Relationship Between Deep Vein Thrombosis and Pulmonary ...

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Instructions 1. Review the stated learning objectives at the beginning of the CME article and determine if these objectives match your individual learning needs. 2. Read the article carefully. Do not neglect the tables and other illustrative materials, as they have been selected to enhance your knowledge and understanding. 3. The following quiz questions have been designed to provide a useful link between the CME article in the issue and your everyday practice. Read each question, choose the correct answer, and record your answer on the CME REGISTRATION FORM at the end of the quiz. 4. Type or print your full name and address and your date of birth in the space provided on the CME Registration Form. 5. Indicate the total time spent on the activity (reading article and completing quiz). Forms and quizzes cannot be processed if this section is incomplete. All participants are required by the accreditation agency to attest to the time spent completing the activity. 6. Complete the Evaluation portion of the CME Registration Form. Forms and quizzes cannot be processed if the Evaluation portion is incomplete. The Evaluation portion of the CME Registration Form will be separated from the quiz upon receipt at ORTHOPEDICS. Your evaluation of this activity will in no way affect the scoring of your quiz. 7. Send the completed form, with your $15 payment (check or money order in US dollars drawn on a US bank, or credit card information) to: ORTHOPEDICS CME Quiz, PO Box 36, Thorofare, NJ 08086, OR take the quiz online. Visit www. ORTHOSuperSite.com for details. 8. Your answers will be graded, and you will be advised whether you have passed or failed. Unanswered questions will be considered incorrect. A score of at least 80% is required to pass. If a passing score is achieved, Vindico Medical Education will issue an AMA PRA Category 1™ certificate within 4-6 weeks. 9. Be sure to mail the CME Registration Form on or before the deadline listed. After that date, the quiz will close. CME Registration Forms received after the date listed will not be processed. CME ACCREDITATION This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Vindico Medical Education and ORTHOPEDICS. Vindico Medical Education is accredited by the ACCME to provide continuing medical education for physicians. Vindico Medical Education designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This CME activity is primarily targeted to orthopedic surgeons, hand surgeons, head and neck surgeons, trauma surgeons, physical medicine specialists, and rheumatologists. There is no specific background requirement for participants taking this activity. FULL DISCLOSURE POLICY In accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial Support, all CME providers are required to disclose to the activity audience the relevant financial relationships of the planners, teachers, and authors involved in the development of CME content. An individual has a relevant financial relationship if he or she has a financial relationship in any amount occurring in the last 12 months with a commercial interest whose products or services are discussed in the CME activity content over which the individual has control. Drs Bosque and Coleman have no relevant financial relationships to disclose. Dr Di Cesare is a consultant for Stryker. Dr Aboulafia, CME Editor, has no relevant financial relationships to disclose. Dr D’Ambrosia, Editor-in-Chief, has no relevant financial relationships to disclose. The staff of ORTHOPEDICS have no relevant financial relationships to disclose. UNLABELED AND INVESTIGATIONAL USAGE The audience is advised that this continuing medical education activity may contain references to unlabeled uses of FDA-approved products or to products not approved by the FDA for use in the United States. The faculty members have been made aware of their obligation to disclose such usage.

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Relationship Between Deep Vein Thrombosis and Pulmonary Embolism Following THA and TKA Jose Bosque Jr, MD; Sheldon I. Coleman, MD; Paul Di Cesare, MD

educational objectives As a result of reading this article, physicians should be able to: 1. Recognize the clinical importance of an acute episode of venous thromboembolism and its potential long-term sequelae. 2. Know where venous thromboembolism is most likely to originate in orthopedic patients and the conditions in which it may become symptomatic. 3. Understand the clinical importance of pulmonary embolism and the conditions that may promote its development in patients undergoing orthopedic surgery. 4. Distinguish between the views of the AAOS and ACCP regarding the relationship between deep vein thrombosis and pulmonary embolism.

Abstract Patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) are at risk for venous thromboembolisms, including deep vein thrombosis and pulmonary embolism. Most deep vein

thromboses are asymptomatic, but they can lead to long-term morbidity to the same extent as symptomatic events. The risk of complications of venous thromboembolisms depends on the location of thrombi; potential long-term compli-

Drs Bosque, Coleman, and Di Cesare are from the Department of Orthopaedic Surgery, UC Davis Medical Center, Sacramento, California. The material presented in any Vindico Medical Education continuing education activity does not necessarily reflect the views and opinions of ORTHOPEDICS or Vindico Medical Education. Neither ORTHOPEDICS nor Vindico Medical Education nor the authors endorse or recommend any techniques, commercial products, or manufacturers. The authors may discuss the use of materials and/or products that have not yet been approved by the US Food and Drug Administration. All readers and continuing education participants should verify all information before treating patients or using any product. Ruth Sussman, PhD, provided editorial support, with funding from Ortho-McNeil Janssen Scientific Affairs, LLC. Address correspondence to: Sheldon I. Coleman, MD, Department of Orthopaedic Surgery, UC Davis Medical Center, 4860 Y St, Ste 3800, Sacramento, CA 95817 ([email protected]). doi: 10.3928/01477447-20120222-12

ORTHOPEDICS | ORTHOSuperSite.com

Deep Vein Thrombosis and Pulmonary Embolism | Bosque et al

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cations include recurrent venous thromboembolism, postthrombotic syndrome, and chronic thromboembolic pulmonary hypertension. Risk of recurrence persists for several years after the initial event. Approximately 20% of recurrent events are pulmonary embolisms, and approximately half of those are fatal. The causal relationship between deep vein thrombosis and pulmonary embolism remains controversial. Some consider them distinct clinical entities, while others have found asymptomatic distal deep vein thrombosis to be associated with elevated risk of developing pulmonary embolism. Unique coagulation factors may be associated with orthopedic surgery patients that differentiate them from patients undergoing other types of surgery. Symptomatic and asymptomatic deep vein thrombosis can lead to the development of recurrent venous thromboembolism, pulmonary embolism, postthrombotic syndrome, and chronic thromboembolic pulmonary hypertension, all of which are associated with reduced quality of life and increased health care expenditures. Thromboprophylaxis is therefore important in patients undergoing THA or TKA. However, traditional anticoagulants are not ideal, particularly for long-term use. Orthopedic surgeons should be aware of the causes and potential sequelae of venous thromboembolism and of the new thromboprophylactic agents that can help prevent it.

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eep vein thrombosis and pulmonary embolism, the 2 manifestations of venous thromboembolism, are major health concerns and are responsible for significant mortality, morbidity, and resource expenditure. Approximately 600,000 Americans suffer from venous thromboembolism each year, and at least 100,000 deaths are directly or indirectly related to this condition.1 Risk factors for venous thromboembolism include surgery, cancer, increasing age, obesity, and acute medical illness.2

MARCH 2012 | Volume 35 • Number 3

Major orthopedic surgeries, especially total hip arthroplasty (THA) and total knee arthroplasty (TKA), are particularly high-risk procedures for venous thromboembolism. In fact, deep vein thrombosis is one of the most common complications after THA or TKA.2 The incidence of clinically asymptomatic, objectively confirmed deep vein thrombosis in patients after THA and TKA was 40% to 60% in those not receiving thromboprophylaxis.2 Combined prevalence rates are reported to be 0.9% to 28% for pulmonary embolism and 0.1% to 2% for fatal pulmonary embolism following THA and TKA, respectively. This article describes the natural history of deep vein thrombosis and pulmonary embolism in THA and TKA, examines deep vein thrombosis as a predictor of recurrent venous thromboembolism and pulmonary embolism, and describe the long-term sequelae of deep vein thrombosis and pulmonary embolism.

Natural History of Deep Vein Thrombosis and Pulmonary Embolism In THA and TKA, Virchow’s triad— venous stasis, endothelial injury, and hypercoagulability—is involved in the formation of thrombi during the perioperative period. Blood flow disruption in the femoral vein leading to venous stasis may occur as a result of limb positioning during the procedure, localized postoperative swelling, and decreased postoperative ambulation.3,4 A significant reduction in venous capacitance and outflow occurs during THA and may be exacerbated during dislocation of the hip and insertion of the femoral prosthesis.3,4 In addition, tourniquet use in TKA may increase the formation of lowerextremity thrombi.3,4 Endothelial injury may occur during positioning of the extremity with femoral vein kinking, thermal injury from bone cement, and calf vein distension.4,5 Hypercoagulability occurs as the result of local and systemic

activation of coagulation intra- and postoperatively. Increased levels of multiple markers of thrombus generation, including prothrombin, thrombin–antithrombin, and fibrinopeptide A, have been demonstrated during the procedure.6 These findings, along with venous ultrasound and venographic studies,7,8 provide strong evidence for a thrombogenic process that begins during the perioperative period. Using serial venography after unilateral TKA of 42 legs, Maynard et al8 found distal deep vein thrombosis in 45% and a popliteal thrombus in 5% of legs 24 hours postoperatively. However, although the thrombogenic process begins intraoperativly, venous thromboembolism risk extends anywhere from 3 to 6 weeks and thereafter postoperatively.5,9 Studies of patient databases estimate that approximately 50% to 75% of surgery-related venous thromboembolism events occur after discharge.5 The median time until diagnosis of a symptomatic deep vein thrombosis has been found to be 21.5 days after THA and 9.7 days after TKA.10 Warwick et al10 found that the diagnosis of venous thromboembolism was made after hospital discharge in 2.3% (6639) of THAs and 1.7% (8326) of TKAs. The risk of complications, including pulmonary embolism, depends on the location of the thrombi. Postoperatively, deep vein thrombosis usually begins in the veins of the calf, often originating in the valve cusps,7,11 and 75% to 80% will occur in the operated leg.5,12,13 Calf thrombosis accounts for 50% to 80% of the overall frequency of thromboembolic disease after THA and TKA, respectively,13-17 whereas proximal deep vein thrombosis develops in 10% to 25%, respectively.4,14,18 Once the calf thrombus develops, it can further enlarge and propagate proximally. Studies using serial duplex ultrasound have observed propagation rates of 17% to 23% after THA and TKA, respectively.13,16 Although the majority of symptomatic episodes of deep vein thrombosis start in the calf veins, symptoms are uncommon until propagation to the proximal veins occurs.12

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Rates of symptomatic deep vein thrombosis after THA and TKA range from 2.1% to 12.5%, with 50% to 85% of events occurring proximal to the knee.19,20 If left untreated, approximately 50% of patients with symptomatic proximal deep vein thrombosis will develop a symptomatic pulmonary embolism13 and have a 5% to 10% risk of fatal pulmonary embolism.21

Long-term Sequelae of Deep Vein Thrombosis and Pulmonary Embolism Venous thromboembolism is a disease with long-term complications that include recurrent venous thromboembolism, postthrombotic syndrome, and chronic thromboembolic pulmonary hypertension. Recurrent Venous Thromboembolism Venous thromboembolism recurrences are common during the first 6 to 12 months after the first event, but the risk persists for several years.22-24 In a prospective cohort study, Prandoni et al25 followed 528 patients with first-episode deep vein thrombosis with at least 3 months of oral anticoagulant use and found a venous thromboembolism recurrence incidence of 24.3% after 5 years and 29.7% after 8 years. Twenty percent of the recurrent venous thromboembolism episodes were pulmonary embolisms, which were fatal more than half the time.25 Several studies reported that patients who present with pulmonary embolism are at a greater risk for recurrent pulmonary embolism than are patients with an isolated deep vein thrombosis.26 These findings have led some to suggest that deep vein thrombosis and pulmonary embolism are distinct clinical entities with different natural histories.27 However, other studies suggest that patients with pulmonary embolisms and isolated deep vein thromboses may have a similar venous thromboembolism-specific prognosis. In a retrospective, population-based study of residents of an entire New England metropolitan area, Spencer et al27 found

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that isolated deep vein thromboses and pulmonary embolisms had similar incidence rates at 3 years postoperatively. The patients who presented with pulmonary embolisms or isolated deep vein thromboses experienced rates of subsequent pulmonary embolism and overall venous thromboembolism of 5.9% vs 5.1% and 15.0% vs 17.9%, respectively.27 Further study of the recurrence rates of patients who present with symptomatic pulmonary embolism vs isolated deep vein thrombosis is warranted. It is critical to distinguish between idiopathic deep vein thrombosis or pulmonary embolism and deep vein thrombosis or pulmonary embolism with an identifiable medical cause, such as trauma or surgery.28-31 After an initial episode of deep vein thrombosis or pulmonary embolism, fatal pulmonary embolism is significantly less common if that event is caused by THA or TKA than if it is idiopathic.31 In comparing different types of operations, Hansson et al32 found a lower risk of venous thromboembolism recurrence among orthopedic surgery patients; the multivariate relative risk of recurrent venous thromboembolism was 0.21 (95% confidence interval [CI], 0.070.65; P5.07) after orthopedic surgery and 0.67 (95% CI, 0.27-1.64; P5.38) within 3 months after any other surgery. This evidence suggests the existence of unique coagulation factors associated with orthopedic surgery patients and procedures that should be further investigated. Postthrombotic Syndrome In addition to the risk of recurrent venous thromboembolism, patients with a venous thromboembolism may also develop postthrombotic syndrome, a chronic and potentially disabling condition characterized by edema, pain, venous ectasia, and, in severe cases, painful leg ulcers.33 With acute symptomatic deep vein thrombosis present, the incidence of postthrombotic syndrome symptoms have ranged from as low as 23% to approxi-

mately 65%.34 In a prospective study of 355 patients with symptomatic deep vein thrombosis, Prandoni et al25 observed a cumulative postthrombotic syndrome incidence of 17% after 1 year and 29% after 8 years of follow-up. Risk for developing postthrombotic syndrome after asymptomatic deep vein thrombosis is of particular interest in orthopedic surgery because the majority of deep vein thromboses that occur after TKA are asymptomatic. Siragusa et al35 evaluated 217 THA and TKA patients with asymptomatic deep vein thrombosis and found that 24% developed postthrombotic syndrome in the following 2 to 4 years. Similarly, in a series of 132 TKA and THA patients with asymptomatic deep vein thrombosis who were followed for 18 months, Schindler and Dalziel36 found a postthrombotic syndrome incidence rates of 16.7%. However, Ginsberg et al37 suggested that the risk for symptomatic postthrombotic syndrome after THA and TKA in asymptomatic deep vein thrombosis patients tends to be lower. In their study, 255 patients who underwent THA or TKA within the previous 2 to 7 years had postthrombotic syndrome incidence rates between 4% and 6%.37 The authors proposed that these lower rates were due to the use of prophylaxis to reduce the incidence of venous thromboembolism and the subsequent risk of associated complications.37 Also, all patients in the study with asymptomatic deep vein thrombosis received warfarin for 6 to 12 weeks regardless of the location of thrombi, whereas only the proximal thrombi patients in the study by Schindler and Dalziel36 received warfarin; those with distal thrombi received aspirin after hospital discharge. Although most asymptomatic deep vein thromboses will not cause acute pulmonary embolism, these studies suggest its clinical importance. Chronic Thromboembolic Pulmonary Hypertension Chronic thromboembolic pulmonary hypertension may occur following a single



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or recurrent episode of pulmonary embolism, and if it is left untreated, progressive right ventricular dysfunction with ultimate right heart failure can occur.38 Estimates of the incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism range from 0.5% to 3.8%.38 For every 100 cases of pulmonary embolism, 3 cases of chronic thromboembolic pulmonary hypertension will occur, with a cumulative incidence of 1% to 5% within 2 years after the embolic event.39 In addition, approximately 40% of chronic thromboembolic pulmonary hypertension cases originate from asymptomatic venous thromboembolism.39 Deep Vein Thrombosis as a Predictor of Subsequent Venous Thromboembolism Rates of asymptomatic deep vein thrombosis without prophylaxis in THA and TKA range from 20% to 58%, with 1.5% to 8% detected in the femoral vein.36 Even with the use of prophylaxis, rates of asymptomatic deep vein thrombosis remain high at 34% to 61%, of which 2.5% to 9.1% are located proximally to the knee.36 In a study exploring the relationship between asymptomatic deep vein thrombosis and symptomatic venous thromboembolism in patients undergoing THA and TKA who received prophylactic enoxaparin, Quinlan et al40 determined that the ratio of asymptomatic deep vein thrombosis at hospital discharge to symptomatic venous thromboembolism within the next 3 months was approximately 5:1 for THA and 21:1 for TKA. It is well recognized that patients with symptomatic deep vein thromboses are at increased risk of developing symptomatic or fatal pulmonary embolism.11 However, in many cases, the deep vein thrombosis is silent, and the clinical presentation of pulmonary embolism remains variable.1 Clinical signs suggestive of pulmonary embolism are not specific but may include tachycardia, dyspnea, rales, chest pain, fever, and neck vein distention.41 Even when a precise clinical diagnosis


of thromboembolism is lacking, vague symptoms such as unilateral leg swelling or unexplained tachycardia warrant a thorough physician workup.41 Kim et al42 conducted a randomized, controlled, prospective trial that showed that no elevated risk of symptomatic or asymptomatic pulmonary embolism was associated with calf thrombi in post-THA patients who did not receive deep vein thrombosis prophylaxis. Of the 300 THA (200 bilateral and 100 unilateral) patients in the study, venographic studies at 6 or 7 days postoperatively showed the presence of calf thrombi in 22 (11%) and 8 (8%) bilateral and unilateral patients, respectively.42 Lung perfusion scans were negative in these thrombotic patients on their seventh or eighth postoperative day, and on repeat postoperative scanning of these same patients at 6 months.42 According to the American Academy of Orthopaedic Surgeons (AAOS), a lack of consistent evidence exists establishing the association between symptomatic deep vein thrombosis and pulmonary embolism in patients undergoing THA and TKA.43 Parvizi et al44 conducted a retrospective, cross-sectional study on 1495 patients, with the majority consisting of THA and TKA patients (326 [21.0%] primary hips and 656 [42.2%] primary knees). The investigators diagnosed deep vein thromboses in 115 (7.5%) patients, pulmonary embolism in 163 (11.0%) patients, and deep vein thrombosis and pulmonary embolism in 27 (1.8%) patients.44 According to the AAOS, this low rate of patients diagnosed with both deep vein thrombosis and pulmonary embolism calls into question the approach of using aggressive measures to treat deep vein thrombosis for the purpose of lowering the incidence of pulmonary embolism.43 Some investigators suggest that longterm anticoagulation with currently available agents be used judiciously to avoid bleeding disorders requiring blood transfusions or periprosthetic infections.45-47 Furthermore, AAOS claims that tradition-

al anticoagulant drugs may be associated with higher all-cause mortality rates after THA and TKA.43 However, the American College of Chest Physicians (ACCP) maintains that a consistent association between deep vein thrombosis and pulmonary embolism is demonstrated in imaging studies, as well as in the results of clinical trials that have shown a reduction of both deep vein thrombosis and pulmonary embolism with the use of anticoagulants vs placebo or untreated controls.2 The ACCP guidelines, which are based on results from randomized clinical trials and are widely used in THA and TKA, consider all patients undergoing THA and TKA to be at risk of venous thromboembolism and recommend the use of thromboprophylaxis with anticoagulants such as low-molecular-weight heparin or vitamin K antagonists in this population.48 Some investigators have found asymptomatic distal deep vein thrombosis to be associated with an elevated risk of developing pulmonary embolism. In a series of studies by Pellegrini et al,49,50 investigators found that THA patients with asymptomatic calf deep vein thrombosis had an elevated risk of developing clinically significant pulmonary embolism within 8 weeks postoperatively. Of 174 patients, the 13 who received no anticoagulation at discharge were diagnosed with isolated deep vein calf thrombi by contrast venography within 7 to 10 days.49 Of these 13 patients, 4 (31%) subsequently developed pulmonary embolism.49 In another study, Pellegrini et al50 assumed that no pulmonary embolisms arose directly from deep calf thrombosis; they estimated that at least 1 in 5 fatal postoperative pulmonary embolisms resulted from untreated calf disease after THA.

Conclusion Venous thromboembolism is a major health problem in the United States and can be associated with long-term morbidity. Therefore, thromboprophylaxis is not just for the prevention of pulmonary

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embolism, but also for venous thromboembolism prevention in general. Both symptomatic and asymptomatic deep vein thrombosis predispose patients to the development of recurrent venous thromboembolism, pulmonary embolism, postthrombotic syndrome, and chronic thromboembolic pulmonary hypertension, all of which are associated with reduced quality of life and substantial health care expenditures.51 Ongoing research is needed to further elucidate the causal relationship between deep vein thrombosis and pulmonary embolism. The unique coagulation profiles of orthopedic surgery patients and procedures should be considered and further explored because currently available anticoagulation medications, such as vitamin K antagonists, are associated with a host of complications, particularly with long-term use.44-46 However, newer oral anticoagulants, such as direct thrombin inhibitors and Factor Xa inhibitors, show promise. A greater understanding of the causes of deep vein thromboses and pulmonary embolisms and an awareness of the benefits and risks associated with newer agents will aid orthopedic surgeons in selecting optimal thromboprophylaxis to prevent deep vein thrombosis and pulmonary embolisms, both during hospitalization and after discharge.

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arthroplasty: a cross-sectional study. Arch Intern Med. 2000; 160:669-672. 38. Wittine LM, Auger WR. Chronic throm boembolic pulmonary hypertension. Curr Treat Options Cardiovasc Med. 2010; 12:131-141. 39. Lang IM, Klepetko W. Update on chronic thromboembolic pulmonary hypertension, a frequently undiagnosed condition. Rev Esp Cardiol. 2009; 62:120-125. 40. Quinlan DJ, Eikelboom JW, Dahl OE, Eriksson BI, Sidhu PS, Hirsh J. Association between asymptomatic deep vein thrombosis detected by venography and symptomatic venous thromboembolism in patients undergoing elective hip or knee surgery. J Thromb Haemost. 2007; 5:1438-1443. 41. Della Valle CJ, Steiger DJ, DiCesare PE. Thromboembolism following hip and knee arthroplasty: diagnosis and treatment. J Am Acad Orthop Surg. 1998; 6:327-336. 42. Kim YH, Yoo JH, Kim JS. Factors leading to decreased rates of deep vein thrombosis and pulmonary embolism after total knee arthroplasty. J Arthroplasty. 2007; 22:974-980. 43. American Academy of Orthopaedic Surgeons. Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty: evidence-based guidelines and evidence report. http://www.aaos.org/Research/ guidelines/VTE/VTE_full_guideline.pdf. Accessed November 4, 2011. 44. Parvizi J, Jacovides CL, Bican O, et al. Is deep vein thrombosis a good proxy for pulmonary embolus? J Arthroplasty. 2010; 25(6 suppl):138-144.

45. Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med. 2003; 139:893-900. 46. Walsh M, Preston C, Bong M, et al. Relative risk factors for requirement of blood transfusion after total hip arthroplasty. J Arthroplasty. 2007; 22:1162-1167. 47. Büller HR, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004; 126(3 suppl);401S-428S. 48. Eikelboom JW, Karthikeyan G, Fagel N, Hirsh J. American Association of Orthopedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ: what are the implications for clinicians and patients? Chest. 2009; 135:513-520. 49. Pellegrini VD Jr, Clement D, Lush-Ehmann C, et al. The John Charnley Award. Natural history of thromboembolic disease after total hip arthroplasty. Clin Orthop Relat Res. 1996; 333:27-40. 50. Pellegrini VD Jr, Langhans MJ, Totterman S, et al. Embolic complications of calf thrombosis following total hip arthroplasty. J Arthroplasty. 1993; 8:449-457. 51. Colwell CW. The ACCP guidelines for thromboprophylaxis in total hip and knee arthroplasty. Orthopedics. 2009; 32(12 suppl):67-73.

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