10 – Does the development of a hematoma as a result of the administration of VTE prophylaxis increase the risk of subsequent arthrofibrosis?

Julian Maempel, Eustathios Kenanidis, Nikolaos Milonakis, Eleftherios Tsiridis.

Response/Recommendation: There is a lack of robust data to link prophylactic anticoagulation after orthopaedic surgery to hematoma that result in arthrofibrosis.  One retrospective database study demonstrated an increased risk of manipulation under anesthetic/lysis of adhesions after anterior cruciate ligament reconstruction (ACLR) in patients administered prophylaxis with an agent other than aspirin (ASA), as compared to patients receiving no thromboprophylaxis.

Strength of Recommendation: Limited.

Rationale: Venous thromboembolism (VTE) events are widely feared sequelae of orthopaedic surgery, and thromboprophylaxis is widely employed to reduce the incidence of VTE. Joint stiffness is a potentially devastating complication of orthopaedic surgery, and its incidence varies widely depending on the underlying diagnosis, joint involved, or procedure performed1–4. The relationship between hematoma and the risk of arthrofibrosis following an orthopaedic procedure is poorly understood. Studies assessing the incidence of arthrofibrosis are complicated by the lack of a universal definition of arthrofibrosis and by the fact that not all joint stiffness is due to arthrofibrosis5. Haemarthrosis and joint immobilization have been linked to joint stiffness in experimental conditions6, however, little is known about the relationship between haemarthrosis and arthrofibrosis in vivo, with most clinical data in this regard pertaining to bleeding diatheses such as hemophilia, which is a separate area of study7.

Few prospective studies report on the incidence of hematoma or haemarthrosis and compare the use of thromboprophylaxis with placebo or no intervention8,9. Therefore, it is challenging to draw firm conclusions as to whether the administration of thromboprophylaxis increases the risk of these particular adverse events. In addition, the multitude of agents and regimes available across a wide gamut of orthopaedic procedures further complicate the interpretation of results and generalization of the findings of the few studies in this field is impossible.

There is a lack of scientific evidence to support or refute a link between prophylactic anticoagulation and the development of arthrofibrosis secondary to consequent bleeding events.

Venous Thromboembolic Prophylaxis and Haematoma formation

Some authors have linked the use of anticoagulant agents for VTE thromboprophylaxis with hematoma formation10, while others have compared rates of hematoma or bleeding events between patients receiving different chemoprophylactic regimes11–15. The endpoint of hematoma or haemarthrosis may be difficult to objectively and consistently diagnose across studies and any relationship between these and thromboprophylaxis may be conditioned by both the agent used and the procedure undertaken. Therefore, the results of single studies cannot be generalized to other procedures or drugs.

Studies comparing the use of thromboprophylaxis with placebo, or no intervention provide information on the effect of thromboprophylaxis on the risk of hematoma/haemarthrosis formation. One meta-analysis of studies comparing low-molecular-weight heparin (LMWH) to placebo for thromboprophylaxis after total hip arthroplasty (THA) demonstrated a reduction in non-fatal pulmonary embolism (PE) (odds ratio [OR]=0.14, 95% confidence interval [CI] 0.03-0.74, p=0.029) at the expense of increased risk of hematoma formation (7/147 or 4.76% in the LMWH group and 0/149 in the placebo group; p=0.015)10. However, the authors recommended caution in interpreting reported results regarding hematoma formation since these figures were based on only two studies8,9. Kaye et al., randomized 170 low-risk patients undergoing knee arthroscopy to receive either ASA (325 mg once daily for 14 days) or no intervention16. No VTE were recorded and there was one case of arthrofibrosis, but the authors did not state which group this occurred in. Another prospective randomized controlled trial (RCT) evaluated 76 patients undergoing hip fracture surgery to receive or not to receive prophylaxis with fondaparinux17. Curiously, no information was given as to whether the “non-fondaparinux control group” received placebo, no treatment, or alternative anticoagulants. One patient suffered wound necrosis and hematoma and one developed a hematoma, both in the fondaparinux group. No other placebo-controlled studies were identified in the field of orthopaedic joint surgery, and this may relate to the ethical implications of withholding VTE prophylaxis in modern practice.

Other authors have reported the incidence of surgical site hematoma or haemarthrosis using different chemoprophylactic agents.

The RE-NOVATE RCT compared two different doses of dabigatran etexilate (220 mg or 150 mg) with enoxaparin for VTE thromboprophylaxis after THA in 3,494 patients12. Post-procedural hematoma were noted in 1% of higher dose dabigatran patients, 3% of lower dose dabigatran patients, and 2% of enoxaparin patients. There were eight re-operations due to bleeding. The authors concluded that oral dabigatran was as effective as enoxaparin in reducing VTE risk, with a similar safety profile.

Researchers from the RECORD programme pooled the results from four phase III RCT comparing rivaroxaban with enoxaparin for VTE prophylaxis after THA and total knee arthroplasty (TKA)13. The incidence of haemarthrosis and of excessive wound hematoma was similar across the two groups.

An RCT of 900 TKA compared routine anticoagulation (4 weeks of enoxaparin) with risk stratification and selective anticoagulation (with four weeks of ASA 325 mg once daily for lower-risk patients or two weeks of enoxaparin followed by two weeks of ASA for higher-risk patients). The authors reported haemarthrosis in 6 of 706 TKA receiving LMWH and none of the 194 TKA receiving ASA14. Additionally, 8 TKA in the LMWH group developed a subcutaneous hematoma with wound gaping, while none of the ASA cohort did. Patients receiving LMWH were eight times more likely to suffer wound complications (p=0.0005). However, there may have been selection bias since this was a secondary analysis in a study primarily not designed to compare different chemoprophylactic agents.

A retrospective study of 917 patients undergoing hip fracture surgery compared patients receiving mechanical prophylaxis and one of three chemoprophylactic agents (ASA, dextran-40 or enoxaparin)11. No difference in thromboembolic prophylaxis efficacy, hemorrhagic or wound complications was noted; however, use of enoxaparin (3.8%) was associated with a significant increase (p<0.01) in wound hematoma compared with dextran-40 (1.6%) and ASA (2.4%).

Non-comparative studies have quantified the risk of hematoma for some chemoprophylactic agents15,18–20. Lotke et al., reported a 0.3% (9 of 3,042) re-operation rate for hematoma after TKA in patients receiving ASA thromboprophylaxis (325 mg twice daily for six weeks). In addition, eight knees underwent needle aspiration for post-operative effusion or hematoma. A prospective multicenter observational study of 1,009 patients receiving bemiparin thromboprophylaxis after THA or TKA reported that 16.1% (95% CI, 13.8–18.5%) developed surgical wound hematoma/bruising but none required reintervention or prolonged hospitalization. There were 13 surgical site major bleeding cases, of which 3 related to joint haemarthrosis.  The authors combined hematoma with bruising for analysis, so it is not possible to ascertain the true rate of hematoma formation in this study19. Hosaka et al., retrospectively reviewed 935 TKR (454 receiving fondaparinux, and 481 enoxaparin)15 and reported that fondaparinux use resulted in documented knee enlargement (p<0.0005) and subcutaneous knee hematoma (p=0.035) more often than enoxaparin. A retrospective study of 113 patients receiving either enoxaparin or rivaroxaban for VTE prophylaxis after TKA reported no VTE in either group, with one hematoma in the group managed with rivaroxaban and none in the enoxaparin group20. The authors of some case-reports21 and limited case-series22 have attributed post-operative hematoma to the use of prophylactic anticoagulation, however, it is not possible to draw conclusions from these studies.

In summary, there is weak evidence based on a small series of seven cases to suggest that LMWH thromboprophylaxis after THA may be associated with hematoma formation10. Prospective RCT have reported similar efficacy and incidence of hematoma formation for enoxaparin compared to rivaroxiban13 and dabigatran12. Data from secondary analyses in an RCT that was not designed to compare chemoprophylactic agents suggested that ASA may be associated with a lower incidence of wound complications than LMWH after TKA14. Data from a single retrospective study of hip fracture surgery suggests that enoxaparin may be associated with higher rates of wound haematomata than ASA and dextran-4011. One other retrospective study reported a higher incidence of hematoma with fondaparinux thromboprophylaxis as compared to enoxaparin after TKA15.

Arthrofibrosis in the context of thromboprophylaxis or haematomata

In a retrospective case-control study of 2,424 patients undergoing ACLR, Huleatt et al., reported that patients suffering from postoperative hematoma needing evacuation were at (3.55 times) higher risk of manipulation under anesthesia (MUA) and/or lysis of adhesions (LOA) for arthrofibrosis23. Although statistically significant on univariate analysis, this did not remain significant upon regression analysis adjusting for confounding factors. The authors did not discuss the use or otherwise of thromboprophylactic agents in this cohort.

Thirteen patients in a small retrospective series of 56 TKA with post-operative stiffness had been treated for VTE with therapeutic dose LMWH. Three of these had developed haemarthrosis which prevented them from following the usual rehabilitation program24. The authors claimed this provided some evidence that treatment of VTE with LMWH might predispose to arthrofibrosis but did not support this statement with statistical analysis or report how many patients received therapeutic dose LMWH without developing arthrofibrosis or state the incidence of arthrofibrosis with chemoprophylactic anticoagulation.

Two studies correlated the use of specific antithrombotic agents with the risk of developing arthrofibrosis postoperatively.  A retrospective study of 874 TKA reported the risk of developing arthrofibrosis requiring MUA was 9%, being 8% for patients receiving standard LMWH prophylaxis and 26% in those who received therapeutic dose warfarin due to pre-existing thrombophilic tendencies or medical conditions (p<0.0001). Despite finding other potential predictors of arthrofibrosis (e.g., gender), the authors did not undertake regression analysis to account for confounders.

A retrospective insurance database study of 14,081 patients undergoing ACLR identified 191 patients who underwent either MUA or LOA for arthrofibrosis post-operatively25. Only 499 patients (3.5%) received pharmacologic prophylaxis post-operatively. The rate of MUA/LOA was lowest in the group with no thromboprophylaxis (1.3%), followed by those receiving ASA (1.9%) and those prescribed any agent other than ASA (4.3%). Regression analysis confirmed an increased risk of MUA/LOA for arthrofibrosis (2.6 times) following ACLR for those prescribed a thromboprophylactic agent other than ASA, compared with patients who received no thromboprophylaxis (p=0.004). No statistically significant difference was demonstrated between thromboprophylaxis with ASA and either of the other groups.

In summary, one retrospective study of patients undergoing ACLR showed an apparent relationship between postoperative hematoma requiring evacuation and risk of MUA/LOA, but this was not statistically significant after adjusting for confounding factors.  Two relatively small retrospective series have suggested that therapeutic anticoagulation may be associated with an increased risk of knee stiffness after TKR. One large retrospective database study did show a statistically significant relationship between intervention for arthrofibrosis and prophylactic anticoagulation with agents other than ASA, relative to patients receiving no thromboprophylaxis.


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