PATHOGENESIS

Multiple perioperative factors place the patient undergoing THA at risk for developing lower extremity venous thrombi. Thrombogenesis can often be related to Virchow’s triad of venous stasis, endothelial injury, and hypercoagulability. Each of these risk factors is present during the sequential stages of THA. Hip dislocation and positioning of the lower extremity for canal preparation and stem insertion result in obstruction of femoral venous outflow and subsequent stasis in the lower extremity. Regional edema and decreased patient mobilization after surgery may also contribute to decreased venous return. Extremes of internal rotation during positioning of the lower extremity have the potential to compress the femoral vessels and initiate secondary endothelial injury, and heat release from the use of exothermic bone cement may cause additional damage to the endothelium. Finally, a relative hypercoagulable state can develop during THA. Blood loss during the procedure can result in reduced serum levels of antithrombin III (AT III) and inhibition of the fibrinolytic pathway. Moreover, canal preparation and stem insertion have been shown to result in increased serum levels of markers of thrombus generation including prothrombin F1.2, thrombin-antithrombin, fibrinopeptide A, and D-dimer. Collectively these data suggest that initiating events that stimulate thrombus formation arise during surgery, and therefore the true goal of any prophylactic agent is to prevent further clot formation and propagation.

EPIDEMIOLOGY

Thromboembolic disease is the most common complication after THA and is ultimately responsible for more than 50% of the postoperative mortality associated with this procedure. In the absence of prophylaxis, asymptomatic deep venous thrombosis may develop in 40% to 60% of patients and proximal thrombosis in 10% to 40% of patients after THA ( Table 53-1 ). The majority of these thrombi remain clinically silent and resolve without detection or further sequelae. However, a small number of patients undergoing THA (2% to 5%) will experience symptoms related to thromboembolic disease. Untreated thrombi have the potential to migrate proximally and in some cases embolize to the pulmonary circulation. With the shortened duration of hospital stays, symptomatic thromboembolism often manifests after discharge from the acute care setting. In one study approximately 20% of patients undergoing major joint surgery who had a negative venogram at discharge developed venous thrombosis over the subsequent 3 weeks. Other studies have suggested that although the cumulative incidence of symptomatic deep venous thrombosis was low after THA, the majority of symptomatic events (76%) occurred after hospital discharge ( Fig. 53-1A ).

Targets for anticoagulant drugs. LMWH, low-molecular-weight heparin.

(Reproduced with modification from Petitou M, Lormeau JC, Choay J: Chemical synthesis of glycosaminoglycans: New approaches to antithrombotic drugs. Nature 350(Suppl):30-33, 1991. Reprinted with permission.)

Currently there is no reliable strategy to determine which arthroplasty patients will develop symptoms related to lower extremity thrombosis. Up to 50% of patients who developed thromboembolism after THA have no associated risk factors, underscoring the difficulty in identifying susceptible patients. Nonetheless, there are identifiable predisposing factors that have been associated with the development of symptomatic venous thromboembolism in this cohort of patients ( Table 53-2 ). The most relevant risk factors that have been associated with the development of thromboembolic disease after hip surgery include a history of prior thromboembolic disease, obesity (body mass index >25), delay in ambulation after surgery, and female gender. Factor V Leiden mutation, antiphospholipid antibody syndrome, protein C and S deficiency, and impairment of the fibrinolytic system may increase the risk of symptomatic thromboembolic disease after hip arthroplasty in some patients. The presence of genetic polymorphisms, particularly prothrombin G20210A and AT III, has been associated with increased risk of thrombosis in patients undergoing THA. However, because the overall rate of thrombophilic disorders in the general population is low, preoperative genetic screening for THA patients has not been recommended.

PROPHYLACTIC REGIMENS AFTER TOTAL HIP ARTHROPLASTY

The markedly increased risk of thromboembolic disease after THA mandates the use of prophylaxis in the perioperative period. Although pharmacologic and mechanical approaches have been used extensively for over 30 years, there remains no consensus as to the ideal prophylactic regimen. Randomized trials are the gold standard for evaluating the efficacy of any new drug, and numerous well-designed randomized trials have been conducted to evaluate the efficacy of various prophylactic regimens. In general, these investigations have employed venography as a surrogate outcome measure. It is questionable whether or not these asymptomatic clots in the calf are clinically relevant. Is it a fair tradeoff to have a lower rate of asymptomatic distal calf clot formation with a new drug regimen, but a higher rate of bleeding? Ideally, the focus should be on proximal clots and symptomatic deep venous thrombosis and pulmonary embolism.

CHEMOPROPHYLACTIC REGIMENS

Various targets for anticoagulant drugs are outlined in Figure 53-2 .

A, Venogram demonstrating a thrombosis in the deep femoral vein (arrow). B, Saggital image from color Doppler ultrasound demonstrates blood flow in the femoral artery but not in the common femoral vein (arrow).

Warfarin

Warfarin remains the most commonly used agent in North America after THA. Warfarin exerts its anticoagulant effect by inhibiting the vitamin K–dependent carboxylation of clotting factors II, VII, IX, and X, as well as protein C and protein S. Warfarin has been demonstrated to decrease the prevalence of deep venous thrombosis in THA by approximately 60% and proximal venous thrombosis by 70% when compared with prevalence in patients who had not received prophylaxis. Warfarin’s primary advantages over other prophylactic options are its relatively low cost and its oral route of administration. However, there are several drawbacks related to its use. Warfarin has a delayed onset of action, which may render patients relatively unprotected in the early postoperative period, at which time they may be at greatest risk for the development of thrombosis. Moreover, frequent monitoring of either the prothrombin time or international normalized ratio (INR) is required for appropriate dose adjustment. In addition, warfarin interacts with other medications, herbs, and food products as a result of its metabolism in the cytochrome P450 system of the liver. Of note, the combination of warfarin and nonsteroidal anti-inflammatory agents has been shown to result in a 13-fold increase in hemorrhagic peptic ulcers in elderly patients. Finally, warfarin has been associated with a 1% to 5% incidence of major postoperative hemorrhage after hip arthroplasty.

Warfarin’s efficacy has been compared with that of other prophylactic agents in both cohort studies and randomized clinical trials ( Table 53-3 ). A recent meta-analysis was performed on all identified randomized controlled trials from 1966 to 1998, comparing low-molecular-weight heparins, warfarin, aspirin, low-dose heparin, and pneumatic compression devices. In this review, patients receiving warfarin had the lowest incidence of proximal deep venous thrombosis (6.3%) and symptomatic pulmonary embolism (0.16%). The risk of major postoperative bleeding in patients receiving warfarin therapy was no higher than that in patients treated with placebo. Warfarin has also been compared directly with low-molecular-weight heparins in a number of randomized multicenter trials. Collectively these studies have demonstrated a similar or lower incidence of asymptomatic deep venous thrombosis in patients receiving a low-molecular-weight heparin when compared with those receiving warfarin. However, in one study the rate of major bleeding episodes was found to be higher in patients receiving a low-molecular-weight heparin.

TABLE 53-3

RESULTS FROM RANDOMIZED CLINICAL TRIALS COMPARING WARFARIN WITH LOW-MOLECULAR-WEIGHT HEPARIN AFTER TOTAL HIP ARTHROPLASTY

Study	Patients	Successful Venography	Overall DVT (%)	Proximal DVT (%)	Pulmonary Embolism (%)	Major Bleeding (%)
Hull et al
Warfarin	388	363	10.7	1.0	NA	4.2
Fragmin	388	354	24	3.0	NA	5.1
The RD Heparin Arthroplasty Group
Warfarin	218	174	11.0	6.0	0	4.0
RD Heparin	211	178	7.0	3.0	0	4.0
Francis et al
Warfarin	279	190	26.0	8.0	NA	1.0
Dalteparin	271	192	15.0	5.0	NA	4.0
Colwell et al
Warfarin	1495	NA *	3.7	NA	0.6	0.8
Enoxaparin	1561	NA *	3.6	NA	0.4	1.2
Hamulyak et al
Warfarin	342	257	20.0	5.8	NA	2.8
Nadroparine	330	260	17.0	6.5	NA	1.5

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