Preventing Thromboembolism in Total Knee Arthroplasty

Venus Vakhshori, MD

Mary Kate Erdman, MD

Jay R. Lieberman, MD

Total knee arthroplasty (TKA) is effective in relieving pain, increasing mobility, and improving quality of life for patients. Despite the overall success of this procedure, patients undergoing TKA are at risk for developing symptomatic venous thromboembolic disease. Since total joint arthroplasty is usually an elective procedure performed in relatively healthy individuals, pulmonary embolism (PE) may be a devastating complication. In some cases, the first manifestation of venous thromboembolic disease may be a symptomatic or fatal PE. Therefore, selection of an effective method of prophylaxis is an essential part of the care of patients undergoing arthroplasty.¹ Despite the completion of a number of well-designed clinical trials that have assessed the efficacy and safety of a variety of modalities for prophylaxis, the ideal method of prophylaxis is still to be determined. The selection of a prophylactic regimen is influenced not only by its ability to prevent symptomatic venous thromboembolism (VTE) without causing bleeding complications, but also by decreased duration of hospital stay.¹

TKA differs from total hip arthroplasty (THA) with regard to VTE in a number of critical elements. First, the overall deep vein thrombosis (DVT) rate is higher in patients undergoing TKA than in those undergoing THA without prophylaxis.¹,²,³ This may be secondary to the routine use of a tourniquet and intraoperative flexion of the knee.⁴ Second, it is more difficult to suppress venous thrombus formation in patients undergoing TKA than in those undergoing THA despite the use of the same prophylactic regimens.⁵,⁶,⁷ Finally, a postoperative hematoma is more likely to require reoperation in a TKA patient than in a THA patient, making this bleeding complication more costly in the setting of TKA.¹,⁸,⁹ In this chapter, we review the available data on VTE prophylaxis after TKA.

PATHOGENESIS

The triad of venous stasis, hypercoagulability, and endothelial injury is associated with thrombus formation and is present in the perioperative period in patients undergoing TKA.¹⁰,¹¹ Histologically, thrombi originate near a region of reduced venous flow. They are composed of alternating “red” layers, composed of fibrin and red blood cells, which have been implicated in thrombus origination, and “white” layers, composed of platelets and neutrophils, which play a major role in thrombus propagation.¹¹,¹²,¹³ Venous stasis often occurs in these patients as a result of the use of a tourniquet on the thigh, persistent knee flexion, and reduced postoperative mobility.¹,⁸,⁹,¹⁴ After tourniquet deflation, there are increased levels of thrombosis markers, including prothrombin fragment 1.2, plasmin/alpha2-antiplasmin complex, D-dimer, fibrinopeptide A, and thrombin-antithrombin complexes.¹⁵,¹⁶,¹⁷ The trauma of the procedure itself can result in a sustained activation of tissue factor and other clotting factors, which then localizes at the sites of vascular injury and areas of venous stasis.¹¹,¹⁸,¹⁹ These changes are evident as early as 4 hours after surgery, suggesting that venous thrombosis occurs intraoperatively or in the immediate postoperative period, and may benefit from early prophylaxis.¹⁵,¹⁶,¹⁷ In addition, postoperative reduction in antithrombin III levels and inhibition of the endogenous fibrinolytic system may allow for continued thrombus growth (Fig. 50-1).¹,¹¹,¹⁴,²⁰,²¹

EPIDEMIOLOGY

The literature demonstrates that without prophylaxis, the prevalence of asymptomatic, venographically verified postoperative DVT is 40% to 80% and 0.3% to 3.0% for PE following TKA.¹,⁸,⁹,²² Factors associated with the development of VTE include prior VTE, prolonged immobilization, varicose veins, obesity, advanced age, and cardiac dysfunction (Table 50-1).¹¹,²³,²⁴ Even in the absence of these risk factors, however, all patients undergoing a TKA are at increased risk for development of DVT or PE.⁹,¹⁴,²⁵ A majority of venographically documented DVT occurs within 24 hours after surgery.²⁶ Proximal venous thrombi, even those that are nonocclusive and asymptomatic, show an association with proximal DVT extension and symptomatic or fatal PE.¹⁴,²⁷,²⁸ In contrast, most distal thrombi, found in veins located below the knee, are small, clinically insignificant, and usually do not require treatment with therapeutic anticoagulation.²⁹,³⁰,³¹ Thrombosis of the veins in the calf is generally an asymptomatic, self-limiting process that spontaneously resolves, but in some cases there will be proximal clot propagation. There is low risk of development of chronic venous insufficiency.²⁹,³⁰ However, complications of a distal thrombus may occur more frequently in patients who have had a total joint arthroplasty.¹⁴,²⁸,³² Using duplex ultrasonography to
screen patients who had arthroplasty, Oishi et al found that within 2 weeks after surgery, 17% of patients with a distal DVT had proximal propagation of their thrombus.²⁸ Due to the high risk of DVT and the risk of fatality in the case of pulmonary embolism, postoperative VTE prophylaxis is essential in limiting thrombus formation and preventing propagation and embolism.

FIGURE 50-1 Coagulation pathways. Both the contact activation (intrinsic) and tissue factor activation (extrinsic) pathways converge, which leads to activation of factor X and the subsequent formation of thrombin. The prothrombin time (PT) measures the function of the extrinsic and common pathways. The partial thromboplastin time (PTT) measures the function of the intrinsic and common pathways.

TABLE 50-1 Risk Factors for Venous Thromboembolic Disease

Clinical risk factors	Prior venous thromboembolic disease Paralysis or prolonged immobility Obesity Advanced age
	Fractures of the pelvis, hip, femur, or tibia
	Varicose veins
	Surgery involving the abdomen, pelvis, lower extremities
	Congestive heart failure
	Myocardial infarction Diabetes mellitus
	Stroke Smoking
Hemostatic abnormalities	Antithrombin III deficiency
	Protein C deficiency
	Protein S deficiency
	Dysfibrinogenemia
	Presence of lupus anticoagulant and antiphospholipid antibodies
	Myeloproliferative disorders
	Heparin-induced thrombocytopenia
	Disorders of plasminogen and plasminogen activation

RISK STRATIFICATION

Providing effective VTE prophylaxis while reducing the risk of bleeding events in elective total joint arthroplasty patients has triggered significant interest in risk stratification paradigms. Despite potent anticoagulants, early-mobilization protocols, and advancements in regional anesthesia, the rate of symptomatic PE following TKA has held constant over time.³³ Cote et al performed a systematic review including 18 multicenter prospective randomized controlled trials assessing the efficacy of VTE prophylaxis regimens after elective TKA. In an analysis of pooled data comparing rates of symptomatic PE in studies published before 2006 versus studies published in 2006 or later, the estimated rate of symptomatic PE increased by 0.0006% (P > .999) despite all the advances associated with TKA during that time period.³³ These results suggest that a cohort of patients possess nonmodifiable risk factors, and PE after TKA is not a “never event” even with the most potent prophylaxis regimen. Accurate assessment of a TKA patient’s risk profile and tailoring of their postoperative VTE prophylaxis regimen accordingly defines the principle of risk stratification, a critical concept in the future of arthroplasty.

There have been multiple attempts to identify TJA patients with higher risk profiles for VTE events; however, no validated risk assessment tool currently exists.³⁴,³⁵,³⁶,³⁷ Bohl et al utilized the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database to identify independent risk factors in elective TJA patients for the development of symptomatic PE; these risk factors were subsequently assigned a point value which helped define thresholds between low-, medium-, and high-risk patients.³⁷ This was validated against a single-center registry of TJA patients. The patients thought to be at increased risk for VTE were older than 70 years, female, obese, and undergoing a TKA. There are notable limitations to this instrument: the NSQIP database does not contain data on personal history of symptomatic VTE and there are no specific recommendations for prophylaxis for low-, medium-, and high-risk patients. Despite these limits, it does equip the provider with a means by which to stratify a patient’s risk for developing symptomatic PE in the postoperative setting. In the absence of robust, validated risk stratification instruments that provide recommendations for specific VTE prophylaxis regimens, a safe and effective plan must be made through shared decision making between the patient and physician.

TABLE 50-2 Summary of AAOS Guidelines Regarding Venous Thromboembolism (VTE) Prevention³⁸,³⁹,⁴⁰

American Academy of Orthopaedic Surgeons (AAOS) 2011 Guidelines for Preventing Venous Thromboembolism Before Elective Hip or Knee Arthroplasty³⁸,³⁹
Recommendation	Grade
1.	Recommend against the use of routine postoperative duplex ultrasonography screening of patients who undergo elective hip or knee arthroplasty	Strong
2.	Recommend assessment of the risk of VTE by determining whether these patients had a previous VTE	Weak
3.	Cannot recommend for or against routinely assessing patients for risk factors other than a history of previous thromboembolism	Inconclusive
4.	Recommend assessment for known bleeding disorders like hemophilia and the presence of active liver disease which increase risk for bleeding and bleeding-associated complications	Consensus
5.	Cannot recommend for or against routinely assessing patients for risk factors for bleeding and bleeding-associated complications other than a known bleeding disorder or active liver disease	Inconclusive
6.	Recommend discontinuation antiplatelet agents (e.g., aspirin, clopidogrel) before undergoing elective hip or knee arthroplasty	Moderate
7.	Recommend the use of pharmacologic agents and/or mechanical compressive devices for the prevention of VTE in patients undergoing elective hip or knee arthroplasty, and who are not at elevated risk beyond that of the surgery itself for VTE or bleeding	Moderate
8.	Cannot recommend for or against specific prophylactic options	Inconclusive
9.	Recommend patients and physicians discuss the duration of prophylaxis	Consensus
10.	Recommend pharmacologic prophylaxis and mechanical compressive devices in patients undergoing elective hip or knee arthroplasty and who have also had a previous VTE	Consensus
11.	Recommend mechanical compressive devices in patients undergoing elective hip or knee arthroplasty and who also have a known bleeding disorder and/or active liver disease	Consensus
12.	Recommend early mobilization for patients following elective hip and knee arthroplasty	Consensus
13.	Recommend neuraxial anesthesia for patients undergoing hip and knee arthroplasty to help limit blood loss	Moderate
14.	Cannot recommend for or against use of inferior vena cava filters to prevent PE in patients undergoing elective hip and knee arthroplasty who also have a contraindication to chemoprophylaxis and/or known residual venous thromboembolic disease	Inconclusive
Readers are strongly encouraged to consult the full guidelines and evidence report for this information and create individualized treatment decisions for each patient.

VTE PROPHYLAXIS AFTER TKA

A variety of pharmacologic and mechanical approaches have been used to decrease the risk of VTE after TKA. Pharmacologic options include aspirin, vitamin K antagonists, unfractionated heparin, low-molecular-weight heparin (LMWH), fondaparinux, direct factor Xa inhibitors, and dabigatran. Mechanical approaches have included early mobilization, use of graded compression stockings, and use of sequential intermittent pneumatic compression boots. The most recent American Academy of Orthopaedic Surgeons (AAOS) clinical practice guidelines for VTE prevention were released in 2011.³⁸,³⁹,⁴⁰ This update to the 2007 guidelines included a more comprehensive statistical analysis and increased granularity in the grading schema (Table 50-2). Ultimately, however, no specific prophylactic regimen was
able to be recommended at that time given the available evidence. Partly in response to criticism from the orthopedic community, the American College of Chest Physicians (ACCP) published guidelines in 2012 focused on the reduction of symptomatic VTE events.⁴¹ Although the ACCP guidelines favored LMWH for its safety and efficacy profile, a wide variety of pharmacologic agents and home compression devices were considered reasonable alternatives in TJA patients compared to no prophylaxis at all (Table 50-3).

TABLE 50-3 Summary of ACCP Guidelines Regarding Venous Thromboembolism Prevention⁴¹

American College of Chest Physicians (ACCP) 2012 Guidelines for Prevention of Venous Thromboembolism in Orthopaedic Surgery Patients⁴¹
Recommendation	Grade
In patients undergoing THA or TKA, one of the following agents should be used for a minimum of 10-14 days, rather than providing no antithrombotic prophylaxis.
Low-molecular-weight heparin (LMWH)	1B
Fondaparinux	1B
Apixaban	1B
Dabigatran	1B
Rivaroxaban	1B
Low-dose unfractionated heparin	1B
Adjusted-dose vitamin K antagonist	1B
Aspirin	1B
Intermittent pneumatic compression device (IPCD)	1C
In patients undergoing THA or TKA, regardless of IPCD use or the length of treatment, LMWH should be used in preference to other alternative agents	2B
In patients undergoing major orthopedic surgery, thromboprophylaxis should be extended in the outpatient period for up to 35 d from the day of surgery rather than for only 10-14 d.	2B
THA, total hip arthroplasty; TKA, total knee arthroplasty. Readers are strongly encouraged to consult the full guidelines and evidence report for this information and create individualized treatment decisions for each patient. (1B = strong recommendation, moderate-quality evidence. 1C = strong recommendation, low-quality evidence. 2B = weak recommendation, moderate-quality evidence.)

Aspirin

The use of aspirin for thromboprophylaxis after TKA has been increasing.⁴² Aspirin irreversibly inactivates cyclooxygenase (COX)-1, inhibits prostaglandin H₂ formation, inhibits platelets, and acetylates coagulation proteins including fibrinogen, promoting fibrinolysis.⁴³ Platelet inactivation by aspirin subsequently inhibits the release of multiple factors involved in venous thrombosis, including fibrinogen, thrombospondin, and von Willebrand factor, and prevents thrombin formation catalyzed by the calcium ion-dependent complex of tissue factor and activated factor VII.⁴³

The Pulmonary Embolism Prevention (PEP) trial assessed 4088 patients undergoing hip and knee arthroplasty (including 1440 TKA patients) and 13,356 patients undergoing hip fracture surgery, randomized to either 160 mg of aspirin daily or placebo. In hip fracture patients, symptomatic VTE events were reduced by 36%. However, no statistically significant differences were seen in the arthroplasty group.⁴⁴ The rate of symptomatic DVT in the arthroplasty group given aspirin was 0.73%, compared to 0.93% in the placebo group. The rate of PE was 0.43% in patients receiving aspirin, and 0.49% in those receiving placebo.⁴⁴ There was no difference in bleeding rates as defined by evacuation of a hematoma (0.4% with aspirin vs. 0.4% with placebo).⁴⁴ There were statistical limitations to this study including that 24% of patients randomized to the aspirin group received aspirin or another nonsteroidal anti-inflammatory drug (NSAID) within the 48 hours prior to randomization.

In a large registry study evaluating 41,537 patients undergoing TKA receiving no chemo-thromboprophylaxis, aspirin only, anticoagulant only (LMWH, warfarin, or factor Xa inhibitors), or both aspirin and anticoagulant, aspirin was found to be noninferior to other anticoagulants in terms of VTE (no chemo-thromboprophylaxis = 4.79%, aspirin only = 1.16%, anticoagulant only = 1.42%, aspirin and anticoagulant = 1.31%) and bleeding events (no chemothromboprophylaxis = 1.50%, aspirin only = 0.90%, anticoagulant only = 1.14%, aspirin and anticoagulant = 1.35%).⁴⁵ In a prospective, cross-over study, 4651 TJA patients received either 325 mg or 81 mg of aspirin twice daily with a subsequent switch to the alternative dosing regimen during their therapy course. Preliminary analysis showed no statistical difference in VTE rates between lower-and higher-dose groups (0.1% vs. 0.3%, respectively). There was a slightly lower, but not statistically significant, difference, in rates of gastrointestinal bleeding or ulceration between lower- and higher-dose groups (0.3% vs. 0.4%, respectively).⁴⁶ This study provides support for the use of lower-dose aspirin in patients without significant risk factors for the development of postoperative VTE.

A recent multicenter, double-blind, randomized, controlled trial was conducted with TKA and THA patients to determine if extended prophylaxis with aspirin was safe and effective. All patients received 5 days of once-daily 10 mg of rivaroxaban. The patients were then randomized to either an additional 9 days (for TKA patients) of oncedaily 10 mg of rivaroxaban or a control group that received once-daily 81 mg of aspirin. In the TKA patients, there was no difference in the rate of VTE (0.86% with rivaroxaban vs. 0.87% with aspirin; P = 1.00). There was also no difference in major bleeding in the TKA patients (0.25% with rivaroxaban vs. 0.62% with aspirin; P = .29).² Other trials have shown similarly low rates of VTE and bleeding with aspirin, especially when used in conjunction with early ambulation and pneumatic compression boots.⁴⁷,⁴⁸,⁴⁹,⁵⁰,⁵¹,⁵²,⁵³,⁵⁴

Aspirin has multiple advantages, including its oral administration, no requirement for monitoring, low cost, lower
bleeding risk, and high patient compliance.⁴⁷,⁴⁸,⁴⁹,⁵⁰,⁵¹,⁵²,⁵³,⁵⁴,⁵⁵ Long-term high-dose aspirin use may lead to epigastric pain, heartburn, nausea, or gastrointestinal bleeding.⁵⁶ The major limitation with determining the true efficacy of aspirin is the need for data from multicenter, randomized trials comparing the efficacy and safety of aspirin versus the new, more potent anticoagulant agents (e.g., rivaroxaban, dabigatran, or apixaban).

Vitamin K Antagonists

Warfarin, a potent anticoagulant, has a long track record in preventing VTE after TKA. It functions by blocking the transformation of vitamin K in the liver, and thereby inhibiting production of vitamin K-dependent clotting factors II, VII, IX, and X (Fig. 50-1).⁵⁷ The rate of symptomatic PE with the use of warfarin prophylaxis is between 0.31% and 0.9%.⁵⁸ Multiple randomized trials comparing warfarin to LMWH have shown that while LMWH was more effective in limiting asymptomatic thrombi and overall DVT formation, there was no difference in rates of post discharge symptomatic events, including PE. Higher rates of bleeding were seen with the use of LMWH.⁵,⁵⁹,⁶⁰,⁶¹,⁶²,⁶³,⁶⁴,⁶⁵

The major advantages of warfarin prophylaxis include a proven track record, oral administration, low cost, and adjustable dosing. The magnitude of anticoagulation can be titrated for each patient based on the international normalized ratio (INR). A target INR of 2.0 (range 1.8-2.5) provides effective prophylaxis and limits bleeding complications. Disadvantages of warfarin use include frequent laboratory monitoring of the INR, interaction with many other medications and foods complicating the ability to maintain a therapeutic level, and the delayed onset of its anticoagulant effect which may leave a patient vulnerable to VTE.¹,⁸,⁵⁷,⁶⁶ Despite close monitoring, patients receiving warfarin for chemical thromboprophylaxis are within their targeted INR range for approximately half the duration of their treatment course.⁶⁷ Additionally, there is a 0.4% to 5% incidence of major bleeding.¹,⁵,⁸,⁵⁹,⁶⁰,⁶³,⁶⁴,⁶⁵,⁶⁸ If the INR needs to be returned to normal, such as in the case of life-threatening bleeding, prothrombin complex concentrates, fresh frozen plasma, or intravenous or oral vitamin K may be required.⁶⁹ Warfarin reversal via transfusion can quickly reverse the anticoagulation properties of warfarin, but it is also associated with immunologic reactions, infection, and transfusion related injuries.⁷⁰

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