CHAPTER 29 Deep Vein Thrombosis Prophylaxis following Unicompartmental Knee Arthroplasty
Introduction
Venous thromboembolic disease (VTED) represents a spectrum of pathology ranging from asymptomatic deep vein thrombosis (DVT) to fatal pulmonary embolism (PE). Historically, VTED was one of the most feared complications of lower extremity total joint arthroplasty (TJA), with rates of fatal PE as high as 3.4%.1 General surgical studies demonstrated that, before 1990, PE accounted for approximately 10% of in-hospital deaths.2,3 However, modern orthopaedic surgical techniques, anesthetic care, and rehabilitation protocols have vastly improved the incidence of VTED and death after TJA. The Global Orthopaedic Registry found that only 0.3% of total knee arthroplasty (TKA) patients died within 3 months after TKA.4 The National Registry for England and Wales demonstrated that the overall mortality rates at 1 year were actually 66% lower than age- and gender-matched controls from the general population.5,6 Nevertheless, VTED remains a significant concern for patients and surgeons alike. DVT is still the most frequent in-hospital complication after TKA4 and the most common reason for emergency readmission.7
Etiopathogenesis Of Vted
The etiopathogenesis of VTED is multifactorial. Known as Virchow’s triad,8 the combination of venous stasis, endothelial injury, and hypercoagulability are predispositions for VTED. Undergoing TJA exposes patients to all three of these states. Venous stasis can occur intraoperatively with manipulation of the limb, kinking of the vessels, and use of the tourniquet, and postoperatively during recuperation. A certain degree of endothelial injury inevitably happens from the physical nature of surgery and the hypoxic, hypothermic conditions during tourniquet inflation.9–11 The cause of intraoperative hypercoagulability is not certain, but the 10–15% venographic incidence of DVT in the upper or contralateral limbs clearly demonstrates an iatrogenic systemic diathesis for clotting.7 Further evidence is that over 80% of DVTs after TKA are already present by the first postoperative day.12 In addition to the numerous surgery-related components of VTED, there are many patient-based risk factors as well (Box 29–1).
Sequelae Of Vted
While fatal PE is the most devastating consequence of VTED, it is relatively rare. The 90-day rate after TKA was 0.22% after almost 27,000 patients in the Scottish Registry,13 and that for symptomatic, nonfatal PE was 0.41% in over 200,000 patients in a California database.14 Approximately 25–30% of untreated symptomatic distal DVTs can propagate to proximal veins15 and are associated with a greater embolic risk.16,17 Asymptomatic VTED may not pose an immediate clinical problem, but at least three well-recognized sequelae can cause significant morbidity. Characterized by chronic venous insufficiency, pain, swelling, and recurrent ulcers, postphlebitic or postthrombotic syndrome (PTS) can develop in 25% of patients within 3 years after a DVT.18,19 Although there is no gold standard for diagnosing PTS,20 there is evidence that the incidence of developing PTS may not necessarily be significantly elevated in patients who experience DVT after TKA,21,22 and the use of thromboprophylaxis may not be effective in allaying that risk.23,24 A second concern is recurrent VTED. An initial DVT has been shown to be an independent risk factor for subsequent DVTs.25,26 Third, chronic pulmonary hypertension leading to right ventricular hypertrophy and right heart failure is a serious condition that can develop in 3.8% of patients at 2 years after an acute episode of PE.27
Modernization Of Thromboprophylaxis
Modern developments have significantly mitigated the surgery-related risk factors for VTED after TJA. Forty years ago, the average patient underwent 2.4 hours of operation, 1650 ml of blood loss, 3 units of transfusion, 1 week of bed rest, and 3 weeks of hospitalization.1,7 Warfarin was typically started 5 days postoperatively. Without thromboprophylaxis, the rates of DVT after TKA are exceedingly high, with proximal clots occurring in as many as 22% of patients at 14 days.28 The last randomized, placebo-controlled study was over 20 years ago, and it is unlikely that another would ever be ethically approved. Although the need for some form of thromboprophylaxis is rarely questioned, there is considerable debate between two main governing bodies, the American College of Chest Physicians (ACCP) and the American Academy of Orthopaedic Surgeons (AAOS), regarding the type and extent of prevention necessary after TJA.
ACCP Guidelines
The eighth edition of the Clinical Practice Guidelines on antithrombotic agents was published in 2008 by the ACCP, an organization formed by practitioners in multiple fields such as pulmonology, critical care medicine, and cardiology.29 In their analysis, the ACCP used objectively diagnosed DVT or PE as end points and examined only randomized controlled trials (RCTs) or meta-analyses of RCTs.30 Some of their stronger recommendations for TKA were: against using aspirin (acetylsalicylic acid; ASA) or low-dose unfractionated heparin as the only means of prophylaxis (Grade 1A); continuing thromboprophylaxis for at least 10 days (Grade 1A) and extending it to 35 days (Grade 2B); using a high-risk dose of low-molecular-weight heparin (LMWH) started preoperatively or postoperatively, or fondaparinux started 6–24 hours postoperatively, or warfarin started preoperatively with a target international normalized ratio (INR) of 2.5 (range, 2–3) (Grade 1A); and using intermittent pneumatic compression devices (IPCDs) in patients with a high risk of bleeding (Grade 1A).31 Because there are no prospective RCTs comparing multimodal prophylaxis to single modalities, the ACCP did not make any recommendations for or against it. Although the ACCP accepts that DVT is not a perfect surrogate for PE and that PE is the most important outcome for patients, it believes that DVT is a valid surrogate for PE based on a consistent correlation on imaging studies and parallel reduction of both entities with antithrombotic agents.30,32 In addition, because of the relative rarity of PE and death after TJA, the sample size necessary to prove a statistical difference in either entity with thromboprophylaxis would near 30,000 patients for each arm of an RCT.6,33
Risks of Bleeding
Pharmaceutical thromboprophylaxis is not without risk of bleeding. The ACCP recommendations were based on studies with no date criterion, including those published far before the introduction of modern surgical and rehabilitation protocols. Many orthopaedists feel that the ACCP unduly focused on the prevention of all VTED at the expense of iatrogenic hemorrhage.34 The challenge in achieving the appropriate balance was aptly put by Freedman et al.33 “The decision regarding prophylaxis against thromboembolic disease depends primarily on which events one is attempting to prevent: all DVTs, proximal DVTs, all PEs, fatal PEs, death, or all of the above. When considering the issue of safety, one must determine which adverse consequences are important: minor wound-bleeding, major wound-bleeding, or major nonwound bleeding (gastrointestinal or intracerebral hemorrhage).”
AAOS Guidelines
In 2008, the AAOS published their own clinical guidelines addressing specific concerns with the ACCP recommendations.35 First, only studies with patient recruitment since 1996 were included to better reflect the true underlying risk of VTED with modern protocols. Second, in addition to RCTs, large prospective cohort studies (>100 patients) were included. Third, instead of relying on the incidence of DVT as the primary efficacy outcome, prevention of symptomatic PE was used as the main goal of thromboprophylaxis. The AAOS challenged the validity and appropriateness of DVT, especially asymptomatic cases, as a proxy for PE or representative of clinical benefit.36 Fourth, a formal consideration of the benefits and harms of potent thromboprophylaxis was made in the context of TJA. Patients who return to the operating room within 30 days after TKA have a significantly increased risk for deep infection or for requiring other major surgery.37 Each day of prolonged wound drainage is associated with a 42% increased risk of infection.38 Fifth, in order to choose the appropriate aggressiveness of prophylaxis, the AAOS emphasized the need to risk-stratify each patient in terms of PE and hemorrhage. The ACCP, in contrast, considered all TJA patients to be high-risk candidates for VTED. The most important distinctions of the AAOS guidelines are the allowance of ASA as the sole chemoprophylaxis except in patients with elevated risk for PE, a lower target INR with warfarin of ≤2.0, and the avoidance of LMWH in patients with elevated risk of bleeding. In addition, mechanical prophylaxis and early mobilization are recommended in all patients.35
Warfarin
Warfarin (Coumadin; Bristol-Myers Squibb, Princeton, NJ) acts at multiple sites in the clotting cascade, inhibiting the synthesis of vitamin K–dependent factors II, VII, IX, and X. It is a time-honored method of anticoagulation, but has several drawbacks. Because of its effect on endogenous anticoagulants protein C and protein S, warfarin is initially prothrombotic, and even with early administration, the INR does not usually reach its target range until 36 hours. Unlike most other anticoagulants, warfarin requires frequent INR monitoring and close titration of doses in order to prevent catastrophic bleeding. This can be challenging in the presence of numerous diet and drug interactions. Contemporary rates of hemorrhage while on warfarin range from 1.2% to 3.7%,39–41 and at-risk medical patients have a 0.3% risk of bleeding for each additional month while on therapy.42,43 A meta-analysis of warfarin prophylaxis found a 45% incidence of DVT, 8.2% of asymptomatic PE, and 0.4% of symptomatic PE after TKA.44
Low-Molecular-Weight Heparin
Enoxaparin (Lovenox; Sanofi-Aventis, Bridgewater, NJ) and the less commonly used dalteparin (Fragmin; Pfizer, Brooklyn, NY) are LMWHs. Unlike commercial unfractionated heparin (molecular weight 12–15 kDa), enoxaparin is smaller and more uniform in weight (molecular weight 5 kDa).7 Its anticoagulant effect is mediated by enhanced inactivation of factor Xa and, to a lesser extent, factor IIa.45 Enoxaparin has many advantages, including a more predictable dose response, a dose-independent mechanism of clearance, a longer plasma half-life, and lower incidence of heparin-induced thrombocytopenia than unfractionated heparin.46 Unlike warfarin, no regular laboratory monitoring is necessary other than a baseline and an early platelet count to rule out heparin-induced thrombocytopenia. Several disadvantages are high cost (~$40 per dose) and painful route of administration (subcutaneous injection). Enoxaparin is associated with lower DVT and hemorrhage rates than unfractionated heparin.7,47 Compared to warfarin, enoxaparin is generally more efficacious after TKA in preventing distal DVT (24% vs. 34%), proximal DVT (2% vs. 11%), and pulmonary embolism (0% vs. 0.6%),48 but multiple studies4,7 have demonstrated a significantly higher incidence of major hemorrhage (5.2% vs. 2.3%) and clinically important operative site bleeding (6.9% vs. 3.4%).48
Aspirin
Aspirin is inexpensive and easy to administer, does not need monitoring, and has undergone a recent resurgence secondary to increased attention to bleeding complications from other agents. By inhibiting the production of thromboxane, ASA exerts an antiplatelet effect and is often used to prevent arterial tree embolism. For patients intolerant of ASA, dipyridamole (Persantine; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT) or clopidogrel bisulfate (Plavix; Bristol-Myers Squibb, Princeton, NJ) is typically substituted. To reduce the risk of gastrointestinal ulcer, a histamine2 antagonist (e.g., ranitidine) or proton pump inhibitor (e.g., omeprazole) is administered. The Antiplatelet Trialists’ Collaboration49 and Pulmonary Embolism Prevention Trial50 provided some evidence that aspirin may be effective in reducing VTED, but the data were somewhat confounded by multiple factors, including nonorthopaedic patients and concomitant anticoagulants.7 Although there are no recent well-controlled studies examining the relative effectiveness and efficacy of ASA,51 it is increasingly being used as one facet of a multimodal regimen. However, several large cohort studies have demonstrated its efficacy and safety in this context. When ASA (325 mg twice a day for 6 weeks) is combined with early mobilization, mechanical prophylaxis, and hypotensive epidural or regional anesthesia, rates of VTED and bleeding are exceedingly low, with 2.5–10.2% DVT, 0–0.1% fatal PE, and 0.2–0.5% hematoma or minor distant bleeding.51–53 A recent review of multiple studies presented debatable evidence that the rate of all-cause mortality and incidence of nonfatal PE were significantly lower with multimodal prophylaxis and ASA compared to patients receiving LMWH and other heparin derivatives.54,55
New Pharmaceutical Agents
There are several newer anticoagulants that have received recent press. Fondaparinux (Arixtra; GlaxoSmithKline, London, UK) is a synthetic pentasaccharide analog of the antithrombin binding site of heparin.7 By triggering a conformational change in antithrombin, fondaparinux indirectly enhances inactivation of factor Xa, but unlike enoxaparin, does not affect factor IIa.45 Although associated with lower rates of VTED after TKA than enoxaparin, it is also associated with a higher incidence of major bleeding.56 Thrombin, an enzyme that converts soluble fibrinogen to insoluble fibrin and enhances clot formation, is the target of several oral medications such as ximelagatran (Exanta; AstraZeneca, London, UK) and dabigatran (Pradaxa; Boehringer Ingelheim Pharmaceuticals). Apixaban (Pfizer; Bristol-Myers Squibb) and rivaroxaban (Xarelto; Ortho-McNeil Pharmaceutical, Raritan, NJ) are direct factor Xa inhibitors, but data from clinical trials are only emerging and, along with dabigatran, they are not currently approved within the United States.45 Ximelagatran has been discontinued secondary to hepatotoxicity during clinical trials.
Duration of Thromboprophylaxis
The appropriate postoperative duration of pharmaceutical thromboprophylaxis is debatable. Like the ACCP, the AAOS does not provide a strong or high-grade recommendation beyond providing a range between 2 and 6 weeks for warfarin and ASA.35 Regarding LMWH and fondaparinux in TKA, the ACCP recommends a 35-day extended course while the AAOS feels that they have not been sufficiently evaluated for periods longer than 12 days.31,35 Although the risk for VTED is highest within the first several days after surgery, the ongoing process of clot formation and lysis persists7 and the risk remains elevated for at least 90 days.57 Several studies have shown that, while short-duration anticoagulant therapy significantly decreases the risk of VTED, approximately 1 in 32 of these patients will have a symptomatic nonfatal VTED-related event and 1 in 1000 will have a fatal PE within the following 3 months.46,58,59 A cost-utility analysis of enoxaparin showed that prolonged therapy led to increased health benefits through reduction of VTED, but at a significantly increased overall monetary cost.60 This study, however, did not consider the ramifications of bleeding complications from additional anticoagulation. There is little evidence in this regard, but one study found that the additional enoxaparin did not increase the risk of major hemorrhage and only increased minor bleeding slightly from 2.5% to 3.7%.59
Mechanical Thromboprophylaxis
The concept behind mechanical thromboprophylaxis is the replication of normal skeletal muscular contractions enhancing venous return. The most commonly used methods are graduated compression stockings (GCSs) and intermittent pneumatic compression devices (IPCD). GCSs statically provide a gradient of pressure ranging from 18 mm Hg at the ankle to 8 mm Hg at the thigh and prevent venous distention and pooling of blood.7,61 Achieving the correct fit and maintaining the stocking in position are not only sometimes difficult, but also essential to its function. A recent study demonstrated that about half of all applied GCSs produced a “reversed” gradient of pressure and the incidence of DVT was greater than four times higher than in patients with correctly fitted stockings.62 Intermittent pneumatic compression devices actively squeeze the lower extremity to 40 mm Hg for 12 seconds each minute (calf and thigh IPCDs) or 130 mm Hg for 3 seconds every 20 seconds (foot pumps).7 Although smaller and quieter IPCDs have been developed, their main disadvantage is patient discomfort. Nevertheless, they have been found to be highly effective compared to placebo (62% risk reduction) and GCSs (47% risk reduction),63 and even comparable to LMWH.33,44 There is evidence that mechanical thromboprophylaxis is protective by both enhancing fibrinolysis and decreasing procoagulation activation.7 Concomitant use of GCSs with IPCDs may reduce the hematogenous preload and emptying velocity of the veins, but there is little evidence to judge the merit of simultaneous mechanical modalities.7 Because thrombogenesis often occurs during surgery and because of the beneficial systemic effect of mechanical thromboprophylaxis, IPCDs should be started intraoperatively on the nonsurgical limb.
Inferior Vena Cava Filters
Inferior vena cava (IVC) filters are used in approximately 0.5% of TJA patients for either treatment or prophylaxis of VTED.64 The most common indications are contraindication to anticoagulation, failure of anticoagulation, cessation of anticoagulation secondary to bleeding, and saddle embolus.64 Although multiple studies have demonstrated strong efficacy of IVC filters in preventing PE in high-risk patients (0–3.1% incidence),64–67 they should not be used without careful consideration. There is evidence that IVC filters may not affect overall mortality rates, and their presence is associated with an increased risk of primary or recurrent DVT.68–70 While removal can theoretically reduce the long-term risk of an indwelling filter, actual retrieval rates are low secondary to filter site thrombosis and incorporation into the vessel wall, and range from only 13% to 64%.64,71 Complications associated with filter insertion are low, but can occur in up to 11% of cases during retrieval.64,65
Hypotensive Regional Anesthesia
Regional anesthesia, most commonly a spinal (subarachnoid) or epidural injection before TKA, when combined with hypotensive protocols, is thought to enhance lower extremity blood flow in the immediate postoperative period.72 Epidural anesthesia causes a blockade of the sympathetic cardioaccelerator fibers originating from the upper thoracic spinal segments.73 Although there appears to be no significant change in either thrombin generation or fibrinolytic activity during tourniquet elevation intraoperatively,74 several studies have found that neuraxial anesthesia compared to general anesthesia decreased rates of proximal DVT from 9% to 4% after TKA,75 and the odds of DVT by 44% and PE by 55%.76 A review of 2500 total hip arthroplasties (THAs) performed with hypotensive epidural anesthesia reported rates of symptomatic and fatal PE at 0.42% and 0.04%.77 Although the intraoperative hematologic impact of hypotensive anesthesia may be blunted for TKA with the use of a tourniquet, deliberate hypotension has been shown to decrease blood loss and transfusion requirements in orthopaedic procedures.78 The exact definition of hypotension varies between institutions from a mean arterial pressure of 50 mm Hg to 70 mm Hg.78 A combination of an opioid and local anesthetic typically provides adequate analgesia and neural blockade for patient comfort and surgery, yet allows early recovery of sensory and motor function in the early postoperative period to start rehabilitation.79 Nevertheless, epidurals can fail in up to 20% of cases, and adjuvant pain control protocols should be in place to smooth the transition if an infusion catheter is removed at 24 hours.79
The timing of anticoagulation is critical when patients have received or are receiving neuraxial anesthesia. To reduce the risk of spinal or epidural hematoma and potential paraplegia, needle placement should be at least 10–12 hours apart from the nearest dose of LMWH and infusion catheters should not be placed or removed if the patient has an elevated INR.51 Contraindications to hypotensive anesthesia include severe aortic or mitral stenosis and occlusion of the carotid artery, and extreme care should be taken in patients with congestive heart failure, uncontrolled hypertension, or severe atherosclerosis. Cerebral hypoperfusion, myocardial infarction, and renal failure are all potential risks.80
Routine Screening And Risk Stratification
Although routine screening in asymptomatic patients for VTED, specifically DVT, prior to hospital discharge to tailor levels of thromboprophylaxis may be intuitively appealing, both the AAOS and ACCP recommend against it.33,35 Early surveillance imaging for DVT is a poor predictor of overall VTED risk and should not be used as a guide to decide whether extended thromboprophylaxis is necessary.77,81,82 Risk stratification, in contrast, is likely more effective at protecting both high- and low-risk patients, and at the same time minimizing their risk for bleeding. In a study of 1179 TJA patients, individuals were stratified according to their risk factors.83 The low-risk group received ASA for 1 month while the high-risk group received LMWH for 10 days, then ASA for 1 month, or warfarin (INR 2–2.5) for 6 weeks or otherwise prescribed for a preexisting condition. All patients received IPCDs and early mobilization, and 82% had epidural anesthesia plus supplemental general sedation. Mean length of stay was 5 days, and all patients underwent Doppler ultrasound 24 hours prior to discharge. Low-risk patients and high-risk patients on LMWH who were found to have a proximal DVT or experienced a PE were switched to warfarin for 3–6 months. The overall rates were 5.2% asymptomatic DVT, 0.4% symptomatic DVT, 0.25% symptomatic PE, 0% fatal PE, 0.4% wound hematoma, and 0.17% nonfatal GI bleeding. Of note, this study differed from many RCTs by including “all comers” and not excluding high-risk individuals. Particularly interesting was that the incidence of hemorrhage and hematoma was 35 times higher in the patients who received non-ASA drug therapy either as thromboprophylaxis (high-risk group) or for treatment of VTED.83
Differences Between Unicompartmental Knee Arthroplasty And Tka And Tha
There are many important differences between THA, TKA, and unicompartmental knee arthroplasty (UKA) germane to thromboprophylaxis and VTED. First, intravasation and embolization of bone marrow fat during medullary canal preparation are commonly implicated as the sentinel event in activation of the clotting cascade.84,85 With traditional instrumentation, violation of the canal is significantly less during UKA than THA and TKA. Second, because patients eligible for a UKA typically have smaller deformities than those undergoing TKA, they require lesser soft tissue releases for balancing the knee. In addition, the exposure necessary to perform a UKA is less invasive than a TKA. These factors reduce the risk of hematoma formation postoperatively. One must remember, however, that the knee has less soft tissue coverage and is much less forgiving than the hip in regard to wound healing. Third, there is generally less blood loss and a more rapid recovery period after a UKA than a TKA. The traditional perception that TKA is the highest VTED risk orthopaedic procedure has been challenged by new evidence,58 and additional research may demonstrate that UKA incurs a significantly lower risk than TKA. Fourth, the generation and nature of DVT vary between TKA and THA, and may be distinct in UKA as well. Routine thromboprophylaxis in THA has changed the distribution of DVT from primarily proximal (50–60%) to nearly all distal (>90%). In TKA, however, 90% of all DVTs begin distally with or without prophylaxis. When proximal thrombi are present, in TKA they are usually contiguous with distal clots and do not extend beyond the popliteal vein, but in THA they are separate from distal clots and occur near the lesser trochanter.7
Our Protocol And Experience
At our institution, UKA is utilized in approximately 16% of knee arthroplasty patients. In a review of 1000 UKA cases, within 90 days postoperatively, there was only one (0.1%) symptomatic DVT, three (0.3%) hematomas requiring reoperation, and five (0.5%) blood transfusions for anemia.86 Our thromboprophylaxis protocol for UKA is oral ASA 325 mg twice daily for 6 weeks (low risk); LMWH subcutaneous injection 30 mg twice daily or 40 mg once daily for 2 weeks, then ASA for an additional 4 weeks (moderate risk); and dose-adjusted warfarin (target INR 2.0) for 6–12 weeks (high risk). Clopidogrel bisulfate is used in ASA-intolerant patients. A general medical consultant assists in risk stratification. All patients receive IPCDs intraoperatively on the opposite limb and both IPCDs and GCSs are started bilaterally in the recovery room. Rehabilitation, including full weight-bearing and range-of-motion exercises, is initiated on the day of surgery. The average hospitalization is 1.4 days. We do not perform routine screening ultrasounds in asymptomatic patients. When it can be safely utilized, hypotensive epidural anesthesia is preferred. If neuraxial anesthesia is contraindicated, a femoral nerve block is used instead.81,86,87 We also use perioperative cyclooxygenase-2 inhibitors; aggressive antiemetic medications; periarticular soft tissue injections with ketorolac, epinephrine, and ropivacaine prior to wound closure; long-acting oral narcotics for 24 hours; and short-acting oral narcotics for breakthrough pain.88 These measures facilitate rapid recovery, early mobilization, consistent pain relief, and early discharge, leading to very low rates of both VTED and bleeding.
1 Coventry M, Beckenbaugh R, Nolan D, Ilstrup D. 2,012 total hip arthroplasties: a study of postoperative course and early complications. J Bone Joint Surg [Am]. 1974;56:273-284.
2 Lindblad B, Eriksson A, Bergqvist D. Autopsy-verified pulmonary embolism in a surgical department: analysis of the period from 1951 to 1988. Br J Surg. 1991;78:849-852.
3 Sandler D, Martin J. Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis? J R Soc Med. 1989;82:203-205.
4 Cushner F, Agnelli G, Fitzgerald G, Warwick D. Complications and functional outcomes after total hip arthroplasty and total knee arthroplasty: results from the Global Orthopaedic Registry (GLORY). Am J Orthop. 2010;39:22-28.
5 , National Joint Registry 4th Annual Report. Available at www.njrcentre.org.uk accessed September 20, 2008
6 Cusick L, Beverland D. The incidence of fatal pulmonary embolism after primary hip and knee replacement in a consecutive series of 4253 patients. J Bone Joint Surg [Br]. 2009;91:645-648.
7 Pellegrini V, Sharrock N, Paiement G, et al. Venous thromboembolic disease after total hip and knee arthroplasty: current perspectives in a regulated environment. Instr Course Lect. 2008;57:637-661.
8 Virchow R. Thrombose und Embolie: Gefassentzundung und septische Infektion. Frankfurt: Von Meidinger & Sohn; 1856.
9 Malone P, Morris C. The sequestration and margination of platelets and leucocytes in veins during conditions of hypokinetic and anaemic hypoxia: potential significance in clinical postoperative venous thrombosis. J Pathol. 1978;125:119-129.
10 Naesh O, Haljamae H, Skielboe M, et al. Purine metabolite washout and platelet aggregation at reflow after tourniquet ischaemia: effect of intravenous regional lidocaine. Acta Anaesthesiol Scand. 1995;39:1053-1058.
11 Ogawa S, Gerlach H, Esposito C, et al. Hypoxia modulates the barrier and coagulant function of cultured bovine endothelium. J Clin Invest. 1990;85:1090-1098.
12 Maynard M, Sculco T, Ghelman B. Progression and regression of deep vein thrombosis after total knee arthroplasty. Clin Orthop Relat Res. 1991;273:125-130.
13 Howie C, Hughes H, Watts A. Venous thromboembolism associated with hip and knee replacement over a ten-year period: a population-based study. J Bone Joint Surg [Br]. 2005;87:1675-1680.
14 SooHoo N, Lieberman J, Ko C, Zingmond D. Factors predicting complication rates following total knee replacement. J Bone Joint Surg [Am]. 2006;88:480-485.
15 Kearon C. Natural history of venous thromboembolism. Circulation. 2003;107:122-130.
16 Moser K, Le Moine J. Is embolic risk conditioned by location of deep venous thrombosis? Ann Intern Med. 1981;94:439-444.
17 Pellegrini VJ, 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.
18 Kahn S, Ginsberg J. Relationship between deep venous thrombosis and the postthrombotic syndrome. Arch Intern Med. 2004;164:17-26.
19 Prandoni P, Lensing A, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125:1-7.
20 Kahn S, Solymoss S, Lamping D, Abenhaim L. Long-term outcomes after deep vein thrombosis: postphlebitic syndrome and quality of life. J Gen Intern Med. 2000;15:425-429.
21 Ginsberg J, Gent M, Turkstra F, et al. Postthrombotic syndrome after hip or knee arthroplasty: a cross-sectional study. Arch Intern Med. 2000;160:669-672.
22 McAndrew C, Fitzgerald S, Kraay M, Goldberg V. Incidence of postthrombotic syndrome in patients undergoing primary total knee arthroplasty for osteoarthritis. Clin Orthop Relat Res. 2010;468:178-181.
23 Khuangsirikul S, Sampatchalit S, Foojareonyos T, Chotanaphuti T. Lower extremities’ postthrombotic syndrome after total knee arthroplasty. J Med Assoc Thai. 2009;92:S39-S44.
24 Schindler O, Dalziel R. Post-thrombotic syndrome after total hip or knee arthroplasty: incidence in patients with asymptomatic deep venous thrombosis. J Orthop Surg. 2005;13:113-119.
25 Laporte S, Tardy B, Quenet S, et alPREPIC Study Group. The location of deep-vein thrombosis as a predictive factor for recurrence and cancer discovery after proximal deep-vein thrombosis [letter]. Haematologica. 2003;88:ELT08.
26 Heit J, Mohr D, Silverstein M, et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism. Arch Intern Med. 2000;160:761-768.
27 Pengo V, Lensing A, Prins M, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350:2257-2264.
28 Cushner F, Nett M. Unanswered questions, unmet needs in venous thromboprophylaxis. Orthopedics. 2009;32:62-66.
29 Guyatt G, Cook D, Jaeschke R, et al. Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):123S-131S.
30 Eikelboom J, 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. Chest. 2009;135:513-520.
31 Geerts W, Bergqvist D, Pineo G, et alAmerican College of Chest Physicians. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):381S-453S.
32 Eikelboom J, Hirsh J. Response. Chest. 2009;136:1700-1701.
33 Freedman K, Brookenthal K, Fitzgerald RJ, et al. A meta-analysis of thromboembolic prophylaxis following elective total hip arthroplasty. J Bone Joint Surg [Am]. 2000;82:929-938.
34 Johanson N, Lachiewicz P, Lieberman J, et al. Prevention of symptomatic pulmonary embolism in patients undergoing total hip or knee arthroplasty. J Am Acad Orthop Surg. 2009;17:183-196.
35 Lachiewicz P. Comparison of ACCP and AAOS guidelines for VTE prophylaxis after total hip and total knee arthroplasty. Orthopedics. 2009;32:74-78.
36 Weber K, Zuckerman J, Watters W, Turkelson C. Deep vein thrombosis prophylaxis. Chest. 2009;136:1699-1700.
37 Galat D, McGovern S, Hanssen A, et al. Early return to surgery for evacuation of a postoperative hematoma after primary total knee arthroplasty. J Bone Joint Surg [Am]. 2008;90:2331-2336.
38 Patel V, Walsh M, Sehgal B, et al. Factors associated with prolonged wound drainage after primary total hip and knee arthroplasty. J Bone Joint Surg [Am]. 2007;89:33-38.
39 Amstutz HA, Friscia D, Dorey F, Carney B. Warfarin prophylaxis to prevent mortality from pulmonary embolism after total hip replacement. J Bone Joint Surg [Am]. 1989;71:321-326.
40 Paiement G, Wessinger S, Hughes R, Harris W. Routine use of adjusted low-dose warfarin to prevent venous thromboembolism after total hip replacement. J Bone Joint Surg [Am]. 1993;75:893-898.
41 Pellegrini VJ, Clement D, Lush-Ehmann C, et al. The natural history of thromboembolic disease following hospital discharge after total hip arthroplasty. Clin Orthop Relat Res. 1996;333:27-40.
42 Landefeld C, Cook E, Flatley M, et al. Identification and preliminary validation of predictors of major bleeding in hospitalized patients starting anticoagulation therapy. Am J Med. 1987;82:703-713.
43 Landefeld C, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med. 1989;87:144-152.
44 Westrich G, Haas S, Mosca P, Peterson M. Meta-analysis of thromboembolic prophylaxis after total knee arthroplasty. J Bone Joint Surg [Br]. 2000;82:795-800.
45 Friedman R. New oral anticoagulants for thromboprophylaxis after total hip or knee arthroplasty. Orthopedics. 2009;32:79-84.
46 Colwell C. The ACCP guidelines for thromboprophylaxis in total hip and knee arthroplasty. Orthopedics. 2009;32:67-73.
47 Geerts W, Jay R, Code K, et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996;335:701-707.
48 Fitzgerald R, Spiro T, Trowbridge A, et al. Prevention of venous thromboembolic disease following primary total knee arthroplasty. J Bone Joint Surg [Am]. 2001;83:900-906.
49 Collaborative overview of randomized trials of antiplatelet therapy: III. Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients: Antiplatelet Trialists’ Collaboration. BMJ. 1994;308:235-246.
50 Prevention of pulmonary embolism and deep venous thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) Trial. Lancet. 2000;355:1295-1302.
51 Daniel J, Pradhan A, Pradhan C, et al. Multimodal thromboprophylaxis following primary hip arthroplasty: the role of adjuvant intermittent pneumatic calf compression. J Bone Joint Surg [Br]. 2008;90:562-569.
52 Della Valle A, Serota A, Go G, et al. Venous thromboembolism is rare with a multimodal prophylaxis protocol after total hip arthroplasty. Clin Orthop Relat Res. 2006;444:146-153.
53 Lotke P, Lonner J. The benefit of aspirin chemoprophylaxis for thromboembolism after total knee arthroplasty. Clin Orthop Relat Res. 2006;452:175-180.
54 Eriksson B, Friedman R, Cushner F, Lassen M. Letter to the Editor. Potent anticoagulants are associated with a higher all-cause mortality rate after hip and knee arthroplasty. Clin Orthop Relat Res. 2008;466:2009-2011.
55 Sharrock N, Della Valle A, Go G, Salvati E. Potent anticoagulants are associated with a higher all-cause mortality rate after hip and knee arthroplasty. Clin Orthop Relat Res. 2008;466:714-721.
56 Bauer K, Eriksson B, Lassen M, Turpie A, Steering Committee of the Pentasaccharide in Major Knee Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med. 2001;345:1305-1310.
57 Pederson A, Sorensen H, Mehnert F, et al. Risk factors for venous thromboembolism in patients undergoing total hip replacement and receiving routine thromboprophylaxis. J Bone Joint Surg [Am]. 2010;92:2156-2164.
58 Douketis J, Eikelboom J, Quinlan D, et al. Short-duration prophylaxis against venous thromboembolism after total hip or knee replacement. Arch Intern Med. 2002;162:1465-1471.
59 Eikelboom J, Quinlan D, Douketis J. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet. 2001;358:9-15.
60 Haentjens P, De Groote K, Annemans L. Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee embolism: a cost-utility analysis. Arch Orthop Trauma Surg. 2004;124:507-517.
61 Coleridge-Smith P, Hasty J, Scurr J. Deep vein thrombosis: effect of graduated compression stockings on distension of the deep veins of the calf. Br J Surg. 1991;78:724-726.
62 Best A, Williams S, Crozier A, et al. Graded compression stockings in elective orthopaedic surgery: an assessment of the in vivo performance of commercially available stockings in patients having hip and knee arthroplasty. J Bone Joint Surg [Br]. 2000;82:116-118.
63 Vanek V. Meta-analysis of effectiveness of intermittent pneumatic compression devices with a comparison of thigh-high to knee-high sleeves. Am Surg. 1998;64:1050-1058.
64 Bass A, Mattern C, Voos J, et al. Inferior vena cava filter placement in orthopedic surgery. Am J Orthop. 2010;39:435-439.
65 Emerson RJ, Cross R, Head W. Prophylactic and early therapeutic use of the Greenfield filter in hip and knee joint arthroplasty. J Arthroplasty. 1991;6:129-135.
66 Golueke P, Garrett W, Thompson J, et al. Interruption of the vena cava by means of the Greenfield filter: expanding the indications. Surgery. 1988;103:111-117.
67 Vaughn BK, Knezevich S, Lombardi AVJr, Mallory TH. Use of the Greenfield filter to prevent fatal pulmonary embolism associated with total hip and knee arthroplasty. J Bone Joint Surg [Am]. 1989;71:1542-1548.
68 PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: The PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation. 2005;112:416-422.
69 Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med. 1998;338:409-415.
70 Gorman P, Qadri S, Rao-Patel A. Prophylactic inferior vena cava (IVC) filter placement may increase the relative risk of deep venous thrombosis after acute spinal cord injury. J Trauma. 2009;66:707-712.
71 Strauss E, Egol K, Alaia M, et al. The use of retrievable inferior vena cava filters in orthopaedic patients. J Bone Joint Surg [Br]. 2008;90:662-667.
72 Davis F, Laurenson V, Gillespie W, et al. Leg blood flow during total hip replacement under spinal or general anesthesia. Anaesth Intensive Care. 1989;17:136-143.
73 Kleinert K, Theusinger O, Nuernberg J, Werner C. Alternative procedures for reducing allogeneic blood transfusion in elective orthopedic surgery. Hosp Special Surg J. 2010;6:190-198.
74 Sharrock N, Go G, Williams-Russo P, et al. Comparison of extradural and general anaesthesia on the fibrinolytic response to total knee arthroplasty. Br J Anaesth. 1997;79:29-34.
75 Sharrock N, Haas S, Hargett M, et al. Effects of epidural anesthesia on the incidence of deep-vein thrombosis after total knee arthroplasty. J Bone Joint Surg [Am]. 1991;73:502-506.
76 Rodgers A, Walker N, Schug S, et al. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. BMJ. 2000;321:1493-1497.
77 Westrich G, Farrell C, Bono J, et al. The incidence of venous thromboembolism after total hip arthroplasty: a specific hypotensive epidural anesthesia protocol. J Arthroplasty. 1999;14:456-463.
78 Paul J, Ling E, Lalonde C, Thabane L. Deliberate hypotension in orthopedic surgery reduces blood loss and transfusion requirements: a meta-analysis of randomized controlled trials. Can J Anesth. 2007;54:799-810.
79 Maheshwari A, Blum Y, Shekhar L, et al. Multimodal pain management after total hip and knee arthroplasty at the Ranawat Orthopaedic Center. Clin Orthop Relat Res. 2009;467:1418-1423.
80 Lieberman J, Huo M, Hanway J, et al. The prevalence of deep venous thrombosis after total hip arthroplasty with hypotensive epidural anesthesia. J Bone Joint Surg [Am]. 1994;76:341-348.
81 Berend KR, Lombardi AVJr. Multimodal venous thromboembolic disease prevention for patients undergoing primary or revision total joint arthroplasty: the role of aspirin. Am J Orthop. 2006;35:24-29.
82 Pellegrini VJ, Donaldson C, Farber D, et al. The Mark Coventry award: prevention of readmission for venous thromboembolism after total knee arthroplasty. Clin Orthop Relat Res. 2006;452:21-27.
83 Dorr L, Gendelman V, Maheshwari A, et al. Multimodal thromboprophylaxis for total hip and knee arthroplasty based on risk assessment. J Bone Joint Surg [Am]. 2007;89:2648-2657.
84 Mohanty K, Powell J, Musso D, et al. The effect of a venous filter on the embolic load during medullary canal pressurization: a canine study. J Bone Joint Surg [Am]. 2005;87:1332-1337.
85 Sharrock N, Go G, Harpel P, et al. Thrombogenesis during total hip replacement. Clin Orthop Relat Res. 1995;319:16-27.
86 Lombardi AVJr, Berend KR, Tucker TL. The incidence and prevention of symptomatic thromboembolic disease following unicompartmental knee arthroplasty. Orthopedics. 2007;30:41-43.
87 Berend KR, Morris MJ, Lombardi AVJr. Unicompartmental knee arthroplasty: incidence of transfusion and symptomatic thromboembolic disease. Orthopedics. 2010;33:1-3.
88 Lombardi AVJr, Berend K, Adams J. A rapid recovery program: early home and pain free. Orthopedics. 2010;33:656.
89 Berend KR, Lombardi AVJr, Mallory TH, et al. Ileus following total hip or knee arthroplasty is associated with increased risk of deep venous thrombosis and pulmonary embolism. J Arthroplasty. 2004;19:82-86.
90 Mantilla C, Horlocker T, Schroeder D, et al. Risk factors for clinically relevant pulmonary embolism and deep venous thrombosis in patients undergoing primary hip or knee arthroplasty. Anesthesiology. 2003;99:552-560.
91 Rozner M. The American Society of Anesthesiologists physical status score and risk of perioperative infection. JAMA. 1996;275:1544.
92 Charlson M, Pompei P, Ales K, MacKenzie C. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis. 1987;40:373-383.
