Coagulation and Blood Management

Alexander R. Orem, MD, MS

David S. Jevsevar, MD, MBA

Dr. Jevsevar or an immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of MedScape; has received research or institutional support from DePuy, A Johnson & Johnson Company; and serves as a board member, owner, officer, or committee member of the American Association of Hip and Knee Surgeons. Neither Dr. Orem nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter.

ABSTRACT

The prevention of venous thromboembolic disease is a challenge faced by virtually all orthopaedic surgeons. There is a wide spectrum of strategies for mechanical prophylaxis as well as chemical prophylactic agents available for use with varying levels of efficacy and risk of complication. In addition, achieving the goal of decreasing perioperative blood loss and minimizing the risk of allogeneic blood transfusion after many common orthopaedic procedures has been helped significantly by the use of tranexamic acid, but many questions continue to be investigated regarding its safety and most effective routes of administration. Multimodal approaches to decreasing the risk of perioperative venous thromboembolism and reducing the rate of allogeneic blood transfusions after orthopaedic procedures appear to be the most effective.

Keywords: allogeneic blood transfusion; anticoagulation; safety; tranexamic acid; venous thromboembolic disease

Introduction

Every orthopaedic surgeon will experience the related challenges of trying to prevent venous thromboembolic disease while simultaneously working to minimize perioperative blood loss and the risk of allogeneic blood transfusion. It is imperative that surgeons are aware of the most recent guidelines, recommendations, and research that can inform decisions to manage these conditions. To prevent venous thromboembolism (VTE), there are many mechanical and chemical strategies available with risks and benefits to each. For blood management, the use of tranexamic acid (TXA) has become the predominant strategy to minimize blood loss and decrease risk of blood transfusion after joint replacement surgery. Research continues to establish the most effective indications for TXA as well as to determine the appropriate safety guidelines for its use. In general, effective perioperative management of the risk of excess coagulation or bleeding requires a multimodal approach and careful examination of patient and surgical factors.

Anticoagulation

Venous thromboembolism (VTE) is a spectrum of conditions ranging from asymptomatic deep vein thrombosis (DVT) to fatal pulmonary embolism (PE) that is a potential postoperative complication for most surgical procedures including orthopaedic surgeries. Orthopaedic surgeons should be aware of the surgical and patient-specific factors that contribute to VTE. Assessing these individual risk factors for VTE and weighing them against the possible risks associated with anticoagulation afford the orthopaedic surgeon a paradigm to effectively integrate the current mechanical and pharmacological treatments along with numerous published evidence-based clinical practice guidelines (CPGs) and utilize that information in limiting the risk of VTE in orthopaedic patient care.

Risk of Venous Thromboembolism

The historical rates of nonprophylaxis patients with postoperative (or nonsurgical) VTE are variable within orthopaedic surgery but have been reported as high as 65% to 80% in high-risk populations, with 2% to 7% incidence of fatal PE.¹ While much of the initial research
on VTE in orthopaedics was related to hip and knee surgery, VTE has been reported in most orthopaedic specialty patients. Pediatric orthopaedic patient risk for VTE is lower (0.058%) than adults, but at-risk patients should be assessed for VTE prophylaxis requirements. As the practice of orthopaedic surgery has moved in the direction of more ambulatory (outpatient) procedures, VTE risk assessment could have considerable impact on choice and duration of care for patients with higher risk profiles.

VTE prophylaxis is available in several forms ranging from mechanical prophylaxis using various compression devices to pharmacological prophylaxis including intravenous (IV) or subcutaneous heparin formulations and oral agents including aspirin (acetylsalicylic acid, ASA), warfarin, factor IIa direct thrombin inhibitors (dabigatran), and factor Xa inhibitors (low-molecular-weight heparins [LMWHs], fondaparinux, apixaban, and rivaroxaban). Familiarity with the mechanism of action of each modality, the potential risks of that modality for a specific patient and procedure, and the existing guideline recommendations are helpful in prescribing appropriate care.

Types of Venous Thromboembolism Prophylaxis

Mechanical

Mechanical VTE prophylaxis is used in many surgical specialties as the sole prophylactic treatment and has evidence for efficacy in orthopaedic spine procedures where the risks of bleeding associated with pharmacological therapy outweigh the benefits. Intermittent pneumatic compression (IPC) is a common form of DVT prophylaxis, and the antithrombotic effect of IPC is thought to be the result of increased venous velocity and stimulation of endogenous fibrinolysis. The American College of Chest Physicians (ACCP) guidelines recommend using battery-powered (portable) IPC devices because of greater patient acceptance and compliance.² The Surgical Care Improvement Project (SCIP) recommends use of either IPC or venous foot pumps. Compliance to the prescribed treatment protocol is of concern in the ambulatory setting. IPC can also be challenging to use in many orthopaedic conditions, where fracture, open wounds, and external fixators can limit applicability. Mechanical prophylaxis is routinely used intraoperatively where possible, and also commonly as an adjunct VTE prophylactic measure with other pharmacological therapies.

The rate of VTE in spine surgery has been reported between 0.3% and 31% and mechanical prophylaxis has been used as an isolated treatment in spine surgery.³ The evidence base supporting this practice is limited, and further research into appropriate VTE prophylaxis in this population is warranted. VTE rates in shoulder surgery are not as well delineated, with smaller studies reporting incidences of PE of 0.6% to 3%.⁴ Most authors recommend the use of mechanical VTE devices with pharmacological therapy based on patient risk factors.

Pharmacological

Aspirin

Aspirin inhibits the aggregation of newly produced platelets irreversibly and minimizes the risk of thrombosis via its inhibitory effect on cyclooxygenase (COX)-1. The antiplatelet effect of ASA lasts for the 7-to 10-day life of the platelets. The use of ASA has increased since its inclusion in the 2012 ACCP VTE Guidelines. It is attractive because of its efficacy, low cost, relative ease of use, lack of laboratory monitoring, and patient acceptance. Studies report using ASA in combination with other therapies, including mechanical prophylaxis. The additive effect of ASA plus mechanical prophylaxis has not been proven.⁵ ASA has also been used post discharge in combination with LMWH with noninferior effect on VTE and a lower bleeding risk.⁶ ASA has a documented lower incidence of bleeding complications, which may help to explain the observed decreased rate of periprosthetic joint infection of 0.4% compared with 1.5% with warfarin.⁷

The optimal dosage of ASA is unclear, but orthopaedic surgeons should consider using the minimal dosage of ASA needed to achieve VTE prophylaxis goals. In several trials, 160 mg of ASA has been shown to be an efficacious regimen.⁸ Gastrointestinal bleeding remains a concern with the use of ASA, and a history of gastrointestinal bleeding should be factored into the decision for use by the orthopaedic surgeon.

Warfarin

Warfarin acts as a vitamin K-dependent clotting inhibitor affecting factors II, VII, IX, and X (Figure 1). Warfarin has a long history of clinical use for VTE prophylaxis in arthroplasty patients, and its efficacy and adverse effect profiles are generally understood by the orthopaedic community. It requires individualized patient dosing and close outpatient monitoring with laboratory testing for its duration of use. Because of the longer half-life of warfarin, initially achieving appropriate blood international normalized
ratio (INR) levels can be challenging. Bridging therapy, where LMWH is used to anticoagulate the patient until a therapeutic INR is reached, has been shown to be efficacious for VTE prophylaxis but also with an increased risk for clinically important bleeding episodes.⁹ Maintenance of adequate INR levels can be difficult to accomplish, and the effect of warfarin can be altered by a number of different foods. High INR levels associated with the use of warfarin can lead to life-threatening bleeding, hematoma formation, and wound problems.

Figure 1 Diagram showing the coagulation cascade and pharmacologic targets. Aspirin, an antiplatelet agent, is not shown. (Reproduced with permission from Lieberman JR, Heckmann N: Venous thromboembolic disease prophylaxis after total hip arthroplasty, in Lieberman JR, Berry DJ, eds: Advanced Reconstruction: Hip 2. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2017, pp 379-386.)

Low-Molecular-Weight Heparins and Indirect Factor Xa Inhibitors

LMWHs bind antithrombin (AT) to inactivate factor Xa and prevent the conversion of prothrombin to thrombin, as well as prevent the conversion of fibrinogen to fibrin. Fondaparinux binds and enhances the anti-Xa activity of AT to a much greater extent but does not directly inhibit factor Xa. Both agents are approved by the U.S. FDA for VTE prophylaxis in both hip and knee arthroplasty patients. These agents do not require laboratory test monitoring but are given by subcutaneous injection. Because of the requirement for injection, patient compliance can be adversely affected. A study of trauma patients at a Level 1 Trauma Center showed that patients prefer the use of oral anticoagulants for VTE prophylaxis when indicated.¹⁰ Several randomized controlled trials (RCTs) have compared LMWH with warfarin, finding similar VTE prophylaxis efficacy but increased bleeding risk.¹¹^,¹² RCTs comparing fondaparinux with LMWH found fondaparinux decreased VTE events but with increased risk for major bleeding complications.¹³^,¹⁴

Direct Factor Xa Inhibitors

Apixaban and rivaroxaban are oral anticoagulants that work by directly inhibiting factor Xa. They are approved by the FDA for VTE prophylaxis in hip and knee arthroplasty patients. These anticoagulants also do not require routine laboratory monitoring. Multiple clinical trials have compared apixaban 2.5 mg twice daily with enoxaparin at enoxaparin dosages of 40 mg daily and 30 mg twice daily.¹⁵^,¹⁶ In these studies, apixaban reduced clinically relevant bleeding episodes by 16%. Multiple trials compared rivaroxaban 10 mg daily with enoxaparin dosing of 40 mg daily and one trial, with enoxaparin dosing of 30 mg twice daily.¹⁷^,¹⁸ Rivaroxaban significantly reduced the rate of VTE events by 45% but was also associated with an increase
in clinically relevant bleeds of 27%. The dosing regimen used in most of these studies started these agents at 6 to 8 hours after surgery. Some have advocated for the delayed start of these agents until 18 to 24 hours postoperatively.¹⁹

Direct Thrombin Inhibitors

Dabigatran is a direct thrombin inhibitor, inhibiting both free and fibrin-bound thrombin. Dabigatran is FDA approved for hip arthroplasty only in the United States. Most clinical trials have compared dabigatran dosages of 150 mg or 220 mg daily with enoxaparin 30 mg twice daily, and one trial compared the same dosages of dabigatran with enoxaparin 30 mg twice daily.²⁰^,²¹ At the 150 mg dosage, there was an increase in VTE events of 19% with no difference in bleeding complications. The 220 mg dosage showed no difference in VTE events or bleeding risk.

Figure 2 Illustration demonstrating relative risk (RR) of bleeding versus RR of venous thromboembolism (VTE). The black circle at the origin (1.0, 1.0) shows enoxaparin, the referent therapy. The RR of bleeding, either major or nonmajor clinically relevant bleeding, is represented in the vertical axis and the RR of VTE is represented in the horizontal axis. Each cross shows the 95% confidence intervals of the RR from a meta-analysis. (Reprinted from Venker BT, Ganti BR, Lin H, Lee ED, Nunley RM, Gage BF: Safety and efficacy of new anticoagulants for the prevention of venous thromboembolism after hip and knee arthroplasty: A meta-analysis. J Arthroplasty 2017;32:645-652, Copyright 2017, with permission of Elsevier.)

A recent meta-analysis of the newer oral anticoagulants for VTE prophylaxis graphically compared the relative risk of VTE with the relative risk of bleeding and is a helpful guide to the use of these agents.²² (Figure 2).

Risk Stratification

More recent work on VTE prophylaxis has centered on the concept of risk stratification, specifically identifying those patient populations and patient comorbidities that create increased risk for VTE complications. One study retrospectively reviewed institutional data on more than 25,000 patients who had received either warfarin or ASA.²³ Independent risk factors for VTE in this patient population included total knee arthroplasty, elevated Charlson Comorbidity Index, atrial fibrillation, postoperative DVT, chronic obstructive
pulmonary disease, anemia, depression, and obesity. The authors created a risk nomogram of low-( PE rate 0.35%), medium- (PE rate 1.4%), and high-risk (PE rate of 9.3%) patients, but also found that anticoagulant choice was not predictive of symptomatic PE. Another group used the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database to analyze independent risk factors for symptomatic PE in 72,673 total hip arthroplasty (THA) and 45,800 total knee arthroplasty (TKA) patients.²⁴ Female sex, body mass index (BMI) of 25 to 30 kg/m², BMI ≥ 30 kg/m², age ≥ 70, and TKA were found to be independent risk factors, and the authors developed a risk stratification point system. This risk stratification scoring system was then validated at a single, high-volume institution. The observed symptomatic PE rate in this study was 0.44%, 1.51%, and 2.60% for low-, medium-, and high-risk patients, respectively, according to the scoring system.

Published Guidelines for Venous Thromboembolism Prevention

The publication of the ACCP 2012 Guidelines for Prevention of Venous Thromboembolism in Orthopaedic Surgery Patients provided a significant directional change from their previous guidelines.² In response to concern from the orthopaedic community and the release of the American Academy of Orthopaedic Surgeons 2011 Guidelines for Preventing Venous Thromboembolism Before Elective Hip or Knee Arthroplasty, the ACCP no longer used the screening for asymptomatic VTE events as their outcome of interest.²⁵ The ACCP also weighed the benefits of VTE prophylaxis against the risks of bleeding. With the convergence of guideline recommendations and the Surgical Care Improvement Project’s (SCIP’s) acceptance of ASA as an acceptable prophylaxis treatment, greater harmonization of VTE prophylaxis has occurred. The Orthopaedic Trauma Association recently published consensus recommendations on VTE prophylaxis in orthopaedic trauma patients.²⁶ Research continues into risk stratification and optimal VTE prophylaxis choice, including the Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement (PEPPER) Trial which is an open-label, randomized, parallel assignment trial in 25,000 patients comparing ASA, warfarin (target INR of 2.0), and rivaroxaban. Further study of VTE prevention in orthopaedic patients at risk is necessary.

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