Venous Thromboembolic Disease and Fat Embolism Syndrome

Vincent D. Pellegrini Jr, MD

Dr. Pellegrini or an immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of DePuy, A Johnson & Johnson Company; has received research or institutional support from Synthes; and serves as a board member, owner, officer, or committee member of the American Orthopaedic Association, the Association of American Medical Colleges, Board of Directors, Chair, the Council of Faculty and Academic Societies, AAMC, the Health Volunteers Overseas/Orthopaedics Overseas, Board of Directors, and the South Carolina Orthopaedic Association, Board of Directors.

INTRODUCTION

Venous thromboembolic disease (VTED) and the fat embolism syndrome (FES) have a similar underlying pathophysiology that depends on intravasation of the adipose tissue of the bone marrow into the vascular tree. Marrow fat is an intense activator of the clotting cascade and is responsible for the hypercoagulable state following long bone trauma and instrumentation of the intramedullary canal during total hip and knee replacement. In both conditions, the lung acts as an essential filter in clearing the embolic material from the bloodstream and determining the nature of the body’s response to the embolic insult. The differences in the clinical presentation of the two conditions depend upon the size and aggregate volume of the embolus as well as the nature of the embolic material invoking a response from the lung. The embolic material in VTED primarily is clotted blood, and in fat embolism syndrome, it consists of fat globules enmeshed in platelets. Considering that musculoskeletal injury and related surgical procedures often involve disruption of the marrow fat, it is no wonder that these clinical conditions can uniquely complicate the course of orthopaedic treatment. Orthopaedic surgeons must understand the pathophysiology and treatment of these conditions not only for effective patient care and communication with consulting physicians but, even more importantly, to place the specific treatment of these complications into the context of overall management of the patient. Only the orthopaedic surgeon is best positioned to balance the risks of pulmonary embolism with those of perioperative bleeding when prescribing VTED prophylaxis after total joint arthroplasty.

VENOUS THROMBOEMBOLIC DISEASE

Historically, the most significant perioperative threat to the life of a patient undergoing arthroplasty is VTED, and specifically pulmonary embolism (PE). In a series of 7,959 total hip arthroplasties (THAs) from 1962 to 1973, the overall incidence of PE was 7.89% and the incidence of fatal PE was 1.04%.¹ As Charnley² stated, “The possibility of fatal pulmonary embolism after total hip replacement is a hip surgeon’s constant worry…no matter how rare this might be.” Additionally, bleeding complications related to VTED prophylaxis have become the most common cause of hospital readmission after hip or knee replacement. It is no wonder that VTED remains one of the most controversial topics in contemporary orthopaedics.

Deep vein thrombosis (DVT) is the most common precursor of PE. The predominant form of DVT after total knee arthroplasty (TKA) is in the calf distal to the trifurcation, probably initiated by stasis. Proximal DVT after TKA
typically results from propagation of a calf clot (Figure 1). Proximal thrombi, specifically segmental clots in the femoral vein at the level of the lesser trochanter, predominate after THA and are likely initiated by intimal injury resulting from torsion of the vein during femoral preparation (Figure 2). PE traditionally was diagnosed by pulmonary arteriography (Figure 3) but now is most sensitively identified by CT of the chest. In the general population, the frequency of autopsy-proven fatal PE is 2.5 times that of symptomatic nonfatal PE.³ Independently, DVT is responsible for morbidity related to chronic venous insufficiency. Five years after surgery, signs and symptoms of postthrombotic syndrome were found in 67% of patients with asymptomatic, venographically confirmed DVT, compared with 32% of patients who had a negative postoperative venogram. Moreover, postthrombotic morbidity is more common after idiopathic than after postoperative DVT,⁴ probably because postoperative thrombosis is typically nonocclusive and flow past the thrombus is maintained.

FIGURE 1 Contrast venogram showing calf thrombosis extending proximally to the popliteus vein after total knee arthroplasty (TKA).

FIGURE 2 Contrast venogram showing segmental proximal femoral vein thrombosis at the level of the lesser trochanter after total hip arthroplasty (THA).

EPIDEMIOLOGY

BEFORE ROUTINE PROPHYLAXIS

Historically, the risk of DVT in an unprotected patient was 70% to 84% after THA or TKA; the risk of symptomatic PE approached 15%, and the risk of fatal PE was 1% to 3.4%.⁵^,⁶ Coventry et al⁵ reported a 3.4% fatal PE rate after 2,012 consecutive THAs from 1969 to 1971; the average duration of surgery was 2.4 hours, the average blood loss was 1,650 mL, patients were on bed rest for 1 week, and the mean postoperative hospital stay was 3 weeks. Since that time, the incidence of VTED after total joint arthroplasty has steadily declined, the reasons for which are widely accepted as being the adoption of routine pharmacologic and/or mechanical prophylaxis regimens as well as improved surgical techniques, earlier mobilization, and anesthetic management.⁷^,⁸ Data from two studies with a 3- to 6-month follow-up revealed a fatal PE rate as low as 0.12% to 0.35% in 4,594 patients who underwent THA without any type of chemoprophylaxis.⁸^,⁹ Compared with earlier studies,
these patients benefited from more rapid postoperative mobilization and a shorter length of hospital stay. To achieve further reduction in the likelihood of fatal PE by using potent anticoagulants, it is necessary to balance the incremental benefit of eliminating PE against the increased risk of bleeding complications.¹⁰

FIGURE 3 Pulmonary arteriogram revealing the presence of pulmonary emboli.

AFTER ROUTINE PROPHYLAXIS

Routine prophylaxis for VTED after THA or TKA became the standard of care in North America after it was endorsed by the National Institutes of Health (NIH) Consensus Conference in 1986.¹¹ Low-intensity warfarin was the agent most commonly used by orthopaedic surgeons during the past three decades¹²^,¹³; while its use has considerably reduced the incidence of DVT, screening venography revealed persistent asymptomatic venous thrombi in 15% to 25% of patients after THA and in 35% to 50% after TKA.⁷ A smaller reduction in venographic DVT after TKA than after THA has been observed with the use of newer anticoagulant agents, resulting in an overall risk of DVT that is two to three times greater after TKA than after THA despite use of contemporary prophylaxis.⁷ Clinically important bleeding events in patients on warfarin prophylaxis were reduced with acceptance of low-intensity anticoagulation from 8% to 12% with a prothrombin time index of 2.0 to 1% to 2% with a prothrombin time index target of 1.3 to 1.5 (International Normalized Ratio [INR] 2.0 to 2.5).¹⁴ Although these data suggest that VTED is more refractory to standard prophylaxis after TKA than after THA, 85% to 90% of thrombi after TKA occur in the deep calf veins below the venous trifurcation, and the immediate risk of embolization is much smaller.⁶ In contrast, the distribution of DVT after THA historically was 40% proximal and 60% distal.⁴^,⁷ Recent studies suggest less than 10% of thrombi after THA are proximal in location, and 85% to 90% of all DVTs after THA or TKA now occur in the calf with current prophylaxis¹⁵^,¹⁶^,¹⁷ Yet, longitudinal surveillance studies found that 17% to 23% of these distal thrombi extend to the more proximal veins of the thigh, where they acquire considerable embolic potential.¹⁸^,¹⁹ The considerable embolic potential of postoperative calf thrombi suggests that anticoagulant prophylaxis should be continued for several weeks after surgery.¹⁵

PATHOGENESIS

Virchow triad, consisting of stasis, hypercoagulability, and damage to the intimal wall, remains the basis of our conceptual understanding of the mechanism of coagulation. Perturbations in elements of the triad are responsible for the abnormalities of thrombosis after musculoskeletal injury, disease, or surgery. Recent discoveries and improved understanding of the clotting cascade form the basis of new approaches to prevent and treat thrombotic disease (Figure 4).

FAMILIAL THROMBOPHILIA AND FACTOR V LEIDEN

Familial thrombophilia is the heritable tendency to develop severe and recurrent VTED, often spontaneously. This condition has not been adequately explained by any deficiency of circulating anticoagulants; levels of proteins C and S as well as antithrombin III were rarely found to be low in patients with familial thrombophilia. Mutations in genetic material encoding proteins C and S or antithrombin III were found to account for fewer than 5% of all incidences of familial thrombophilia.²⁰ In 1994, a single amino acid substitution of glutamine for arginine in the protein C cleavage region of factor V was reported to occur in 50% of patients with familial thrombophilia, compared with 3% to 7% of the general population.²¹ This single nucleotide substitution, known as factor V Leiden, is responsible for resistance of activated factor V to cleavage inactivation by protein C, which normally provides a physiologic check on the clotting cascade.

Variable phenotypic expression of factor V Leiden is now accepted as being responsible for a host of clinical disease
states related to thrombosis. More than half of all individuals with factor V Leiden will develop DVT in the presence of a single additional risk factor, such as a long bone fracture or total joint arthroplasty. The incidence of factor V Leiden was 26% among men older than 60 years with primary spontaneous DVT. Mixed findings have been reported from preliminary investigations of activated protein C resistance and VTED after total joint arthroplasty, and two North American studies of patients who had undergone THA or TKA found no correlation between the presence of factor V Leiden (or depletion of any other circulating anticoagulant) and the occurrence of VTED.²²^,²³ This negative observation
can be explained by the effect of a potent thrombogenic stimulus associated with violation of the medullary canal during total joint arthroplasty, which is intense enough to overshadow any heritable predisposition to thrombosis imparted by factor V Leiden.

FIGURE 4 Schematic diagram showing the clotting cascade, with critical points of interference by anticoagulant agents. FPA = fibrinopeptide A; FPB = fibrinopeptide B; HMWK = high-molecular-weight kallikrein; KAL = kallikrein; PT = prothrombin time; PTT = partial thromboplastin time. (Adapted with permission from Stead RB: Regulation of hemostasis, in Golhaber SZ, ed: Pulmonary Embolism and Deep Venous Thromboembolism. Philadelphia, PA, WB Saunders, 1985, p 32.)

THROMBOGENESIS AFTER MUSCULOSKELETAL INJURY

It has long been recognized that VTED is more refractory to standard prophylaxis after orthopaedic procedures than after general surgical procedures. This phenomenon was first recognized as the inefficacy of subcutaneous heparin for DVT prevention after THA, despite the successful use of subcutaneous heparin after major abdominal or chest surgery. The discrepancy was found to be secondary to a decline in circulating levels of antithrombin III (a binding intermediary necessary for the heparins to be clinically effective), that occurred in conjunction with a decline in several other acute-phase reactants after skeletal injury or manipulation of the medullary canal (as occurs during total joint arthroplasty).²⁴

The findings by Geerts et al²⁵ in a series of polytrauma patients with multiple injuries and an injury severity score higher than 9 underscore the influence of skeletal trauma on the clotting cascade. Contrast venography of 349 patients showed an overall DVT prevalence of 58% and a proximal DVT rate of 18%. Like patients who undergo total joint arthroplasty, most of these patients were asymptomatic; only 3 of 201 DVTs (1.5%) were clinically evident. The influence of fracture on the clotting cascade was shown by a DVT incidence of 61% with pelvic fracture, 77% with tibial shaft fracture, and 80% with femoral shaft fracture; isolated femoral or tibial shaft fracture was associated with a relative DVT risk almost five times as high as that of the overall group. Spinal cord injury was associated with an 81% incidence of DVT and an odds ratio of 8.5, compared with the total group.²⁵

The same investigators subsequently studied the impact of VTED prophylaxis on 344 patients with polytrauma who were randomly assigned to one of two anticoagulant protocols.²⁶ Patients receiving unfractionated heparin had an overall DVT incidence of 44% (60 of 136 patients), compared with 31% of those receiving enoxaparin (40 of 129 patients, P = 0.014); the rates for proximal DVT were 15% (20 of 136) and 6% (8 of 129), respectively (P = 0.012). These findings highlight the relative ineffectiveness of unfractionated heparins for clinical thromboprophylaxis when circulating levels of antithrombin III have been reduced. Major bleeding complications were five times more common with enoxaparin therapy (2.9%) than with heparin (0.6%, P = 0.12). Because of their propensity for causing increased bleeding, fractionated heparins should be used cautiously for VTED prophylaxis in patients with polytrauma and especially in those with closed head trauma, a visceral injury, or an expectation of delayed surgical fracture repair (especially if the pelvis is involved).

THROMBOGENESIS DURING ANESTHESIA AND TOTAL JOINT ARTHROPLASTY

It is now accepted that the principal thrombogenic stimulus associated with THA occurs intraoperatively. More specifically, femoral preparation is closely linked with intense activation of the clotting cascade as well as torsion or complete obstruction of the femoral vein. Sharrock et al²⁷ measured markers of thrombin generation and fibrin formation in circulating blood during THA and found that the process of thrombosis does not begin immediately but is delayed until preparation of the femoral canal. Elevation of prothrombin F1.2, thrombin-antithrombin complexes, fibrinopeptide A, and D-dimer was most pronounced during insertion of the cemented femoral implant and continued to increase throughout the first hour after surgery. Mean values for three of the four markers were significantly higher after insertion of a cemented femoral implant than after insertion of a noncemented component. Mean pulmonary artery pressures peaked and central venous oxygen tension reached a nadir after reduction of the hip. These measurements suggest the delayed collection of embolic medullary contents in the lung resulting from kinking of the femoral vein during component insertion. Mechanical manipulation while the limb is being positioned for femoral preparation also is likely to cause local intimal injury to the femoral vein, may cause the unique finding of segmental femoral thrombi after total hip arthroplasty, and completes an across-the-board disturbance in the Virchow triad (along with hypercoagulability and stasis) in this high-risk scenario.

A subsequent investigation of the efficacy of short-acting anticoagulants for blunting the intraoperative activation of the clotting cascade during THA found that standard heparin administered intravenously after socket implantation significantly inhibited fibrin formation at 10 units/kg and completely suppressed fibrin formation at 20 units/kg.²⁸ With a 30- to 40-minute half-life, the dose of unfractionated heparin in theory briefly increased the bleeding risk, but no additional intraoperative bleeding was clinically evident. This anticoagulation strategy targets primary prevention of intraoperative clot formation rather than secondary prevention of the postoperative extension of existing thrombi. Epidural anesthesia, when evaluated by contrast venography as an outcome measure for DVT, has a similarly beneficial influence on thrombogenesis and VTED prophylaxis.²⁸^,²⁹ The mechanism for reducing the risk of venous thromboembolism with epidural anesthesia or epidural analgesia has been the subject of much conjecture. Inhibition of platelet and leukocyte adhesion and stimulation of endothelial fibrinolysis have been proposed as mechanisms but have not been substantiated by controlled studies. Rather, the sympathectomy effect of epidural blockade, resulting in increased lower extremity blood flow and mitigating the adverse effects of stasis, is most likely to be responsible for reducing the risk of venous thrombosis. Regardless of the type of anticoagulant prophylaxis, several clinical studies found an incremental 40% to 50% reduction in the risk of venographic
DVT when regional anesthesia was used compared with general anesthesia.³⁰ The incidence of fatal PE also is reduced when epidural anesthesia is used rather than general anesthesia; a retrospective review of THA and TKA by Sharrock et al³¹ reported a 0.12% rate of fatal in-hospital PE (7 of 5,874 patients) when general anesthesia was used between 1981 and 1986, compared with a 0.02% rate (2 of 9,685 patients, P = 0.03) when epidural anesthesia was used between 1987 and 1991. Continued use of the epidural catheter for postoperative analgesia was found to benefit VTED prophylaxis. In another study which utilized warfarin exclusively as VTE prophylaxis, 322 consecutive patients undergoing THA who received epidural anesthesia and 48-hour postoperative epidural analgesia demonstrated an overall venographic DVT rate of 8.9%, with proximal thrombi in 2.3% of patients.²⁹ Both aspirin, as an antiplatelet agent, and regional anesthesia have been observed to decrease expression of VTED (specifically, clinical PE) after total joint arthroplasty.²⁸^,²⁹^,³⁰^,³¹

THROMBOPROPHYLAXIS

Several issues have clouded the introduction of safe and effective antithrombotic prophylaxis—(1) industry-sponsored drug trials, (2) uncertainty of surrogates for clinically meaningful events, and (3) debate between the American Academy of Orthopaedic Surgeons (AAOS) and the American College of Chest Physicians (ACCP) with each emphasizing different aspects of anticoagulation efficacy. During the past 30 plus years, many relatively selective anticoagulant drugs have been introduced, but the evidence for prevention of fatal PE after THA and TKA has changed very little. The Institute of Medicine has identified this area as a priority for comparative effectiveness research, and the Agency for Healthcare Research and Quality Evidence-based Practice Center project³²^,³³ twice, in 2012 and 2017, noted a paucity of high-quality studies with lack of clear consensus and a clear tradeoff between lowered VTE risk and increased frequency of major bleeding after major orthopaedic surgery. Specifically noted was the difficulty in separating surrogate outcomes from clinically meaningful events. Most studies evaluated “total DVT” despite its questionable clinical significance. Nonetheless, the Joint Commission and Surgical Care Improvement Project now mandate VTE prophylaxis for all patients undergoing THA or TKA, according to prevailing guidelines.³⁴

The guidelines of the ACCP historically have been based on the goal of reducing the frequency of DVT (as a surrogate for fatal PE), using prospective randomized clinical studies for the underlying data set.³⁵ From 1992 until 2012, the ACCP guidelines endorsed the use of fractionated heparins, full-intensity warfarin (INR 2.0 to 3.0), and synthetic pentasaccharide and specifically recommended against the use of aspirin for VTE prophylaxis. The guideline of the AAOS was intended to reduce the incidence of clinical PE while avoiding bleeding that could result in wound hematoma and secondary infection, both of which can require revision surgery and prosthesis removal. In the first AAOS clinical practice guideline on the subject, released in 2007 and published in 2009,³⁶ patients were stratified into four risk groups, with a recommendation for the elective use of ACCP-recommended agents. The use of aspirin or low-intensity warfarin was endorsed for patients at high risk of bleeding by the AAOS, because the rates of clinical PE with these agents are comparable to those of ACCP-recommended agents, and rates of bleeding are lower. Both ACCP and AAOS supported the use of adjunctive pneumatic compression.³⁶

These disparate recommendations are predicated on studies utilizing vastly different scientific methodologies³⁷ Prospective randomized clinical trials found a reduction in the incidence of lower limb clots discovered on contrast venography with the use of potent new anticoagulants but were unable to confirm a commensurate reduction in fatal PEs.¹⁵^,¹⁶^,¹⁷ These studies were insufficiently powered for discerning a difference in bleeding events, however, and may have had bias related to industry funding. Observational studies found low PE event rates, comparable to those with newer ACCP-endorsed agents, with the use of aspirin,²⁸^,³⁸^,³⁹^,⁴⁰ low-intensity warfarin (INR 2.0),¹⁴^,⁴¹^,⁴² and multimodal prophylaxis regimens predicated on use of mechanical compression devices. In 2011, the AAOS released the second, and still current, version of its clinical practice guideline for VTE prophylaxis after THA and TKA,⁴³ and less than 6 months later, the ACCP released the ninth edition of its guidelines for antithrombotic therapy and thrombosis prevention,⁴⁴ which loosely defined a compromise middle ground.⁴⁵^,⁴⁶ The AAOS no longer specifically endorsed aspirin, and the ACCP awarded aspirin the same level of recommendation as every other form of chemoprophylaxis, including unfractionated heparin. The AAOS provides no recommendation for any single chemoprophylaxis agent, and the ACCP’s level 1-B endorsement of all agents was equally nondiscriminating. The ACCP considered effectiveness in preventing clinical thromboembolic events to be tempered by a new appreciation of patient-perceived importance of bleeding. An ongoing study, The Comparative Effectiveness of Pulmonary Embolism Prevention after Hip and Knee Replacement (PEPPER) trial, is a large pragmatic study funded by the Patient-Centered Outcomes Research Institute (PCORI) comparing aspirin, warfarin, and rivaroxaban in 25,000 patients undergoing THA or TKA.⁴⁷ The two primary endpoints are an aggregate of clinical DVT, PE, and all-cause mortality, and clinically important bleeding events; patient-reported outcomes will align clinical results after operation with types of VTED prophylaxis. These end points represent clinically relevant surrogates, rather than thrombi discovered on venography or lung imaging of asymptomatic patients, and the large sample size of the PEPPER trial allows concurrent study of both anticoagulant effectiveness in preventing clots and safety in avoidance of untoward bleeding events. The ideal prophylaxis is yet to be determined, but it must represent a balance between the risk of fatal PE and the morbidity of anticoagulation-associated bleeding.

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