Persistent Effusions and Recurrent Hemarthrosis After Total Knee Arthroplasty
Stuart B. Goodman, MD, PhD, FRCSC, FACS, FBSE, FICORS
Jiri Gallo, MD, PhD
PART 1. PERSISTENT EFFUSIONS AFTER TOTAL KNEE ARTHROPLASTY
Introduction
A patient’s expectation after total knee arthroplasty (TKA) is a knee that is painless and functional in terms of movement, strength, and endurance without signs of inflammation. This section will focus predominantly on patients with an early chronic effusion of unknown etiology after TKA.
Definition
A chronic effusion is defined as occurrence of a significant amount of joint fluid in the TKA after the first 3 months postoperatively. Conversely, a small amount of joint fluid is a normal finding after TKA. Although no data are available, we propose that repeated aspirations for swelling of the TKA indicate that the TKA is not functioning normally and should be further investigated. For the diagnosis of simple recurrent effusion, the aspirated joint fluid should not be bloody (indicative of hemarthrosis). If the data including the appearance/content of joint fluid support the diagnosis of prosthetic-joint infection (PJI), the case is reclassified from chronic effusion to PJI. Similarly, bloody fluid requires a different diagnostic and therapeutic approach (see below).
Epidemiology
There are two peaks in the incidence of chronic effusion post TKA; the first is early postoperatively (usually up to 2 years). The second peak, more common occurrence, is late and begins between the 10th and 20th year postoperatively at which time aseptic loosening or polyethylene wear becomes a concern.
True data for “chronic effusion of unknown etiology,” including the cases with effusion associated with hypersensitivity, are not known, but these are generally rare. The cumulative percent revision of primary TKA at 3 years is between 0.9% and 3.0% depending on age and gender according to the 2018 Annual Report of the Australian Orthopaedic Association National Joint Replacement Registry.1 The incidence of early chronic effusion as a reason of revision is included in this interval. Less than 5% of all the reasons for reoperation of TKA performed between 2006 and 2015 were so-called “other reasons” (meaning other than infection, loosening, wear, fracture, femoropatellar problems, and instability), according to the Swedish Knee Arthroplasty Register Annual Report for 2017.2 According to data from the Czech national registry of TKA, 0.85% of TKAs (period 2015-2018) were reoperated due to chronic effusion of unknown etiology as of October 18, 2018.3
Etiology of Persistent Effusion
An effective and individualized strategy for treatment is based on the correct diagnosis for the chronic effusion. There are multiple etiologies that can lead to a chronic effusion after TKA (Table 60-1). Generally, an increased amount of joint fluid in the TKA is associated with mechanical and/or biological stimuli. Compared to the mechanical causes, the biological etiologies have clear pathogenic mechanisms leading to overproduction of joint fluid.
Biological Reasons
First, PJI must be excluded as the cause of failure. With infection, the pseudosynovial cells are stimulated as part of the host complex response to microbial invasion. A significant amount of fluid can be transported into the joint cavity via alteration of the vessel network in the synovial subintima as part of septic inflammation by the mechanism of “plasma-leakage.”4 Unfortunately, even if the joint fluid is clear and standard diagnostic tests are negative, microorganisms might still be the cause of a chronic joint effusion after TKA.
The process of aseptic loosening can be also accompanied by persistent effusion of the TKA (see Chapter 62). Briefly, prosthetic by-products from implant surfaces due to wear or corrosion interact with cells in the pseudosynovium, triggering an inflammatory response that leads to hyperproduction of joint fluid.5 A chronic effusion
after TKA may predate the clinically evident pathology by months and years, however is very rare early after surgery.
after TKA may predate the clinically evident pathology by months and years, however is very rare early after surgery.
TABLE 60-1 Classification of Chronic Effusions After TKA According to Etiology (Modified by Niki et al23) | ||||||||||||||||
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Hypersensitivity to implant metals and products of corrosion6 is linked to the type IV (delayed) type of immune response mediated by lymphocytes. This could induce chronic inflammation associated with chronic effusion. Surprisingly, there still are relatively few conclusions available for clinical practice despite extensive research.7
In addition, persistent effusion after TKA can be associated with the primary disease that led to TKA surgery, such as an increase in the activity of rheumatoid arthritis. The pathogenic mechanism leading to effusion and joint destruction in rheumatoid arthritis is inflammation due to autoimmune synovitis.8,9,10 Similarly, urate crystals or calcium pyrophosphate dihydrate crystal deposition disease can lead to increased joint fluid after TKA.11 The aspirate is typically cloudy and opaque, and may be colored raising the possibility of PJI.12
Pigmented villonodular synovitis (PVNS) can occur also after primary TKA in either a localized or diffuse form. The true incidence of this association is not known as only case reports have been documented in the literature.13 A proliferative disease of the pseudosynovium could be associated with the inflammatory host response to prosthetic by-products. However, there is a question of the border between “normal” and abnormal proliferation of the pseudosynovium, as all patients who undergo exposure to prosthesis by-products (the difference is only in the amount) exhibit morphological transformation of the pseudosynovium.
Finally, repetitive blood leakage into TKA can induce synovitis and chronic effusion (recurrent hemarthrosis) as is seen in hemophilic diseases.14
Mechanical Reasons
There is a wide range of knee instability that could be associated with pain and persistent effusion after TKA.15 The mechanism by which joint fluid is produced in unstable knees has not been fully elucidated at this time. It is thought to be associated with traumatization of the synovium when it is repetitively stretched during usage of an unstable TKA which may cause repetitive subclinical bleeding into the joint cavity. Also, an excessive and asymmetric wear of polyethylene associated with instability might contribute to overproduction of joint fluid.
The Tissues That Produce the Synovial Fluid After TKA
Histological studies of tissues retrieved from TKA cases describe synovium-like tissue (also called pseudosynovium) covering the inner part of the TKA capsule.16 In a stable, functional, and nonirritated TKA, the pseudosynovial tissue is thin and discrete (Fig. 60-1). On the other hand, pseudosynovium can vary widely in morphology, structure, and size with instability or aseptic loosening (Fig. 60-2).
Surprisingly, this tissue has not been extensively analyzed, compared to what has been accomplished with total hip arthroplasty.5,17,18 This is peculiar as the amount of joint fluid is much higher in TKA than in THA, and the tissue is easily available at the time of surgery. Thus, one must deduce the morphological and functional characteristics of the synovium after TKA from the studies of native knees. Despite that, the biological signals directing the development/homeostasis of the pseudosynovium are different compared to the native or osteoarthritic joint.
A surface layer consisting of pseudosynovial macrophage-like cells (analogous to Type A cells) and fibroblast-like cells (analogous to Type B cells) is on the inner surface of the pseudosynovium (Fig. 60-3). A fibrous tissue layer, whose size and structure depends on the age of the TKA, is located immediately beneath the surface layer and is analogous to the supporting sublining layer in native joint synovium. When a TKA is healthy
and stable, this sublining tissue consists of a thin but relatively well-organized fibrous tissue containing fibroblasts, capillaries, and small arterioles/venules, as well as sympathetic and sensory nerves similar to the native joint. Alternatively, a hypertrophic and proliferative fibrous tissue layer with signs of degradation, including zones of necrosis, is typical for the aseptic loosening (Fig. 60-3).
and stable, this sublining tissue consists of a thin but relatively well-organized fibrous tissue containing fibroblasts, capillaries, and small arterioles/venules, as well as sympathetic and sensory nerves similar to the native joint. Alternatively, a hypertrophic and proliferative fibrous tissue layer with signs of degradation, including zones of necrosis, is typical for the aseptic loosening (Fig. 60-3).
 FIGURE 60-1 A: This shows a pseudosynovial membrane covering the distal femur around a right stable TKA 23 years after the index surgery. B: The polyethylene liner retrieved during the same surgery shows minor wear combined with oxidative degradation of the polyethylene surface. TKA, total knee arthroplasty. |
 FIGURE 60-2 A: This shows hypertrophic changes in the pseudosynovial tissue retrieved from a left TKA with aseptic loosening 18 years after the index surgery. B: The polyethylene liner retrieved during the same surgery shows gross polyethylene damage combining pitting, burnishing, and delamination. TKA, total knee arthroplasty. |
 FIGURE 60-3 A: Histomorphology of a pseudosynovial membrane retrieved during a surgery of a stable TKA without gross polyethylene damage. B: Histomorphology of a pseudosynovial membrane retrieved during a surgery for aseptically loosened TKA. H & E. Scale bar: 200µm. TKA, total knee arthroplasty. |
In response to inflammatory or mechanical signals, an inflammatory macrophage population differentiates from monocytes. These are attracted to the joint by specific chemokines from the pseudosynovial circulatory network. In the case of late effusions, specific pro-inflammatory chemokines are expressed as a part of host response to prosthetic by-products (mainly wear particles).19 Contrary, an early chronic effusion after TKA is poorly understood.
Inflammatory macrophages and other immune cells produce a broad range of pro-inflammatory substances including those stimulating surface pseudosynovial cells to excessive production of joint fluid and/or opening an influx of plasma ultrafiltrate into the joint cavity. Their local counterpart are resident-tissue macrophages that are able to resolve inflammation, restore tissue organization, and maintain the “healthy” native joint.20 However, this regulatory action is insufficient and not fully understood in the case of chronic effusion after TKA.
Clinical Picture
There is no clinical picture specific for “chronic effusion” after TKA. Generally, the knee can be asymptomatic in the early stages. With an increasing amount of fluid, there are subjective symptoms like pain, pressure in the joint, and a feeling of joint fullness during function.
Diagnostic Workup
A systematic approach to diagnosis of an effusion after TKA is important. Evaluation consists of a thorough history and physical examination, laboratory tests (examination of blood, joint fluid, and pseudosynovium), and imaging. Effusions occurring very early suggest infection or instability. Late effusions are often associated with mechanical loosening, residual/late instability, or wear.
TABLE 60-2 List of Methods Contributing to Identification of Persistent Effusion After TKA; Methods Intended for Infection are Excluded | ||||||||||||||||||
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Aspiration of Joint Fluid
Aspiration is the key step for diagnosis. It should be done under strictly aseptic conditions. Generally, joint fluid aspirated from a stable and healthy TKA is not significantly different from that obtained from a native knee joint.21 However, there can be a wide difference among the patients with TKA in terms of cellular and biochemical content.22
JOINT FLUID EXAMINATION
Regardless of the time after the surgery, the critical task of diagnostic workup is to exclude infection/aseptic loosening/instability as a cause of persistent effusion.
If infection is excluded, the following methods could contribute to the etiology of persistent effusion (Table 60-2). Analysis of joint fluid can distinguish between noninfective inflammatory and noninflammatory causes. One study presents a role for a fluorescence-activated cell sorter for phenotypic characteristics of joint fluid cells.23 The authors were able to distinguish between aseptic/septic signals as well as to identify cases of hypersensitivity and effusions associated with an increased activity of rheumatoid arthritis.
New more precise techniques are available for detailed analysis. Flow cytometry allows simultaneous quantification of many surface proteins using fluorescently labeled antibodies. In addition, sophisticated computational techniques are needed to analyze, visualize, integrate, and interpret these datasets.24,25 Single-cell flow and mass cytometry analysis has been developed, allowing examination of tiny amounts of joint fluid.26 In addition, synovial fluid metabolites might help differentiate between low-grade and high-grade inflammatory joint pathologies.27
BIOPSY
Pseudosynovium can be easily and safely obtained by means of the arthroscopic techniques (there are no data supporting fine-needle biopsy in this case). Small parts of tissue are taken with the grasping forceps under direct visual control. Generally accepted rules for tissue sampling in terms of number or place are lacking. Usually, places with hypertrophic pseudosynovium are sampled. After removal, small tissue samples are put in transport containers filled with a fixation solution, usually formalin (10% mixture of water and formaldehyde). Special solutions (e.g., for RNA analysis etc.) are required for immunogenetic examination.
A number of studies evaluated the contribution of histopathological examination in distinguishing between septic and nonseptic causes of TKA failure. In addition, there are protocols proposed for the classification of synovitis28,29 characterizing tissue samples as low- or high-grade synovitis. However, there is no study specific for interpreting biopsies from patients suffering from chronic noninfective effusion after TKA.
IMMUNOLOGICAL TESTS
A plethora of immunological tests analyzing serum/joint fluid/tissue samples have been described.30 These may help identify differences between noninfectious causes of persistent effusion after TKA as the pathophysiology of joint effusion and its chronicity is tightly associated either with immune reaction on the stimuli from prosthetic by-products or the inability to control the immune response to prosthetic by-products. In general, the inflammatory response is coordinated by hundreds of genes, a large number of cells, cytokines and other substances. Currently there is not a single test available that could characterize a particular immune response in toto. Only small parts of the immune response can be detected by a particular test, and we begin to understand what benefits the results of diagnostic immunology might provide using bioinformatics. Levels of inflammatory mediators (cytokines, enzymes, eicosanoids) can be determined in blood synovial fluid samples. Particular functions of neutrophils, lymphocytes can be assessed separately as well as the type of immune response (Th1, Th2, Th17 etc.). There is also diagnostic potential in detection of basophils, eosinophils, macrophages, and other immune cells. Quantification of a particular immune population can be readily accomplished by flow cytometry that has become a standard test in the sorting of leukocyte populations/subpopulations (including their state of differentiation, activation, clonality etc.). Clinical immunophenotyping could open a new avenue for better understanding of the previously homogenous set of non-infected and/or non-rheumatologic joint fluids including those associated with an implant pathology. Importantly, diagnostic rheumatology and immunology can also help differentiate other infection-related diseases like mycobacterial arthritis, Lyme borreliosis or other reactive arthritis. A gene expression signature that occurs as a result of an altered or unaltered immunopathology including persistent production of synovial joint fluid can be determined in the future. Together, these tests should stay in hands of clinical immunologists and rheumatologists.
IMAGING STUDIES
Radiography is important in the diagnostic workup for a TKA complication. Imaging can detect loosening of the implant, gross instability, periprosthetic osteolysis as well as other implant-related pathology.
Detailed evaluation of the bone-implant interface can be assessed on computed tomography using metal reduction reconstruction algorithms, and dual-energy data acquisition combined with postprocessing techniques in order to reduce metal artifacts.31 Magnetic resonance can identify both the periprosthetic bone defects32 and pathology of periprosthetic soft tissues.33 Thickening of pseudosynovium and low-to-intermediate signal intensity similar to skeletal muscle is typical of polyethylene wear-induced synovitis.34 One large retrospective study reported that magnetic resonance imaging can distinguish between pseudosynovium induced by infection, prosthetic by-products, and other stimuli.35 It can also be clinically useful in patients with recurrent hemarthrosis and vascular complications.
Treatment
An algorithmic approach is presented (Fig. 60-4). If there is a suspicion that an infection could be the cause of persistent effusion, one should follow the recent guidelines for the PJI therapy. Generally, modifiable causes should be targeted via reoperation (Table 60-3).
Persistent Effusion of Unknown/Unmodifiable Etiology
There is lack of evidence on the approach to persistent effusion after TKA of unknown etiology. This occurs when the knee (TKA) feels stable, the bone bed is intact, function is acceptable, but the effusion reoccurs.
Considering the pathogenic mechanisms underlying chronic inflammation in periprosthetic pseudosynovium, anti-inflammatory strategies might be used to resolve persistent effusion after TKA. These strategies could direct the functional state of pseudosynovium macrophages and fibroblasts into M2 anti-inflammatory phenotype as well as reduce the number or activity of neutrophils.38 In this way, anti-inflammatory, homeostatic macrophages/fibroblasts as well as resident-tissue cells could resolve the sterile inflammation without surgery. Unfortunately, the majority of these approaches have not been studied in patients after TKA (Table 60-4).
 FIGURE 60-4 Algorithm for approaching persistent noninfective effusion after TKA. AL, aseptic loosening; EBR, external beam radiotherapy; PVNS, pigmented villonodular synovitis; RSO, radiosynoviorthesis; TKA, total knee arthroplasty.
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