematic Review. J Arthroplasty. 2020;35(3):886-892. doi:10.1016/j.arth.2019.09.043
11. Oberweis BS, Nukala S, Rosenberg A, et al. Thrombotic and bleeding complications after orthopedic surgery. Am Heart J. 2013;165(3):427-433.e1. doi:10.1016/j.ahj.2012.11.005
12. Tafur AJ, McBane R, Wysokinski WE, et al. Predictors of major bleeding in peri-procedural anticoagulation management. J Thromb Haemost. 2012;10(2):261-267. doi:10.1111/j.1538-7836.2011.04572.x
13. Shaw JR, Douketis J, Le Gal G, Carrier M. Periprocedural interruption of anticoagulation in patients with cancer-associated venous thromboembolism: An analysis of thrombotic and bleeding outcomes. J Thromb Haemost. 2019;17(7):1171-1178. doi:10.1111/jth.14468
14. Tafur AJ, Clark NP, Spyropoulos AC, et al. Predictors of Bleeding in the Perioperative Anticoagulant Use for Surgery Evaluation Study. J Am Heart Assoc. 2020;9(19):e017316. doi:10.1161/JAHA.120.017316
15. Borre ED, Goode A, Raitz G, et al. Predicting Thromboembolic and Bleeding Event Risk in Patients with Non-Valvular Atrial Fibrillation: A Systematic Review. Thromb Haemost. 2018;118(12):2171-2187. doi:10.1055/s-0038-1675400
16. Suen K, Westh RN, Churilov L, Hardidge AJ. Low-Molecular-Weight Heparin and the Relative Risk of Surgical Site Bleeding Complications: Results of a Systematic Review and Meta-Analysis of Randomized Controlled Trials of Venous Thromboprophylaxis in Patients After Total Joint Arthroplasty. J Arthroplasty. 2017;32(9):2911-2919.e6. doi:10.1016/j.arth.2017.04.010
17. Gesell MW, González Della Valle A, Bartolomé García S, et al. Safety and efficacy of multimodal thromboprophylaxis following total knee arthroplasty: a comparative study of preferential aspirin vs. routine coumadin chemoprophylaxis. J Arthroplasty. 2013;28(4):575-579. doi:10.1016/j.arth.2012.08.004
18. Nam D, Nunley RM, Johnson SR, Keeney JA, Clohisy JC, Barrack RL. The Effectiveness of a Risk Stratification Protocol for Thromboembolism Prophylaxis After Hip and Knee Arthroplasty. J Arthroplasty. 2016;31(6):1299-1306. doi:10.1016/j.arth.2015.12.007
19. Nam D, Nunley RM, Johnson SR, Keeney JA, Clohisy JC, Barrack RL. Thromboembolism Prophylaxis in Hip Arthroplasty: Routine and High Risk Patients. J Arthroplasty. 2015;30(12):2299-2303. doi:10.1016/j.arth.2015.06.045
20. Kulshrestha V, Kumar S. DVT prophylaxis after TKA: routine anticoagulation vs risk screening approach – a randomized study. J Arthroplasty. 2013;28(10):1868-1873. doi:10.1016/j.arth.2013.05.025
21. Mont MA, Jacobs JJ, Boggio LN, et al. Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Am Acad Orthop Surg. 2011;19(12):768-776. doi:10.5435/00124635-201112000-00007
22. Gomez D, Razmjou H, Donovan A, Bansal VB, Gollish JD, Murnaghan JJ. A Phase IV Study of Thromboembolic and Bleeding Events Following Hip and Knee Arthroplasty Using Oral Factor Xa Inhibitor. J Arthroplasty. 2017;32(3):958-964. doi:10.1016/j.arth.2016.09.021
23. Anderson DR, Dunbar M, Murnaghan J, et al. Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty. N Engl J Med. 2018;378(8):699-707. doi:10.1056/NEJMoa1712746
24. Nieto JA, Espada NG, Merino RG, González TC. Dabigatran, rivaroxaban and apixaban versus enoxaparin for thomboprophylaxis after total knee or hip arthroplasty: pool-analysis of phase III randomized clinical trials. Thromb Res. 2012;130(2):183-191. doi:10.1016/j.thromres.2012.02.011
25. Vulcano E, Gesell M, Esposito A, Ma Y, Memtsoudis SG, Gonzalez Della Valle A. Aspirin for elective hip and knee arthroplasty: a multimodal thromboprophylaxis protocol. Int Orthop. 2012;36(10):1995-2002. doi:10.1007/s00264-012-1588-4